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I-cell disease stands for inclusion cell disease. It is a genetically inherited lysosomal storage disease clinically similar to Hurler syndrome (without mucopolysaccharides) and originally characterized by the presence of intracytoplasmic inclusions in fibroblasts (“inclusion cells” or “I cells”).

GNPTA Deficiency; Inclusion Cell Disease; Leroy Disease; Mucolipidosis II (ML II); N-Acetylglucosaminyl-1-Phosphotransferase Deficiency.

Genetic disorder involving abnormal trafficking of lysosomal enzymes. The disease was classified as mucolipidosis type II because it had clinical characteristics of both the mucopolysaccharidoses and the sphingolipidoses.

1:640,000 live births in the Netherlands. In the French Canadian population of Saguenay Lac Saint-Jean of the province of Quebec, the estimated prevalence at birth is 1:6184, giving a carrier frequency of 1/39. No ethnic or sexual predilection. Life expectancy is reduced (first decade); patients usually die of pneumonia or congestive heart failure.

Autosomal recessive. Caused by a deficiency of the enzyme N-acetylglucosaminyl-1-phosphotransferase, which is produced by the GNPTA gene located at chromosome band 4q21-q23.

The disease results from abnormal enzyme transport. The deficiency is N-acetylglucosamine-1-phosphotransferase, a membrane enzyme that catalyzes the formation of mannose-6-phosphate (Man-6-P) on nascent lysosomal enzymes (by ribosomes). This Man-6-P component is recognized by Man-6-P receptors, which direct the transfer of lysosomal enzymes into lysosomes. This failed internalization results in release of lysosome enzymes into the extracellular medium instead. Although all cells are deficient in phosphotransferase activity, not all cells are deficient in lysosomal enzyme content, indicating that some cells have Man-6-P-independent pathways. The functional deficiency of lysosomal enzymes results in abnormal cell architecture (vacuolization and formation of inclusions) in cells of mesenchymal origin, which involves several tissues of the body: skeletal system (abnormal trabeculation of bone and cartilage), heart valves (vacuolization leading to thickening of the valves), renal glomerules, and liver fibroblasts of the periportal spaces.

Clinical history and physical findings. Elevated levels of lysosomal enzymes (e.g., arylsulfatase A) in serum and body fluids. Deficient enzymes can be demonstrated in cultured fibroblasts. Microscopy of fibroblasts shows numerous “inclusion bodies” for which the disease is named.

I-cell disease has many clinical and radiographic features similar to Hurler syndrome, but with earlier presentation and without mucopolysaccharides. Striking gingival hyperplasia can distinguish this disease from Hurler syndrome. Other features include kyphoscoliosis, wedging of vertebral bodies, craniofacial abnormalities, and restricted joint movements. Repeated upper respiratory infections (bronchitis and pneumonia) are frequent. Severe mucosal thickening of the epiglottis, larynx, and trachea increases with age. Macroglossia is often present. Hepatomegaly is prominent with hernias. Severe psychomotor retardation, developmental delay, myelopathy, and neonatal hypotonia are important neurologic characteristics. Mental status is variable but can present with severe progressive psychomotor retardation. The cardiovascular anomalies include hypertrophic cardiopathy, cardiomegaly, and aortic insufficiency. Death within the first decade is usually from bronchopneumonia or congestive heart failure. No specific treatment is available. Physical therapy may delay progression of joint immobility. Nasal continuous positive airway pressure has been shown to reduce respiratory infections. Successful ...

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