I-Cell Disease

At a glance

I-cell disease is a genetically inherited lysosomal storage disease that is caused by a defective phosphotransferase enzyme that is located in the Golgi apparatus. This mucolipidosis II (ML II) is a particularly severe form of mucoliposis that resembles clinically the Hurler Syndrome but without mucopolysaccharides. It is originally characterized by the presence of intracytoplasmic inclusions in fibroblasts (“inclusion cells” or “I cells”). Clinical features include by the age of 6 months, severe failure to thrive and developmental delays, abnormal skeletal development, coarse facial features, and restricted articular movements. Other characteristics include mental retardation, dwarfism, hepatomegaly, splenomegaly, and cardiac valvular anomalies. These young patients are often affected with recurrent respiratory tract infections, particularly pneumonia, bronchitis, and otitis media. Children with ML II generally die before their seventh year of life as a result of congestive heart failure and recurrent respiratory tract infections.

Synonyms

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

Nature

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.

Incidence

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 1:6,184, 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.

Genetic inheritance

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.

Pathophysiology

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.

Diagnosis

Clinical history and physical findings. The presence of elevated levels of lysosomal enzymes (eg, arylsulfatase A) in serum and body fluids are present. Deficient enzymes can be demonstrated in cultured fibroblasts. Microscopy of fibroblasts shows numerous “inclusion ...