A father with Huntington disease has a daughter whose symptoms began at age 25, earlier than his own onset at age 45. Molecular testing shows expansion of a CAG repeat beyond 40 copies in the HTT gene. The primary pathogenic mechanism of the expanded huntingtin protein is:

• A Loss of enzymatic function of a lysosomal hydrolase
• B Toxic gain of function from an elongated polyglutamine tract with misfolded nuclear aggregates ✓
• C Haploinsufficiency of a transcription regulator required for striatal neuron survival
• D Defective DNA repair leading to accumulated somatic mutations

Explanation

Huntington disease is an autosomal dominant disorder caused by CAG expansion encoding a polyglutamine tract in huntingtin. The mutant protein acquires a toxic gain of function, forms intranuclear inclusions, sequesters transcription factors, and causes death of striatal neurons, particularly those using GABA. Atrophy of the caudate nucleus and putamen produces the chorea and cognitive decline. Haploinsufficiency mechanisms apply to tumor suppressors such as RB1, not to this triplet-repeat gain-of-function disease.

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.