A 60-year-old man with a 20-year history of progressive chorea, cognitive decline, and psychiatric symptoms is diagnosed with Huntington disease. His father had similar symptoms starting at age 55. The disease is caused by CAG repeat expansion in exon 1 of the HTT gene. The mutant huntingtin protein exerts toxicity primarily through which mechanism?

• A Loss of normal huntingtin function only
• B Haploinsufficiency of the wild-type allele
• C Toxic gain of function due to expanded polyglutamine tract ✓
• D Dominant-negative inhibition of the normal protein

Explanation

Huntington disease is caused by a toxic gain of function from the expanded CAG repeat, which translates into an abnormally long polyglutamine tract in the huntingtin protein. This leads to protein misfolding, intranuclear inclusion formation, and selective neuronal death, especially in the striatosis. Although some loss of normal huntingtin function may occur, the dominant inheritance pattern and the fact that homozygous patients do not have dramatically earlier onset confirm that gain of toxicity, not haploinsufficiency, is the primary mechanism.

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.