A 38-year-old man is evaluated for psychiatric symptoms and choreiform movements. His father had a similar illness beginning at age 45. MRI shows symmetric atrophy of the caudate nuclei with compensatory dilatation of frontal horns. Genetic testing confirms expansion of CAG repeats. Which mechanism explains the neuronal death in this disorder?
- A Gain-of-function toxic polyglutamine aggregation of huntingtin with transcriptional dysregulation ✓
- B Loss of function of a mitochondrial enzyme leading to excitotoxic glutamate injury
- C Defective DNA mismatch repair causing somatic repeat instability only in germline cells
- D Autoimmune destruction of GABAergic medium spiny neurons by anti-basal ganglia antibodies
Explanation
Huntington disease is an autosomal dominant CAG trinucleotide expansion in HTT encoding polyglutamine stretches. The mutant huntingtin gains a toxic function: misfolded N-terminal fragments aggregate intracellularly, disrupt proteostasis, impair mitochondrial function and axonal transport, and alter transcription, selectively killing GABAergic medium spiny neurons of the striatum, starting in the caudate. Anticipation occurs through paternal transmission because expansions enlarge during spermatogenesis. The other mechanisms describe Leigh syndrome, fragile X dynamics, and Sydenham chorea respectively.
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.