A man with Huntington disease has a son who developed choreiform movements and cognitive decline at age 28, earlier than the father's onset at age 50. Molecular testing shows the son carries a larger CAG expansion than his father. The mechanism best explaining this intergenerational increase is:

• A Somatic instability of the repeat within striatal neurons after birth
• B Expansion of the CAG repeat during oogenesis, causing anticipation through the maternal line
• C Expansion of the CAG repeat during spermatogenesis, causing anticipation through the paternal line ✓
• D Paternal genomic imprinting silencing the normal HTT allele

Explanation

In Huntington disease, an autosomal dominant polyglutamine disorder caused by expanded CAG repeats in HTT on chromosome 4, further expansion occurs during spermatogenesis, so anticipation with juvenile onset is seen almost exclusively when the father transmits the allele. This contrasts with myotonic dystrophy, where severe congenital cases are transmitted by mothers. Somatic instability contributes to progression within an individual but not to transmission across generations.

Reference: Robbins and Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.