A 4-month-old boy of Ashkenazi Jewish descent presents to the pediatric clinic with his parents reporting an exaggerated startle response to loud sounds over the past 2 weeks. On examination, you note hypotonia and developmental regression. Fundoscopy reveals a cherry-red macular spot bilaterally. The condition marked **B** in the diagram is suspected. Which of the following biochemical findings would confirm this diagnosis?
A. Markedly reduced hexosaminidase A activity with normal hexosaminidase B activity
B. Markedly reduced hexosaminidase A and B activity
C. Markedly reduced galactocerebrosidase activity
D. Markedly reduced acid sphingomyelinase activity
Explanation
Why markedly reduced hexosaminidase A activity with normal hexosaminidase B activity is right
The condition marked B (Tay-Sachs disease) is caused by mutations in the HEXA gene on chromosome 15q23, which encodes the alpha-subunit of hexosaminidase A. This results in deficiency of HEX-A enzyme activity while hexosaminidase B (encoded by HEXB) remains normal. This distinctive pattern — isolated HEX-A deficiency with preserved HEX-B — is the diagnostic hallmark and distinguishes Tay-Sachs from Sandhoff disease (which shows deficiency of both HEX-A and HEX-B). The clinical presentation of exaggerated startle (hyperacusis), hypotonia, developmental regression, and cherry-red macular spot in an Ashkenazi Jewish infant is classic for infantile-onset Tay-Sachs, and the biochemical confirmation is reduced HEX-A with normal HEX-B activity measured in serum, leukocytes, or fibroblasts (Nelson Pediatrics 21e; ACMG Carrier Screening Guideline).
Why each distractor is wrong
Markedly reduced hexosaminidase A and B activity: This pattern is diagnostic of Sandhoff disease, which results from mutations in the HEXB gene encoding the beta-subunit. Both HEX-A and HEX-B are deficient because the beta-subunit is shared by both enzymes. This is not the pattern seen in Tay-Sachs.
Markedly reduced acid sphingomyelinase activity: This is the biochemical defect in Niemann-Pick disease (marked A in the diagram), not Tay-Sachs. Niemann-Pick A also presents with neurodegeneration but typically includes hepatosplenomegaly, which is absent in Tay-Sachs.
Markedly reduced galactocerebrosidase activity: This is the enzyme defect in Krabbe disease (marked C in the diagram), a different lysosomal storage disorder affecting galactocerebroside metabolism. Krabbe presents with different clinical features including early irritability and developmental regression but lacks the cherry-red spot.
