A 6-month-old infant has progressive neurological deterioration with macrocephaly, a cherry-red spot on macula, exaggerated startle response, and hypotonia. Hexosaminidase A activity is absent. Which sphingolipid accumulates, and in which organelle?
- A Glucocerebroside accumulates in lysosomes of macrophages (Gaucher disease)
- B GM2 ganglioside accumulates in lysosomes of neurons — Hex A normally cleaves the terminal GalNAc from GM2 in lysosomes ✓
- C Sphingomyelin accumulates in lysosomes of neurons and macrophages (Niemann-Pick type A)
- D Ceramide accumulates in the endoplasmic reticulum, blocking Golgi trafficking
Explanation
Tay-Sachs disease (GM2 gangliosidosis type 1) results from deficiency of hexosaminidase A (alpha-subunit mutation, HEXA gene). Hex A normally catabolizes GM2 → GM3 by cleaving the terminal N-acetylgalactosamine (GalNAc). Without Hex A, GM2 accumulates in neuronal lysosomes (lysosomes are the site of all sphingolipid catabolism). Neuronal storage causes cytoplasmic ballooning, axonal dysfunction, and the characteristic cherry-red spot (fovea lacks ganglion cells, showing choroidal vasculature through the thin fovea against the lipid-laden pale macula). Sandhoff disease = Hex B deficiency (both A and B absent), accumulates GM2 AND GA2.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.