mucolipidosis

Mucolipidosis refers to a group of autosomal recessive lysosomal storage disorders caused by defective trafficking of lysosomal hydrolases to the lysosome. The spectrum primarily includes mucolipidosis type II (I-cell disease) and mucolipidosis type III (pseudo-Hurler polydystrophy and related subtypes such as type III alpha/beta and type III gamma). These conditions arise from mutations that impair the function of N-acetylglucosamine-1-phosphotransferase, leading to deficient tagging of lysosomal enzymes with mannose-6-phosphate and misdirection of these enzymes out of the cell. As a result, lysosomes contain insufficient hydrolases and accumulate undegraded substrates, producing widespread cellular and tissue damage.

Clinical features vary by subtype. Mucolipidosis II typically presents in infancy with severe multisystem involvement, including characteristic coarse facial features, gingival hyperplasia, skeletal abnormalities (dysostosis multiplex), short stature, joint stiffness, developmental delay, hypotonia, and hepatosplenomegaly. Eye involvement such as corneal clouding may occur, and recurrent respiratory infections are common. Mucolipidosis III usually has a later onset and a milder course, with progressive skeletal issues, joint contractures, and variable developmental impact; intellectual impairment can be milder or absent.

Diagnosis is suggested by clinical and radiographic findings (dysostosis multiplex) and supported by laboratory results showing elevated activities of multiple lysosomal enzymes in plasma due to misrouting, with reduced lysosomal enzyme activity in cells. Genetic testing identifies pathogenic variants in GNPTAB (types II and III alpha/beta) or GNPTG (type III gamma). Prenatal testing is possible in affected families.

Management is supportive and multidisciplinary, focusing on growth, nutrition, ortho/skeletal care, respiratory support, hearing and vision monitoring, and management of organomegaly. The prognosis is generally poorer for mucolipidosis II, with most affected individuals having limited survival into early childhood, while mucolipidosis III has a more variable and often longer course.