A 42-year-old man develops progressive choreiform movements and cognitive decline; his father had similar symptoms beginning in his late thirties. MRI shows atrophy of the caudate nuclei. Genetic testing reveals one allele with 48 CAG repeats in HTT. The pathogenesis of this disease is best described as:

• A Loss of function of a ubiquitously expressed transcriptional co-repressor
• B Dominant-negative inhibition of a nuclear receptor by mutant protein sequestration
• C Haploinsufficiency of a mitochondrial enzyme leading to impaired oxidative phosphorylation
• D Toxic gain of function from an abnormally long polyglutamine tract that misfolds and aggregates ✓

Explanation

Huntington disease is a polyglutamine disease caused by CAG expansion beyond 40 repeats in HTT. The expanded huntingtin misfolds, forms intranuclear aggregates, and confers a novel toxic property on the protein, hence gain of function. Loss of function models fail because mice lacking huntingtin die early without reproducing the striatal degeneration, and homozygous humans are no worse than heterozygotes, which directly refutes options A and B.

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.