A 6-month-old infant with cherry-red spot on fundoscopy, progressive neurodegeneration, and foam cells in the bone marrow has absent hexosaminidase A (Hex A) activity. Hex A is composed of α and β subunits. Which specific subunit mutation causes Tay-Sachs, and what accumulates in neurons?

• A Mutation in HEXB gene (β subunit); GM1 ganglioside accumulates — causing Sandhoff disease
• B Mutation in both α and β subunits equally; galactocerebroside accumulates
• C Mutation in GM2 activator protein; sphingomyelin accumulates in neurons and liver
• D Mutation in HEXA gene (α subunit); GM2 ganglioside accumulates because Hex A (αβ) and Hex B (ββ) differ — only Hex A with the GM2 activator protein degrades GM2 ✓

Explanation

Tay-Sachs disease is caused by mutations in HEXA (encoding the α subunit). Hex A (αβ heterodimer) degrades GM2 ganglioside in lysosomes when bound to the GM2 activator protein. Hex B (ββ homodimer) is intact in Tay-Sachs but cannot degrade GM2 because it lacks the α subunit required for GM2 activator binding. Therefore only GM2 ganglioside accumulates — predominantly in neurons — causing progressive neurodegeneration and cherry-red spot. Sandhoff disease involves HEXB mutations (β subunit deficiency), abolishing both Hex A and Hex B activity and causing accumulation of both GM2 and its glycolipid precursors. Niemann-Pick involves sphingomyelin accumulation.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.