A 6-month-old infant presents with progressive neurological deterioration, loss of previously acquired skills, a cherry-red spot on fundoscopy, and hepatosplenomegaly. Bone marrow biopsy shows 'foam cells.' Enzyme assay reveals absent hexosaminidase A AND B activity. This presentation is MOST consistent with:
- A Tay-Sachs disease (hexosaminidase A deficiency, GM2 gangliosidosis)
- B Sandhoff disease (hexosaminidase A and B deficiency, GM2 and globoside accumulation with organomegaly) ✓
- C Gaucher disease (glucocerebrosidase deficiency)
- D Niemann-Pick disease type A (sphingomyelinase deficiency)
Explanation
Sandhoff disease is caused by mutations in the HEXB gene encoding the beta-subunit shared by both hexosaminidase A (alpha-beta heterodimer, degrading GM2 ganglioside) and hexosaminidase B (beta-beta homodimer, degrading globosides). This distinguishes Sandhoff from Tay-Sachs (isolated HexA/alpha-subunit deficiency, no organomegaly since globosides cannot accumulate). In Sandhoff, both GM2 ganglioside and globosides accumulate — ganglioside accumulation in neurons causes the cherry-red spot and neurodegeneration, while globoside accumulation in visceral organs causes the hepatosplenomegaly and foam cells absent in Tay-Sachs.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.