I-cell disease (mucolipidosis II)
Log in to starLast updated 2mo ago
An infant presents with coarse facial features, skeletal abnormalities, and severe developmental delay. Serum lysosomal enzyme levels are markedly elevated, but intracellular enzyme activity is deficient. Fibroblasts show dense cytoplasmic inclusions on microscopy.
AR; GNPTAB (N-acetylglucosamine-1-phosphotransferase alpha/beta subunits)
- Defective phosphotransferase cannot add mannose-6-phosphate (M6P) tags to lysosomal enzymes
- Without the M6P tag, enzymes are secreted extracellularly instead of being targeted to lysosomes
- Results in lysosomal enzyme deficiency inside cells but elevated levels in serum
- Coarse facial features (Hurler-like but more severe)
- Skeletal dysplasia (dysostosis multiplex)
- Severe psychomotor delay
- Gingival hyperplasia
- Restricted joint mobility (vs hypermobility in MPS)
- Cardiomyopathy
- Serum lysosomal enzymes are elevated (key diagnostic clue: enzymes are in the blood, not in the lysosomes where they belong)
- Dense inclusions in fibroblasts ("inclusion cells" → "I-cells")
- Elevated serum lysosomal enzymes (multiple enzymes elevated simultaneously)
- Decreased intracellular enzyme activity in fibroblasts
- GNPTAB gene testing
- Fibroblast inclusions on microscopy
- Supportive and multidisciplinary; no curative therapy. Enzyme replacement is not effective (the defect blocks lysosomal targeting of many enzymes, not a single deficiency)
- Manage airway and recurrent respiratory infections, cardiac valvular and myopathic disease, and feeding difficulties
- Physical therapy for joint contractures; orthopedic and developmental support
- Genetic counseling; the infantile (alpha/beta) form is typically fatal in early childhood
"I-cell = Inclusion cell": the "I" stands for the dense Inclusions seen in fibroblasts under microscopy.
"Enzymes In the wrong place": in I-cell disease, lysosomal enzymes are In the blood (elevated serum levels) instead of Inside the lysosomes. The M6P address tag is missing, so enzymes get mailed to the wrong location.
I-cell vs Hurler: Both have coarse features and dysostosis multiplex, but I-cell has elevated serum enzymes (vs normal/low in MPS) and restricted joints (vs joint laxity in MPS).