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 fibroblastsLab 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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