A 38-year-old man develops choreiform movements and psychiatric disturbance followed by cognitive decline. His father had similar symptoms beginning at age 50. MRI shows disproportionate atrophy of the caudate nuclei with boxcar ventricles. What genetic mechanism underlies this disease?

• A Point mutation in the APP gene on chromosome 21
• B CAG trinucleotide repeat expansion in the HTT gene with anticipation through paternal transmission ✓
• C GAA trinucleotide repeat expansion in the frataxin gene
• D CGG repeat expansion leading to methylation of the FMR1 gene

Explanation

Huntington disease is caused by expansion of CAG repeats in the HTT gene encoding huntingtin, producing a polyglutamine tract and toxic gain of function. The repeats expand further in successive generations, and because spermatogenesis amplifies the expansion, anticipation is classically seen with paternal transmission. GAA expansion in frataxin causes Friedreich ataxia, CGG expansion causes fragile X syndrome, and APP mutations cause familial Alzheimer disease. Caudate atrophy correlates with the chorea and cognitive decline.

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.