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Kallmann syndrome

2007-05-14T13:53:00.000-07:00

Category: Disorder
Target System: Endocrine System
Specific Target Glands: Pituitary Gland and Hypothalamus

Alternative titles; symbols
KMS
KS
Hypogonadotropic Hypogonadism and Anosmia; HHA
Dysplacia Olfactogenitalis of De Morsier
Anosmic Hypogonadism

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Kallmann syndrome is an example of hypogonadism (decreased functioning of the sex hormone-producing glands) caused by a deficiency of gonadotropin-releasing hormone (GnRH), which is created by the hypothalamus. Kallmann syndrome is also known as hypothalamichypogonadism, familial hypogonadism with anosmia, or hypogonadotropic hypogonadism, reflecting its disease mechanism.

Kallmann syndrome is a form of secondary hypogonadism reflecting the fact the primary cause of the defect in sex hormone production lies within the pituitary and hypothalamus rather than a physical defect of the testes or ovaries themselves.

Kallmann syndrome consists of congenital, isolated, idiopathic hypogonadotropic hypogonadism and anosmia. The gene responsible for the X-linked form of Kallmann syndrome, KAL1, encodes a protein, anosmin, that plays a key role in the migration of GnRH neurons and olfactory nerves to the hypothalamus.

Kallmann syndrome was described in 1944 by Franz Josef Kallmann, a German-American geneticist. However, others - such as the Spanish doctor Aureliano Maestre de San Juan - had noticed a correlation between anosmia and hypogonadism in 1856.

The most well known person who has Kallmann syndrome in modern times is the jazz vocalist Jimmy Scott. In 2004, Canadian writer Brian Brett published a memoir, Uproar's Your Only Music, about growing up with Kallmann syndrome.

Clinical Features

Males with Kallmann syndrome show anosmia due to agenesis of the olfactory lobes, and hypogonadism secondary to deficiency of hypothalamic gonadotropin-releasing hormone (GnRH). Transmitting females have partial or complete anosmia. In the course of molecular genetic studies of X-linked Kallmann syndrome, Hardelin et al. (1992) found instances of renal agenesis and also pointed to mirror movements of the hands (bimanual synkinesia), pes cavus, high-arched palate, and cerebellar ataxia. Synkinesia, which is one of the more frequent findings, may be attributable to lack of inhibitory fibers connecting the 2 hemispheres through the corpus callosum (Nass, 1985). Colorblindness was also segregating in families described by Kallmann et al. (1944); however, the information was too limited to give conclusive evidence on possible X-linkage of this syndrome.

De Morsier (1954) collected 28 reported cases of agenesis of the olfactory lobes in which complete autopsy was performed and found that abnormalities of the sexual organs, mainly cryptorchidism and testicular atrophy, had been noted in 14. He suggested that the genital atrophy is secondary to involvement of the hypothalamus as well as the olfactory lobes.

Hockaday (1966) described 2 cases. In the second case, the father was found to have 'complete anosmia on testing.' Thus, this may have been an autosomal dominant form of the disorder. Anosmia must be inquired about in cases of hypogonadism since patients rarely volunteer the information. Indeed, the patient is sometimes unaware of anosmia so that tests are necessary. Pittman (1966) found anosmia in 16 of 28 cases of hypogonadotropic hypogonadism.

Ballabio (1993) reported the consensus from an NIH conference on Kallmann syndrome that no patient of molecularly confirmed X-linked Kallmann syndrome has intact smell. In a single family, 1 brother was hyposmic and had normal gonadal development, whereas 2 brothers and 2 maternal cousins had the full-blown Kallmann syndrome phenotype. There was agreement that the intrafamilial variability of the phenotype in the autosomal forms of Kallmann syndrome (for which no molecular test is available) is extensive. Several families have been described in which affected individuals have either hypogonadism or anosmia or both. On the contrary, in the X-linked families, the phenotype seems to be consistent within families.

Males et al. (1973) studied 6 unrelated subjects, 5 males and 1 female, with hypogonadism and anosmia. All the males had small genitals and decreased sexual hair. Gynecomastia and eunuchoid habitus were seen in 4. All 6 had a radiographically normal sella turcica. Testicular biopsies of the males showed decreased numbers of germ cells and a spermatogenic state at the primary spermatocyte stage. Leydig cells were not histologically identifiable. The affected female had 2 brothers with anosmia and hypogonadism. Urine gonadotropins were low in the 2 patients tested. Basal urinary 17-hydroxycorticosteroids were normal in those tested. A metyrapone test suggested low levels of ACTH in 2. One male patient at operation showed agenesis of the olfactory bulbs and tracts. The authors stated that the Kallmann syndrome is probably the expression of a disorder of hypothalamic regulation involving the control of those releasing factors needed for effective pituitary function. Additionally, it is interesting to note that there is some evidence for a relationship between olfactory acuity (perhaps to detect pheromones) and the gonadal and adrenal system in laboratory test animals.

Unilateral renal agenesis has been described in several patients with Kallmann syndrome (Wegenke et al., 1975; Hermanussen and Sippell, 1985). Kirk et al. (1994) reported a systematic study of kidneys in 17 affected persons from 6 families with Kallmann syndrome, including a family with an association of Kallmann syndrome and ichthyosis and interstitial deletion within the short arm of the X chromosome. Unilateral renal agenesis was found in 6 males in 4 families. Moreover, in 2 families (including a family in which all 4 patients demonstrated normal kidneys), there were male infants who died with bilateral renal agenesis. In the family with an association of Kallmann syndrome and ichthyosis, unilateral renal agenesis was found in 2 of 4 affected persons, although all 4 had the same X-chromosome deletion. Presumably, normal renal development requires expression of the Kallmann product (Kalig1/AMDLX), but mutation or absence of this product is not invariably associated with renal agenesis.

Birnbacher et al. (1994) made the diagnosis of X-linked Kallmann syndrome in a 3-month-old infant who presented with hypogonadism, a small penis, and bilateral cryptorchidism. He showed an inadequate response of luteinizing hormone and follicle stimulating hormone to the administration of luteinizing hormone-releasing hormone and of testosterone to human chorionic gonadotropin. A maternal uncle had hypogonadism and anosmia and also showed an impaired LH and FSH response to LHRH. MRI showed hypoplasia of the rhinencephalon in both cases.

Dode et al. (2003) stated that bimanual synkinesia had been observed in 75% of X-linked Kallmann syndrome cases; they described bimanual synkinesia, i.e., mirror movements of the hands, in 2 affected members in a family with an autosomal dominant form of Kallmann syndrome. Highly arched palate, which can be regarded as a mild anomaly of palatal fusion, is a common feature of KAL1. Dode et al. (2003) found cleft palate or cleft lip in several individuals with KAL2.

Biochemical Features

Bardin et al. (1969) concluded that patients with Kallmann syndrome have a defect in both pituitary and Leydig cell function. They demonstrated impaired secretion of FSH and LH and thought there to be Leydig cell insensitivity to gonadotropin. Treatment with chorionic gonadotropin can correct cryptorchidism and establish fertility, even in adult males. Schroffner and Furth (1970) found failure of response to clomiphene, as measured by plasma levels of gonadotropins.

With respect to neuroendocrine phenotype, Oliveira et al. (2001) observed that 8 Kallmann syndrome men with documented KAL1 mutations had completely apulsatile LH secretion, whereas those with autosomal modes of inheritance demonstrated a more variable spectrum with evidence of enfeebled (but present) GnRH-induced LH pulses. They concluded that patients with KAL1 mutations have apulsatile LH secretion consistent with a complete absence of GnRH migration of GnRH cells into the hypothalamus, whereas evidence of enfeebled GnRH-induced LH pulses may be present in autosomal Kallmann syndrome cases.

Diagnosis

The diagnosis is often one of exclusion found during the workup of delayed puberty. The presence of anosmia together with micropenis in boys should suggest Kallmann syndrome (although micropenis alone may have other causes).

Pathogenesis

Bick et al. (1989) described a male infant with the combination of ichthyosis, Kallmann syndrome, and chondrodysplasia punctata as a contiguous gene syndrome due to deletion of the terminal part of Xp, with the breakpoint at Xp22.31. The mother showed the same deletion of one X chromosome. Bick et al. (1989) studied an 18-week-old male fetus from this mother affected with the deletion syndrome (contiguous gene syndrome) that included steroid sulfatase deficiency, chondrodysplasia punctata, and Kallmann syndrome. The olfactory bulbs and tracts were absent and a horseshoe kidney was found. Wray et al. (1989) presented results of studies in the mouse supporting the hypothesis that all LHRH cells in the central nervous system arise from a discrete group of progenitor cells in the olfactory placode and that a subpopulation of these cells migrate into forebrain areas where they subsequently establish an adult-like distribution. During normal embryologic development, the olfactory placode in the nose gives rise to the olfactory nerve and nervus terminalis. Luteinizing-hormone-releasing hormone (LHRH)-secreting cells of the hypothalamus arise from the nervus terminalis and migrate from the nose through the cribriform plate along the olfactory tract to the hypothalamus. In the aborted fetus, Bick et al. (1989) showed by immunocytochemical analysis that the LHRH-immunoreactive cells and the olfactory nerve failed to reach their normal position, ending prematurely at the meninges. Absence of LHRH-secreting cells in the hypothalamus explains the deficiency of this hormone in Kallmann syndrome. Failure of the olfactory nerve to induce the formation of the olfactory bulb and tract explains the absence of the latter structures. Thus, Bick et al. (1989) appear to have demonstrated that Kallmann syndrome is a defect in neuronal migration. Dode et al. (2003) found that loss-of-function mutations in fibroblast growth factor receptor-1 (FGFR1; 136350) caused an autosomal form of Kallmann syndrome. They proposed that the KAL1 gene product, the extracellular matrix protein anosmin-1, is involved in FGF signaling, that there is an interaction between anosmin-1 and FGFR1, and that the higher prevalence of the disease in males is due to gender difference in anosmin-1 dosage, because KAL1 partially escapes X inactivation.

Pathophysiology

Under normal conditions, GnRH travels to the pituitary gland via the hypophyseal portal system, where it triggers production and release of gonadotropins (LH and FSH) from the gonadotropes. When GnRH is low, the pituitary does not create the normal amount of gonadotropins. The gonadotropins normally increase the production of gonadal steroids, so when they are low, these steroids will be low as well.

In Kallmann syndrome, the GnRH neurons do not migrate properly from the olfactory placode to the hypothalamus during development. The olfactory bulbs also fail to form or have hypoplasia, leading to anosmia or hyposmia.

Kallmann syndrome can be inherited as an X-linked recessive trait, in which case there is a defect in the KAL1 gene, which maps to chromosome Xp22.3. KAL encodes a neural cell adhesion molecule, anosmin-1. Anosmin-1 is normally expressed in the brain, facial mesenchyme, mesonephros and metanephros. It is required to promote migration of GnRH neurons into the hypothalamus. It also allows migration of olfactory neurons from the olfactory bulbs to the hypothalamus.

An autosomal dominant gene on chromosome 8 {8p12} (KAL-2 or FGFR-1 (fibroblast growth factor receptor 1)) is thought to cause about 10% of cases. There is some recent evidence to suggest a degree of linkage between the KAL-1 and FGFR-1 genes.

An additional autosomal cause of Kallmann syndrome has been reported Dode et al.2006) by a mutations in the prokineticin receptor-2 gene (PROKR2)(KAL-3) at position 20p13 and its ligand prokineticin 2 (PROK2)(KAL-4) at position 3p21.1. It was noted that mutations in these genes brought about various degrees of olfactory and reproductive dysfunction, but not the other symptoms seen in KAL-1 and KAL-2 forms of Kallmann Syndrome. The authors of the paper suggested that up to 30% of all Kallmann Syndrome cases can be linked to known genetic mutations.

Inheritance

Sparkes et al. (1968) described X-linked inheritance of hypogonadotropic hypogonadism with anosmia in 2 brothers and their half sister. The 3 affected sibs had the same mother who, despite having minor signs of the disorder (late menarche and irregular menses), had 9 liveborn children. The affected girl had no menses or breast development at age 18 and her ovaries were histologically exactly like those of the fetus. The father had anosmia. This may have been the autosomal recessive form with heterozygous expression in the father or the autosomal dominant form.

Hermanussen and Sippell (1985) reported a presumably X-linked recessive kindred. All carrier females had normal sexual and olfactory function. Hipkin et al. (1990) described male twins who were identical by DNA fingerprinting; one had full-blown manifestations of Kallmann syndrome, whereas the other showed normal sexual development and only hyposmia. In a second family, Hermanussen and Sippell (1985) observed 16-year-old twin sisters of whom one had retarded pubertal development and total anosmia, and the other, proven to be monozygotic by blood grouping and HLA typing, had undergone a normal menarche but showed total anosmia. The authors pointed out that sporadic cases of Kallmann syndrome have appeared only in families in which isolated anosmia is present. (Whether a heritable form of anosmia distinct from the Kallmann syndrome exists is unclear.) They suggested that there is an acquired hypothalamic GnRH deficiency on the basis of preexisting anosmia. Oliveira et al. (2001) observed that of their X-linked cases confirmed by mutation analysis, only 1 of 3 pedigrees appeared X-linked by inspection, whereas the other 2 contained only affected brothers. Female members of 3 known KAL1 mutation families exhibited no reproductive phenotype and were not anosmic, whereas 3 families with anosmic women were not found to carry KAL1 mutations. The authors concluded that obligate female carriers in families with KAL1 mutations have no discernible phenotype.

Epidemiology

Kallmann syndrome occurs at a rate of 1 in 10,000 male births and 1 in 50,000 female births. It may be inherited as an X-linked condition, an autosomal dominant condition or as an autosomal recessive condition. Statistics are sparse, but it seems that autosomal dominant is the most common form of heredity.

One recent paper (Quinton, 2004) quoted an incidence in males of 0.025%, or 1 in 4,000, with the female incidence being 3 to 5 times less.

Even though mutations in the KAL-1 gene on the X chromosome can cause Kallmann syndrome, only 11-14% of patients with Kallmann syndrome have detectable KAL-1 mutations.

Autosomal dominant mutations have been described with the FGFR-1 (8p12) gene, sometimes referred to as the KAL-2 gene. This is thought to cause about 10% of cases.

Autosomal recessive mutations of the GnRH receptor gene (4q13.2) have also been reported (Quinton, 2004). This defect appears to produce a wider spectrum of physical symptoms than with the other gene defects, and the defect lies in the ability of the pituitary gland to recognize GnRH, rather than the ability of the hypothalamus to produce GnRH. It is debateable as to whether this is in fact Kallmann syndrome since the GnRH receptor development is not related to anosmia.

There may also be no obvious family history of inheritance (sporadic cases). However, it is possible for Kallmann syndrome genes to be passed on to children of a sporadic case.

Treatment

Treatment is directed at restoring the deficient hormones -- known as hormone replacement therapy (HRT). Males are administered human chorionic gonadotropin (hCG) or testosterone. Females are treated with oestrogen (estrogen) and progestins.

To induce fertility in males or females, GnRH (aka LHRH) is administered by an infusion pump, or hCG/hMG/FSH/LH combinations are administered through regular injections. Fertility is only maintained whilst actually being treated with these hormones. Once fertility treatment stops it is necessary to revert to the normal HRT of testosterone for men and oestrogen + progestins for women.

The main health risk, for both men and women, of untreated Kallmann Syndrome is osteoporosis. Therefore, regular bone density scans (every 2 years or so) are advisable, even if being treated with HRT. Additional medication specifically for osteoporosis is necessary in some cases.

Cytogenetics

Guioli et al. (1992) described a patient with Kallmann syndrome who carried an X;Y translocation resulting from abnormal pairing and recombination between the X-linked Kallmann syndrome gene and its homolog on the Y. The translocation created a recombinant, nonfunctional KAL gene identical to the normal X-linked gene with the exception of the 3-prime end that was derived from the Y. The findings indicated that the 3-prime portion of the Kallmann syndrome gene is essential for its function and cannot be substituted by the Y-derived homologous region, although a 'position effect' remained a formal possibility. In a clinical assessment and molecular analysis of KAL1 and FGFR1 (136350, mutations in which cause KAL2, 147950) in 28 patients with Kallmann syndrome, Sato et al. (2004) found submicroscopic deletions at Xp22.3 involving VCXA (300533), STS (308100), KAL1, and OA1 (300500) in 3 familial cases and 1 sporadic male case affected by a contiguous gene syndrome.

Mapping

Ballabio et al. (1986) studied a large Italian pedigree in which 5 males had a syndrome, following a pattern of X-linked inheritance, characterized by steroid sulfatase-deficient ichthyosis (STS; 308100) and Kallmann syndrome. No crossing-over with Xg or with the probe DXS143 was found. No evidence of deletion was found in the probe studies. Thus, the Kallmann locus appears to be in the distal region of Xp, although Ballabio et al. (1986) did not reject the possibility that the Kallmann syndrome in their family was due to an allele at the STS locus. By linkage to the hypervariable repeat sequence CRI-S232 (DXS278), Meitinger et al. (1990) narrowed the location of the KAL1 gene to Xp22.3; maximum lod score = 6.5 at theta = 0.03. Using pulsed field gel analysis of DNAs from patients with terminal deletions of Xp, Petit et al. (1990) mapped the Kallmann syndrome locus to a deletion interval of 350 kb at most, located between 8,600 and 8,950 kb from Xpter. Franco et al. (1991) mapped a gene, which they called KALIG1 (Kallmann syndrome interval gene-1), to the Kallmann syndrome critical region on the distal short arm of the human X chromosome. They showed that the gene shares homology with molecules involved in cell adhesion and axonal pathfinding, further supporting the notion that a molecular defect in this gene causes the neuronal migration defect underlying the syndrome.

Cloning

Legouis et al. (1991) sequenced 67 kb of genomic DNA corresponding to a deletion interval containing at least part of the Kallmann gene. They found 2 candidate exons, identified by multiparameter computer programs, in a cDNA encoding a protein of 679 amino acids. This candidate gene, ADMLX (adhesion molecule-like, X-linked), was interrupted in its 3-prime coding region in the Kallmann patient, in which the proximal end of the KAL deletion interval was previously defined. A 5-prime-end deletion was detected in another Kallmann patient. The predicted protein sequence showed homologies with the fibronectin type III repeat. Thus, ADMLX encodes a putative adhesion molecule consistent with the defect of embryonic neuronal migration. Del Castillo et al. (1992) demonstrated that the KAL1 gene consists of 14 exons spanning 120 to 200 kb that correlate with the distribution of domains in the predicted protein including 4 fibronectin type III repeats. The homologous locus, KALP, on Yq11 has several large deletions and a number of small insertions, deletions, and base substitutions which indicate that it is a nonprocessed pseudogene. The sequence divergence between KAL1 and KALP in humans, and the chromosomal location of KAL homologous sequences in other primates, suggest that KALP and the steroid sulfatase pseudogene on Yq11 were involved in the same rearrangement event on the Y chromosome during primate evolution. Incerti et al. (1992), who localized the KALP pseudogene to Yq11.2, came to similar conclusions.

Legouis et al. (1993) determined the entire coding sequence of chicken and quail KAL cDNAs and demonstrated an overall identity of 73% and 72%, respectively, with human KAL cDNA. This corresponds to 76% and 75% identity at the protein level.

Gene Function

Soussi-Yanicostas et al. (1996) showed that the KAL protein is N-glycosylated, secreted in the cell culture medium, and localized at the cell surface. Upon transfection of Chinese hamster ovary (CHO) cells with human KAL cDNA, the corresponding encoded protein was produced. Several lines of evidence indicated that heparan-sulfate chains of proteoglycan(s) are involved in the binding of the KAL protein to the cell membrane. The authors generated polyclonal and monoclonal antibodies to the purified KAL protein. With these, they detected and characterized the protein encoded by the KAL gene in the chicken central nervous system at late stages of embryonic development. The protein is synthesized by definite neuronal cell populations, including Purkinje cells in the cerebellum, mitral cells in the olfactory bulbs, and several subpopulations in the optic tectum, and the striatum. The protein, with an approximate molecular mass of 100 kD, was named anosmin-1 by the authors in reference to the deficiency of the sense of smell that characterizes Kallmann disease. Anosmin-1 was thought to be an extracellular matrix component. Since heparin treatment of cell membrane fractions from cerebellum and tectum resulted in the release of the protein, Soussi-Yanicostas et al. (1996) suggested that 1 or several heparan-sulfate proteoglycans are involved in the binding of anosmin-1 to the membranes in vivo.

reported that KAL is localized on the cell surface and it appears to be secreted as a diffusible molecule. They demonstrated that KAL undergoes proteolytic cleavage to yield a diffusible component and that this diffusible form is incorporated into the extracellular matrix. Rugarli et al. (1996) reported that KAL encodes a predicted 680-amino acid polypeptide with a protease inhibitor domain that is followed by 4 fibronectin type III repeats. Because the low abundance of this protein hampered biochemical characterization, they carried out transfection experiments to overexpress human and chick KAL in eukaryotic cells. Rugarli et al. (1996) postulated that once incorporated into the extracellular matrix of the olfactory bulb, KAL might promote the ultimate migration and target recognition of olfactory axons.

Soussi-Yanicostas et al. (2002) showed that anti-anosmin-1 antibodies blocked the formation of the collateral branches of rat olfactory bulb output neurons (mitral and tufted cells) in organotypic cultures. Moreover, anosmin-1 greatly enhanced axonal branching of these dissociated neurons in culture. Coculture experiments with either piriform cortex or anosmin-1-producing CHO cells demonstrated that anosmin-1 is a chemoattractant for the axons of these neurons, suggesting that this protein, which is expressed in the piriform cortex, attracts their collateral branches in vivo. The authors concluded that anosmin-1 has a dual branch-promoting and guidance activity and is involved in the patterning of mitral and tufted cell axon collaterals to the olfactory cortex.

Bulow et al. (2002) showed that expression of the C. elegans homolog of KAL1 in selected sensory and interneuron classes caused a highly penetrant, dosage-dependent, and cell autonomous axon-branching phenotype. In a different cellular context, heterologous C. elegans Kal1 expression caused a highly penetrant axon-misrouting phenotype. The axon-branching and -misrouting activities required different domains of the KAL1 protein. In a genetic modifier screen, Bulow et al. (2002) isolated several loci that either suppressed or enhanced the Kal1-induced axonal defects, 1 of which codes for an enzyme that modifies specific residues in heparan sulfate proteoglycans, namely heparan 6-O-sulfotransferase (604846). Bulow et al. (2002) hypothesized that KAL1 binds by means of a heparan sulfate proteoglycan to its cognate receptor or other extracellular cues to induce axonal branching and axon misrouting.

Molecular Genetics

Isolated GNRH deficiency is a heritable condition characterized by a functional deficit in GNRH secretion. Georgopoulos et al. (1997) determined the frequency of KAL1 gene mutations in subjects with sporadic GNRH deficiency. Only 1 of 21 (5%) with sporadic GNRH deficiency had a KAL1 gene mutation (a deletion of 14 bases starting at codon 464). In each of 3 different patients with an X-linked mode of inheritance, 3 mutations were detected. These were a single base substitution introducing a stop codon at position 328, another encoding a phe517-to-leu substitution and a 9-base deletion at the 3-prime exon-intron splice site of exon 8. These data indicated that the incidence of mutations in the coding region of the KAL1 gene in patients with sporadic GNRH deficiency is low.

Hardelin et al. (1993) reported results of a mutation search of the KAL gene in 21 unrelated males with familial Kallmann syndrome. In 2 families, large Xp22.3 deletions that included the entire KAL gene were detected by Southern blot analysis. By sequencing each of the 14 coding exons and splice site junctions in the other 19 patients, they found 9 point mutations at separate locations in 4 exons and 1 splice site. They emphasized the high frequency of unilateral renal aplasia in X-linked Kallmann patients; 6 of 11 males with identified alterations of the KAL gene showed this feature.

Parenti et al. (1995) reported the cases of 3 brothers with X-linked ichthyosis and variable expression of Kallmann syndrome. All 3 had the same deletion, which spared the first exon of the KAL1 gene; however, 1 brother had only mild hyposomia and normal pubertal progression, whereas the others were severely affected. The reason for the variability was unclear.

Maya-Nunez et al. (1998) described a contiguous gene syndrome due to deletion of the first 3 exons of the KAL1 gene and complete deletion of the steroid sulfatase gene (308100). The 20-year-old subject had hypogonadism, anosmia, and generalized ichthyosis. They found reports of complete deletion of both the STS and the KAL genes in 6 families, and 1 previous description of 3 sibs with complete deletion of the STS gene and partial deletion of the KAL gene. The KAL gene is proximal to the STS gene, with its 3-prime end oriented toward the telomere. It was therefore surprising that the 5-prime end of the KAL gene was deleted. This was said to be the first report of a deletion (or a point mutation) in this region of the KAL gene. The involvement of the conserved cysteine-rich N-terminal region which corresponds to the whey acidic protein motif of the KAL gene demonstrated the importance of this specific region for the function of the gene.

Oliveira et al. (2001) examined 101 individuals with idiopathic hypogonadotropic hypogonadism with or without anosmia and their families to determine their modes of inheritance, incidence of KAL1 mutations, genotype-phenotype correlations, and, in a subset of 38 individuals, their neuroendocrine phenotype. Of the 101 patients, 59 had true Kallmann syndrome (hypogonadotropic hypogonadism and anosmia/hyposmia), whereas, in the remaining 42, no anosmia was evident in the patients or their families. Of the 59 Kallmann syndrome patients, 21 were familial and 38 were sporadic cases. Mutations in the coding sequence of KAL1 were identified in only 3 familial cases (14%) and 4 of the sporadic cases (11%). Oliveira et al. (2001) concluded that confirmed mutations in the coding sequence of the KAL1 gene occur in the minority of Kallmann syndrome cases, and that the majority of familial (and presumably sporadic) cases of Kallmann syndrome are caused by defects in at least 2 autosomal genes.

Sato et al. (2004) studied 25 male and 3 female Japanese individuals with Kallmann syndrome aged 10 to 53 years. Ten males were from 5 families, and the remaining 15 males and 3 females were apparently sporadic cases. Sequencing all exons of the KAL1 and FGFR1 (136350) genes showed 6 novel and 2 recurrent intragenic KAL1 mutations in 7 familial and 4 sporadic male cases and 2 novel intragenic FGFR1 mutations in 2 sporadic male cases. Clinical assessment in the 15 males with KAL1 mutations showed normal and borderline olfactory function in 2 males and right-side dominant renal lesion in 7 males, in addition to variable degrees of hypogonadotropic hypogonadism in all the 15 males and olfactory dysfunction in 13 males. Clinical features in the remaining 11 cases with no demonstrable KAL1 or FGFR1 mutations included right renal aplasia in 1 female and cleft palate, cleft palate with perceptive deafness, and dental agenesis with perceptive deafness in 1 male each, in addition to a variable extent of hypogonadotropic hypogonadism and olfactory dysfunction.

Dode et al. (2006) described a patient with Kallmann syndrome who was heterozygous for 2 mutations: one in the KAL1 gene (308700.0012) and the other in the PROKR2 gene (607123.0001), raising the possibility of digenic inheritance.

Other Features

Krams et al. (1999) used a quantitative MRI protocol to determine if the mirror movements characteristic of X-linked Kallmann syndrome result from loss of transcallosal inhibition, as proposed by Nass (1985), or from an abnormal ipsilateral corticospinal tract, as suggested by electrophysiologic studies. Volumetric comparisons were made of men with X-linked Kallmann syndrome, all of whom had mirror movements, with normal controls, and men with autosomal Kallmann syndrome (147950, 244200), which is not associated with mirror movements. Bilateral hypertrophy of the corticospinal tracts was found in the X-linked patients only. Hypertrophy of the corpus callosum was found in both the X-linked and autosomal Kallmann syndrome patients. The findings of Krams et al. (1999) supported the hypothesis that the mirror movements seen in X-linked Kallmann syndrome result from abnormal development of ipsilateral corticospinal tracts.

Genotype/Phenotype Correlations

Quinton et al. (1996) performed detailed neurologic examinations of Kallmann syndrome subjects for phenotype-genotype correlation. They studied 27 Kallmann syndrome subjects, including 12 males with X-linked disease and 3 females; 6 male and 2 female normosmics with isolated GnRH deficiency; 1 male with a KMS variant; and 1 obligate female carrier. Evidence for X-linked disease came from pedigree analysis and mutation analysis of the KAL locus. All 8 normosmics, 3 males with KMS, and the female carrier had normal olfactory bulbs and sulci. Three new mutations at the KAL locus were identified, including 2 single exon deletions and 1 point mutation. No coding sequence mutations were found in 2 pedigrees with clear X-linked inheritance, suggesting that these cases may be due to mutations in pKAL, the 5-prime promoter region. No clear phenotype-genotype relationship was made between specific phenotypic anomalies and KAL mutations. Involuntary mirror movements of the upper limbs were present in 10 of 12 cases of X-linked KMS but in none of the other subjects.

Although a mental or intellectual disturbance was described in the original report of Kallmann syndrome (Kallmann et al., 1944), analyses of the genotype-phenotype relationship showed that Kallmann syndrome patients with mental disorders have large deletions on Xp22.3 that extend beyond the KAL1 locus (Nagata et al., 2000). In contrast, almost all patients with mutations restricted to the KAL1 locus are free of mental disturbance. Prager and Braunstein (1993) speculated that another gene located close to KAL1 is responsible for the mental disturbance.

Allelic Variants

.0001 Kallmann Syndrome 1 [KAL1, 3300-BP DEL]

Bick et al. (1992) studied 77 families in which one or more men had hypogonadotropic hypogonadism, characterized by hypogonadism and low serum concentrations of testosterone, luteinizing hormone, and follicle-stimulating hormone. None had evidence of deficiency of any other pituitary hormone or of a hypothalamic or pituitary mass lesion. Among the 77 families, the probands had anosmia in 52, hyposmia in 7, and a normal sense of smell in 18. In 10 of the families some affected members were brothers, and in 6 families some belonged to at least 2 generations related through female members, indicating a pattern of X-linked inheritance. In only 1 family was an abnormality on Southern blot analysis discovered. Bick et al. (1992) demonstrated that this patient and his brother had inherited from their mother a 3,300-bp deletion entirely confined within the 210-kb KALIG1 gene. They sequenced the 5-prime and 3-prime boundaries of the deleted region. A 6-bp homology (CAAATT) was found at the deletion breakpoint. It is possible that this short stretch of sequence homology was involved in the molecular mechanism that underlay the event producing the deletion. Similar nonhomologous recombinations as the basis of intragenic deletions have been postulated (Woods-Samuels et al., 1991; Bernatowicz et al., 1992). The deletion included the penultimate exon which encodes one of the domains of the KALIG1 gene that is homologous with molecules involved in neural cell adhesion. In this family, 1 brother was born with microphallus, scrotal hypoplasia, and an undescended testis. His brother had normal genitalia at birth, but by 4 months of age his testes had retracted and his penis appeared involuted, closely resembling his brother's genitalia at the same age. Both had anosmia; their mother had a normal sense of smell.

.0002 Kallmann Syndrome 1 [KAL1, TRP237TER]

Hardelin et al. (1992) sought intragenic mutations in the KAL candidate gene in 18 unrelated patients. With the PCR, 2 exons of the gene were amplified in genomic DNA. They identified 3 different base substitutions--all leading to a stop codon--and 1 single-base deletion responsible for a frameshift. In 1 patient with a rather extensively affected family, they found a TGG-to-TGA transition at codon 237 converting tryptophan to stop. In addition to bilateral cryptorchidism and anosmia, the boy had synkinesia, minor motor epilepsy, and unilateral renal aplasia. A brother who had died at 1 day of age had only one kidney.

.0003 Kallmann Syndrome 1 [KAL1, ARG257TER]

In a patient in whom micropenis and bilateral cryptorchidism was recognized at birth and who later showed anosmia, typical mirror movements of the hands (bimanual synkinesia) and mild bilateral pes cavus, Hardelin et al. (1992) found a CGA-to-TGA transition at codon 257 resulting in a change of arginine to stop.

.0004 Kallmann Syndrome 1 [KAL1, TRP258TER]

In an 11-year-old boy with unilateral cryptorchidism, anosmia, left ptosis, synkinesia, and unilateral renal aplasia, Hardelin et al. (1992) found a TGG-to-TGA transition resulting in conversion of tryptophan-258 to stop.

.0005 Kallmann Syndrome 1 [KAL1, 1-BP DEL, PRO277FS]

In an 8-year-old boy with micropenis, bilateral cryptorchidism, anosmia, and bilateral pes cavus, Hardelin et al. (1992) found deletion of one C from codon 277 (CCC-to-CC, which normally codes for proline) resulting in frameshift. The brother of the patient also had Kallmann syndrome and marked pes cavus, and both had high-arched palate.

.0006 Kallmann Syndrome 1 [KAL1, EX3-5DEL ]

Maya-Nunez et al. (1998) found KAL gene defects in 7 of 12 unrelated males studied with X-linked KMS. One had a deletion from exon 3 to exon 5. The deletion comprised only part (exon 5) of the coding region of the first fibronectin type III-like repeat of the KAL protein. The rest of the deletion comprised part of the conserved cysteine-rich N-terminal region that corresponds to the whey acidic protein motif.

.0007 Kallmann Syndrome 1 [KAL1, GLU514LYS]

Maya-Nunez et al. (1998) found KAL gene defects in 7 of 12 unrelated males studied with X-linked KMS. Six patients had a previously unidentified missense mutation in exon 11, which was a G-to-A transition at codon 514 (GAA to AAA) resulting in a glu514-to-lys substitution. The fact that the same missense mutation was found in 6 of the 12 patients indicated that the mutation was derived from a common ancestor or resulted from a mutation hotspot.

.0008 Kallmann Syndrome 1 [KAL1, EX5DEL]

In a male patient with Kallmann syndrome, Soderlund et al. (2002) identified a complete deletion of exon 5 of the KAL1 gene, which occurred within the region encoding the first fibronectin type III-like repeat of the KAL1 protein.

.0009 Kallmann Syndrome 1 [KAL1, 11-BP DUP, NT158]

In a male patient with Kallmann syndrome, Soderlund et al. (2002) identified a novel duplication of nucleotides 158-168 in exon 1 of the KAL1 gene; this 11-bp insertion caused a termination codon (TGA) within the same exon. The duplication was located in the conserved cysteine-rich N-terminal region that corresponds to the whey acidic protein motif, affecting the KAL1 protein either by interrupting the normal transcription or by stopping the translation at the stop codon.

.0010 Kallmann Syndrome 1 [KAL1, ARG262TER]

In a male patient with Kallmann syndrome, Soderlund et al. (2002) identified a novel arg262-to-ter (R262X) mutation in exon 6 of the KAL1 gene. The stop codon in exon 6 was located within the region encoding the first fibronectin type III-like repeat of the KAL1 protein.

.0011 Kallmann Syndrome 1 [KAL1, EX3-13 DEL ]

Massin et al. (2003) described clinical heterogeneity in 3 brothers with Kallmann syndrome who carried a large deletion (exons 3-13) in KAL1. All 3 had a history of hypogonadotropic hypogonadism with delayed puberty. Although brain MRI showed hypoplastic olfactory bulbs in the 3 sibs, variable degrees of anosmia/hyposmia were shown by olfactometry. In addition, these brothers had different phenotypic anomalies, i.e., unilateral renal aplasia (sibs B and C), high-arched palate (sib A), brachymetacarpia (sib A), mirror movements (sibs A and B), and abnormal eye movements (sib C). Sib A suffered from a severe congenital hearing impairment, a feature that had been reported in Kallmann syndrome but had not yet been ascribed unambiguously to the X-linked form of the disease. The authors concluded that the variable phenotype, both qualitatively and quantitatively, in this family further emphasizes the role of putative modifier genes, and/or epigenetic factors, in the expressivity of X-linked Kallmann syndrome.

.0012 Kallmann Syndrome 1 [KAL1, SER396LEU ]

In a sporadic case of Kallmann syndrome, Dode et al. (2006) identified heterozygosity for a ser396-to-leu mutation in the KAL1 gene and heterozygosity for a leu173-to-arg mutation in the PROKR2 gene (607123.0001). The mutation in the KAL1 gene modifies the first amino acid residue of the linker between the second and third fibronectin-like type III repeats of the predicted protein; this residue is conserved among orthologous proteins from vertebrates and invertebrates. The mutation in the PROKR2 gene was identified in 6 unrelated Kallmann syndrome patients. Neither mutation was found in control individuals, raising the possibility of digenic inheritance.

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Infantile Spasm (West Syndrome)

2007-05-13T16:49:00.001-07:00

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Drug Category: Vitamins -- These agents are essential for normal metabolic processes.

Drug Name	Pyridoxine (vitamin B-6) -- A 2004 American Academy of Neurology and Child Neurology Society practice parameter concluded that "there is insufficient evidence to recommend pyridoxine for the treatment of infantile spasms (Level U, Class III and IV evidence)." Two distinct treatment situations exist in which pyridoxine is used in patients with West syndrome: (1) IV administration during diagnostic EEG to assess whether patient's seizures and EEG abnormalities are related to pyridoxine deficiency. In this approach, administer 50-100 mg IV during diagnostic EEG; if dramatic improvement noted in EEG, patient believed to have pyridoxine-dependent seizures (2) Long-term oral administration: Effectiveness of long-term oral high-dose pyridoxine in West syndrome has been investigated in multiple open-label studies with promising results; most patients who respond to long-term oral high-dose pyridoxine do so within 1-2 wk of initiation.
Pediatric Dose	Initial dose: 10-20 mg/kg/d PO Titration: Increase by 10 mg/kg q3d Maintenance dose: 15-50 mg/kg/d PO (approximately 100-400 mg/d)
Contraindications	Documented hypersensitivity; do not administer IV to infants with cardiac disease
Interactions	Can decrease phenobarbital and phenytoin serum concentrations
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Usually well tolerated; adverse events include decreased appetite, nausea, vomiting, paresthesias, diarrhea, somnolence, and headache; abnormal liver function tests and low serum folic acid levels have been noted in some patients; long-term (cumulative) adverse effects can include severe sensory peripheral neuropathy, movement disorders, and ataxia

Complications:

* Complications include dose-related, idiosyncratic, or long-term adverse effects from medications, including death.

Prognosis:

* The long-term overall prognosis is poor and is related directly to the etiology.

o Infants with idiopathic West syndrome have a better prognosis than do infants with symptomatic West syndrome. Only 14% of infants with symptomatic West syndrome have normal or borderline normal cognitive development, compared to 28-50% of infants with idiopathic West syndrome. Mental retardation is severe in 70% of patients, often with psychiatric problems such as autistic features or hyperactivity. Infrequently spasms may persist in adulthood. Fifty to seventy percent of patients develop other seizure types. Eighteen to fifty percent of patients will develop Lennox Gastaut syndrome.

o Subsets of patients among the symptomatic West syndrome group seem to have a better prognosis. A retrospective study of 17 children with trisomy 21 and infantile spasms found that 13 of 16 survivors were seizure free for more than 1 year and 10 no longer were taking anticonvulsants.

o A study of 15 children with neurofibromatosis type 1 and infantile spasms also reported a relatively benign seizure and cognitive outcome.

o Prognosis appears to be worse in infants with other seizure types, persistent EEG abnormalities, poor response to ACTH, and delayed initiation of treatment. One study showed that later onset, normal-to-mild psychomotor delay at the time of diagnosis, and good seizure control were factors related to better prognosis.

Medical/Legal Pitfalls:

* Failure to inform the patient's family of the risk for severe adverse effects, including death, from the use of either ACTH or oral steroids

* Failure to inform the patient's family of the risk for severe idiosyncratic reactions from two commonly used antiepileptic medications for West syndrome

o Valproate - Hepatotoxicity, pancreatitis

o Lamotrigine - Steven-Johnson syndrome, toxic epidermal necrolysis

* Failure to inform the patient's family of signs and symptoms to watch for that indicate severe adverse effects or idiosyncratic reactions

* Failure to instruct the family on what to do if they notice signs and symptoms indicating severe adverse effects or idiosyncratic reactions

* Failure to fully investigate and identify possible causes of the patient's West syndrome, including identification of tuberous sclerosis (a common cause of West syndrome), which can have implications for the entire family

* Failure to recognize signs and symptoms of West syndrome, which could result in failure to select an appropriate AED with proven efficacy; this could increase the risk for uncontrolled seizures that in turn increase the risk for injury and death.

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Infantile Spasm (West Syndrome)

2007-05-13T15:18:00.000-07:00

Category: Seizure Disorder
Target System: Central Nervous System

Synonyms and related keywords: infantile spasms, hypsarrhythmia, developmental delay, West syndrome, mental retardation, epilepsy syndrome

Background: West syndrome is composed of the triad of infantile spasms, an interictal EEG pattern termed hypsarrhythmia, and mental retardation, although the diagnosis can be made even if one of the 3 elements is missing (according to the international classification). This severe epilepsy syndrome is an age-dependent expression of a damaged brain. The term “infantile spasms” has been used to describe the seizure type, the epilepsy syndrome, or both. In this article, the term “infantile spasms” is synonymous with West syndrome.

The syndrome's namesake, Dr W J West, gave the first detailed description of infantile spasms, as they occurred in his child. In a letter to the editor of The Lancet in 1841, West described the events as “bobbings” that “cause a complete heaving of the head forward towards his knees, and then immediately relaxing into the upright position … these bowings and relaxings would be repeated alternately at intervals of a few seconds, and repeated from 10 to 20 or more times at each attack, which attack would not continue more than 2 or 3 minutes; he sometimes has 2, 3 or more attacks in the day.”

This detailed clinical description was followed approximately 100 years later by the report of the typical interictal EEG pattern termed hypsarrhythmia. Most patients with infantile spasms have some degree of developmental retardation.

The eponym West syndrome was created in the early 1960s by Drs. Gastaut, Poirier, and Pampiglione.

Pathophysiology: Infantile spasms are believed to reflect abnormal interactions between the cortex and brainstem structures. Focal lesions early in life may secondarily affect other sites in the brain, and hypsarrhythmia may represent this abnormal activity arising from multiple brain sites. The frequent onset of infantile spasms in infancy suggests that an immature central nervous system may be important in the pathogenesis. The brain-adrenal axis also may be involved. One theory states that the effect of different stressors in the immature brain produces an abnormal excessive secretion of corticotropin-releasing hormone, causing spasms. The clinical response to adrenocorticotropic hormone (ACTH) and glucocorticoids can be explained by suppression of corticotropin-releasing hormone (CRH) production.

Frequency:

* In the US: Infantile spasm constitutes 2% of childhood epilepsies but 25% of epilepsy with onset in the first year of life. The rate of infantile spasm is estimated between 2.5 to 6.0 per 10,000 live births. Its prevalence rate is 1.5-2.0 per 10,000 children aged 10 years or younger.

* Internationally: Infantile spasm occurs in 0.05 (Estonia) to 0.41 (Oulu, Finland) of 1000 live births and in 1.4% (Estonia), 4.2% (Odense, Denmark), and 7.6% (Tampere, Finland) of children with epilepsy.

Mortality/Morbidity: The premature death rate ranges from 5-31%. The upper limit comes from a study of 214 Finnish children with a history of infantile spasms who were followed for a mean of 25 years (range, 20-30 y). Most of the deaths (61%) occurred at or before age 10 years, while only 10% occurred after age 20 years.

Sex: Although males are affected slightly more often than females, no significant gender difference is noted.

Age: Ninety percent of infantile spasms begin in those younger than 12 months. Peak onset is at age 4-6 months.

History:

* Ictal manifestations

o Spasms begin with a sudden, rapid, tonic contraction of trunk and limb musculature that gradually relaxes over 0.5-2 seconds.

+ Contractions can last 5-10 seconds.

+ The intensity may vary from a subtle head nodding to a powerful contraction of the body.

+ Infantile spasms usually occur in clusters, often several dozens, separated by 5-30 seconds.

+ Spasms frequently occur just before sleep or upon awakening. They can be observed during sleep, although this is rare.

o Spasms can be flexor, extensor, or a mixture of flexion and extension.

+ Flexor spasms consist of brief contractions of the flexor muscles of the neck, trunks, and limbs, resulting in a brief jerk. They may resemble a self-hugging motion and often are associated with a cry. The patient then relaxes, and the jerk repeats. These attacks occur in clusters throughout the day and last anywhere from less than 1 minute to 10-15 minutes or longer in some patients.

+ Extensor spasms consist of contractions of the extensor musculature with sudden extension of the neck and trunk with extension and abduction of the limbs. Extensor spasms and asymmetric or unilateral spasms often are associated with symptomatic cases.

+ Mixed spasms are the most common type, consisting of flexion of the neck and arms with extension of the legs, or flexion of the legs with extension of the arms.

+ In different series the frequency of the 3 spasm types were 42-50% mixed, 34-42% flexor, and 19-23% extensor.

* Interictal manifestations: An arrest or regression in psychomotor development accompanies the onset of spasms in 70-95% of patients.

* Family history: A family history of infantile spasms is uncommon but as many as 17% of patients may have a family history of any epilepsy.

Physical:

* General physical examination

o Physical examination can be important in helping to identify specific etiologies that may have both systemic and neurological symptoms (eg, tuberous sclerosis complex).

o Often a patient with infantile spasms has normal findings on general physical examination. No pathognomonic physical findings are present in patients with infantile spasms.

o If abnormalities in the general physical examination are noted (eg, adenoma sebaceum, ash leaf macules), specific etiologies may be suggested.

o Use a Wood lamp to examine the skin.

o Patients may exhibit moderate-to-severe growth delay; this is a nonspecific finding and more a reflection of the underlying brain injury than of a specific epilepsy syndrome.

* Neurologic examination

o The neurologic examination in patients with infantile spasms demonstrates abnormalities in mental status function, specifically deficits in cognitive function consistent with developmental delay or regression.

o Abnormalities in level of consciousness, cranial nerve function, and motor/sensory/reflex examination are nonspecific findings and more a reflection of the underlying brain injury or effect of anticonvulsant medications than of the syndrome.

o No pathognomonic findings are present on neurologic examination in patients with infantile spasms.

Causes: Infantile spasms (West syndrome) can be classified according to its suspected etiology as symptomatic, cryptogenic, or idiopathic.

* Symptomatic

o Patients are diagnosed with symptomatic infantile spasms if an identifiable factor is responsible for the syndrome. Virtually any disorder that can produce brain damage can be associated with infantile spasms.

o The list of etiologies can be subdivided into prenatal disorders, perinatal disorders, and postnatal disorders.

+ Prenatal disorders include hydrocephalus, microcephaly, hydranencephaly, schizencephaly, polymicrogyria, Sturge-Weber syndrome, incontinentia pigmenti, tuberous sclerosis, trisomy 21, hypoxic-ischemic encephalopathies, congenital infections, and trauma.

+ Perinatal disorders include hypoxic-ischemic encephalopathies, meningitis, encephalitis, trauma, and intracranial hemorrhages.

+ Postnatal disorders include pyridoxine dependency, nonketotic hyperglycinemia, maple syrup urine disease, phenylketonuria, mitochondrial encephalopathies, meningitis, encephalitis, degenerative diseases, biotinidase deficiency, and trauma.

o Evaluating children with infantile spasms for possible tuberous sclerosis is critical, as this is the single most common disorder, comprising 10-30% of prenatal cases. Tuberosis sclerosis is an autosomally dominant inherited disease with variable manifestations including cardiac tumors, kidney tumors, cutaneous malformations such as ash-leaf hypopigmented lesions, and seizures. In more than a few patients, the family diagnosis of tuberous sclerosis is found only after a child presents with infantile spasms, and an extensive workup of the child and subsequently the family reveals the genetic disease.

o Of patients with infantile spasms, 70-75% have symptomatic epilepsy. This percentage depends on the degree of sophistication of diagnostic studies. Development of more exquisite neurodiagnostic techniques will alter the relative proportion of symptomatic, cryptogenic, and idiopathic cases.

* Cryptogenic

o Patients have cryptogenic infantile spasms if no cause is identified but a cause is suspected and the epilepsy is presumed to be symptomatic.

o The proportion of cryptogenic cases varies from 8-42%. This wide range may be related to variations in the definition of the term "cryptogenic" and the age of diagnosis, since assessment of developmental level in early infancy is difficult.

* Idiopathic

o Patients may be considered to have idiopathic infantile spasms if normal psychomotor development occurs prior to the onset of symptoms, no underlying disorders or definite presumptive causes are present, and no neurological or neuroradiological abnormalities exist. Some investigators use the terms "idiopathic" and "cryptogenic" interchangeably.

o The percentage of idiopathic cases reportedly is 9-14%.

* Family history: A family history of infantile spasms is uncommon but as many as 17% of patients may have a family history of any epilepsy.

Other Problems to be Considered:

Benign myoclonus of early infancy
Myoclonic-astatic epilepsy

Lab Studies:

* Prior to initiating therapy, consider obtaining some or all of the following laboratory studies:

o Complete blood count with differential, liver panel, renal panel with electrolytes and glucose, calcium, magnesium, phosphorus, and urinalysis with microscopic examination

o Metabolic workup including glucose, liver panel, serum lactate and pyruvate, plasma ammonia, serum and urine amino acids, urine organic acids, and serum biotinidase

o Blood, urine, and cerebrospinal fluid cultures if an infection is suspected

o Cerebrospinal fluid analysis for cell count, glucose, protein, bacterial and viral culture, lactate, pyruvate, and amino acids

Imaging Studies:

* Overview

o About 70-80% of patients have abnormal findings on neuroimaging studies.

o Magnetic resonance imaging (MRI) of the brain provides a more detailed evaluation than does a computed tomography (CT) scan of the brain.

o Imaging studies should be obtained prior to starting ACTH or steroid therapy, as these therapies are associated with the appearance of apparent brain atrophy as treatment continues.

* CT scan

o Structural brain anomalies such as hydrocephalus, hydranencephaly, schizencephaly, and agenesis of corpus callosum can be recognized easily by CT scans.

o In addition, cerebral calcifications can be observed in patients with tuberous sclerosis or congenital infections.

* MRI: MRI scans are superior to CT scans in detecting areas of cortical dysgenesis, disorders of neuronal migration, or disorders of myelination.

Other Tests:

* Electroencephalogram

o Always perform an EEG in patients with suspected infantile spasms, since the diagnosis depends on the presence of specific EEG findings.

o If possible, obtain prolonged video-EEG telemetry to record both waking and sleep EEG to assist in confirming a suspected diagnosis. A routine 20-minute EEG may not capture the patient while both awake and asleep and thus may miss specific important EEG findings.

* Interictal electroencephalogram

Click image for a full size view

o Hypsarrhythmia is the characteristic interictal EEG pattern and consists of chaotic, high- to extremely high-voltage polymorphic delta and theta rhythms with superimposed multifocal spikes and wave discharges (see Image above). Multiple variations of this pattern are possible, including focal or asymmetric hypsarrhythmia.

o In one study of 77 patients with infantile spasms, unilateral hypsarrhythmia and asymmetric ictal EEG changes during spasms often occurred together and correlated with focal or asymmetric cerebral lesions on imaging studies. Patients with symmetric hypsarrhythmia and infantile spasms rarely had focal or asymmetric cerebral lesions on imaging studies (most had structural diffuse brain lesions) and overall had better chances for a normal outcome.

o In a study of 26 patients with infantile spasms, 6 patients (23%) had asymmetric hypsarrhythmia. All 6 had symptomatic infantile spasms and 5 had focal abnormalities on examination or imaging study (4 ipsilateral to the lesion, 1 contralateral). These focal abnormalities may identify a subset of patients with West syndrome who are candidates for focal cortical resections.

* Ictal electroencephalogram

o Eleven different types of ictal patterns have been identified in patients with West syndrome.

o In one study, the most common pattern found in 38% of patients with seizures was a high-voltage, frontal dominant, generalized slow-wave transient followed by voltage attenuation, also termed an electrodecremental episode. These electrodecremental episodes were a feature in 71% of the seizures.

o No close correlation exists between the type of seizure and the EEG pattern.

* Ophthalmic examination: Ophthalmic examination may reveal chorioretinitis from congenital infections, chorioretinal lacunar defects in patients with Aicardi syndrome, or retinal tubers in patients with tuberous sclerosis.

* Wood lamp: Tuberous sclerosis is the single most common recognizable cause of West syndrome. Therefore, a careful examination of the skin for the characteristic hypopigmented lesions of tuberous sclerosis is mandatory. The unaided bedside identification of these lesions may be more difficult in patients with light complexions.

Procedures:

* Lumbar puncture

o In young infants with early onset of West syndrome, consider a lumbar puncture as part of a full sepsis workup to look for signs of meningitis.

o In older infants in whom no clear signs of infection are present, a lumbar puncture also is useful in evaluating metabolic causes of West syndrome such as nonketotic hyperglycinemia.

Treatment

Medical Care:

* The goals of treatment for infants with West syndrome are the best quality of life with no seizures, the fewest adverse effects from treatment, and the least number of medications.

* Medications such as ACTH and conventional antiepileptic medications (AEDs) are the mainstay of therapy for infants with West syndrome. Unfortunately, no one medical treatment gives satisfactory relief for all infants with West syndrome.

* The various medical treatment options for infants with West syndrome can be divided into 2 major groups:

o Commonly used first-line treatments (ie, ACTH, prednisone, vigabatrin, pyridoxine [vitamin B-6])

o Second-line treatments (ie, benzodiazepines, valproic acid, lamotrigine, topiramate, zonisamide)

Surgical Care:

* Focal cortical resection: In some patients, resection of a localized region can lead to freedom from seizures.

Consultations:

* Pediatric neuropsychologists can assess intellectual function and educational needs and advise on nonpharmacologic management of behavioral problems.

* Pediatric psychiatrists can advise on pharmacologic management of behavioral problems.

* Neurosurgeons can help assess whether the infant is a candidate for focal resection.

* Dietitians can assist in the institution and maintenance of the ketogenic diet.

Diet:

* The ketogenic diet has been employed successfully to treat a variety of seizure types. However, the role of the ketogenic diet in the treatment of infants with West syndrome is not defined.

Medication

The goals of treatment for infants with West syndrome are the best quality of life with no seizures, the fewest adverse effects from treatment, and the least number of medications.

Drug Category: Hormonal agents -- These agents cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Drug Name	Corticotropin (Acthar, ACTH) -- A 2004 American Academy of Neurology and Child Neurology Society practice parameter concluded that (i) "ACTH is probably effective for the short-term treatment of infantile spasms and in resolution of hypsarrhythmia (Level B)" and (ii) "There is insufficient evidence to recommend the optimum dosage and duration of treatment with ACTH for the treatment of infantile spasms (Level U)." A 2004 multicenter, randomized, controlled trial in the UK compared hormonal therapy (either oral prednisolone or intramuscular tetracosactide depot, a synthetic analogue of ACTH) to vigabatrin in 107 infants with infantile spasms. More infants assigned hormonal treatments (73%) had no spasms on days 13 and 14 compared to infants assigned vigabatrin (54%, p=0.043). A follow-up study demonstrated that, although hormone treatment controlled spasms better than vigabatrin initially, by age 12-14 months, both groups had similar seizure-free rates. Older studies suggest ACTH's efficacy (percentage of infants with West syndrome reaching seizure freedom) is between 50% and 67%. Associated with serious, potentially life-threatening adverse effects. Must be administered IM, which is painful to infant and unpleasant for parent to perform. Daily dosages expressed as U/d (most common), U/m²/d, or U/kg/d. Prospective single-blind study demonstrated no difference in effectiveness of high-dose, long-duration corticotropin (150 U/m²/d for 3 wk, tapering over 9 wk) versus low-dose, short-duration corticotropin (20-30 U/d for 2-6 wk, tapering over 1 wk). With respect to spasm cessation and improvement in patient's EEG; hypertension was more common with larger doses.
Pediatric Dose	Not established; 5-40 U/d IM for 1-6 wk to 40-160 U/d IM for 3-12 mo suggested; some authors recommend 150 U/m²/d IM for 6 wk or 5-8 U/kg/d IM in divided doses for 2-3 wk
Contraindications	Documented hypersensitivity; porcine protein hypersensitivity; scleroderma; recent surgery; congestive heart failure; primary adrenal insufficiency; hypercortisolism; active herpes infection; active tuberculosis; herpes simplex ocular infection; thromboembolic disease; active serious bacterial, viral, or fungal infection
Interactions	Avoid vaccines and immunizations during therapy Amphotericin B can decrease response; acetazolamide or other carbonic anhydrase inhibitors can cause hypernatremia, hypocalcemia, hypokalemia, and edema; diuretics can reduce natriuretic and diuretic effects; potassium-depleting diuretics can cause hypokalemia; phenytoin, barbiturates, and rifampin can decrease effects; estrogens can potentiate effects; salicylates or NSAIDs can cause GI ulceration; can reduce growth response to growth hormone (somatropin); warfarin can decrease anticoagulation response
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Avoid vaccines and immunizations during therapy Because of increased risk of infection, hypertension, hypertrophic cardiomyopathy, and electrolyte disturbances, careful and frequent clinical and laboratory monitoring of patient is essential Caution in Cushing disease, hypertension, hypokalemia, hypernatremia, diverticulitis, ulcerative colitis or intestinal anastomosis, renal disease, diabetes mellitus, hypothyroidism, hepatic disease

Drug Name	Prednisone (Deltasone, Orasone, Meticorten) -- A 2004 American Academy of Neurology and Child Neurology Society practice parameter concluded that "there is insufficient evidence that oral corticosteroids are effective in the treatment of infantile spasms (Level U)." Few comparative studies between ACTH and prednisone have been performed; one double-blind, placebo-controlled, crossover study demonstrated no difference between low-dose ACTH (20-30 U/d) and prednisone (2 mg/kg/d), while second prospective, randomized, single-blinded study demonstrated high-dose ACTH at 150 U/m²/d was superior to prednisone (2 mg/kg/d) in suppressing clinical spasms and hypsarrhythmic EEG in infants with infantile spasms. A 2004 multicenter, randomized, controlled trial in the UK compared hormonal therapy (either oral prednisolone or intramuscular tetracosactide depot, a synthetic analogue of ACTH) to vigabatrin in 107 infants with infantile spasms. More infants assigned hormonal treatments (73%) had no spasms on days 13 and 14 compared to infants assigned vigabatrin (54%, p=0.043). A follow-up study demonstrated that, although hormone treatment controlled spasms better than vigabatrin initially, by age 12-14 months, both groups had similar seizure-free rates.
Pediatric Dose	2 mg/kg/d PO for 2-4 wk
Contraindications	Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; GI disease
Interactions	Barbiturates, phenytoin, rifabutin, and rifampin can increase metabolism of prednisone; hyperthyroidism can increase metabolism of prednisone; hypothyroidism can decrease metabolism of prednisone; isoproterenol in patients with asthma can increase risk of cardiac toxicity, clinical deterioration, myocardial infarction, congestive heart failure, and death
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Prolonged therapy can affect metabolic, GI, neurologic/behavioral, dermatologic, and endocrine systems; metabolic adverse events can include (but are not limited to) fluid retention and electrolyte disturbances (eg, hypernatremia, hypokalemia, hypokalemic metabolic alkalosis, hypocalcemia), edema, hypertension, and hyperglycemia GI adverse events can include nausea, vomiting, abdominal pain, anorexia, diarrhea, constipation, gastritis, esophageal ulceration, weight loss, and delayed growth Neurological and behavioral adverse events reported during prolonged administration can include headache, insomnia, restlessness, mood lability, anxiety, personality changes, and psychosis Visual adverse events may include exophthalmos, retinopathy, posterior subcapsular cataracts, and ocular hypertension Dermatological adverse events reported during therapy can include skin atrophy, diaphoresis, impaired wound healing, facial erythema, hirsutism, ecchymosis, and easy bruising Endocrinological adverse events from prolonged use include hypercorticism and physiologic dependence Idiosyncratic reactions include pancreatitis and dermatological hypersensitivity reactions (allergic dermatitis, angioedema, urticaria); avoid vaccination with live-virus vaccines; avoid abrupt discontinuation if patient has been on long-term therapy Caution in congestive heart failure, hypertension, glaucoma, GI disease, diverticulitis, intestinal anastomosis, hepatic disease, hypoalbuminemia, peptic ulcer disease, renal disease, osteoporosis, diabetes mellitus, hypothyroidism, coagulopathy or thromboembolic disease, or potential impending GI perforation

Drug Category: Anticonvulsants -- These agents are used to manage severe muscle spasms.

Drug Name	Vigabatrin -- A 2004 American Academy of Neurology and Child Neurology Society practice parameter concluded that (i) "Vigabatrin is possibly effective for short-term treatment of infantile spasms (Level C, Class III and IV evidence)." (ii) "Vigabatrin is also possibly effective for short-term treatment of infantile spasms in majority of children with tuberous sclerosis (Level C, Class III and IV evidence)." (iii) "Serious concerns about retinal toxicity in adults suggest that serial ophthalmologic screening is required in patients on vigabatrin. However, data are insufficient to make recommendations regarding the frequency or type of screening that would be of value in reducing the prevalence of this complication in children (Level U, Class IV studies)." Not approved by FDA in US, but available in many countries worldwide. Multiple studies (both open label and double blind) have reported some effectiveness in stopping seizures in infants with West syndrome, especially when caused by tuberous sclerosis. A 2004 multicenter, randomized, controlled trial in the UK compared hormonal therapy (either oral prednisolone or intramuscular tetracosactide depot, a synthetic analogue of ACTH) to vigabatrin in 107 infants with infantile spasms. More infants assigned hormonal treatments (73%) had no spasms on days 13 and 14 compared to infants assigned vigabatrin (54%, p=0.043). A follow-up study demonstrated that, although hormone treatment controlled spasms better than vigabatrin initially, by age 12-14 months, both groups had similar seizure-free rates.
Pediatric Dose	Initial dose: 40 mg/kg/d in 2 divided doses Maintenance doses: 40-150 mg/kg/d
Contraindications	Documented hypersensitivity
Interactions	None reported
Precautions	Dose-dependent adverse effects include hyperactivity, agitation, sedation, depression, psychosis, drowsiness, insomnia, facial edema, ataxia, nausea and/or vomiting, stupor, and somnolence; idiosyncratic reactions include visual field constriction; may exacerbate myoclonic and absence seizures in some patients; long-term reactions (ie, cumulative adverse effects) include weight gain; lower doses in patients with renal dysfunction

Drug Category: Benzodiazepines -- A 2004 American Academy of Neurology and Child Neurology Society practice parameter concluded that "there is insufficient evidence to recommend benzodiazepines for the treatment of infantile spasms (Level U, Class III and IV evidence)."

By binding to specific receptor sites, these agents appear to potentiate the effects of GABA and facilitate inhibitory GABA neurotransmission and other inhibitory transmitters.

Drug Name	Clonazepam (Klonopin) -- Considered second-line AED therapy against spasms associated with West syndrome. Adverse effects and development of tolerance limit usefulness over time. Nitrazepam and clobazam not approved by FDA in US but are available in many countries worldwide.
Pediatric Dose	Maintenance dose: 0.01-0.2 mg/kg/d PO
Contraindications	Documented hypersensitivity; significant liver disease; acute narrow-angle glaucoma
Interactions	Decreases plasma levels of phenytoin, phenobarbital, and carbamazepine; potentiates CNS depression induced by other anticonvulsants and alcohol; may reduce renal clearance of digoxin; cimetidine and erythromycin decrease clearance
Pregnancy	D - Unsafe in pregnancy
Precautions	Dose-dependent adverse effects include hyperactivity, sedation, drooling, incoordination, drowsiness, ataxia, fatigue, confusion, vertigo, dizziness, amnesic effect, and encephalopathy; considered least-sedating benzodiazepine; long-term (cumulative) adverse effects include tolerance and dependence; considered to have longest time to development of tolerance; adjust dose or discontinue therapy in presence of renal or liver function impairment, since metabolism occurs in liver and metabolites are excreted in urine

Drug Category: Anticonvulsants -- These agents prevent seizure recurrence and terminate clinical and electrical seizure activity.

Drug Name	Valproic acid (Depakote, Depakene, Depacon) -- A 2004 American Academy of Neurology and Child Neurology Society practice parameter concluded that "there is insufficient evidence to recommend valproic acid for treatment of infantile spasms (Level U, Class III and IV evidence)." Considered effective second-line AED therapy against spasms associated with West syndrome.
Pediatric Dose	Initial dose: 10-15 mg/kg/d PO divided bid/tid Titration: 5-10 mg/kg/d increments at weekly intervals until therapeutic effect achieved or toxic effects occur Maintenance dose: 15-60 mg/kg/d PO
Contraindications	Documented hypersensitivity; history of hepatotoxicity or pancreatitis (patients at high risk for hepatotoxicity include <2 y, multiple concomitant AEDs including phenobarbital, underlying metabolic disease such as defect in fatty acid oxidation, and developmental delay)
Interactions	Cimetidine, salicylates, felbamate, and erythromycin may increase toxicity; rifampin may significantly reduce levels; in children, salicylates decrease protein binding and metabolism of valproate; may result in variable changes of carbamazepine concentrations, with possible loss of seizure control; may increase diazepam and ethosuximide toxicity (monitor closely); may increase phenobarbital and phenytoin levels while either one may decrease valproate levels; may displace warfarin from protein binding sites (monitor coagulation tests); may increase zidovudine levels in HIV-seropositive patients
Pregnancy	D - Unsafe in pregnancy
Precautions	Dose-dependent adverse effects include asthenia, nausea, vomiting, somnolence, tremor, and dizziness; less common adverse effects include thrombocytopenia and parotid swelling; idiosyncratic reactions include hepatotoxicity and pancreatitis; long-term (cumulative) adverse effects include hair loss and weight gain

Drug Name	Lamotrigine (Lamictal) -- A 2004 American Academy of Neurology and Child Neurology Society practice parameter concluded that "there is insufficient evidence to recommend lamotrigine for the treatment of infantile spasms (Level U, Class III and IV evidence)." Lamotrigine inhibits release of glutamate and inhibits voltage-sensitive sodium channels, leading to stabilization of neuronal membrane. Effectiveness in West syndrome has been investigated in open-label studies with promising results. Initial dose, maintenance dose, titration intervals, and titration increments depend on concomitant medications.
Pediatric Dose	Combination with AEDs that induce hepatic CYP-450 enzyme system WITHOUT valproate Initial starting dose: 0.6 mg/kg/d PO for 2 wk; 1.2 mg/kg/d for wk 3-4; 5-15 mg/kg/d thereafter; after week 4, dosage increment not to exceed 1.2 mg/kg/d q1-2wk until maintenance dose achieved; maximum daily dose is 400 mg/d Combination WITH valproate with or without other AEDs that induce hepatic CYP-450 enzyme system Initial starting dose: 0.15 mg/kg/d PO for 2 wk; 0.3 mg/kg/d for weeks 3-4; 1-5 mg/kg/d thereafter; after week 4, dosage increment not to exceed 0.3 mg/kg/d q1-2wk until maintenance dose achieved; usual maximum daily dose is 200 mg/d
Contraindications	Documented hypersensitivity; history of erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis; erythema multiforme; Stevens-Johnson syndrome; toxic epidermal necrolysis
Interactions	Affected by concomitant AEDs; when used in conjunction with medications that induce hepatic CYP-450 microsomal enzymes (eg, phenobarbital, carbamazepine, phenytoin), clearance enhanced; conversely, when used in conjunction with medications that inhibit hepatic CYP-450 microsomal enzymes (eg, valproate), clearance diminished; lower starting doses, slow titration rate (ie, 2-wk or greater intervals between dosage increases), and smaller increments are needed
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Dose-dependent adverse effects include ataxia, diplopia, dizziness, headache, nausea, and somnolence; idiosyncratic reactions include Stevens-Johnson syndrome and toxic epidermal necrolysis; no long-term (cumulative) adverse effects noted to date Risk factors for associated severe dermatologic reactions include younger age (children more than adults), co-medication with valproic acid, rapid rate of titration, and high starting dose; give careful attention to initial starting dose, titration rate, and co-medications; prompt evaluation of any rash is prudent and imperative; approximately 10-12% of patients develop non–life-threatening rash that usually resolves rapidly upon withdrawal and occasionally without changing dosage

Drug Name	Topiramate (Topamax) -- A 2004 American Academy of Neurology and Child Neurology Society practice parameter concluded that "there is insufficient evidence to recommend topiramate for the treatment of infantile spasms (Level U, Class III and IV evidence)." Topiramate is a sulfamate-substituted monosaccharide with broad spectrum of antiepileptic activity that may have state-dependent sodium channel blocking action, potentiates inhibitory activity of neurotransmitter GABA. May block glutamate activity. Effectiveness in West syndrome has been investigated in one open-label study with promising results.
Adult Dose	Initial starting dose: 2-3 mg/kg/d PO; increment of 2-3 mg/kg q3-4d Maintenance dose: 15-20 mg/kg/d PO
Pediatric Dose	Initial starting dose: 2-3 mg/kg/d PO; increment of 2-3 mg/kg q3-4d Maintenance dose: 15-20 mg/kg/d PO
Contraindications	Documented hypersensitivity
Interactions	May increase phenytoin plasma levels; may decrease valproate plasma levels; phenytoin and carbamazepine decrease levels
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Dose-dependent adverse effects include irritability, ataxia, dizziness, fatigue, nausea, somnolence, psychomotor slowing, concentration, constipation, and speech problems; if CNS adverse effects occur, reduce concomitant AEDs, slow titration, or reduce dose; no idiosyncratic reactions noted; oligohidrosis and nephrolithiasis reported

Drug Name	Zonisamide (Zonegran) -- A 2004 American Academy of Neurology and Child Neurology Society practice parameter concluded that "there is insufficient evidence to recommend zonisamide for the treatment of infantile spasms (Level U, Class III and IV evidence)." Effectiveness in West syndrome has been investigated in 5 open-label studies with promising results.
Pediatric Dose	Initial dose: 1-2 mg/kg/d PO; increase 1-2 mg/kg/d q2wk Maintenance dose: 8-12 mg/kg/d PO
Contraindications	Documented hypersensitivity
Interactions	Phenytoin, phenobarbital, carbamazepine, and valproate decrease half-life; no effect on steady-state plasma concentrations of other AEDs
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Dose-dependent adverse effects include headache, anorexia, nausea, dizziness, ataxia, paresthesia, difficulty concentrating, irritability, and somnolence; idiosyncratic reactions include severe rash (Stevens-Johnson syndrome, toxic epidermal necrolysis) with reporting rate of 46 per million patient-years of exposure; oligohidrosis and nephrolithiasis reported

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References

2007-05-13T14:19:00.000-07:00

Our team would like to thank the following primary source sites. Without them, our research would not be possible.

Wikipedia
http://www.wikipedia.org/

eMedicine
http://www.emedicine.com/

I-Cell Disease (Mucolipidosis Type II)

2007-05-13T12:42:00.000-07:00

Category: Lysosomal Storage Disorder
Target System: Multi-system
Severely Affected System: Skeletal System

Taylor was born with a rare disease called I-cell. She was traced when she was three years old. She is ventilator dependent. Taylor is a very happy child and the ventilator does not seem to bother her in her daily activity. Sadly Taylor passed away on September 22, 2005.

Synonyms and related keywords: I-cell disease, mucolipidosis type II, mucolipidosis II, ML2, ML II, N-acetylglucosaminyl-1-phosphotransferase deficiency, GNPTA deficiency, inclusion cell disease, I-cell disease, I cell disease

Background: I-cell disease is an inherited lysosomal storage disorder. It first was described in 1967 by Leroy and DeMars when they reported a patient with clinical and radiographic features similar to Hurler syndrome (mucopolysaccharidoses 1H [MPS 1H]) but with an earlier onset of symptoms and no evidence of mucopolysacchariduria. One unique feature of this disease was the presence of phase-dense intracytoplasmic inclusions in the fibroblasts of patients. These cells were termed inclusion cells, or I-cells; thus, the disease was designated I-cell disease. Spranger and Wiedermann subsequently classified this disease as mucolipidosis type II (ML II) because it had clinical characteristics of the mucopolysaccharidoses and the sphingolipidoses.

Pathophysiology: Early enzymologic studies showed that cultured fibroblasts from patients with I-cell disease were deficient in a number of lysosomal enzymes. Furthermore, these enzymes were found to be present in excess in tissue culture media and in extracellular fluids, such as serum and urine. It was observed subsequently that I-cell disease fibroblasts were able to internalize and use lysosomal enzymes produced by normal cells, whereas normal or other lysosomal disease fibroblasts were incapable of internalizing lysosomal enzymes secreted by the I-cell disease fibroblasts.

The above findings suggested that a biochemical marker signal may be required for proper trafficking of the lysosomal enzyme, from the site of its production in the endoplasmic reticulum to the lysosome itself. This marker was identified later as a mannose-6-phosphate residue on the lysosomal enzyme that interacts with a specific receptor on the lysosomal membrane, which then triggers endocytosis into the lysosome. The biochemical defect in I-cell disease involves the first step in the addition of the mannose-6-phosphate moiety. The enzyme that catalyzes this reaction is uridine diphospho (UDP)-N-acetylglucosamine:N-acetylglucosaminyl-1- phosphotransferase.

Like many of the lysosomal storage diseases, the functional deficiency of lysosomal enzymes results in abnormal cell architecture. In the case of I-cell disease, the characteristic finding is abnormal vacuolization or inclusions that appear in the cytoplasm. These are observed in cells of mesenchymal origin, especially fibroblasts. The most severely affected system is the skeletal system, in which trabeculation of bone and cartilage structures are abnormal. Muscular tissue, including cardiac muscle, is relatively spared; however, significant vacuolization is present in the connective tissue cells that are in the heart valves. This leads to thickening of the valves, which results in clinically significant valvular disease. Other sites where abnormal cell vacuolization occurs include the renal glomerular podocytes and in the fibroblasts of the periportal spaces in the liver. Hepatocytes and Kupffer cells are not affected.

Interestingly, although psychomotor retardation is a major manifestation of this disease, the pathologic findings in CNS tissue are not as striking as in other organs. Among reported findings is the presence of lamellar bodies in spinal ganglia neurons and in anterior horn cells; however, these findings are not consistent in all patients. Vacuolization of peripheral Schwann cells is minimal but not enough to impair normal myelination.

Frequency:

* Internationally: I-cell disease is a rare disorder that has no ethnic predilection. Very little population data are available, but a recent study from the Netherlands reported a frequency of approximately 1 in 640,000 live births.

Mortality/Morbidity: Death from pneumonia or congestive heart failure usually occurs within the first decade of life.

Race: No predilection exists.

Sex: I-cell disease is inherited as an autosomal recessive trait. Both sexes are affected equally.

Age: Clinical manifestations can be present at birth or may present in the first few months of life.

Clinical

History: Developmental delay and growth failure are common presentations of I-cell disease. Psychomotor deterioration is rapid and progressive. Some physical signs, such as hip dislocations, inguinal hernias, hepatomegaly, joint limitation, and skin changes, may be present at birth. Coarse facial features and skeletal abnormalities become more conspicuous with time. The full clinical picture usually is evident by the first year of life.

* Growth failure and failure to thrive are rapidly progressive.

o Birthweight and length may be decreased.

o Linear growth decelerates during the first year of life and ceases by age 2 years.

o Head circumference usually is preserved.

* Developmental delay is severe and often the presenting symptom.

o Infants smile and follow and grasp objects, but they are unable to roll over or support weight on their legs.

o Generalized hypotonia and poor head control are present.

o Motor delay usually is more severe than cognitive delay.

o A wide degree of variability in patients with I-cell disease may exist.

* Coarse facial features

o The characteristic facies is similar to that observed in Hurler syndrome.

o Gingival hypertrophy is a distinguishing feature.

* Radiographic findings

o These findings are similar to those observed in Hurler syndrome, a condition with which I-cell disease may be confused.

o In early infancy, periosteal new bone formation leads to cloaking of the long bones.

o The tubular bones of the upper extremities are short and widened, and the phalanges are bullet-shaped.

o Anterior beaking and wedging of the vertebrae occur. This results in a lumbar gibbus deformity and kyphoscoliosis.

o Widening of the ribs occurs.

* Frequent upper respiratory tract infections: These patients are plagued by recurrent bouts of pneumonia, bronchitis, and otitis media.

Physical:

* Coarse facial features

o High narrow forehead

o Puffy eyelids, epicanthal folds

o Flat nasal bridge, anteverted nares

o Long philtrum

o Prominent gingival hyperplasia and macroglossia

* Musculoskeletal abnormalities

o Congenital hip dislocation

o Joint stiffness and claw hand deformities

o Lumbar gibbus deformity and kyphoscoliosis

* Abdomen

o Umbilical and inguinal hernias

o Diastasis recti

o Mild hepatomegaly

* Cardiovascular findings: Murmur of aortic insufficiency may be present.

* Ophthalmologic findings: Corneas may be clear or hazy.

* Neurologic findings: Generalized hypotonia may be observed.

Causes:

* I-cell disease is an autosomal recessive disorder caused by a deficiency of the enzyme UDP-N-acetylglucosamine:N-acetylglucosaminyl-1- phosphotransferase. Deficiency of this phosphotransferase prevents the addition of the mannose-6-phosphate recognition marker as the lysosomal enzymes are modified in the Golgi apparatus before being transported to the lysosome; therefore, lysosomal enzymes cannot be endocytosed into the lysosome for normal processing and use.

* The UDP-N-acetylglucosamine:N-acetylglucosaminyl-1- phosphotransferase enzyme is the product of the GNPTA gene, which has been mapped to chromosome band 4q21-q23. A variety of mutations in this gene have been reported in patients with I-cell disease.

Effect of conditioned medium and leupeptin on the processing of b-GAL precursor in I-cell disease fibroblasts

Lab Studies:

Biochemical diagnosis can be made in 2 ways.

· N-acetylglucosaminyl-1-phosphotransferase activity can be measured in white blood cells (WBCs) or in cultured fibroblasts.

· Various lysosomal enzyme activities can be measured in serum and in cultured fibroblasts. The activities of beta-hexosaminidase, iduronate sulfatase, and arylsulfatase A are deficient in cultured fibroblasts but are 10-20 times normal in serum. Assays for lysosomal enzymes in leukocytes are not reliable because of mannose-6-phosphate–independent targeting pathways.

Imaging Studies:

Radiography

· The characteristic bone changes are similar to those observed in the mucopolysaccharidoses.

· The classic finding is dysostosis multiplex, with a cloaking appearance of the long tubular bones, anterior beaking and wedging of the vertebral bodies, widening of the ribs, proximal pointing of the metacarpals, and bullet-shaped phalanges.

Brain imaging

· Brain imaging is not necessary to make the diagnosis of I-cell disease, although it often has been obtained during an evaluation of developmental delay.

· MRI and CT findings can be variable and nonspecific and may not aid in the diagnosis. Reported MRI and CT findings include completely normal scans with normal myelination, cerebral atrophy, and nonspecific white matter changes.

Histologic Findings: A unique finding in I-cell disease is the presence of numerous intracytoplasmic inclusions in cells of mesenchymal origin that are observed on electron microscopy. These inclusions are membrane-bound vacuoles that are filled with fibrillogranular material. The contents of these vacuoles have not been well characterized; however, they appear to contain a variety of lipids, mucopolysaccharides, and oligosaccharides.

Treatment

Medical Care:

* Available treatment for I-cell disease remains limited.

* Bone marrow transplantation has been attempted in a small number of patients.

o Data are limited, but, in at least one case, lysosomal enzyme levels seemed to normalize after transplant.

o Although progression of the disease theoretically should cease, preexisting damage usually is irreversible.

o Seriously consider the risks and benefits of bone marrow transplantation in the medical decision-making process.

* Efforts can be made to maximize overall health maintenance.

o Because these children have progressive failure to thrive, nutritional supplementation may be beneficial.

o Promptly treat recurrent respiratory infections with antibiotics.

Consultations:

* Genetics

o For initial evaluation and diagnosis

o To provide genetic counseling for recurrence risks

o To provide prenatal testing for future offspring

* Neurology/development

o For initial evaluation of developmental delay

o To recommend physical interventional services, such as physical therapy, occupational therapy, and speech therapy

* Cardiology: Baseline and serial evaluations are recommended because patients with I-cell disease eventually develop valvular disease and signs of poor cardiac function.

Medication

Drug therapy currently does not exist to correct the lysosomal storage disorder. See Treatment.

Complications:

* Recurrent respiratory infections, such as pneumonia and otitis media, are frequent.

* Depending on the extent of neurologic compromise, aspiration pneumonia also can become a recurrent problem.

* Congestive heart failure results from chronic valvular insufficiency.

* Atlantoaxial instability can develop because of abnormally shaped cervical vertebrae. If this occurs, patients should be monitored and, eventually, surgically stabilized to avoid the risk of spinal cord injury.

Prognosis:

* Psychomotor retardation is progressive, and death from cardiopulmonary complications usually occurs by the end of the first decade.

Patient Education:

* Care must be given in educating families about the genetic basis of this disorder, including recurrence risks, identification of carriers, and the availability of prenatal diagnosis for future at-risk pregnancies.

Special Concerns:

· Genetic counseling

--Counsel families of patients with I-cell disease about the recurrence risks of an autosomal recessive disorder.

--In addition, discuss the availability of prenatal diagnosis for future offspring. The diagnosis of I-cell disease can be made by the measurement of UDP-N-acetylglucosamine:N-acetylglucosaminyl-1- phosphotransferase activity in chorionic villi or cultured amniocytes.

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Hageman Trait

2007-05-09T13:19:00.000-07:00

Category: Rare Disorder
Target System: Circulatory System

Other names:

F12 Deficiency
Hageman Factor Deficiency
HAF Deficiency

This somewhat mysterious deficiency was first discovered in 1955 and named after John Hageman, the first patient diagnosed with the condition. The incidence of Factor XII deficiency is estimated at 1 in 1 million. This deficiency is inherited in an autosomal recessive fashion, which means it affects men and women equally. It has been reported that factor XII levels seem to be lower among Asians, than any other ethnic group.

The mystery of Factor XII centers on how the protein is a step in the process of forming a clot, but people with the deficiency usually do not experience bleeds and normally do not require treatment. Having a low factor XII level has little to no clinical significance.

Even with major surgery, bleeding manifestations are extremely rare. In fact, most people only get diagnosed by chance, or during pre-screening blood tests for surgery. Since bleeding time is usually normal, diagnosis is made by a prolonged activated partial thromboplastin time (aPTT) test. A specific factor XII assay is necessary to confirm the initial diagnosis.

Clinical Features

This deficiency was usually discovered because of the practice in some hospitals of routinely performing whole blood clotting times before surgical operations (McCain et al., 1959). Ratnoff and Steinberg (1962) analyzed data on 55 cases in 37 families. Parental consanguinity was present in at least 2 instances. Some heterozygotes show partial deficiency of Hageman factor. The Japanese case reported by Miwa et al. (1968) had first-cousin parents. Egeberg (1970) described 4 Norwegian families with deficient factor XII (about half normal). Unlike the usual experience of no abnormality, they showed a slight to moderate bleeding tendency and a high incidence of cerebral apoplexy occurring at a relatively early age. Some of the patients had attacks of local edema, severe headache, abdominal pain, and various forms of allergy. Braulke et al. (1993) presented data suggesting that reduced levels of factor XII activity may be a risk factor for repeated spontaneous abortions. Gordon et al. (1981) showed that both the clot-promoting activity and the antigenic properties of Hageman factor are lower in Orientals than in American whites. Factor XII deficiency seemingly inherited as an autosomal dominant was reported by Bennett et al. (1972). The authors hypothesized that the gene could be allelic with that responsible for the autosomal recessive form.

Superficial migratory thrombophlebitis (Samlaska et al., 1990) and leg ulcer (Goodnough et al., 1983; Lammle et al., 1991) have been documented as skin manifestations of factor XII deficiency. Sato-Matsumura et al. (2000) reported 2 individuals with factor XII deficiency presenting with livedo and painful leg ulcers who improved dramatically after anticoagulant therapy. They suggested that factor XII deficiency may lead to a hypercoagulative state in some individuals, predisposing them to painful ulcers and livedo.

In a study of 150 consecutive patients with retinal vein occlusion (RVO) compared with age- and gender-matched controls, Kuhli et al. (2004) found that factor XII deficiency was highly prevalent in RVO patients 45 years of age or younger. By contrast, the prevalence of factor XII deficiency in RVO patients older than 45 years appeared similar to that seen in healthy individuals.

Koster et al. (1994) and Girolami et al. (2004) concluded that severe (homozygous) factor XII deficiency is not a cause of deep-vein thrombosis. In a study of myocardial infarction and arterial thrombosis in severe (homozygous) factor XII deficiency, Girolami et al. (2005) likewise concluded that the role of the coagulation factor deficiency in the pathogenesis of arterial thrombosis is minor.

Mapping

The F12 gene, site of defects resulting in factor XII deficiency, maps to chromosome 5q33-qter (Royle et al., 1988).

Soria et al. (2002) conducted a genomewide linkage screen to localize genes that influence variation in F12 levels. Two loci were detected: one on chromosome 5 and another on chromosome 10 (lod scores 4.73 and 3.53, respectively). On chromosome 5, the peak lod score occurred in the 5q33-qter region, where the F12 gene is located. Addition of the 46C/T polymorphism (234000.0004) in the F12 gene increased the multipoint lod score to 10.21. A bivariate linkage analysis of F12 activity and thrombosis further improved the linkage signal (lod = 11.73) and provided strong evidence that this quantitative trait locus (QTL) has a pleiotropic effect on the risk of thrombosis (P = 0.004). Linkage analysis conditional on 46C/T indicated that this polymorphism alone cannot explain the chromosome 5 signal, implying that other functional sites must exist. These results represented the first direct genetic evidence that a QTL in or near the F12 gene influences both F12 activity and susceptibility to thrombosis and suggested the presence of one or more functional variants in F12.

Molecular Genetics

Bernardi et al. (1987) found that the factor XII gene alteration in the Hageman trait was detected by the TaqI restriction enzyme in 2 affected brothers and 11 members of the paternal lineage. Gene deletion was excluded. The TaqI polymorphic site was located within the 5-prime portion of the gene and the mutation in the polymorphic site was judged to be the cause of the factor XII deficiency. This may represent a CpG mutation of the sort that is found in a number of other genes such as the gene for hemophilia A (306700).

Animal Model

Renne et al. (2005) found that F12-deficient mice, like F12-deficient humans, had normal bleeding times and no spontaneous bleeding. However, in vivo fluorescence microscopy showed that, even though initial adhesion of platelets at sites of injury was unaffected in F12-deficient mice, subsequent formation and stabilization of 3-dimensional thrombi was severely impaired. This defect was observed in several locations in the vascular system in response to different types of injury and was completely reversed by infusion of human F12. Renne et al. (2005) concluded that F12-induced intrinsic coagulation is important for clotting in vivo, suggesting that F12 may be a target for antithrombotic therapy.

History

Roberts (2003) gave an account of the medical and scientific career of Oscar Ratnoff (born in 1916), who discovered both Hageman factor (factor XII) and Fitzgerald factor. Ratnoff is credited with recruiting Earl Davie to the field of blood coagulation, to which Davie introduced modern biochemical and molecular biologic techniques. Ratnoff and Davie (1964) and, independently and simultaneously, Macfarlane (1964) proposed the waterfall hypothesis of blood coagulation. Ratnoff was long resistant to the use of a system of Roman numerals for the various clotting factors.

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G(M2) Gangliosidosis, Type I

2007-05-09T11:26:00.000-07:00

Category: Disorder
Target System: Central Nervous System
Specific Target: Nerve cell of the brain

also known as "Tay-Sachs disease"

Tay-Sachs disease (abbreviated TSD, also known as "G(M2) gangliosidosis Type I") is a genetic disorder, fatal in its most common variant known as Infantile Tay-Sachs disease. TSD is inherited in an autosomal recessive pattern. The disease occurs when harmful quantities of a fatty acid derivative called a ganglioside accumulate in the nerve cells of the brain. Gangliosides are lipids, components of cellular membranes, and the ganglioside GM2, implicated in Tay-Sachs disease, is especially common in the nervous tissue of the brain.

The disease is named after the British ophthalmologist Warren Tay who first described the red spot on the retina of the eye in 1881, and the American neurologist Bernard Sachs who described the cellular changes of Tay-Sachs and noted an increased prevalence in the Eastern European Jewish (Ashkenazi) population in 1887. It has been suggested that asymptomatic carriers of Tay-Sachs (those with one defective version of HEXA and one normal gene) may have a selective advantage, but this has never been proven.

Research in the late 20th century demonstrated that Tay-Sachs disease is caused by mutations on the HEXA gene on chromosome 15. A large number of HEXA mutations have been discovered, and new ones are still being reported. These mutations reach significant frequencies in several populations. French Canadians of southeastern Quebec and have a carrier frequency similar to Ashkenazi Jews, but they carry a different mutation. Many Cajuns of southern Louisiana carry the same mutation that is most common in Ashkenazi Jews. Most HEXA mutations are rare, and do not occur in genetically isolated populations. The disease can potentially occur from the inheritance of two unrelated mutations in the HEXA gene, one from each parent.

Signs and Symptoms

Tay-Sachs disease is classified in variant forms, based on the time of onset of neurological symptoms. The variant forms reflect diversity in the mutation base.

All patients with Tay-Sachs disease have a "cherry-red" spot, easily observable by a physician using an ophthalmoscope, in the back of their eyes (the retina). This red spot is the area of the retina which is accentuated because of gangliosides in the surrounding retinal ganglion cells (which are neurons of the central nervous system). The choroidal circulation is showing through "red" in this region of the fovea where all of the retinal ganglion cells are normally pushed aside to increase visual acuity. Thus, the cherry-red spot is the only normal part of the retina seen. Microscopic analysis of neurons shows that they are distended from excess storage of gangliosides.

* Infantile TSD. Infants with Tay-Sachs disease appear to develop normally for the first six months of life. Then, as nerve cells become distended with gangliosides, a relentless deterioration of mental and physical abilities occurs. The child becomes blind, deaf, and unable to swallow. Muscles begin to atrophy and paralysis sets in. Death usually occurs before the age of 4 or 5.

* Juvenile TSD. Extremely rare, Juvenile Tay-Sachs disease usually presents itself in children between 2 and 10 years of age. They develop cognitive, motor, speech, and swallowing difficulties; unsteadiness of gait (ataxia), and spasticity. Patients with Juvenile TSD usually die between 5-15 years.

* Adult/Late Onset TSD. A rare form of the disorder, known as Adult Onset Tay-Sachs disease or Late Onset Tay-Sachs disease (LOTS), occurs in patients in their 20s and early 30s. LOTS is frequently misdiagnosed, and is usually non-fatal. It is characterized by unsteadiness of gait and progressive neurological deterioration. Symptoms of LOTS, which present in adolescence or early adulthood, include speech difficulties (dysarthria), swallowing difficulties (dysphagia), unsteadiness of gait (ataxia), spasticity, cognitive decline, and psychiatric illness, particularly schizophrenic-like psychosis. Patients with LOTS frequently become full-time wheelchair users in adulthood, but many live full adult lives if psychiatric and physical difficulties are accommodated. Psychiatric symptoms and seizures can be controlled with medications.

Etiology and Pathogenesis

The condition is caused by insufficient activity of an enzyme called hexosaminidase A that catalyzes the biodegradation of fatty acid derivatives known as gangliosides. Hexasaminidase A is a vital hydrolytic enzyme, found in the lysosomes, that breaks down lipids. When Hexasaminidase A is no longer functioning properly, the lipids accumulate in the brain and cause problems. Gangliosides are made and biodegraded rapidly in early life as the brain develops. Patients and carriers of Tay-Sachs disease can be identified by a simple blood test that measures hexosaminidase A activity. TSD is a recessive genetic disorder, meaning that both parents must be carriers in order to give birth to an affected child. Even then, there is only a 25% chance with each pregnancy of having a child with TSD. Prenatal monitoring of pregnancies is available.

Hydrolysis of GM2-ganglioside requires three proteins. Two of them are subunits of hexosaminidase A, and the third is a small glycolipid transport protein, the GM2 activator protein (GM2A), which acts as a substrate specific cofactor for the enzyme. Deficiency in any one of these proteins leads to storage of the ganglioside, primarily in the lysosomes of neuronal cells. Tay-Sachs disease (along with GM2-gangliosidosis and Sandhoff disease) occurs because a genetic mutation inherited from both parents inactivates or inhibits this process. Most Tay-Sachs mutations appear not to affect functional elements of the protein. Instead, they cause incorrect folding or assembly of the enzyme, so that intracellular transport is disabled.

The disease results from mutations on chromosome 15 in the HEXA gene encoding the alpha-subunit of the lysosomal enzyme beta-N-acetylhexosaminidase A. More than 90 mutations have been identified to date in the HEXA gene, and new mutations are still being reported. These mutations have included base pair insertions and deletions, splice site mutations, point mutations, and other more complex patterns. Each of these mutations alter the protein product, and thus inhibit the function of the enzyme in some manner. In recent years, population studies and pedigree analysis have shown how such mutations arise and spread within small founder populations.

For example, a four base pair insertion in exon 11 (1278insTATC) results in an altered reading frame for the HEXA gene. This mutation is the most prevalent mutation in the Ashkenazi Jewish population, and leads to the infantile form of Tay-Sachs disease. The same mutation occurs in the Cajun population of southern Louisiana, an American ethnic group that has been isolated for several hundred years because of linguistic differences. Researchers have traced carriers from several Louisiana families to a single founder couple, not known to be Jewish, that lived in France in the 18th century.

An unrelated mutation, a long sequence deletion, occurs with similar frequency in families with French Canadian ancestry, and has the same pathological effects. Like the Ashkenazi Jewish population, the French Canadian population grew rapidly from a small founder group, and remained isolated from surrounding populations because of geographic, cultural, and language barriers. In the early days of Tay-Sachs research, the mutations in these two populations were believed to be identical. Some researchers claimed that a prolific Jewish ancestor must have introduced the mutation into the French Canadian population. This theory became known as the "Jewish Fur Trader Hypothesis" among researchers in population genetics. However, subsequent research has demonstrated that the two mutations are unrelated, and pedigree analysis has traced the French Canadian mutation to a founding family that lived in southern Quebec in the late 17th century.

Tay-Sachs Disease can potentially result from the inheritance of two unrelated mutations in the HEXA gene, one from each parent. Classic infantile TSD results when a child has inherited mutations from both parents that completely inactivate the biodegradation of gangliosides. Late onset forms of the disease occur because of the diverse mutation base. Patients may technically be heterozygotes, but with two different HEXA mutations that both inactivate, alter, or inhibit enzyme activity in some way. When a patient has at least one copy of the HEXA gene that still enables some hexosaminidase A activity, a later onset form of the disease occurs.

Testing and prevention

Screening for Tay-Sachs disease was one of the first great successes of the emerging field of genetic counseling and diagnosis. Jewish communities, both inside and outside of Israel, embraced the cause of genetic screening from the 1970s on. Success with Tay-Sachs disease lead Israel to become the first country to offer free genetic screening and counseling for all couples. Israel has become a leading center for research on genetic disease. Both the Jewish and Arab/Palestinian populations in Israel contain many ethnic and religious minority groups, and Israel's initial success with Tay-Sachs disease has lead to the development of screening programs for other diseases.

Genetic screening for carriers of Tay-Sachs disease is possible because an inexpensive enzyme assay test is available. It detects lower levels of the enzyme hexosaminidase A in serum. Developed during the 1970s, the enzyme assay test is not as precise as genetic testing based on polymerase chain reaction (PCR) techniques; however, it is cost effective for much broader use and allows screening for a disease that is rare in most populations. PCR testing is more effective when the ancestry of both parents is known, allowing for proper selection of genetic markers. Genetic counselors, working with couples that plan to conceive a child, assess risk factors based on ancestry to determine which testing methods are appropriate.

Proactive testing has been quite effective in eliminating Tay-Sachs occurrence amongst Ashkenazi Jews. Of the 10 babies born with Tay-Sachs in North America in 2003, none were born to Jewish families. In Israel, only one child was born with Tay-Sachs in 2003, and preliminary results from early 2005 indicated that none were born with the disease in 2004. Three approaches have been used to prevent or reduce the incidence of Tay-Sachs disease in the Ashkenazi Jewish population:

* Prenatal diagnosis and selective abortion. If both parents are identified as carriers, prenatal genetic testing can determine whether the fetus has inherited a defective copy of the gene from both parents. For couples who are willing to terminate the pregnancy, this eliminates the risk of Tay-Sachs, but selective abortion raises ethical issues for many families.

* Mate selection. In Orthodox Jewish circles, the organization Dor Yeshorim carries out an anonymous screening program so that couples who are likely to conceive a child with Tay-Sachs or another genetic disorder can avoid marriage. Nomi Stone of Dartmouth College describes this approach. "Orthodox Jewish high school students are given blood tests to determine if they have the Tay-Sachs gene. Instead of receiving direct results as to their carrier status, each person is given a six-digit identification number. Couples can call a hotline, if both are carriers, they will be deemed 'incompatible.' Individuals are not told they are carriers directly to avoid any possibility of stigmatization or discrimination. If the information were released, carriers could potentially become unmarriageable within the community." Anonymous testing eliminates the stigma of carriership while decreasing the rate of homozygosity in this population. Stone notes that this approach, while effective within a confined population such as Hasidic or Orthodox Jews, may not be effective in the general population.

* Preimplantation genetic diagnosis. By retrieving the mother's eggs for in vitro fertilization and conceiving a child outside the womb, it is possible to test the embryo prior to implantation. Only healthy embryos are selected for transfer into the mother's womb. In addition to Tay-Sachs disease, PGD has been used to prevent cystic fibrosis, sickle cell anemia, Huntington disease, and other genetic disorders. However this method is expensive. It requires invasive medical technologies, and is beyond the financial means of many couples.

Therapy

There is currently no cure or treatment for TSD. Even with the best care, children with Infantile TSD die by the age of 5, and the progress of Late-Onset TSD can only be slowed, not reversed. However, research is ongoing. Several methods of treatment are being investigated, although significant hurdles remain before any of them pass the experimental stages.

* Enzyme replacement therapy. The goal would be to replace the missing enzyme, a process similar to insulin injections for diabetes. However, the enzyme has proven to be too large to pass through the blood into the brain through the blood-brain barrier. Blood vessels in the brain develop junctions so small that many toxic (or large) molecules cannot enter into nerve cells and cause damage. Researchers have also tried instilling the enzyme into cerebrospinal fluid, which bathes the brain. However, neurons are unable to take up the large enzyme efficiently even when it is placed next to the cell, so the treatment is still ineffective.

* Gene therapy. The most recent option explored by scientists has been gene therapy. If the defective genes were to be replaced throughout the brain, Tay-Sachs could theoretically be cured. However, researchers working in this field believe that they are years away from the technology to transport the genes into neurons, which would be as difficult as transporting the enzyme. Currently, most research involving gene therapy involves developing a method of using a viral vector to transfer new DNA into neurons. Another approach to gene therapy, under study at Duke University, uses stem cells from umbilical cord blood in an effort to replace the defective gene. Although the Duke University approach has been effective with Krabbé disease, the researchers have not yet reported any results for Tay-Sachs.

* Metabolic therapy. Other highly experimental methods being researched involve manipulating the brain's metabolism of GM2 gangliosides. One experiment has demonstrated that, by using the enzyme sialidase, the genetic defect can be effectively bypassed and GM2 gangliosides can be metabolized so that they become almost inconsequential. If a safe pharmacological treatment can be developed, one that causes the increased expression of lysosomal sialidase in neurons, a new form of therapy, essentially curing the disease, could be on the horizon. Metabolic therapies under investigation for Late-Onset TSD include treatment with the drug OGT 918 (Zavesca).

Epidemiology

Historically, Eastern European people of Jewish descent (Ashkenazi Jews) have a high incidence of Tay-Sachs and other lipid storage diseases. Documentation of Tay-Sachs in this Jewish population reaches back to 15th century Europe. In the United States, about 1 in 27 to 1 in 30 Ashkenazi Jews is a recessive carrier. French Canadians and the Cajun community of Louisiana have an occurrence similar to the Ashkenazi Jews. Irish Americans have a 1 in 50 chance of a person being a carrier. In the general population, the incidence of carriers (heterozygotes) is about 1 in 300.

A continuing controversy is whether heterozygotes, individuals who are carriers of one copy of the gene but do not actually develop the disease, have some selective advantage. The classic case of heterozygote advantage is sickle cell anemia, and some researchers have argued that there must be some evolutionary benefit to being a heterozygote for Tay-Sachs as well. Four different theories have been proposed to explain the high frequency of Tay-Sachs carriers in the Ashkenazi Jewish population:

* Heterozygote advantage with tuberculosis resistance. Being a Tay-Sachs carrier may serve as a form of protection against tuberculosis. TB's prevalence in the European Jewish population was very high, in part because Jews were forced to live in ghettos. However, several statistical studies have demonstrated that grandparents of Tay-Sachs carriers (who are more likely to have been carriers themselves) died proportionally from the same causes as non-carriers.

* Heterozygote advantage because of higher intelligence. Another theory (attributed to Gregory Cochran) proposes that Tay-Sachs and the other lipid storage diseases that are prevalent in Ashkenazi Jews may enhance dendrite growth and promote higher intelligence when present in carrier form, thus providing a selective advantage at a time when Ashkenazi Jews were restricted to intellectual occupations.

* Reproductive compensation. Parents who lose a child because of disease tend to "compensate" by having additional children to replace them, and this may increase the incidence of autosomal recessive disease.

* Founder effect. This hypothesis states that the high incidence of the 1278insTATC mutation is the result of genetic drift, which amplified a high frequency that existed by chance in an early founder population.

Because Tay-Sachs disease was one of the first autosomal recessive genetic disorders for which there was an enzyme assay test (prior to polymerase chain reaction testing methods), it was intensely studied as a model for all such diseases. The researchers of the 1970s often favored theories of heterozygote advantage, but failed to find much evidence for them in human populations. They were also unaware of the diversity of the Tay-Sachs mutation base. In the 1970s, complete genomes had not yet been sequenced, and researchers were unaware of the extent of polymorphism. The contribution to evolution of genetic drift (as opposed to natural selection) was not fully appreciated.

Since the 1970s, DNA sequencing techniques using PCR have been applied to many genetic disorders, and in other human populations. Several broad genetic studies of the Ashkenazi population (not related to genetic disease) have demonstrated that the Ashkenazi Jews are the descendants of a small founder population, which may have gone through additional population bottlenecks. These studies also correlate well with historical information about Ashkenazi Jews. Thus, a preponderance of the recent studies have supported the founder effects theory.

Historical significance

Tay-Sachs disease has become a model for the prevention of all genetic diseases. In the United States before 1970, the disease affected about 50–70 infants each year in Ashkenazi Jewish families. About 10 cases occurred each year in infants from families without identifiable risk factors. Before 1970, the disease had never been diagnosed at the time of birth. Physicians saw the disease for the first time in infants that failed to thrive, and they could do nothing for the parents or family. Although the genetic basis of the disease was understood, antenatal testing was not available, and families with a Tay-Sachs infant faced a one and four probability of another devastating outcome with each future pregnancy.

Michael Kaback, a medical resident in pediatric neurology at Johns Hopkins University, saw two Tay-Sachs families in 1969. At the time, researchers had just uncovered the biochemical basis of the disease as the failure of an enzyme in a critical metabolic pathway. Kaback developed and later automated an enzyme assay test for detecting heterozygotes (carriers). This inexpensive test proved statistically reliable, with low rates of both errors and false positives. For the first time in medical history, it was possible to screen broadly for a genetic disease, and a physician or medical professional could counsel a family on strategies for prevention. Within a few decades, the disease had been virtually eliminated among Ashkenazi Jews. Most cases today are in families that do not have identifiable risk factors.

Kaback and his associates also developed the first mass screening program for genetic disease. Every aspect of this landmark study was meticulously planned, including community liaison, blood-draw procedure, laboratory set-up, assay protocol, and follow-up genetic counseling. On a Sunday in May 1971, more than 1800 young adults of Ashkenazi Jewish ancestry in the Baltimore and Washington D.C. area were voluntarily screened for carrier status. The success of the program demonstrated the efficacy of voluntary screening of an identifiable at-risk populations. Within a few years, these screening programs had been repeated among Ashkenazi Jews throughout the United States, Canada, western Europe, and Israel.

In the first 30 years of testing, from 1969 through 1998, more than 1.3 million persons were tested, and 48,864 carriers were identified. In at-risk families, among couples where both husband and wife were carriers, more than 3000 pregnancies were monitored by amniocentesis or chorionic villus sampling. Of 604 monitored pregnancies where a fetus was diagnosed with Tay-Sachs disease, 583 were terminated. Of the 21 that were not, 20 went on to develop classic infantile Tay-Sachs disease, and the 21st progressed later to adult-onset Tay-Sachs disease. In more than 2500 pregnancies, at-risk families were assured that their children would not be affected by Tay-Sachs disease. Only three fetuses with infantile TSD were incorrectly diagnosed as being unaffected.

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Fabry Disease

2007-05-08T15:35:00.000-07:00

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Further Outpatient Care:

* Genetic counseling is necessary for the proband, and a careful pedigree should be obtained to identify all potentially affected family members. Because Fabry disease is an X-linked recessive trait, all daughters of affected males are carriers, and no sons of affected males have the gene for Fabry disease. Typically, mothers of probands are obligate carriers, and their siblings should be considered at risk.

In/Out Patient Meds:

* See Treatment.

Transfer:

* Transfer to a center with specialists familiar with Fabry disease may be indicated.

Deterrence/Prevention:

* Prenatal testing can be performed in women who are pregnant and are carriers of the gene to identify fetuses affected with Fabry disease. A karyotype should be obtained first to identify if the fetus is male. Enzyme activity can then be measured, using either chorionic villus sampling (CVS) or amniotic fluid samples. If the mutation carried in the family is known, DNA can be isolated from CVS or amniotic fluid samples, and genotyping can be performed.

Complications:

* As with all chronic illnesses, patients are at risk for anxiety disorders, depression, or both.

Prognosis:

* Prognosis for patients with Fabry disease has improved with the more widespread use of advanced medical techniques, such as hemodialysis and renal transplant. ERT has demonstrated favorable results in modifying long-term complications of Fabry disease. Early treatment with ERT to prevent irreversible damage to the organs seems reasonable.

Medical/Legal Pitfalls:

* Failure to appreciate signs and symptoms of Fabry disease (Most patients with the disease experience long delays from the time the first symptoms appear to the time of diagnosis.)

* Failure to perform appropriate laboratory testing

* Failure to provide genetic counseling

Special Concerns:

* See Deterrence/Prevention for concerns in pregnancy.

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Fabry Disease

2007-05-08T13:06:00.001-07:00

Category: Disorder
Target System: Multi system

Synonyms and related keywords: Fabry disease, Anderson-Fabry disease, Fabry's disease, a-galactosidase A deficiency, alpha-galactosidase A deficiency, angiokeratoma corporis diffusum universale, hereditary dystopic lipidosis, GLA deficiency, ceramide trihexosidase deficiency, error in metabolism, error of glycosphingolipid metabolism

Background: Fabry disease is an X-linked lysosomal storage disease that is caused by deficient activity of lysosomal enzyme a-galactosidase A (a-Gal A). Most males with no a-Gal A activity develop the classic phenotype of Fabry disease, which affects multiple organ systems. The first clinical manifestations of the disease, which consist of episodes of severe pain in the extremities (acroparesthesias), hypohidrosis, corneal and lenticular changes, and skin lesions (angiokeratoma) develop in childhood. The rate of disease progression and specific organ damage demonstrate intrafamilial and interfamilial variability. Renal failure, cardiovascular disease, and stroke are the major causes of morbidity and mortality, occurring in the fourth or fifth decade of life.

Pathophysiology: Glycosphingolipids, predominantly globotriaosylceramide (GL-3) and galabiosylceramide, accumulate in the lysosomes of various cells (eg, in the vascular endothelium of multiple organs) owing to a-Gal A deficiency. The accumulation of GL-3 in the lysosomes causes lysosomal and cellular dysfunction; this, in turn, triggers the cascade of cells and tissue ischemia and fibrosis.

Frequency:

In the US: Fabry disease is one of the more common lysosomal storage disorders, affecting approximately 1 in 40,000-60,000 males.

Mortality/Morbidity: Prior to the availability of renal transplant, dialysis, and, more recently, enzyme replacement therapy (ERT), the average age at death in men with classic Fabry disease was 41 years. Renal failure, heart failure and/or myocardial infarction, and stroke were among the most likely causes of death.

Race: Although most patients with Fabry disease are white, the disorder has been described in patients in many ethnic groups, including those with Hispanic, African, Asian, and Middle Eastern ancestry.

Sex: As is expected in X-linked disorders, males with deleterious mutations have little-to-no residual a-Gal A activity. Therefore, these patients experience the full spectrum of disease symptoms. Because of random X inactivation (lyonization), the disease presentation in female carriers is more variable and depends on the normal-to-mutant ratio of a-Gal A in the different tissues. A significant number of female carriers may develop Fabry disease–related symptoms, including acroparesthesias, GI symptoms, renal and cardiac disease, and/or stroke.

Age:

· Most males with classic Fabry disease first manifest symptoms in childhood or early adolescence. The earliest manifestations include acroparesthesias, angiokeratomas, hypohidrosis, and lenticular and corneal changes. Proteinuria usually becomes evident in the second decade of life, and renal insufficiency is typically present in the third decade of life. Cardiovascular and cerebrovascular diseases usually develop in the fourth decade of life.

· Individuals with atypical renal or cardiac variants usually do not have signs or symptoms in childhood. Many of these patients remain asymptomatic well into adulthood, when patients with classic symptoms are severely affected or have died from the disease.

Clinical

History: Fabry disease should be considered in patients with the isolated features detailed below or in those who show signs of multisystemic involvement in a pattern consistent with renal, cardiac, and cerebrovascular involvement. A detailed and complete medical and family history and thorough physical examination are necessary.

A detailed medical and family history should be obtained, with emphasis on the following:

Presence, location, and density of skin rash (angiokeratoma)

Characteristics, frequency, and intensity of pain (acroparesthesia)

Bowel habits, abdominal cramping, vomiting, nausea, and food intolerance

History of abnormal sweating

Heat, cold, and exercise intolerance and easy fatigability

Family history of kidney failure, heart disease, stroke, or other signs or symptoms of Fabry disease in X-linked pattern of segregation

Classic Fabry disease: Patients with classic Fabry disease typically have a-Gal A activity of less than 1% and often demonstrate the full spectrum of symptoms. The 2 categories of classic disease manifestation are as follows:
- Early manifestations
  - Early manifestations generally begin in childhood or adolescence and include the characteristic corneal and lenticular opacities, skin lesions (angiokeratoma), pain in the extremities (acroparesthesia), and decreased ability to sweat (hypohidrosis). In addition, patients may have chronic abdominal pain and diarrhea. Some patients may experience spontaneous relief of these early symptoms during adulthood (eg, symptomatic improvement of acroparesthesias).
  - The earliest reported symptom of Fabry disease is often intermittent or chronic acroparesthesias. These pain episodes are described as burning, tingling, and numbness and are thought to be related to the involvement of the vascular supply and small fibers of the peripheral nervous system. Pain, especially in the hands and feet, may occur daily and may vary in severity. These episodes may occur in both sexes and may begin as early as age 2 years. Pain may be triggered by a body temperature increase due to exercise, fever, emotional stress, or environmental temperature changes. Extreme pain attacks, referred to as Fabry pain crises, usually affect male patients and are described as severe episodes that last several hours to days. These episodes may be accompanied by low-grade fever, body pains, and fatigue.
  - GI manifestations of Fabry disease are common and are believed to be caused by the deposition of GL-3 in the small vessels and the autonomic ganglia of the intestine. GI symptoms often begin in adolescence and may worsen with age. Common manifestations include episodes of postprandial abdominal pain and bloating, followed by multiple bowel movements, diarrhea, nausea, vomiting, and early satiety. Symptoms are generally more frequent and appear earlier in life in males compared with female carriers.
  - Dermal manifestations of Fabry disease include cutaneous vascular lesions (angiokeratomas) and abnormal sweating (anhidrosis or, more commonly, hypohidrosis). Weakening of the capillary wall and vascular ectasia within the epidermis and dermis causes angiokeratomas. They usually manifest at age 5-13 years and initially appear as small, slightly raised, purplish-red, nonblanching angiectases. The number and size of these lesions progressively increase with age. Anhidrosis or hypohidrosis is also frequently reported and is thought to be secondary to lipid accumulation in the eccrine cells of the sweat glands and dysfunction of the autonomic nervous system.
  - Corneal manifestations are reported in more than 70-90% of patients. The best-known ocular symptom is a pattern of whitish spiral streaks in the corneal epithelium known as cornea verticillata.
  - Some patients may have recurrent fevers with no obvious source. Pain usually accompanies the fevers, and an elevated erythrocyte sedimentation rate may be present.
  - Disease symptoms and implications may affect the patient's school performance, level of activity, and mental health.
- Late and serious clinical manifestations of Fabry disease
  - During the late stage of the disease, the progressive deterioration of renal, cardiac, and nervous system function ultimately results in significant morbidity and mortality.
  - Kidney involvement is a prominent feature and is the main cause of premature death in classic Fabry disease. It develops as a result of the progressive accumulation of GL-3 in the renal endothelium and other kidney cell types. Microalbuminuria, proteinuria, and isosthenuria may be apparent in adolescence and early adulthood. Progressive kidney disease is marked by the progression of proteinuria, an increase in serum creatinine levels, and the reduction of the glomerular filtration rate (GFR) during the third decade of life. Long-term hemodialysis is often required, and renal transplantation is usually successful.
  - Fabry-related cardiovascular disease
    - Fabry-related cardiovascular disease is a key cause of premature death.
    - Early signs of cardiac involvement include interventricular septal and left ventricular hypertrophy associated with valvular regurgitation.
    - Clinical signs of congestive heart failure may accompany the progressive concentric LVH and diastolic dysfunction observed in advanced stages of the disease.
    - Mitral valve prolapse and thickening may also be observed.
    - Common initial electrocardiographic abnormalities include sinus bradycardia, nonspecific ST-segment changes, T-wave inversion, and shortened PR interval.
    - Conduction system involvement may be observed as early as the second decade of life, and, as it progresses, the risk of lethal arrhythmias and sudden death increases.
    - Permanent cardiac pacing is needed in approximately 10-20% of patients.
    - Damage to the coronary vascular bed may lead to angina pectoris, variant angina, and myocardial infarction.
    - Predominant involvement of small, penetrating vessels has been reported. This involvement does not necessarily follow the typical patterns observed in atherosclerosis.
  - CNS involvement may be observed on brain MRI as white matter changes. This involvement may be noted as early as the second or third decade of life, typically occurring earlier in males than in females. The primary ischemic-hypoxic damage in CNS results from prothrombotic and occlusive abnormalities, in addition to large-vessel ectasias. Patients may present with transient ischemic attacks, vascular thromboses, seizures, or hemorrhagic or ischemic stroke.
  - Paroxysmal attacks of severe rotational vertigo occur in many patients. Although these episodes are usually brief, some prolonged severe attacks require cessation of activities for several days. Megadolichobasilar compression of the vestibulocochlear nerve has been suggested as a likely cause for these episodes.
  - Sensorineural hearing loss has been frequently documented in patients with Fabry disease and most likely reflects vascular pathology of the inner ear.
  - Peripheral neuropathy in Fabry disease predominantly involves small nerve fibers. The progressive loss of temperature and pain sensation should be assessed during the physical examination.
  - Lymphedema of the legs is a poorly described and a less common manifestation. Often asymmetric, the symptom may start as a transient seasonal event with a tendency to become more severe and extensive over time. This manifestation presumably reflects the progressive GL-3 deposition in the lymphatic vessels and lymph nodes, compromising the lymphatic circulation.
  - Obstructive and constrictive lung diseases have both been documented in a subgroup of patients, often presenting as wheezing, dyspnea, or bronchitis.
  - Priapism has been associated with Fabry disease.
  - Mild anemia is probably due to decreased RBC survival.
  - Poor heat and exercise tolerance is commonly observed in patients. It may start at the early stages of the disease and is reported by both males and females. This poor tolerance is typically attributed to hypohidrosis and acroparesthesias and may become more pronounced in the presence of pulmonary disease or cardiomyopathy in later stages of the disease. Patients may report lack of energy and fatigue.

Atypical Fabry disease: In atypical cases, individuals with residual enzyme activity demonstrate symptoms later in life, and the symptoms are usually limited to one or a few organs. For example, individuals with atypical cardiac variants usually do not have any signs or symptoms in childhood and present mainly with cardiac disease later in adulthood. In various surveys, approximately 3-12% of patients with unexplained left ventricular hypertrophy (LVH) have been diagnosed with the cardiac variant of Fabry disease.

Fabry disease in females: Clinical manifestations in female carriers vary greatly because of random X-chromosome inactivation. Although carriers commonly remain asymptomatic throughout life, many demonstrate clinical symptoms as variable and severe as those of affected males. Affected females may experience early manifestations of the disease, such as acroparesthesia and GI discomfort. Their symptoms may also be as severe and progressive as those seen in males (ie, they may develop renal failure). Females who are asymptomatic at the time of initial assessment should be closely and regularly monitored for any evidence of disease manifestation.

Physical:

Skin symptoms

Angiokeratoma, small punctate reddish-to-bluish angiectases, may be either flat or slightly raised and may blanch with pressure. These are commonly observed as dense clusters of lesions on the umbilicus, flanks, thighs, penis, and scrotum.

Lesions in the oral mucosa and conjunctiva are observed in some patients.

Hypohidrosis and anhidrosis may be observed.

Visual symptoms

Vision is usually not impaired.

A slit-lamp examination reveals cornea verticillata, which manifests as whirl-like white-to–golden-brown opacities that extend from the center to the periphery of the cornea. Cornea verticillata is often prominent in female carriers and may play an important role in the early recognition of Fabry disease. Therefore, in females with either a positive family history or symptoms suggestive of Fabry disease, a slit-lamp examination can be very helpful.

Other possible ocular findings include lens, retinal and conjunctival changes.

Neurological symptoms
- Peripheral neuropathy, specifically loss of temperature and pain sensation, has been reported.
- Hearing deficit may be observed.

Lymphedema symptoms: Asymmetric involvement of the lower extremities with pitting edema has been reported in the absence of significant renal or cardiac disease.

Other symptoms: Characteristic facial appearance, such as coarse facial features, have been described by some authors.

Causes: The gene that encodes a-Gal A has been isolated and sequenced, and more than 245 different mutations (missense, nonsense, splice, deletion, and insertion errors) have been reported. Attempts to correlate genotype with clinical presentation have been confounded by the fact that very few recurrent mutations have been reported. The typical interfamilial variability of the disease phenotype may be due to other modifying factors, which may be genetically or environmentally derived.

Lab Studies:

a-Gal A activity

a-Gal A activity may be measured in plasma, serum, and leukocytes. Tissue biopsies and cultured skin fibroblasts may also be used to measure a-Gal A activity.

In males with the classic or variant phenotype, the disease is readily diagnosed based on low a-Gal A activity.

Female carriers may have a-Gal A activity that ranges from zero to within the reference range. Thus, enzyme assays are rarely helpful in determining female carrier status.

DNA analysis: DNA isolated from blood or biopsy specimens can be used for analysis of the a-Gal A gene sequence to identify the disease-causing mutation. DNA testing is the preferred method for identifying and confirming the carrier status of females in whom enzyme activity is within or near the reference range.

Laboratory tests after diagnosis: After the diagnosis has been confirmed using enzyme assays, DNA testing, or both, carefully assess the patient. A recommended minimum assessment schedule has been developed by the Fabry Board of Advisors ( Eng, 2006)and other experts in the field (Desnick, 2003). The recommended assessment frequency depends on patient age and previous findings. Females and males should undergo the same degree of assessment and monitoring. The following recommended laboratory assessments should be obtained at baseline and at appropriate intervals:

CBC count, serum electrolyte level measurement, and lipid profile

Renal evaluation
- Serum BUN and creatinine levels and 24-hour urine or spot urine measurement for total protein/creatinine, albumin/creatinine, sodium, creatinine, and urinary GL-3 (optional) levels
- Renal biopsy (This may be warranted in atypical cases to exclude any other causes of renal disease.)

Imaging Studies:

CNS evaluation

MRI is used to document evidence of brain ischemic disease.
Magnetic resonance angiography (MRA) may be indicated to assess cerebral vasculopathy.
Peripheral nerves should be periodically assessed using a detailed neurological examination.

Other Tests:

Cardiac evaluation

Ventricular hypertrophy and septal thickening can be demonstrated using echocardiography. If LVH is present, a cardiac MRI with contrast can be performed to evaluate the presence of scarring.
Abnormal ECG findings include sinus bradycardia, nonspecific ST-segment changes, T-wave inversion, and shortened PR interval. Evidence of LVH and previous ischemic injury may also be present.
Holter monitoring in selected patients may provide important information.

Psychosocial evaluation: All health care professionals who treat patients with Fabry disease should be sensitive to the psychosocial burden of a chronic, rare, and progressive disease. In these families, denial, guilt, and anger frequently play a significant role in intrafamilial dynamics. Pay special attention to the history and signs of anxiety disorders, clinical depression, suicidal ideation or attempts, and substance abuse.

Pulmonary evaluation: Perform induced sputum analysis, lung biopsy, or both if severe pulmonary involvement is present (to exclude an intercurrent disease process).

Visual evaluation: Perform slit-lamp microscopy to identify the typical Fabry disease–specific changes in the cornea, lens, retina, and conjunctiva.

Treatment

Medical Care: Disease management strategies should be tailored to the individual according to patient age and disease stage. These strategies include the use of medication to alleviate the symptoms, disease-specific treatment to delay and prevent possible serious organ damage, and adherence to standard health care measures and a healthy lifestyle.

Pain management
- Daily prophylactic doses of neuropathic pain agents (eg, phenytoin, carbamazepine, gabapentin, or a combination of these agents) provide some degree of relief. They are effective in decreasing the frequency and severity of pain episodes or pain crises in most patients.
- Some patients may require more potent analgesics (eg, opioids) for pain management.

Management of GI symptoms
- No specific treatment has been found to control GI symptoms in Fabry disease. However, pancrelipase, metoclopramide, H2 blockers, loperamide, and hydrochloride can ameliorate GI symptoms in some patients.
- Patients with abdominal symptoms often benefit from a change in eating habits that includes frequent small meals.

Management of skin symptoms
- The results of various laser methods used to treat angiokeratomas in patients with Fabry disease have not been promising for patients who are not receiving ERT.
- Lesions that are more pedunculated may be treated with a series of liquid nitrogen treatments prior to laser therapy.

Management of visual symptoms: Ocular symptoms in patients with Fabry disease rarely, if ever, cause significant impairment of vision and, as a rule, do not require treatment.
Management of other symptoms: Symptomatic treatment of renal, cardiovascular, and cerebrovascular complications is warranted.
Enzyme replacement therapy

ERT provides the patient with the biologically functional protein. The infused enzyme is taken up into lysosomes through specific receptors located on the surface of the target cells. Reversal of the metabolic and pathologic abnormalities in the cells and tissues are the key therapeutic goals of ERT. These changes should, in turn, result in improvement of symptoms and prevention of disease complications.
Multiple clinical trials with recombinant a-Gal A (agalsidase beta [Fabrazyme]: Genzyme Corporation, Cambridge, Mass; agalsidase alfa [Replagal]: TKT Corporation, Cambridge, Mass) have been performed to investigate the safety and efficacy of ERT in patients with Fabry disease. The outcomes of these clinical studies were the basis for approval of Fabrazyme and Replagal in most European countries in 2001 and for the approval of Fabrazyme in the United States in 2003. The enzyme is administered intravenously. Replagal is administered intravenously at a dose of 0.2 mg/kg every 2 weeks, and Fabrazyme is administered intravenously at a dose of 1 mg/kg every 2 weeks.
Initial clinical studies with recombinant a-Gal A showed that ERT is safe and well tolerated, except for mild-to-moderate infusion–associated reactions, which have been managed conservatively. During the phase 3 clinical study, Fabrazyme was shown to clear GL-3 from the plasma and capillary endothelium of the major sites of pathology, such as the kidney, heart, and skin.
The clinical benefits of ERT using a-Gal A in patients with advanced Fabry disease were examined in a phase 4 clinical study, which had a double-blind, placebo-controlled design. The rate of progression of renal, cardiac, and cerebrovascular complications and death among patients who received active drug was reduced compared with the placebo group. Therefore, starting ERT immediately after diagnosis to prevent irreversible organ damage is reasonable.
The commercial availability of Replagal and Fabrazyme has allowed treatment for many patients around the world. This increased use has enabled further assessment of the effect of ERT on various clinical manifestations of Fabry disease. A growing body of evidence suggests that ERT is beneficial in improving most disease symptoms. However, the response to ERT may vary, depending in part on tissue-specific differences in drug delivery and disease stage. A summary of the effect of ERT on various manifestations as reported by the authors and others is as follows:
- Improved acroparesthesias
- Improved GI symptoms
- Improvement of hypohidrosis and anhidrosis
- Improvement in the function of C-, –Ad-, and Ab-nerve fibers
- Stabilization of deteriorating renal function.
- Improved cardiac function
- Improved lymphedema
- Improved vertigo
- Stabilization and occasional improvement in hearing
- Reduction in stroke frequency
Current recommendations suggest that ERT should be initiated as early as possible in all males with Fabry disease (including those with end-stage renal disease). Symptomatic female carriers with serious organ system involvement should also be assessed for ERT administration.
The following signs and symptoms suggest serious implications of Fabry disease in females that warrant ERT:
- Uncontrolled pain at any age that requires alteration of lifestyle and interferes with quality of life
- Presence of and a progressive increase in proteinuria, exceeding 300 mg per 24 hours or renal biopsy findings that suggest significant renal involvement
- Patients on dialysis or who have undergone transplantation
- Ischemic heart disease with or without cardiac dysfunction
- Moderate-to-severe heart enlargement (ie, LVH)
- Heart rhythm abnormalities
- Significant brain involvement or MRI changes
- Frequent severe vertigo episodes
- Severe fatigue

Adjunctive therapies and preventive measures
- Use of angiotensin-converting enzyme (ACE) inhibitors and/or blockers in patients with proteinuria is the criterion standard. The dose should be optimized by a nephrologist.
- Control of hypertension is essential.
- Dyslipidemia (most commonly, hypercholesterolemia) should be treated.
- Prophylaxis with antiplatelet or anticoagulant medication can be important in patients who have had transient ischemic attacks or a stroke.
- Permanent cardiac pacing should be considered in high-risk patients.
- Hearing loss can be treated with hearing aids. Patients should avoid excessive noise exposure.
- Patients should be encouraged to maintain a healthy lifestyle, such as avoiding smoking.

Surgical Care: In patients who have undergone renal transplantation, engrafted kidneys from unaffected and noncarrier individuals correct kidney function and remain free of GL-3 storage because the transplanted kidney is capable of producing normal levels of a-Gal A. However, other organ system damage continues unabated in patients who have undergone kidney transplantation. In particular, vascular disease of the heart and brain may continue to progress. Thus, these patients should receive or continue to receive ERT.

Consultations: A multidisciplinary team is essential. Emotional support and family counseling should be an integral part of patient care. In addition, providing patients with the resources to learn about Fabry disease and to contact other patients and families struggling with similar issues may help ameliorate feelings of isolation. Consultations should include the following:

Medical geneticist

Nephrologist

Cardiologist

Ophthalmologist

Pain specialist

Neurologist

Diet: A "renal diet" is recommended for patients with proteinuria and renal failure. A nutritionist should supervise a low-protein and low-sodium diet. Patients are advised to monitor their activity level in order to avoid factors that precipitate symptoms. For example, adequate hydration prior to any physical activity and avoidance of exposure to extreme temperatures are recommended to avoid pain.

Medication

Drug Category: Analgesics -- These agents are used to relieve neuropathic pain. Phenytoin and carbamazepine are 2 medications used to treat acroparesthesias in patients with Fabry disease. Either drug may be used, although some patients benefit from a combination.

Drug Name	Phenytoin (Dilantin) -- Used for analgesia for acroparesthesia. May act in the motor cortex, where it may inhibit spread of seizure activity. Activity of the brainstem centers responsible for the tonic phase of grand mal seizures may also be inhibited. Individualize dose. Administer larger dose before bedtime if dose cannot be equally divided.
Adult Dose	300 mg PO qd
Pediatric Dose	100 mg PO qd
Contraindications	Documented hypersensitivity; sinoatrial block; second- and third-degree AV block; sinus bradycardia; Adams-Stokes syndrome
Interactions	Amiodarone, benzodiazepines, chloramphenicol, cimetidine, fluconazole, isoniazid, metronidazole, miconazole, phenylbutazone, succinimides, sulfonamides, omeprazole, phenacemide, disulfiram, ethanol (acute ingestion), trimethoprim, and valproic acid may increase phenytoin toxicity; effects of phenytoin may decrease when taken concurrently with barbiturates, diazoxide, ethanol (chronic ingestion), rifampin, antacids, charcoal, carbamazepine, theophylline, and sucralfate; may decrease effects of acetaminophen, corticosteroids, dicumarol, disopyramide, doxycycline, estrogens, haloperidol, amiodarone, carbamazepine, cardiac glycosides, quinidine, theophylline, methadone, metyrapone, mexiletine, oral contraceptives, and valproic acid
Pregnancy	D - Unsafe in pregnancy
Precautions	Obtain CBC count and urinalyses when therapy is begun and at monthly intervals for several months to monitor for blood dyscrasias; discontinue if rash appears and do not resume use if rash is exfoliative, bullous, or purpuric; rapid IV infusion may result in death from cardiac arrest marked by QRS widening; caution in patients with acute intermittent porphyria and diabetes (may elevate blood sugar levels); discontinue if hepatic dysfunction occurs

Drug Name	Carbamazepine (Tegretol) -- Indicated for complex partial seizures and trigeminal neuralgia. May block posttetanic potentiation by reducing summation of temporal stimulation. May reduce polysynaptic responses and block posttetanic potentiation. Following therapeutic response, may reduce dose to minimum effective level or discontinue treatment at least once every 3 mo. Doses are typically lower than those used to treat seizures and are administered once daily.
Adult Dose	300 mg PO qd
Pediatric Dose	100 mg PO qd
Contraindications	Documented hypersensitivity; bone marrow depression; administration of MAOIs within previous 14 d
Interactions	Serum levels may increase significantly within 30 d of danazol coadministration (avoid when possible); do not coadminister with MAOIs; cimetidine may increase toxicity, especially if taken in first 4 wk of therapy; carbamazepine may decrease primidone and phenobarbital levels (coadministration may increase carbamazepine levels)
Pregnancy	D - Unsafe in pregnancy
Precautions	Do not use to relieve minor aches or pains; caution with increased intraocular pressure; obtain CBC counts and serum-iron baseline before treatment, during first 2 months, and yearly or every other year thereafter; can cause drowsiness, dizziness, and blurred vision; caution while driving or performing other tasks requiring alertness

Drug Name	Gabapentin (Neurontin) -- FDA-approved oral medication for management of postherpetic neuralgia. Also FDA approved for the treatment of partial seizures in adults and children. Chemical structure similar to the inhibitory neurotransmitter GABA. Appears to work by raising GABA levels by some effect on a GABA transporter protein. Also decreases activity of voltage-gated calcium channels via binding to a secondary protein. Approved for epilepsy in children. Available as tab, cap, and liquid dosage forms.
Adult Dose	100-300 mg PO qd initially; may slowly titrate upward as needed for pain; not to exceed 2400 mg/d
Pediatric Dose	<3> 3-12 years: Not established; limited data suggests 10-15 mg/kg/d PO divided q8h; may gradually titrate upward at 3-d intervals >12 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Antacids may significantly reduce bioavailability of gabapentin (administer at least 2 h following antacids); may significantly increase norethindrone levels ; cimetidine, hydrocodone, and morphine may increase gabapentin AUC; naproxen may increase gabapentin absorption
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Common adverse effects include drowsiness, dizziness, somnolence, and unwanted eye movements; children may experience emotional ability hostility, thought disorder, and hyperkinesia; caution in elderly patients and those with severe renal impairment; abrupt withdrawal may precipitate seizures

Drug Category: Enzyme replacement therapy -- a -Gal A deficiency leads to the accumulation of GSLs with terminal a-galactosyl residues. Clinical manifestations of Fabry disease are reflected in the tissue target sites of lipid storage. The recombinantly produced enzyme a-Gal A is available in Europe and United States.

Drug Name	Agalsidase (Fabrazyme, Replagal) -- Recombinant form of the human enzyme a -Gal A, which is deficient in patients with Fabry disease. Data from clinical trials show a decrease in GL-3 levels following enzyme replacement, reversal in lipid tissue storage, stabilized or improved renal and cardiac function, and reduction or relief of neuropathic pain. Following enzyme replacement, the long-term use of neuropathic pain medication has been reduced. Agalsidase beta (Fabrazyme) is manufactured by Genzyme Corporation (Cambridge, Mass) and is based on expression of the human GLA gene in CHO cells. Agalsidase alfa (Replagal) is manufactured by Transkaryotic Therapies, Inc (Cambridge, Mass) and is based on activation of the human GLA gene expression in human (skin) fibroblasts.
Adult Dose	Initial dose: Fabrazyme: 1 mg/kg IV infused over 4-6 h (initial infusion); subsequent infusions may be administered at a rate of 3-5 mg/min; repeat q2wk Replagal: 0.2 mg/kg IV infused over 40 min q2wk Maintenance dose: Not established
Pediatric Dose	Not established; appropriate time to initiate treatment in children has not been determined
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	May cause IgG antibody production (55% with Replagal, 83% with Fabrazyme); may cause allergic reactions (10% with Replagal, 59% with Fabrazyme), which are prevented by premedication with hydrocortisone and/or antihistamines (standard for Fabrazyme) before IV infusion; infusion-related events (ie, fever, rigors, hypertension) may be reduced or eliminated by slower rate of administration or interruption of treatment

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Ear Cancer

2007-05-08T12:21:00.000-07:00

Category: Cancer
Specific Target: Ear/Ears

Ear cancer or Ear tumor is cancer of one or both ears. It is a relatively rare, slow growing cancer that usually affects men over 60.

Tumors of the ear can be benign or malignant. They can occur on the external ear, or in the ear canal, the middle ear or inner ear. Tumors in different areas of the ear behave differently. Thus, it is necessary to describe tumors based on their site of occurrence, as well as their behavior and treatment.

Tumors of the ear are classified either by location or by their behavior (malignant or benign).

By location:

· Tumors of the external ear
· Tumors of the middle ear

By behavior:

Benign Tumors
1. Cholesteatomas
2. Glomus Tumors
3. Cholesterol granulomas

Malignant Tumors
1. Basal Cell Tumors (see below)
2. Squamous cell Tumors or Squamous cell carcinoma

1. Basal Cell Cancers: These are the most common ear tumors of the external ear. Usually, years of sun exposure causes basal cell tumors (cancers), particularly of the upper portion of the exposed ear. They are the most common cancers of any part of the face including the external ear.

They begin as circular raised areas of skin with central crater-like ulcerations. They enlarge locally and may become ulcerated in the center. Basal cell cancers are more common in the elderly. Also, the fairer the skin, the greater the chance of developing a basal cancer during one's life. Basal cell cancers grow very slowly. Because of this, they are easily cured if treated early. If ignored, however, a basal cell cancer will require very extensive surgery to remove it.

These cancers generally do not metastasize, that is they do not spread to other organs. In most cases they do not break off, enter the bloodstream or travel to other areas of the body. They spread by increasing in size only. Basal cell cancers in early stages can be treated with either surgical excision or local curretment (scraping away the tumor with a sharp looped instrument and peeling down to normal skin).

2. Squamous Cell Cancers: Tumors called squamous cell cancers occur far less commonly than basal cell cancers. However, squamous cell cancers are much more aggressive cancers than basal cell cancers. They spread through the tissues surrounding the site of origin. In addition, squamous cell cancers of the ear can spread to the lymph nodes surrounding the site of origin or to lymph nodes in the neck. Squamous cell cancers of the ear look much like basal cell cancers at an early stage. These tumors may just look like sores. They are generally not painful, but grow more rapidly than basal cell cancers. Early biopsy of any suspicious lesion of the external ear is necessary to identify the presence of a cancer. Arrangements for appropriate removal should be made immediately.

Since squamous cell cancers are much more aggressive, surgical removal must be more extensive.

When squamous cell cancers become large, surgery combined with radiation therapy can also be necessary. The added procedure improves the chance for a complete cure.

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Dandy-Walker Malformation

2007-05-07T13:17:00.001-07:00

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Ultrasound

Findings: Classic abnormal findings described on cranial CT and MRI scans also can be demonstrated on cranial sonography. Commercially available equipment is used with a 3- to 7.5-MHz transducer, depending on the size of the patient's head. Transducers of 5- to 7.5-MHz are used for newborns, and transducers of 3- to 5-MHz are used for older infants.

On US, a large posterior fossa midline cyst, which communicates with the fourth ventricle, is demonstrated best on midline sagittal sections. The anterolaterally displaced hypoplastic cerebellar hemispheres are seen best in the coronal projection. Sagittal and coronal sections can demonstrate the enlargement of the posterior fossa, high position of the tentorium, and dilated third and lateral ventricles.

Scans performed with the transducer not only by using the transfontanel approach but also by placing it directly over the posterior or posterolateral fontanelle can show a large posterior fossa cyst and hypoplastic cerebellar hemispheres.

It is important in these patients to assess the supratentorial compartment for associated anomalies, such as callosal agenesis.

Using US, Dandy-Walker malformation usually is discovered before birth although prominence of the cisterna magna is often confused with Dandy-Walker malformation in utero (see Image below).

Caption: Dandy-Walker malformation. In utero sonogram of Dandy-Walker malformation. Note abnormal cerebellar vermis in association with a posterior fossa cyst (arrow) and splaying of the cerebellar hemispheres. Image courtesy of Ecker et al.

Prenatal diagnosis of Dandy-Walker malformation should not be made before the 18th week of gestation because development of the cerebellar vermis may be incomplete at that time. Although great variability exists in intracranial findings in fetuses, sagittal measurements exceeding 10 mm help confirm the presence of a Dandy-Walker cyst. US examination, including fetal echocardiography, should be directed toward identifying additional supratentorial and extracranial anomalies. Follow-up sonograms are useful for monitoring cyst size and ventriculomegaly. Three-dimensional US reportedly proved most helpful in delineating the exact nature and anatomic level of the anomaly in utero.

Degree of Confidence: US is heavily operator dependent. Associated findings of Dandy-Walker malformation may be missed, such as pachygyria, polymicrogyria, heterotopias, and dural abnormalities.

False Positives/Negatives: Fetal US can demonstrate Dandy-Walker malformation and variant, but caution should be exercised, since the developing normal cerebellum can mimic hypoplasia.

Angiography

Findings: X-ray angiography can demonstrate angiographic features of Dandy-Walker malformation. In the arterial phase, the posterior cerebral vessels are elevated. The superior cerebellar arteries are displaced anterosuperiorly above the posterior cerebral arteries. The posterior inferior cerebellar arteries (PICAs) are shortened, with high tonsillar loop. The inferior vermian branches of the PICA are absent. In some patients, the entire PICA is absent or hypoplastic. In the venous phase, arteriography shows absence of the inferior vermian veins, elevation of the great vein of Galen, and high position of the transverse sinuses.

Treatment/Management

Medical Care:

Physical therapy is often used to help patients improve their abnormal motor functioning. However, many individuals will still continue to have difficulty walking and have poor balance. Another treatment is to give medication to reduce seizures. Seizures are involuntary muscle movements and/or decreased awareness of the environment due to overexcitement of nerve cells in the brain.

Surgical Care:

Treatment usually consists of a shunt to treat associated hydrocephalus. The neurosurgeon can shunt the cyst (cystoperitoneal), the ventricles (ventriculoperitoneal), or both.

To treat the buildup of fluid in the head, a flexible tube called a shunt can be placed in the ventricles of the brain, the inside of the brain, or the posterior fossa (the indented bone in the lower, back part of the skull). From one of these areas, the tube will drain the extra fluid into the space between layers that line the belly. The fluid will then be absorbed along the wall of the belly.

The shunting procedure will decrease the pressure in the head and will thus prevent the head from widening further. Sometimes, more than one tube needs to be placed, such as a tube in a ventricle and a tube in the posterior fossa. If these two spaces are not connecting, the surgeon will connect the tubes to a common valve that drains the fluid.

Unfortunately, the cyst cannot be removed with surgery because it already has blood vessels that go through it and connect to the brain. Taking out the cysts would thus cause too much damage to the brain.

Medication:

No medication could treat this congenital malformation although there are medications that can treat underlying problems.

Diet:

No specific regimen for the malformation. The diet is based on the associated problems of DWS.

Follow Up Treatment/Management

Deterrence/Prevention:

Some cases of congenital brain defects can be prevented with good maternal nutrition, including folic acid supplements. Folic acid is a vitamin that has been shown to reduce the incidence of neural tube defects. The Centers for Disease Control and Prevention recommends that all women of childbearing age consume 0.4 mg of folic acid daily to prevent neural tube defects. All over-the-counter multivitamins contain this amount of folic acid. Pregnant women should avoid exposure to infection, especially during the first trimester. Abstention from drugs and alcohol during pregnancy may reduce risk. Genetic counseling is advisable for parents who have had one child with anencephaly, since the likelihood of having another is increased.

Complications:

The list of complications that have been mentioned in various sources for Dandy-Walker Syndrome includes:

· Hydrocephalus

· Raised intracranial pressure

· Polydactyly

· Papilloedema

· Syndactyly

Prognosis:

The prognosis for patients with Dandy-Walker syndrome is only moderately favorable, even when the hydrocephalus is treated early and correctly. The presence of multiple congenital defects may adversely affect survival. Prognosis for normal intellectual development is variable depending on the severity of the syndrome and associated malformations.

Miscellaneous

Medical/Legal Pitfalls:

· Failure to diagnose Dandy-Walker malformation with hydrocephalus in a neonate or a child can cause serious neurologic complications.

· Faulty diagnosis, such as mega cisterna magna or arachnoid cyst instead of Dandy-Walker malformation, can cause morbidity and mortality.

Special Concerns:

· US can be performed during pregnancy, and the diagnosis of Dandy-Walker malformation can be made antenatally. To confirm the diagnosis and gain detailed information, MRI evaluation can be used antenatally.

· Genetic counseling may be needed because a familial occurrence has been reported. Fetal karyotyping also is recommended for chromosomal analysis.

References

Medfriendly.com
Health of Children
eMedicine
WrongDiagnosis.com

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Dandy-Walker Malformation

2007-05-06T14:36:00.000-07:00

Category: Congenital Malformation
Affected System: Central Nervous System
Specific Target Organ: Brain

Synonyms and related keywords

Dandy-Walker syndrome, Dandy-Walker cyst, Dandy-Walker deformity, Luschka-Magendie foramina atresia

Introduction

Definition:

Dandy-Walker malformation is a rare congenital malformation and involves the cerebellum and fourth ventricle. The condition is characterized by agenesis or hypoplasia of the cerebellar vermis, cystic dilatation of the fourth ventricle, and enlargement of the posterior fossa. A large number of concomitant problems may be present, but the syndrome exists whenever these 3 features are found. Approximately 70-90% of patients have hydrocephalus, which often develops postnatally. Dandy-Walker malformation may be associated with atresia of the foramen of Magendie and, possibly, the foramen of Luschka.

Dandy-Walker malformation first was described by Dandy and Blackfan in 1914. Since the original description, additional studies have reported on the various morphologic features of the syndrome. Not until 1954 did Benda first emphasize that atresia of the cerebellar outlet foramina is not an essential feature of the condition and suggested the now widely accepted term Dandy-Walker malformation.

Studies by D'Agostino in 1963 and Hart et al in 1972 further defined the characteristic triad of Dandy-Walker malformation as consisting of (1) complete or partial agenesis of the vermis, (2) cystic dilatation of the fourth ventricle, and (3) an enlarged posterior fossa with upward displacement of lateral sinuses, tentorium, and torcular herophili. The triad typically is found in association with supratentorial hydrocephalus, which should be considered a complication rather than part of the malformation complex.

Dandy-Walker complex

Classically, posterior fossa cystic malformations have been divided into Dandy-Walker malformation, Dandy-Walker variant, mega cisterna magna, and posterior fossa arachnoid cyst. Precisely differentiating the malformations may not be possible using imaging methods. Dandy-Walker malformation, variant, and mega cisterna magna currently are believed to represent a continuum of developmental anomalies on a spectrum that has been termed the Dandy-Walker complex.

Dandy-Walker complex is characterized by an enlarged posterior fossa, high position of tentorium with upward displacement of the lateral sinuses, torcular herophili associated with varying degrees of vermian aplasia or hypoplasia, and a cystic dilatation of the fourth ventricle that nearly fills the entire posterior fossa. Since the vermis is present in posterior fossa arachnoid cyst, this is considered separately from Dandy-Walker malformation.

Dandy-Walker variant

Dandy-Walker variant consist of vermian hypoplasia and cystic dilatation of the fourth ventricle without enlargement of the posterior fossa (see Image below).

Caption: Dandy-Walker malformation. Dandy-Walker variant in a 13-year-old girl with thoracal scoliosis. Sagittal T1-weighted MRI shows agenesis of the corpus callosum and a hypoplastic inferior vermis. The fourth ventricle is enlarged slightly, but the posterior fossa typically is normal in size.

Mega cisterna magna

The mega cisterna magna consist of an enlarged posterior fossa, secondary to an enlarged cisterna magna, but a normal cerebellar vermis and fourth ventricle (see Image below).

Caption: Dandy-Walker malformation. Mega cisterna magna. Sagittal T1-weighted MRI shows a large retrocerebellar cerebrospinal fluid collection and a normal fourth ventricle and vermis.

Arachnoid cyst

Retrocerebellar arachnoid cysts of developmental origin are uncommon but clinically important. True retrocerebellar arachnoid cysts displace the fourth ventricle and cerebellum anteriorly and show significant mass effect. Differentiation of posterior fossa arachnoid cyst from Dandy-Walker malformation is essential as surgical therapy differs between the two entities (see Image below).

Caption: Dandy-Walker malformation. Posterior fossa arachnoid cyst in a 15-month-old girl with a lumbar pilonidal sinus. Sagittal T1-weighted MRI shows a large posterior fossa cyst that is compressing the cerebellar hemispheres, vermis, fourth ventricle (arrow), and brainstem.

Pathophysiology:

Dandy-Walker malformations are formed during embryogenesis. Insults of varying severity to both the developing cerebellar hemispheres and fourth ventricle currently are believed to be the genesis of the anomaly. The nature and cause of the insult are unknown.

Multiple diverse theories have been offered to explain the diffuse manifestations of Dandy-Walker malformation. To date, no single theory has proven satisfactory; therefore, none has been accepted widely. Theories regarding the origin of the malformation have centered on defects in embryogenesis as below.

Dandy and Blackfan (1914) and Taggart and Walker (1942) believed that the massive dilatation of the fourth ventricle originates in a congenital obstruction of the outlets of Luschka and Magendie. This theory includes the presence of a developmental cerebellar defect that begins before the embryologic differentiation of the fourth ventricle foramina, and results in blockage or atresia of the foramina of Magendie and Luschka. This, in turn, results in cystic transformation of the roof of the fourth ventricle and in an obstructive (noncommunicating) hydrocephalus, in which a cyst arises from compromised absorption of CSF.

The most comprehensive theory concerns dysembryogenesis involving the hindbrain. An insult that leads to developmental arrest in formation of the hindbrain, with lack of fusion of the cerebellum in the midline, can be localized temporally between the 7th and 10th gestational weeks. This results in persistence of the anterior membranous area, which extends and herniates posteriorly. Simultaneous formation of the foramen of Magendie, tentorium, superior longitudinal sinus, straight sinus, torcular herophili, and lateral sinuses helps explain their association with Dandy-Walker malformation.

Differential Diagnosis:

Arachnoid Cyst
Epidermoid, Brain

Other Problems to be Considered:

Isolated fourth ventricle
Mega cisterna magna
Joubert syndrome
Tectocerebellar dysraphia

Differential diagnosis of posterior fossa cystic lesions is summarized below.

Dandy-Walker malformation

Complete or partial cerebellar vermian hypoplasia
Cystic dilatation of fourth ventricle
Large posterior fossa
High torcular and transverse sinuses
Hydrocephalus

Dandy-Walker variant

Varying cerebellar primarily inferior vermian hypoplasia
Varying enlargement of the fourth ventricle
Normal posterior fossa volume

Mega cisterna magna

Normal cerebellar hemispheres and vermis
Large retrocerebellar CSF collection communicates with fourth ventricle
Normal fourth ventricle
Occasionally, quite enlarged posterior fossa

Posterior fossa arachnoid cyst

Noncommunicating posterior fossa cyst
Normal but distorted vermis and cerebellum
Normal but displaced fourth ventricle
Usually enlarged posterior fossa

Diagnosis:

Dandy Walker syndrome is diagnosed with X-rays and a CT (computerized tomography) scan of the brain. CT scanning is a more advanced imaging technique that uses x-rays and computer technology to produces more clear and detailed pictures than a traditional x-ray. Magnetic resonance imaging (MRI) scans of the brain can also be used. MRI scans produce extremely detailed pictures of the inside of the body by using very powerful magnets and computer technology. MRI scans are more detailed and more expensive that CT scans. A rarely used technique to diagnose Dandy Walker syndrome is a ventriculogram. A ventriculogram is a specific x-ray study of the ventricles in the brain. Ventricles are openings in the brain that produce the cushiony fluid that protects the brain and spine.

Signs and Symptoms:

The list of medical symptoms mentioned in various sources for Dandy-Walker Syndrome includes those listed below. Note that Dandy-Walker Syndrome symptoms usually refers to various medical symptoms known to a patient, but the phrase Dandy-Walker Syndrome signs may often refer to those signs that are only noticeable by a doctor:

· Hydrocephalus

· Increased intracranial pressure

· Slow motor development

· Progressive macrocrania (abnormally enlarged skull)

· Symptoms of increased intracranial pressure

- Irritability
- Vomiting
- Convulsions

· Symptoms of cerebellar dysfunction

- Ataxia
- Nystagmus (jerky eyes)

· Increased head circumference

· Bulging occiput (the back of the head)

· Cranial nerve dysfunction

· Abnormal breathing patterns

· Progressive head enlargement

· Vomiting

· Hyperirritability

· Convulsions

· Congested scalp veins

· Bulging anterior fontanelle

· Separated cranial sutures

· Swelling of optic disk

· Slowed heart rate

· Bradypnea

· Long head

· Thinning of occipital squama

· Dilatation of fourth brain ventricle

See also Physical Assessment/Anatomy.

Inheritance:

The etiology is heterogeneous, and familial occurrence also has been reported. A few cases resulting from autosomal recessive genes have been reported, although in most patients, the cause of Dandy-Walker malformation is not known. Genetic counseling is critical to estimate the risk of recurrence of genetic disorders in family members.

Etiologic heterogeneity and low recurrence risk in siblings (1-5%) for Dandy-Walker malformation have been reported. Increased frequency of an association with congenital heart disease, cleft palate, and neural tube defects appears to exist. An unusual case of an infant with both Ellis-van Creveld and Dandy-Walker syndromes and with homozygosity for an unusually long heterochromatic segment of the long arm of chromosome 9 (9qh+) was reported. An extensive tabulation of single gene disorders, chromosomal aberrations, teratogen-induced conditions, sporadic forms, or forms with undetermined inheritance associated with Dandy-Walker malformation also were reported. In a large series, an abnormal karyotype was found in 5 of 17 patients.

Predisposing factors:

Predisposing factors include gestational (first trimester) exposure to rubella, cytomegalovirus, toxoplasmosis, warfarin (Coumadin), alcohol, and isotretinoin.

Frequency:

In the US: The incidence of Dandy-Walker malformation is 1 case per 25,000-35,000 live births. Dandy-Walker malformation accounts for approximately 1-4% of hydrocephalus cases.

Mortality/Morbidity:

Overall mortality rates of 12-50% have been reported in Dandy-Walker malformation in the pediatric neurosurgical literature. Associated congenital anomalies contributed to 83% of postnatal deaths. Mortality rates have improved significantly over the last 30 years as a result of better anesthesia and shunting devices and the reduction of posterior fossa exploration. Sudden and unexpected death is an uncommon but well-recognized occurrence in patients with Dandy-Walker malformation.

The prognosis is difficult to formulate. The prognosis is only moderately favorable, even when hydrocephalus is treated early and correctly. In one study, 3 patients with isolated Dandy-Walker cysts with hydrocephalus diagnosed in utero were treated at birth with shunting, and all 3 had normal outcomes. An extreme range of severity is seen in this malformation. The presence of multiple congenital defects may affect survival adversely. Some people have Dandy-Walker variant their entire lives without any symptoms. Some infants may have it in association with other syndromes, resulting in severe complications or death.

Race:

DWM has not been shown to be more frequent in any particular ethnic group or race. About 85% of babies born with DWM have one or more other congenital malformations, or some type of recognizable syndrome.

Sex:

Dandy-Walker malformation occurs more frequently in females than in males. The male-to-female ratio was 1:3 in one Spanish series.

Age: Depending on the time of onset and degree of hydrocephalus, the age at diagnosis varies from birth to older childhood. Presentation in adulthood has been reported but is unusual. Patients with Dandy-Walker variant are more likely to present in adulthood than in infancy or childhood.

Clinical

History:

Patients with history of gestational (first trimester) exposure to rubella, cytomegalovirus, toxoplasmosis, warfarin (Coumadin), alcohol, and isotretinoin are at risk of developing the disorder.

Physical Assessment/Anatomy:

Most definitions of Dandy-Walker malformation have included the following 3 features: (1) dysgenesis of the vermis, (2) cystic dilatation of the fourth ventricle, and (3) enlargement of the posterior fossa with elevation of the tentorium/torcula.

Dandy-Walker malformation consists of a malformation of the roof of the fourth ventricle and of the cerebellum. The cerebellum is poorly developed, displaced upwards and laterally. The enlarged fourth ventricle balloons out backward (see Image A, Image B below).

Caption: Image A. Dandy-Walker malformation. Sagittal T1-weighted MRI in a 5-year-old girl shows a large posterior fossa cyst elevating the torcular herophili and sinus rectus (small arrow). The hypoplastic vermis is everted over the posterior fossa cyst (large arrow). The cerebellar hemispheres and brainstem (b) are hypoplastic. Thinned occipital squama is seen (arrowheads).

Caption: Image B. Dandy-Walker malformation. Sagittal T1-weighted MRI in an 11-day-old boy shows agenesis of the corpus callosum, hypoplastic brainstem (b), elevated the torcular herophili (lambdoid-torcular inversion, large arrow), a large fourth ventricle, and a markedly hypoplastic vermis that is rotated superiorly (small arrow).

The fourth ventricle is grossly misshapen and is a membrane-wrapped cyst that extends into the foramen magnum. This cyst may lift and displace the posterior portion of the brain, as well as cause an internal obstruction of normal CSF flow with resultant hydrocephalus (see Image C, Image D, Image E).

Caption: Image C. Dandy-Walker malformation. Axial T2-weighted MRI shows hydrocephalus, a large cerebrospinal fluid cyst in the posterior fossa, thinned occipital bone (arrows), and hypoplastic cerebellar hemispheres with a winged appearance (c).

Caption: Image D. Dandy-Walker malformation. Axial T1-weighted MRI shows ventriculomegaly and superiorly displaced posterior fossa cyst.

Caption: Image E. Dandy-Walker malformation. Axial CT scan in a 7-year-old girl with hydrocephalus shows a large cerebrospinal fluid cyst in the posterior fossa and hypoplastic cerebellar hemispheres with a winged appearance (c).

Dandy-Walker malformation may be associated with atresia of the foramen of Magendie and, possibly, the foramen of Luschka.

Common findings of Dandy-Walker malformation include the following:

· Enlarged posterior fossa

· Varying degrees of cerebellar and vermian hypoplasia or complete vermian absence (see Images below)

· Cyst formation in the posterior fossa (see Images below)

· Vermian remnant is everted above the posterior fossa cyst (See Images below)

· Hypoplastic cerebellar hemispheres winged anterolaterally (outward) in front of the cyst (see Images below)

· Absence of the foramina of Luschka and Magendie

· Obstructive hydrocephalus secondary to cystic dilatation of the fourth ventricle (70-90%; see Images below)

· Abnormally high position of the straight sinus, torcular herophili, and tentorium (see Images below)

Caption: Dandy-Walker malformation. Axial T1-weighted MRI shows an elevated anteriorly displaced torcular herophili (arrow) and superiorly displaced posterior fossa cyst.

· Sinus confluence and lateral sinuses elevated above the lambdoid sutures (high tentorial insertion = lambdoid-torcular inversion; see Images below)

· Aqueductal obstruction is an important component since it may affect the need for supratentorial decompression.

· If callosal agenesis coexists (20-25%), development of dilatation of the occipital horns (colpocephaly; see Images below)

· Brainstem possibly compressed and hypoplastic; degree of pontine hypoplasia related directly to degree of cerebellar hypoplasia (see Images below)

· Thinning and bulging of occipital bones (see Images below)

Associated central nervous system (CNS) abnormalities of Dandy-Walker malformation are reported in 70% of children.

· Dysgenesis of corpus callosum (20-25%; see Images below)

· Lipoma of corpus callosum

· Holoprosencephaly (25%)

· Porencephaly

· Dysplasia of cingulate gyrus (25%)

· Schizencephaly

· Polymicrogyria/gray matter heterotopia (5-10%)

· Cerebellar heterotopia

· Occipital encephalocele (7%)

· Microcephaly

· Dermoid cysts

· Malformation of cerebellar folia (25%)

· Malformation of inferior olivary nucleus

· Hamartoma of tuber cinereum

· Syringomyelia

· Klippel-Feil deformity

· Spina bifida

· Lumbosacral meningoceles

· Spinal lipoma

Non-CNS–associated malformations are reported in 20-33% of children.

· Orofacial deformities and cleft palate (6%)

· Polydactyly and syndactyly

· Cardiac anomalies

· Urinary tract abnormalities (polycystic kidneys)

· Cataracts, retinal dysgenesis, and choroid coloboma

· Facial hemangioma

· Hypertelorism

· Meckel-Gruber syndrome

· Neurocutaneous melanosis

Clinical Details:

Patients with Dandy-Walker malformation present with developmental delay, enlarged head circumference, or signs and symptoms of hydrocephalus. The clinical presentation depends to some extent on the combination of the developmental anomalies in the infant.

An estimated 80% of patients had normal ventricles at birth, and by age 1 year, 80% had ventriculomegaly. Hydrocephalus is present in approximately 90% of patients at the time of diagnosis.

If no other anomalies are present, the only symptom can be an abnormal enlargement of the head. Typical signs of increased intracranial pressure seen in older children and adults may be absent in infants secondary to the ability of the head to increase in size. Macrocrania usually is the consequence of hydrocephalus, but in some patients, it results from massive enlargement of the posterior fossa by the posterior fossa cyst. In this situation, macrocrania precedes development of hydrocephalus, giving the skull a characteristic dolichocephalic shape with bulging of the occiput.

Difficulty with balance, spasticity, and poor fine motor control are common. The degree of developmental delay appears to be related to the level of control of hydrocephalus and to the extent of supratentorial anomalies. Interference with respiratory control centers in the brainstem may cause respiratory failure. Seizures occur in 15-30% of patients.

Hearing or visual difficulties, systemic abnormalities, and CNS abnormalities are associated with poor intellectual development. Subnormal intelligence (intelligence quotient <83)>

Causes:

In most cases, the cause of Dandy Walker syndrome is unknown. It has been suggested that abnormalities in chromosomes may cause some cases of Dandy Walker syndrome. Chromosomes are structures in a person's cells that contain genes. Genes are units of material that contain coded instructions as for how certain bodily characteristics (such as eye color) will develop. All of a person's genes come from his/her parents. Some genes are normal whereas others may be abnormal. Abnormal genes can cause diseases.

It has also been suggested that Dandy Walker syndrome can be caused by exposure to an anti-acne (anti-pimple) medication called isotretinoin during the first three months that the baby is developing inside the mother. Other suggested causes are exposure to rubella, cytomegalovirus, toxoplasmosis, warfarin (Coumadin), and alcohol.

Tests/Studies

Preferred Examination:

Dandy-Walker malformation is diagnosed best with the help of US and MRI. US may be the initial examination performed since it can be done portably, without sedation, and allows multiplanar imaging.

The introduction of modern imaging techniques, specifically MRI, has radically changed the evaluation of symptoms related to the posterior fossa.

MRI usually is performed for detailed evaluation of Dandy-Walker malformation lesions and complications after the diagnosis is suspected using computed tomography (CT) and US. MRI can best define the relationship between the cyst and the fourth ventricle and can detect vermian rotation and the presence of signs of vermian dysgenesis.

MRI allows surgeons to view the cerebellum and associated structures accurately and to determine which form the malformation has taken and to what extent the malformation has progressed. MRI also demonstrates which space should be shunted first. Recently, MRI has been used frequently for diagnosis of fetal craniospinal anomalies.

CT scanning also is useful in Dandy-Walker malformation, since it can distinguish between hydrocephalus associated with Dandy-Walker and hydrocephalus with other etiologies.

Classic abnormal findings of Dandy-Walker malformation described on cranial CT and MRI also can be demonstrated on cranial sonography. US is used routinely during the antenatal period as a screening method and is used in particular for postnatal follow-up studies of hydrocephalus. US evaluation of posterior fossa cystic abnormalities in the newborn is best accomplished via a posterolateral fontanelle approach or through the cisterna magna posteriorly.

In recent years, plain radiography has been used primarily in the evaluation of shunt malfunction and for diagnosis of associated anomalies.

Limitations of Techniques:

Plain radiographs have diagnostic importance in the evaluation of shunt malfunction and for evaluation of bone abnormalities.

CT is an effective diagnostic method but exposes the infant to ionizing radiation. Clearly distinguishing subtypes of the Dandy-Walker complex on axial CT images is difficult. In addition, evaluating subtle supratentorial pathologies and associated abnormalities on CT images may not be easy because its routine use is constrained by the axial plane.

MRI is relatively expensive. High-quality MRI images require patient cooperation or sedation.

US is limited because it is heavily operator dependent. US does not image well such abnormalities as the gyral, dural, tentorial, and skull anomalies accompanying Dandy-Walker malformations.

Radiograph

Findings:

On conventional radiographs, the posterior fossa is enlarged disproportionately, with characteristic thinning and bulging of the occiput. Increased pressure from the massively dilated fourth ventricle, along with prominent CSF pulsations through the cyst fluid, causes widening of the diastatic lambdoid sutures and erosive scalloping of the occiput. Torcular herophili and lateral sinus grooves are located high above lambdoid angle (torcular-lambdoid angle inversion).

Degree of Confidence:

Plain radiographs have diagnostic importance in imaging bony abnormalities and in the evaluation of ventriculoperitoneal shunt malfunction.

CT Scan

Findings:

CT is used to diagnose Dandy-Walker malformation and to follow ventricular shunt function in shunted patients. Nonenhanced CT examination successfully delineates multiple components of Dandy-Walker malformation. The components include partial or complete absence of the cerebellar vermis, posterior fossa cyst contiguous with the fourth ventricle, small and widely separated cerebellar hemispheres, anterior and lateral displacement of hypoplastic cerebellar hemispheres, anterior displacement of pons, elevated imprint of the transverse sinuses with thinning and bulging of the bones of the posterior fossa, scalloping of petrous pyramids, and hydrocephalus (see Images below).

Caption: Dandy-Walker malformation. Axial CT scan in a 1-day-old boy shows a large posterior fossa cyst, separation of the lambdoid sutures (large arrows), and concavity of the petrous ridges (small arrows).

Three-dimensional CT and CT angiography studies can be used to evaluate osseous malformation and the relationships between vascular and bony structures. For these studies, 1-mm thickness, an axial plane and 3D reconstruction are used.

Degree of Confidence:

CT scans show the malformation relatively well, but a slice may miss the relevant presence of the vermis. Clearly distinguishing Dandy-Walker complex subtypes using axial CT images is difficult.

False Positives/Negatives:

CT scans show the malformation relatively well, but a slice may miss the relevant presence of the vermis. Clearly distinguishing Dandy-Walker complex subtypes using axial CT images is difficult.

MRI

Findings:

Malformations of the CNS are best delineated using MRI. The diagnosis is straightforward when typical MRI findings are present. MRI usually is required for better anatomic resolution prior to surgical intervention.

Nonenhanced routine cranial MRI can image the altered anatomy and provide excellent images in all projections (sagittal, axial, coronal), of which the sagittal view is one of the most useful (see Images below).

Caption: Dandy-Walker malformation. Dandy-Walker variant in a 13-year-old girl with thoracal scoliosis. Sagittal T1-weighted MRI shows agenesis of the corpus callosum and a hypoplastic inferior vermis. The fourth ventricle is enlarged slightly, but the posterior fossa typically is normal in size.

Hypoplasia or absence of the cerebellar vermis is detected best using thin-sectioned midline sagittal T1-weighted images (see Image above). Wide separation of the cerebellar hemispheres without intervening vermis can be seen in axial or coronal images. In some patients, the inferior lobules of the vermis appear to be hypoplastic, while in others, they appear to be intact. Remnants of the dysplastic upper vermis are rotated anterosuperiorly, compressed, and attached to the tentorium (see Image below).

Axial images alone may be misleading in revealing the upwardly rotated vermis.

Enlarged posterior fossa, cyst formation in the posterior fossa, anterolaterally winged cerebellar hemispheres (winged outward), absence of falx cerebelli, and scalloping of petrous pyramids are well demonstrated on T1-weighted images (see Images below).

Sagittal MRI can help evaluate an abnormally high position of the straight sinus, torcular herophili, tentorium, high tentorial insertion (lambdoid-torcular inversion), hypoplastic and compressed brainstem, and obstructive hydrocephalus secondary to cystic dilatation of the fourth ventricle in patients with Dandy-Walker malformation (see Images above).

CSF flow and cine MRI techniques are valuable imaging methods with which to demonstrate patency of CSF pathways at the level of the incisura or aqueduct of Sylvius. Shunting of the cyst alone in the presence of aqueductal obstruction may result in downward transincisural herniation of the cerebrum and atria of the lateral ventricles. On the contrary, shunting of the lateral ventricles alone when the aqueduct is obstructed may lead to an upward herniation of the posterior fossa cyst resulting in a characteristic snowman appearance in the sagittal plane in the absence of communication. Frequently the hydrocephalus in patients with Dandy-Walker is communicating in type with patency of the aqueduct.

Assessing the presence of associated supratentorial anomalies is important, since the prognosis for patients is much better in the absence of the anomalies (see Images below).

MRI affords an accurate and objective detailed identification of supratentorial anomalies. Recently, MRI (as well as US) has been used as a diagnostic tool during the antenatal period.

Degree of Confidence:

MRI is reliable and is the diagnostic method of choice in differentiating Dandy-Walker malformation from other posterior fossa pathologies.

False Positives/Negatives:

MRI findings in Dandy-Walker malformation may be confused with mega cisterna magna, arachnoid cyst, isolated fourth ventricle, and Joubert syndrome (see Images below).

Caption: Dandy-Walker malformation. Joubert syndrome in an 8-month-old boy. Axial CT scan obtained near the pontomesencephalic junction shows a batwing configuration of the fourth ventricle and unusual definition of the superior cerebellar peduncles at this level (arrows). Vermis is dysgenetic, and the 2 cerebellar hemispheres appose each other in the midline.

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Cadmium Poisoning

Cadmium Poisoning

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Category: Toxicity
Affected System: Multi system

Synonyms and Related Keywords

Cadmium Toxicity, Cadmium Intoxication

Introduction

Definition:

Cadmium has no constructive purpose in the human body. It and its compounds are extremely toxic even in low concentrations, and will bioaccumulate in organisms and ecosystems.

The itai-itai disease ("ouch-ouch disease") was caused by cadmium poisoning.

Diagnosis:

Cadmium poisoning is usually diagnosed by its symptoms, particularly if there is reason to believe that the patient has been exposed to cadmium. Because patients may not request treatment for up to a day following cadmium exposure, diagnosticians should carefully question any patient who shows symptoms consistent with this condition.

Signs and Symptoms:

Acute exposure to cadmium fumes may cause flu like symptoms including chills, fever, and muscle ache. Symptoms may resolve after a week if there is no respiratory damage. More severe exposures can cause tracheo-bronchitis, pneumonitis, and pulmonary edema. Symptoms of inflammation may start hours after the exposure and include cough, dryness and irritation of the nose and throat, headache, dizziness, weakness, fever, chills, and chest pain.

Inhaling cadmium-laden dust quickly leads to respiratory tract and kidney problems which can be fatal (often from renal failure). Ingestion of any significant amount of cadmium causes immediate poisoning and damage to the liver and the kidneys. Compounds containing cadmium are also carcinogenic.

The bones become soft (osteomalacia), lose bone mass and become weaker (osteoporosis). This causes the pain in the joints and the back, and also increases the risk of fractures. In extreme cases of cadmium poisoning, the mere body weight causes a fracture.

The kidneys lose their function to remove acids from the blood in proximal renal tubular dysfunction. The kidney damage inflicted by cadmium poisoning is irreversible and does not heal over time. The proximal renal tubular dysfunction creates low phosphate levels in the blood (hypophosphatemia), causing muscle weakness and sometimes coma. The dysfunction also causes gout, a form of arthritis due to the accumulation of uric acid crystals in the joints because of high acidity of the blood (hyperuricemia). Another side effect is increased levels of chloride in the blood (hyperchloremia). The kidneys can also shrink up to 30%.

Other patients lose their sense of smell (anosmia).

Pathogenesis:

In the 1950s and 1960s industrial exposure to cadmium was high. But as the toxic effects of cadmium became apparent, industrial limits on cadmium exposure have been reduced in most industrialized nations and many policy makers agree on the need to reduce exposure further. While working with cadmium it is important to do so under a fume hood to protect against dangerous fumes. Silver solder, for example, which contains cadmium, should be handled with care. Serious toxicity problems have resulted from long-term exposure to cadmium plating baths.

Buildup of cadmium levels in the water, air, and soil has been occurring particularly in industrial areas. Environmental exposure to cadmium has been particularly problematic in Japan where many people have consumed rice that was grown in cadmium contaminated irrigation water.

Food is another source of cadmium. Plants may only contain small or moderate amounts in non-industrial areas, but high levels may be found in the liver and kidneys of adult animals.

Cigarettes are also a significant source of cadmium exposure. Although there is generally less cadmium in tobacco than in food, the lungs absorb cadmium more efficiently than the gut. This goes for marijuana as well as tobacco.

Aside from tobacco smokers, people who live near hazardous waste sites or factories that release cadmium into the air have the potential for exposure to cadmium in air. However, numerous state and federal regulations in the United States control the amount of cadmium that can be released to the air from waste sites and incinerators so that properly regulated sites are not hazardous. The general population and people living near hazardous waste sites may be exposed to cadmium in contaminated food, dust, or water from unregulated releases or accidental releases. Numerous regulations and use of pollution controls are enforced to prevent such releases.

Workers can be exposed to cadmium in air from the smelting and refining of metals, or from the air in plants that make cadmium products such as batteries, coatings, or plastics. Workers can also be exposed when soldering or welding metal that contains cadmium. Approximately 512,000 workers in the United States are in environments each year where a cadmium exposure may occur. Regulations that set permissible levels of exposure, however, are enforced to protect workers and to make sure that levels of cadmium in the air are considerably below levels thought to result in harmful effects.

Some sources of phosphate in fertilizers contain Cadmium in amounts of up to 100 mg/kg, which can lead to an increase in the concentration of Cadmium in soil. (for example in New Zealand) Nickel-cadmium batteries are one of the most popular and most common cadmium-based products.

Pathophysiology:

The pathophysiology of the heavy metal toxidromes remains relatively constant. For the most part, heavy metals bind to oxygen, nitrogen, and sulfhydryl groups in proteins, resulting in alterations of enzymatic activity. This affinity of metal species for sulfhydryl groups serves a protective role in heavy metal homeostasis as well. Increased synthesis of metal binding proteins in response to elevated levels of a number of metals is the body´s primary defense against poisoning. For example, the metalloproteins are induced by many metals. These molecules are rich in thiol ligands, which allow high-affinity binding with cadmium, copper, silver, and zinc among other elements. Other proteins involved in both heavy metal transport and excretion through the formation of ligands are ferritin, transferrin, albumin, and hemoglobin.

Although ligand formation is the basis for much of the transport of heavy metals throughout the body, some metals may compete with ionized species such as calcium and zinc to move through membrane channels in the free ionic form.

The study of health effects of cadmium with respect to the cardiovascular system and calcium metabolism disproved the hypothesis that exposure to cadmium would lead to an increase in blood pressure and in the prevalence of hypertension and other cardiovascular diseases. On the other hand, there was a positive relationship between urinary cadmium (Cd-U) and both serum alkaline phosphatase activity and urinary excretion of calcium. The regression coefficients obtained after adjustment for significant co-variates indicated that, when Cd-U increased two-fold, serum alkaline phosphatase and urinary calcium rose by 4% and 0.25 mmol/24 h, respectively. These findings suggest that calcium metabolism is gradually affected as cadmium accumulates in the body. The morbidity associated with the latter phenomenon is still unknown, and requires further investigation, preferably in a longitudinal prospective population study, in which the incidence of morbid events would be monitored in relation to the cadmium body burden.

Cadmium derives its toxicological properties from its chemical similarity to zinc an essential micronutrient for plants, animals and humans. Cadmium is biopersistent and, once absorbed by an organism, remains resident for many years (over decades for humans) although it is eventually excreted.

In humans, long-term exposure is associated with renal disfunction. High exposure can lead to obstructive lung disease and has been linked to lung cancer, although data concerning the latter are difficult to interpret due to compounding factors. Cadmium may also produce bone defects (osteomalacia, osteoporosis) in humans and animals. In addition, the metal can be linked to increased blood pressure and effects on the myocardium in animals, although most human data do not support these findings.

The average daily intake for humans is estimated as 0.15µg from air and 1µg from water. Smoking a packet of 20 cigarettes can lead to the inhalation of around 2-4µg of cadmium, but levels may vary widely.

The organ systems affected and the severity of the toxicity vary with the particular heavy metal involved, the age of the individual, and the level of toxicity.

Also see Signs and Symptoms.

Toxico-Kinetics

Absorption

Approximately 2-7% of ingested cadmium is absorbed through the gastrointestinal tract, and its absorption is enhanced when the diet is deficient in calcium, iron, or protein (Lauwerys 1994). Absorption through the respiratory tract is more efficient, ranging from 15% to as much as 50% of an inhaled dose (Lauwerys 1994, Goyer 1996). Both these routes are potential sources of exposure in children.

Metabolism

Cadmium binds to red blood cells, plasma albumin, and metallothionein, which is synthesized in the liver and also by the placenta. Methallothionein may serve as a barrier to protect the fetus (Goyer 1996); however, in cases of excessive maternal exposure, it appears that some cadmium will cross the placenta (Frery 1993).

Cadmium is initially detoxified in the liver through the formation of a metallothionein-cadmium complex, which is slowly released from that organ. Although initially non-toxic, the cadmium-metallothionein complex can be nephrotoxic as it accumulates in the kidneys (Goyer 1996, Dorian 1995).

The average blood level of cadmium in adults without excessive or occupational exposure is about 1 mg/dL or less, as is the amount excreted in the urine in the adult population. Blood and/or urinary cadmium excretions exceeding 5 mg/dL generally indicate excessive exposure (Barnhart 1984). Human breast milk concentrations of cadmium are usually very low.

Frequency/Epidemiology:

Cases of severe acute cadmium poisoning are rare.

Mortality/Morbidity:

Heavy metal toxicities are relatively uncommon. However, failure to recognize and treat heavy metal toxicities can result in significant morbidity and mortality.

Race:

It affects all races.

Age:

Several points are of concern in heavy metal toxicity with respect to age. Generally, children are more susceptible to the toxic effects of the heavy metals and are more prone to accidental exposures. However, company workers, comprising of adults, are no exception.

Sex:

* Little or no difference in prevalence exists.

* Occupations with heavy metal exposure that predominantly involve a particular sex are associated with higher rates of exposure in that sex.

Clinical

History:

* A history of ingestion or exposure is the most critical aspect of diagnosing heavy metal toxicity. A complete history, including occupational, hobby, recreational, and environmental exposure is crucial in diagnosing heavy metal toxicity.

* Most acute presentations involve industrial exposure.

* A history of ingestion often leads to the diagnosis in children.

Physical Assessment:

- Metallic taste and increased salivation
- Irritation of respiratory and gastrointestinal tracts.
- Inhalation can cause respiratory toxicity after a latency period of several hours, including a mild, self-limited illness of fever, cough, malaise, headaches and abdominal pain, similar to metal fume fever.
- At higher doses, chemical pneumonitis may occur, with labored breathing, chest pain, and a sometimes fatal hemorrhagic pulmonary edema.
- Ingested cadmium causes nausea, vomiting, diarrhea, abdominal pain and tenesmus.

Chronic symptoms may include:

- Kidney damage (proteinuria and azotemia) anemia, liver injury (jaundice) and defective bond structure. Chronic obstructive pulmonary disease for those chronically exposed by inhalation.

Causes:

Bioaccumulation of Cadmium in the system.

Test/Studies

Lab Studies:

Three main tests are used for measuring cadmium exposures: cadmium in whole blood, cadmium in urine, and measurement of plasma proteins in urine. A number of other tests may be employed in investigating cadmium-related health effects.

A. Cadmium in Blood

Mainly because of ease of analysis, cadmium in whole blood has been used as a biological indicator of occupational exposures. Cadmium concentrations in blood are mainly a reflection of recent exposure. The ACGIH suggests that monitoring in blood is preferred during the initial year of exposure and whenever changes in the degree of exposure are suspected. In workers not currently exposed, cadmium in blood decreases substantially. When declining blood cadmium levels reach a steady state, they are considered to reflect body burden from previous exposures.

Normal values of cadmium in blood of non-smokers are generally less than 1 ug/l. Higher average values of 1.4 to 4.2 ug/l are found in smokers, though individual blood cadmium levels in smokers may exceed these values.

In 1991, the Ontario Ministry of Labour suggested medical assessment for exposed workers whose blood cadmium level reaches 11 ug/l. However, OSHA recently chose 5 ug Cd/l of whole blood as a level at which further medical surveillance is required of American workers. If this level of cadmium in blood is accompanied by protein in the urine, then OSHA requires workers to be medically removed. A level of 15 ug Cd/l is cause for removal without proteinuria. The ACGIH has also recently proposed a Biological Exposure Index of 5 ug/l of cadmium in blood. The BEI "is intended to prevent the potential for increased urinary excretion of markers of renal dysfunction in almost all workers".

B. Cadmium in Urine

Cadmium concentration in urine is considered to be more reflective of body burden in currently-exposed workers than cadmium in blood, and is the most widely used biological measure of chronic exposure to cadmium. Cadmium in urine increases with age, cigarette smoking, and exposures in the general and occupational environments.

The normal concentration of cadmium in urine is from 0.1 to 1 ug/g creatinine. Until recently, a measure of 10 ug Cd/g creatinine has been regarded as a threshold for kidney effects. However, a number of recent studies have cast doubt on this figure. Evidence of subtle kidney effects are demonstrated at levels a low as 2 ug Cd/g creatinine. Levels of 5 to 1ug Cd/g creatinine are associated with a 10% risk of increased excretion of enzymes and proteins. OSHA recently chose a level of 3 ug Cd/g creatinine as a trigger for enhancing medical surveillance of cadmium. If this level of cadmium in urine is accompanied by proteinuria, then OSHA requires medical removal of the affected worker. A level of 15 ug/g creatinine is cause for removal without proteinuria. The ACGIH has recommended a new Biological Exposure Index (BEI) of 5 ug/g creatinine for cadmium in urine.

C. Markers of early Renal Effects from Cadmium Exposure

While not a measure of cadmium exposure per se, the increase of proteins in urine is a marker of damage to the kidneys which precedes or accompanies most health effects associated with cadmium exposure. One particular protein -- beta2-microglobulin (BMG) -- has been extensively used as an indicator of cadmium-related damage to the proximal tubules of the kidney. BMG excretion may be elevated due to other causes: anti-cancer drugs, antibacterial antibiotics such as streptomycin, anti-inflammatory compounds, myeloma, flu and upper respiratory tract infections. These factors can be readily identified, and need not confound the diagnosis of cadmium-related proteinuria.

Levels of BMG are considered elevated by most investigators at 300 ug/g creatinine, although levels as low as 200 or as high as 500 ug/g creatinine have been suggested as abnormal. OSHA mandates a removal level of 1500 ug BMG/g creatinine, if cadmium levels in blood or urine are elevated.

Exposures to cadmium for 20 years at a level 50 ug/m³ (0.05 mg/m³), the current Ontario limit, give rise to a greatly increased incidence of tubular proteinuria as indicated by output of BMG.

In recent years, a number of other markers for cadmium effects have been recommended. Several of these markers appear to be more sensitive to the early effects of cadmium on the kidney, and/or more stable than BMG in urine. The following markers have been assessed and shown to have significant association with cadmium exposure:

- retinol-binding protein (RBP) in urine;
- albumin in urine;
- N-acetyl-D-glucosaminidase (NAG) in urine;
- metallothionein (MT) in urine;
- urinary transferrin;
- most tubular antigens.

Conventional indicators of renal function such as total urinary protein, serum urea, and serum creatinine are considered insensitive indicators of early renal dysfunction, but may indicate the progression of cadmium-related damage.

Other Tests:

Direct Measurement of Cadmium Concentration in Liver and Kidney

Neutron activation analysis is a new method which allows for the direct measurement of the cadmium burden in the liver and kidney. The technique involves use of an ultrasonic scan to precisely locate the target organs, followed by irradiation with a neutron beam which allows assessment of organ burden by measurement of cadmium-specific gamma rays. The radiation dosage is less than most conventional x-rays.

For workers who have been out of exposure for some time or who have suffered kidney damage, this technique can provide a more accurate measure of body burden and may help in determining if non-specific diseases such as emphysema are cadmium-related. This equipment has been employed in England to resolve compensation disputes. Only one Canadian facility is currently equipped to carry out this kind of analysis -- at McMaster University in Hamilton.

Estimation of liver burden is considered more appropriate because once renal damage occurs, cadmium excretion increases and the kidneys lose their cadmium burden. Liver and kidney burdens increase until a 40 ppm concentration is reached in the liver, after which kidney levels decrease while liver burden continues to rise. One study measured a mean liver cadmium burden of 0.6 ppm in non-exposed controls.

X-ray fluorescence, another technique for in vivo measurement of cadmium body burden, has also been developed recently, but is not generally available at this time.

Cadmium Exposure Limits:

Exposure limits for cadmium and its compounds have declined steadily over time, as the knowledge about cadmium-related diseases has grown. The current Ontario time-weighted average limit of 0.05 mg/m³ is considered too high by many scientists. Ontario is currently considering a new limit of 0.02 mg/m³, to match the lower Dutch limit. The Dutch Working Group of Experts which reviewed cadmium's toxicity in 1980, actually proposed a health-based limit of 0.01 mg/m³. However, this limit was not considered feasible at the time. The cadmium limit is again under review in the Netherlands.

In Sweden, a limit of 0.01 mg/m³ is in effect for all new industries employing cadmium or its compounds.

In 1990, the American Conference of Governmental Industrial Hygienists (ACGIH), an influential body which produces a list of Threshold Limit Values adopted by many governments as enforceable occupational exposure limits, proposed a new total dust limit of 0.01 mg/m³ for cadmium, and a 0.002 mg/m³ respirable dust limit.

In 1992, after an exhaustive review of occupational exposures, toxicity and feasibility issues, the U.S. Occupational Safety and Health Administration adopted a new cadmium limit of 0.005 mg/m³, one-tenth of the current Ontario limit, in order to prevent kidney effects and cancer in exposed workers.

In 1991 and 1992, a lively debate occurred in the scientific literature on the question of a protective occupational exposure limit. Proposed protective limits varied from a low of 0.001 mg/m³ through 0.01 mg/m³. One author suggested a limit in the range of 0.01 - 0.1 mg/m³might be protective, but put some emphasis on 0.02 mg/m³. Although there is no consensus on the level of a protective limit, there is considerable agreement in the scientific community that a limit of 0.05 mg/m³ does not provide sufficient protection, and that kidney effects occur at this level of exposure.

Treatment/Management

Independent Interventions/First Aid:

Route of Exposure	Symptoms	First Aid
NOTE! PREVENT DISPERSION OF DUST! STRICT HYGIENE!		General First Aid: IN ALL CASES CONSULT A DOCTOR!
Inhalation	Cough. Headache. Symptoms may be delayed (see Notes).	Fresh air rest. Half-upright position. Artificial respiration if indicated. Refer for medical attention.
Skin		Remove contaminated clothes. Rinse and then wash skin with water and soap.
Eyes	Redness. Pain.	First rinse with plenty of water for several minutes (remove contact lenses if easily possible) then take to a doctor.
Ingestion	Abdominal pain. Diarrhoea. Headache. Nausea. Vomiting.	Rest. Refer for medical attention.
Notes for ICSC Information
Reacts violently with fire extinguishing agents such as water foam carbon dioxide and halons. Depending on the degree of exposure periodic medical examination is indicated. The symptoms of lung edema often do not become manifest until a few hours have passed and they are aggravated by physical effort. Rest and medical observation are therefore essential. Do NOT take working clothes home.

Consultations:

If intentional ingestion or overdose is suspected, place patient in closely a monitored unit and consult a medical toxicologist and psychiatrist.

* Contact a certified poison control center or medical toxicologist.

* Consult a gastroenterologist if the possibility of corrosive GI effects is present.

Diet:

Eat a balanced diet that provides enough calcium, iron, protein, and zinc.

Medication:

No treatment has been proven effective for cadmium poisoning.

Follow Up Treatment/Management

Further inpatient care:

Encourage patient to eat foods rich in calcium, iron, protein, and zinc.

Further outpatient care:

* Care must be taken to remove the source of heavy metal contamination.

* Report industrial-related toxicities to OSHA or; report childhood cases to the local health department.

Deterrence/Prevention:

· Avoid Smoking.

· Avoid hazardous areas or hazardous work such as welding.

Complications:

Complications include pneumonitis and pulmonary edema. Chronic exposure may cause anemia, emphysema or renal failure, and cadmium may be a risk factor in the development of prostate or lung cancer.

Prognosis:

The prognosis depends on the nature and severity of the cadmium load. Most cases of mild exposure resolve spontaneously after a few days. In other cases, cadmium can lead to permanent damage with shortened lifespan, or even death.

Cadmium may be carcinogenic.

Long-term exposure may also result in bone defects including osteoporosis.

Patient Education:

Teach the patient on how to prevent cadmium poisoning.

Miscellaneous

Medical/Legal Pitfalls:

· Failure to report such toxicity to the local health authorities.

References

NCBI
Healthatoz.com
eMedicine
Pesticideinfo.org
Canoshweb.org

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2007-05-04T14:43:00.001-07:00

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B

Babesiasis (see Babesiosis)
Babesiosis

Babesiosis

2007-05-04T13:46:00.000-07:00

Category: Vector-borne disease
Affected System: Circulatory System

Synonyms and related keywords:

Babesia species, Ixodes tick, parasitic infection, intraerythrocytic parasitic infection, tick bite, babesiosis, hemolytic anemia, thrombocytopenia, atypical lymphocyte formation, acute respiratory distress syndrome, ARDS

Introduction

Definition:

Babesiosis is an intraerythrocytic parasitic infection caused by protozoa of the genus Babesia and transmitted through the bite of the Ixodes tick. The disease most severely affects patients who are elderly, immunocompromised, or have undergone splenectomy. In the United States, Babesiosis is usually an asymptomatic infection in healthy individuals.

Causative Agent:

Babesiosis is caused by hemoprotozoan parasites of the genus Babesia. While more than 100 species have been reported, only a few have been identified as causing human infections. Babesia microti and Babesia divergens have been identified in most human cases, but variants (considered different species) have been recently identified.

Mode of Transmission:

Vector-borne.

Vector:

Ixodid ticks, in particular Ixodes dammini (Ixodes scapularis) and Ixodes ricinus.

Incubation Period:

5-33 days.

Signs and Symptoms:

The disease is a malaria-like syndrome characterized by fever, fatigue, and hemolytic anemia lasting from several days to a few months. Clinically, babesiosis may vary widely -- from asymptomatic infection to a severe, rapidly fatal disease. The first demonstrated case of human babesiosis in the world was reported in Europe in 1957. Since then, there have been at least 28 additional cases in Europe. Most European cases occurred in asplenic individuals; were severe, febrile, and fulminant; and were caused by B divergens, a cattle parasite. In the United States, there have been hundreds of cases of babesiosis (and, in contrast, mostly in people with intact spleens) caused by B microti, mainly from southern New England, and specifically from Nantucket, Martha's Vineyard, Shelter Island, Long Island, and Connecticut.

Differential Diagnosis:

Anemia, Acute
Bites, Insects
Malaria
Tick-Borne Diseases, Colorado
Tick-Borne Diseases, Ehrlichiosis
Tick-Borne Diseases, Introduction
Tick-Borne Diseases, Lyme
Tick-Borne Diseases, Q Fever
Tick-Borne Diseases, Relapsing Fever
Tick-Borne Diseases, Tularemia

Diagnosis:

Mild to severe hemolytic anemia and a normal to slightly depressed leukocyte count are common nonspecific findings in babesiosis. Usually, the diagnosis is based on typical morphologic picture on the blood smear in conjunction with epidemiologic information. A Wright- or Giemsa-stained peripheral blood smear is most commonly used to demonstrate the presence of intraerythrocytic parasites. Rarely, tetrads of merozoites are visible.

The organisms are intraerythrocytic ring forms closely resembling Plasmodium, the organism causing malaria. Three distinguishing features differentiate the two organisms. Babesial organisms usually form tetrads ("Maltese cross"), do not have hemozoin pigments within the affected red blood cells and have extracellular merozoites.

Serologic evaluation with the indirect immunofluorescent antibody test with use of B. microti antigen is available in a few laboratories. The cutoff titer for determination of a positive result varies with the particular laboratory protocol used, but in most laboratories, titers of more than 1:64 are considered consistent with B. microti infection. Tenfold to 20-fold higher titers can be observed in the acute setting, with a gradual decline over weeks to months. The correlation between the level of the titer and the severity of symptoms is poor.

Detection of B. microti by polymerase chain reaction (PCR) was first described in 1992.A more recent study, in which PCR was used prospectively for diagnosing suspected cases in the northeastern United States has shown that PCR is more sensitive and equally specific for the diagnosis of acute cases, in comparison with direct smear examination and hamster inoculation. PCR-based methods may also be indicated for monitoring of the infection.

Pathogenesis:

Of the more than 100 species of Babesia, Babesia microti (in the United States) and Babesia divergens and Babesia bovis (in Europe) cause most infections in humans. B. microti also infects various small mammals and primates, while B. divergens has been found to infect rats and gerbils as well as its main bovine host. Recently, a previously unknown species of Babesia (WA-1) was isolated from an immunocompetent man in Washington state who had clinical babesiosis. Researchers also described another probable new babesial species (MO1) associated with the first reported case of babesiosis acquired in the state of Missouri. MO1 is probably distinct from B. divergens but the two share morphologic, antigenic and genetic characteristics.

Ixodid (or hard-bodied) ticks, in particular Ixodes dammini (Ixodes scapularis) and Ixodes ricinus, are the vectors of the parasite. Ticks ingest Babesia while feeding off the host, and the parasite multiplies within the tick's gut wall. The parasites then spread to the tick's salivary glands. Inoculation into a vertebrate host occurs by a tick larva, nymph or adult. Infection in humans usually occurs from late spring to early fall.

After an infectious tick bite, the parasites invade red blood cells and a trophozoite differentiates, replicating asexually by budding with the formation of two to four merozoites. A second type of undifferentiated trophozoite is also formed that does not replicate but enlarges and differentiates into gametocyte-like forms similar to that seen in Plasmodium species. Merozoites eventually disrupt infected erythrocytes and reinvade other red blood cells.

Pathophysiology:

The parasite only infects red blood cells (RBCs). This significantly affects the hematological system, causing hemolytic anemia, thrombocytopenia, and atypical lymphocyte formation. Alterations in RBC membranes cause decreased conformability and increased red cell adherence, which can lead to development of acute respiratory distress syndrome (ARDS) among those severely affected.

Babesia parasites reproduce in red blood cells, where they can be seen as cross-shaped inclusions (4 merozoites asexually budding but attached together forming a structure looking like a "Maltese Cross") and cause hemolytic anemia, quite similar to malaria.

Note that unlike the Plasmodium parasites that cause malaria, Babesia species lack an exo-erythrotic phase, so the liver is usually not affected.

Frequency:

In the US: Babesiosis is limited to those who live in, or have recently traveled to, the northeastern United States. Few cases have been reported in California, Washington, Wisconsin, and Georgia. Hundreds of cases have been reported since the first domestic case of human babesiosis was reported in 1966. An increasing trend over the past 30 years may be the result of restocking of the deer population, curtailment of hunting, and an increase in outdoor recreational activities. Although the most life-threatening cases occur in patients who are elderly, immunocompromised, HIV infected, or have undergone splenectomy, most patients with babesiosis are asymptomatic, which may result in underreporting of the disease across all age groups.

Internationally: Babesiosis in Europe, caused by a different species of Babesia, is a more devastating disease. Although rare, it is symptomatic and often fatal. Like its US counterpart, babesiosis in Europe is also seen in patients who have undergone splenectomy. Anecdotal reports of babesiosis in China, Mexico, South Africa, and Egypt have been documented.

Epidemiology:

Babesiosis is a vector-borne illness usually transmitted by ticks. (Babesia microti uses the same tick vector, Ixodes scapularis, as Lyme disease does.) In babesia-endemic areas, the organism can also be transmitted by blood transfusion.

Infection with Babesia parasites can be asymptomatic or cause a mild non-specific illness, and therefore many cases go unnoticed. Most diagnosed cases occur in the very young, very old, or persons with underlying medical conditions (such as immunodeficiency). Some cases are identified when patients with another tick-borne illness are screened for babesiosis.

Little is known about the occurrence of Babesia species in malaria-endemic areas, where Babesia can easily be misdiagnosed as Plasmodium.

Mortality/Morbidity:

The US mortality rate is low.

· Most cases are asymptomatic and improve spontaneously without treatment.

· Approximately 25% of patients with babesiosis are co-infected with Lyme disease. These patients experience more severe symptoms for a longer duration than those with either disease alone.

In Europe, babesiosis is a life-threatening disease.

· Of patients with babesiosis, 84% are asplenic, and 53% become comatose and die.

· Of those rare reported cases of subclinical infection, all patients were infected by the same Babesia species that affects patients in the northeastern United States.

Race:

All races.

Age:

Babesiosis affects all age groups with similar frequency; however, patients older than 50 years are at increased risk for severe infection and death.

· No difference in seropositivity exists among age groups.

· Adequate reporting is a major problem, especially in children, because of masking by other infections and the disease's history of occurrence in elderly patients.

Sex:

The male-to-female ratio is about 1:1.

Clinical

History:

Patients report a history of travel to an endemic area between the months of May and September. This is the period during which the Ixodes tick is in its infectious nymph stage; however, most do not recall being bitten by a tick. Incubation period is from 1-4 weeks.

Symptoms:

o Fatigue

o Anorexia

o Arthralgia and myalgia

o Depression

o Dark urine

o Nausea and vomiting

o Cough

o Dyspnea

Physical Assessment:

o Fever

o Shaking chills

o Hepatosplenomegaly

o Jaundice

o Myalgia

o Malaise

Causes:

The causative agent of babesiosis varies according to geographical region.

· In the northeastern United States, infections are caused by Babesia microti, transmitted by the same Ixodes tick that transmits Lyme disease.

· In California and Washington, WA-1, which is similar to Babesia gibsoni, is the causative agent. The arthropod vector has yet to be identified.

· In Europe, the Ixodes tick transmits the infectious agent, Babesia divergens.

· Occasionally, cases of infection via blood transfusion from a donor who lived in or traveled to an endemic area are reported.

Tests/Studies

Lab Studies:

· In individuals who are asymptomatic, lab studies may be unremarkable.

· Giemsa-stained peripheral blood smear

- This test reveals intraerythrocytic parasites (ie, ring forms, no pigment, pathognomonic tetrads [Maltese cross]).

- Smear may be negative in individuals with asymptomatic infection.

- Level of parasitemia does not correspond to severity of disease, although patients who are mildly ill may have less than 1% parasitemia and patients who are severely ill may have greater than 85%. This high level of parasitemia is especially seen in asplenic patients.

· Complete blood count (CBC) with differential indicates hemolytic anemia, thrombocytopenia, atypical lymphocytes, and leukopenia.

· Liver function tests often reveal mildly elevated hepatic transaminases, elevated erythrocyte sedimentation rate (ESR), lactic dehydrogenase (LDH), and serum bilirubin.

· Urinalysis: Hemoglobinuria, proteinuria, and a dark color may be present.

· Direct Coombs test may or may not be positive.

· Pulse oximetry: Hypoxia may be present in patients with severe disease.

Imaging Studies:

· Chest x-ray may be indicated for patients with respiratory complications including pneumonia or ARDS.

Other Tests:

· Immunofluorescence antibody testing

- Use this test to confirm diagnosis when peripheral blood smear is negative.

- Titer of greater than 1:64 is positive.

- A 4-fold rise in titer or a single titer greater than 1:256 is suggestive of acute infection.

- Differentiation of acute and chronic infection may be difficult because titers may increase to very high levels then decrease slowly. This is especially true in endemic areas such as the Northeastern US.

· Enzyme-linked immunosorbent assay (ELISA) immunoglobulin M (IgM) Lyme titer

- This test is used because of the high percentage (25%) of patients co-infected with Lyme disease.

- Co-infection increases the severity of disease; therefore, it is important to diagnose and treat both infections.

· Polymerase chain reaction (PCR) is a highly specific test that can be used to confirm diagnosis.

· Inoculation of a golden hamster with the patient's blood and subsequent antibody analysis of the animal's blood is used to confirm diagnosis when peripheral blood smear and lab tests are equivocal.

· Immunoblot antibody test

- Babesial infection causes a significant antibody response even at low levels of parasitemia.

- The assay is specific for anti–B microti antibodies when at least 2 or more bands on the assay are positive.

- This test has similar sensitivity and specificity for diagnosing babesiosis as that of IFA.

- Potential advantages over IFA include the lack of need for concentrated serum samples and ease of use, as immunoblot assays can be performed by generalist technicians versus trained microscopists.

Procedures:

· Because of the possibility of hemophagocytic syndrome, bone marrow biopsy is indicated in patients whose lab studies reveal pancytopenia and whose physical examination reveals lymphadenopathy.

Treatment/Management

Emergency Department Care:

· Suspicion of babesiosis in a patient with a history of tick bite, fever, chills, and fatigue is crucial.

· Peripheral blood smear or immunologic testing as described is needed to make the diagnosis.

· CBC with differential is important to determine the severity of infection.

· Immediately start patients who are elderly, immunocompromised, or asplenic on a treatment regimen of clindamycin IV and quinine PO or atovaquone IV and azithromycin IV to avoid acute renal failure.

· If the patient is otherwise healthy, supportive care is the only treatment required.

· Intubation and mechanical ventilation may be required for patients who develop respiratory distress or failure.

Consultations:

Consult infectious disease and internal medicine services if admission is indicated.

Medication

Antibiotic and antimalarial therapy should begin immediately after diagnosis to reduce the level of parasitemia. Treatment has historically been with clindamycin and quinine, but a promising first-line alternative may be atovaquone and azithromycin. Patients may have less side effects with the latter combination including decrease tinnitus, vertigo, and gastrointestinal upset. Parasitemia may persist despite treatment with either of the described drug regimens.

Drug Category: Antibiotics -- Therapy should cover all likely pathogens in the context of this clinical setting.

Drug Name	Clindamycin (Cleocin) -- Inhibits bacterial growth, possibly by blocking dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest.
Adult Dose	300-600 mg IV tid for 7 d
Pediatric Dose	20-40 mg/kg/d PO tid for 7 d
Contraindications	Documented hypersensitivity; regional enteritis, ulcerative colitis, hepatic impairment, antibiotic-associated colitis
Interactions	Increases duration of neuromuscular blockade induced by tubocurarine and pancuronium; erythromycin may antagonize effects of clindamycin; antidiarrheals may delay absorption of clindamycin
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adjust dose in severe hepatic dysfunction; no adjustment necessary in renal insufficiency; associated with severe and possibly fatal colitis

Drug Name	Azithromycin (Zithromax) -- Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Treats mild-to-moderate microbial infections. Administer in combination with atovaquone.
Adult Dose	Day 1: 500 mg PO Days 2-7: 250 mg PO
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; hepatic impairment; do not administer with pimozide
Interactions	May increase toxicity of theophylline, warfarin, and digoxin; effects are reduced with coadministration of aluminum and/or magnesium antacids; nephrotoxicity and neurotoxicity may occur when coadministered with cyclosporine
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Site reactions can occur with IV route; bacterial or fungal overgrowth may result from prolonged antibiotic use; may increase hepatic enzymes and cholestatic jaundice; caution in patients with impaired hepatic function, prolonged QT intervals, or pneumonia; caution in hospitalized patients, geriatric patients, or debilitated patients

Drug Category: Antiprotozoals -- May contribute to the eradication of the parasite.

Drug Name	Atovaquone (Mepron) -- May inhibit metabolic enzymes, which in turn inhibits growth of microorganisms. Administer in combination with azithromycin.
Adult Dose	750 mg PO q12h for 7 d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	May increase zidovudine serum levels; coadministration with rifampin or rifabutin may decrease atovaquone levels; atovaquone may decrease levels of TMP-SMZ
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in elderly and in hepatic and renal impairment

Drug Category: Anti-malarials -- These agents are effective in eradicating the parasite.

Drug Name	Quinine sulfate (Formula Q) -- Inhibits growth of parasite by increasing the pH within intracellular organelles and possibly by intercalating into DNA of the parasites.
Adult Dose	650 mg PO tid for 7 d
Pediatric Dose	10-25 mg/kg/d PO for 7 d
Contraindications	Documented hypersensitivity; optic neuritis, tinnitus, G-6-PD deficiency, or history of black water fever
Interactions	Aluminum-containing antacids may delay or decrease quinine bioavailability when administered concurrently; cimetidine increases quinine blood levels and creates the potential for toxicity; rifamycins decrease quinine concentrations by increasing hepatic clearance of quinine (effect can persist for several days after discontinuing rifamycins); concurrent administration of acetazolamide or sodium bicarbonate may increase toxicity by increasing quinine blood levels; quinine may enhance action of warfarin and other oral anticoagulants by decreasing synthesis of vitamin K–dependent clotting factors; digoxin serum concentrations may increase when digoxin administered concurrently with quinine; important to monitor digoxin levels periodically; quinidine may decrease plasma cholinesterase activity, causing a decrease in the metabolism of succinylcholine
Pregnancy	X - Contraindicated in pregnancy
Precautions	Caution in G-6-PD deficiency and tendency to develop granulocytopenia; prolonged treatment or overdosing with quinine may cause cinchonism; quinine has quinidine-like activity and thus can cause cardiac arrhythmias

Follow Up Treatment/Management

Further Inpatient Care:

* Monitor level of oxygenation and watch for development of respiratory complications that present with dyspnea after initiation of treatment.

* Chronology of respiratory distress may be due to endotoxin sensitivity; endotoxin release results from the medication-induced intraerythrocytic death of the parasites.

* In severe cases, exchange transfusion may be the only means of reducing the level of parasitemia. Mechanical ventilation may be necessary should the patient continue to deteriorate.

* Monitor CBC for development of hemophagocytic syndrome. Examine lab results for pancytopenia and examine patient for lymphadenopathy.

* If the patient does not respond to or can not tolerate treatment with clindamycin and quinine, commence alternative treatment with atovaquone and azithromycin.

Deterrence/Prevention:

* Exposure to endemic areas

o Those at risk of severe infection should avoid endemic areas between the months of May and September.

o Cover skin with appropriate clothing, including tucking long pants inside socks.

o Examine skin and pets every day (takes 24 h for infection to be transmitted).

o Wear tick repellent, such as diethyltoluamide and dimethyl phthalate, on skin and clothes.

o People from endemic areas who report a fever within the last 2 months or a history of tick bite are not allowed to donate blood.

Complications:

* Respiratory problems

o Patients who have undergone splenectomy are unable to clear infected RBCs to reduce the level of parasitemia, leading to hypoxemia and subsequent risk of cardiopulmonary arrest.

o In severe cases, damage to RBC membranes, decreased deformability, and cytoadherence to capillaries and venules lead to pulmonary edema and respiratory failure.

o These respiratory problems begin after treatment has been initiated when intraerythrocytic death of parasites has been postulated to cause sensitivity to endotoxin.

o Noncardiogenic pulmonary edema

o ARDS is possibly due to mechanisms such as endotoxemia, complement activation, immune complex deposition, cytoadherence, microemboli, and disseminated intravascular coagulation.

* Relapses

* Postsplenectomy patients may develop hemophagocytic syndrome, acute renal failure, and generalized seizure.

* Coma can occur, possibly due to severe sepsis, ARDS, or multisystem organ failure.

* Co-infection with Lyme disease

Prognosis:

* In the United States, prognosis is excellent; most patients recover spontaneously. Patients who have had their spleen removed are at the greatest risk for severe complications and death.

* In Europe, most symptomatic patients are asplenic, which contributes to a poor prognosis. Over 50% become comatose and die.

Patient Education:

Early removal of ticks is important; the tick must remain attached for at least 24 hours before the transmission of B. microti occurs. Therefore, daily self-examination is recommended for persons who engage in outdoor activities in endemic areas. Pets also must be examined for ticks because they may carry ticks into the home.

Miscellaneous

Medical/Legal Pitfalls:

* Failure to consider diagnosis in children

* Failure to initiate immediate therapy in individuals considered at high risk (ie, asplenic, elderly, immunocompromised)

* Administration of quinine therapy to a patient who is pregnant

Special Concerns:

* Pregnancy

o Do not give quinine to a patient who is pregnant.

o If the infection is subclinical, no drug therapy is needed.

o Combination therapy with clindamycin and quinine or atovaquone and azithromycin is more effective than either atovaquone and azithromycin alone.

* Geriatric patients: Initiate therapy with clindamycin and quinine immediately.

References

eMedicine
Wikipedia
aafp.org

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2007-05-04T13:25:00.000-07:00

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T

Tangier Disease
Tangier Disease Neuropathy (see Tangier Disease)
Tay-Sachs Disease
Tay-Sachs Disease, B Variant (see Tay-Sachs Disease)

Medical Surgical Journal

2007-05-03T13:47:00.000-07:00

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List of Diseases and Disorders

2007-05-03T12:12:00.000-07:00

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A

A-alphalipoprotein Neuropathy (see Tangier Disease)

A-alphalipoprotein Neuropathy

2007-05-03T11:11:00.000-07:00

Category: Disorder
Affected System: Circulatory System

Synonyms and Related Keywords:

alpha High Density Lipoprotein Deficiency Disease, Analphalipoproteinemia, Cholesterol thesaurismosis, Familial High Density Lipoprotein Deficiency Disease, Familial Hypoalphalipoproteinemia, HDL Lipoprotein Deficiency Disease, Lipoprotein Deficiency Disease, Tangier Disease Neuropathy, Familial HDL, Tangier Disease

Introduction

Definition:

A-alphalipoprotein Neuropathy or Tangier disease (TD) is a genetic disorder of cholesterol transport named for the secluded island of Tangier, located off the coast of Virginia. TD was first identified in a five-year-old inhabitant of the island who had characteristic orange tonsils, very low levels of high density lipoprotein (HDL) or 'good cholesterol', and an enlarged liver and spleen.

TD is caused by mutations in the ABCA1 (ATP-binding cassette) gene on chromosome 9q31. ABCA1 codes for a protein that helps rid cells of excess cholesterol. This cholesterol is then picked up by HDL particles in the blood and carried to the liver, which processes the cholesterol to be reused in cells throughout the body. Individuals with TD are unable to eliminate cholesterol from cells, leading to its buildup in the tonsils and other organs.The discovery of this important cholesterol transport gene may lead to a better understanding of the inverse relationship between HDL levels and coronary artery disease, an important killer in the US. New drugs that regulate HDL levels may be developed and such drugs would not only help individuals with TD, but also people with more common disorders such as familial HDL deficiency. This is a good illustration of how research into rare diseases can sometimes help more common disorders.

Differential Diagnosis:

ApoA-I deficiency; ApoA-I/C-III deficiency; ApoA-I/C-III/A-IV deficiency; Familial lecithin:cholesteryl acyltransferase deficiency; Fish eye disease; Obstructive liver disease; Hepatic parenchymal diseases or tumors; Gaucher disease; Niemann-Pick, type C; Wolman disease; Acquired HDL deficiency states.

Diagnosis:

In patients with unexplained hepatic or splenic enlargement, neuropathy, or corneal deposits, examination of the oropharynx and quantification of plasma total cholesterol, HDL-C, low-density lipoprotein cholesterol (LDL-C), and triglycerides are indicated. TD homozygotes have plasma levels of HDL-C and LDL-C that are typically <5%>ABCA1 gene through sequence analysis.

Signs and Symptoms:

People affected by this condition have slightly elevated amounts of fat in the blood (mild hypertriglyceridemia) and disturbances in nerve function (neuropathy). The tonsils are visibly affected by this disorder; they frequently appear orange or yellow and are extremely enlarged. Affected people often develop premature atherosclerosis, which is characterized by fatty deposits and scar-like tissue lining the arteries. Other signs of this condition may include an enlarged spleen (splenomegaly), an enlarged liver (hepatomegaly), clouding of the clear covering of the eye (cornea), and early-onset cardiovascular disease.

Inheritance:

This condition is inherited in an autosomal recessive pattern, which means two copies of the gene in each cell are altered. Most often, the parents of an individual with an autosomal recessive disorder are carriers of one copy of the altered gene but do not show signs and symptoms of the disorder.

Pathogenesis/Pathophysiology:

The ABC1 transporter was identified as the defect in Tangier disease by a combined strategy of gene expression microarray analysis, genetic mapping, and biochemical studies. Patients with Tangier disease have a defect in cellular cholesterol removal, which results in near zero plasma levels of HDL and in massive tissue deposition of cholesteryl esters. Blocking the expression or activity of ABC1 reduces apolipoprotein-mediated lipid efflux from cultured cells, and increasing expression of ABC1 enhances it. ABC1 expression is induced by cholesterol loading and cAMP treatment and is reduced upon subsequent cholesterol removal by apolipoproteins. The protein is incorporated into the plasma membrane in proportion to its level of expression. Different mutations were detected in the ABCA1 gene of 3 unrelated patients. Thus, ABC1 has the properties of a key protein in the cellular lipid removal pathway, as emphasized by the consequences of its defect in patients with Tangier disease.

Frequency/Epidemiology:

Tangier disease is a rare disorder with approximately 50 cases identified worldwide. This disorder was originally discovered on Tangier Island off the coast of Virginia, but has now been identified in people from many different countries.

Mortality/Morbidity:

Tangier disease is rare. Most patients died of the complication rather than of the disease itself.

Race:

Fewer than 100 cases of TD have been reported but exists in many different ethnic groups.

Age:

Age at diagnosis varied from 2 years to 67 years.

Sex:

Both genders.

Clinical

History:

The classic clinical signs of TD are hyperplastic orange-yellow tonsils, splenomegaly, and relapsing peripheral neuropathy, each resulting from cholesteryl ester deposition. A severely reduced HDL-C level in combination with hyperplastic orange-yellow tonsils is virtually pathognomonic for TD. Aside from these findings, the clinical expression of TD is variable, with some patients presenting with hepatomegaly, abnormal rectal mucosa, corneal opacities, anemia, lymphadenopathy, thrombocytopenia, and/or premature coronary heart disease.

Physical Assessment:

· Usually with extremely enlarged orange-yellow tonsils.

· Clouding of the clear covering of the eye (cornea)

· Peripheral neuropathy

· Discoloration of the rectal mucosa

Causes:

Massive tissue deposition of cholesteryl esters. See Pathogenesis/Pathophysiology.

Test/Studies

Lab Studies/Procedure:

A needle will be used to take a sample of blood from a vein, usually from the inside of the elbow or the back of the hand.

First, the area will be cleaned with a germ-killing product (antiseptic). An elastic band is placed around your upper arm to help the vein swell with blood, and the needle is inserted.

The needle is attached to an air-tight tube or syringe, which is used to collect the blood. During the procedure, the band is removed to restore circulation. Once the blood has been collected, the needle is removed, and the needle stick area is covered with a small bandage to stop any bleeding.

Preparations for the test:
Do not eat anything for 9 - 12 hours before the test.

Normal Values:
The normal value ranges may vary slightly among different laboratories.

In general, your risk for heart disease, including a heart attack, increases if your HDL cholesterol level is less than 40 mg/dL. More specifically, men are at particular risk if their HDL is below 37 mg/dL, and women are at particular risk if their HDL if their HDL is below 47 mg/dL.

An HDL 60 mg/dL or above helps protect against heart disease.

Women tend to have higher HDL cholesterol than men.

Treatment/Management

Independent Interventions:

Genetic Counseling

Medical Care:

No clear guidelines exist for treatment. Attempts to significantly raise plasma HDL-C levels have been unsuccessful. Other coronary disease risk factors should be treated, especially in patients with established coronary heart disease.

Consultation:

Individuals with severely reduced HDL levels (<20 mg/dL) may have a specific genetic etiology, such as LCAT deficiency, Tangier disease, or mutations in apo A-I. Ironically, these disorders are not commonly associated with an increased risk of atherosclerosis. Refer patients who may possibly have one of these diagnoses to a specialized lipid center for advanced management. Consultation with the following specialists may be required:

· Lipidologist

· Endocrinologist

· Cardiologist

· Vascular specialist

· Cardiovascular surgeon

· Dietitian

Diet:

Very low-fat diets are associated with low HDL-C levels. However, because no data are available that show reduction of the risk of CHD upon raising the HDL-C levels, no particular dietary interventions are needed for this specific purpose. In fact, increasing the fat content in the patient's diet is not recommended. Dietary management should follow the NCEP guidelines for lowering frequently associated LDL-C, which is the primary target in lipid management, and lowering of LDL levels has been demonstrated to reduce CHD morbidity and mortality in multiple randomized clinical trials.

· The NCEP has recommended a therapeutic lifestyle change diet, which should be incorporated in the treatment of all patients. The following are recommendations:

- Patients should reduce their intake of saturated fats to less than 7% of total calories (energy). Cholesterol intake should be reduced to less than 200 mg/d. Keep trans fatty acids (the HDL-lowering, LDL-raising fats) to a minimum. Polyunsaturated fats should constitute up to 10% of total energy intake and monounsaturated fats up to 20% of total energy intake. Total fat intake, therefore, should be in the range of 25-35% of total energy intake.

- Carbohydrates (complex carbohydrates from grains, whole grains, fruits, and vegetables) should constitute 50-60% of total energy intake.

- Patients should consume 20-30 g/d of fiber.

- The protein content should be approximately 15% of total energy intake.

- The total amount of energy consumed must be balanced in terms of energy intake and expenditure to maintain desirable body weight and to prevent weight gain.

Medication:

There are medications for Hypoalphalipoproteinemia and other underlying diseases associated with TD, however, it could not prevent or treat the genetic defect itself.

Follow Up Treatment/Management

Further Inpatient Care:

· Generally, patients with HA (Hypoalphalipoproteinemia) are discovered during routine lipid profile testing. Such patients are ambulatory and do not usually require hospitalization or inpatient care.

· Inpatient care is usually required for complications arising from accelerated atherosclerosis.

· In patients with secondary causes of HA, inpatient care may become necessary based on the primary pathology.

Further Outpatient Care:

· Provide outpatient care at regular intervals, especially clinical evaluation, lipid profile assessment, and follow-up evaluations for complications such as CHD.

· Monitor frequently for the effectiveness of medical therapy and possible complications of drugs. For example, monitor liver function tests and eye function when treating patients with lipid-lowering agents.

Transfer:

· Patients with TD rarely require transfer, and no specific recommendations are available for this purpose. In patients who are admitted to a health care facility, transfer depends mainly on the underlying condition or the complications of HA or premature atherosclerosis, such as MI, arrhythmia, or hypotension.

Deterrence/Prevention:

· Familial or genetically inheritable forms of HA are not amenable to prevention. Genetic counseling and screening may be applicable in rare cases.

Complications:

· Premature atherosclerosis

· Corneal opacification

Prognosis:

· If diagnosed early and monitored closely, the prognosis for patients with HA is generally reasonably good. The risk derives from the development of complications.

Patient Education:

· Pursue aggressive dietary modification.

· Discuss medications and their potential adverse effects, and monitor for adverse effects.

Miscellaneous

Medical/Legal Pitfalls:

· Patients presenting with TD must be evaluated and observed closely for the development of premature atherosclerosis. Screen such patients at frequent intervals through clinical assessment, stress test, or electron beam computed tomography. Missing the opportunity to diagnose premature atherosclerosis early may have legal implications.

· Siblings and first-degree relatives of patients with TD should be screened for HA and for the development of atherosclerosis.

· HA due to secondary causes must be treated by managing the underlying causes and by using pharmacologic agents to raise HDL levels. Failure to do so may have legal implications.

Special Concerns:

HDL will usually be done as part of an overall lipid profile, where "bad" cholesterol (LDL) and triglycerides will also be measured. The combined information gathered from all of these tests may help your risk of heart attack, stroke, and peripheral vascular disease.

Your health care provider will recommend therapy if your risk is found to be high. Regular exercise can increase HDL levels by several points.

References

Wikipedia
eMedicine
WrongDiagnosis.com

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A-alphalipoprotein Neuropathy