A 14-month-old male infant of Ashkenazi Jewish ancestry presents with developmental regression, exaggerated startle response, loss of head control, hypotonia with brisk deep tendon reflexes, and bilateral cherry-red macular spots on fundoscopy. Enzyme assay shows absent hexosaminidase A activity with normal hexosaminidase B. Both parents are phenotypically normal and confirmed carriers. The pedigree pattern shown demonstrates **A** (autosomal recessive inheritance). Which of the following clinical and genetic features MOST STRONGLY supports this inheritance pattern in this family?

Question

Accepted Answer

D. Affected individuals in both males and females across generations, with unaffected carrier parents having affected children, and a 25% recurrence risk in siblings. ## Why Option 1 is correct

The pedigree pattern in this Tay-Sachs family demonstrates classic autosomal recessive inheritance. The key diagnostic features are: (1) both affected and unaffected individuals of both sexes are present; (2) the proband is affected despite both parents being phenotypically normal (obligate carriers); (3) multiple siblings are affected or carriers; (4) the disease appears in an endogamous population (Ashkenazi Jewish, carrier frequency ~1/27); (5) there is no male-to-male transmission, ruling out X-linked or Y-linked patterns; and (6) the calculated recurrence risk is 25% for each sibling. The HEXA gene mutations (compound heterozygosity on chromosome 15q23-q24) are inherited in an autosomal recessive manner, as documented by Kaback and Desnick. This pattern is pathognomonic for autosomal recessive inheritance.

## Why each distractor is wrong

- **Option 2 (Vertical transmission with affected fathers)**: This describes autosomal dominant inheritance. In the given pedigree, the proband's father is an unaffected carrier, not an affected individual. Dominant inheritance would show affected individuals in every generation with vertical transmission, which is not present here.

- **Option 3 (Maternal transmission exclusively)**: This describes mitochondrial inheritance, where all children of affected mothers are affected regardless of sex. In this family, the proband's mother is an unaffected carrier, and the disease appears in both males and females from carrier parents, not exclusively from affected mothers.

- **Option 4 (Male-to-male transmission)**: This pattern is characteristic of Y-linked inheritance or sometimes X-linked dominant inheritance. The pedigree explicitly shows no male-to-male transmission (the proband's father is unaffected), and both males and females are equally affected, ruling out X-linked recessive inheritance.

**High-Yield:** Tay-Sachs disease is autosomal recessive; look for affected individuals of both sexes from unaffected carrier parents, increased frequency in Ashkenazi Jewish populations, and absence of male-to-male transmission.

[cite: Kaback MM, Desnick RJ. Hexosaminidase A Deficiency. In: GeneReviews. University of Washington, Seattle; updated 2011.]

Answer

A. Vertical transmission through multiple generations with affected fathers passing the disease to all daughters

Answer

B. Male-to-male transmission from father to son, with affected males having all affected sons

Answer

C. Maternal transmission exclusively, with all children of affected mothers showing the disease regardless of sex

Explanation

Why Option 1 is correct

Why each distractor is wrong

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