Clinical meaning
Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by CAG trinucleotide repeat expansion in the huntingtin gene (HTT) on chromosome 4. Normal HTT contains < 26 CAG repeats; 27-35 is intermediate (may expand in offspring); 36-39 shows reduced penetrance; ≥ 40 repeats causes full penetrance. The mutant huntingtin protein contains an expanded polyglutamine tract that misfolds and aggregates, forming intranuclear inclusions. Pathologically, there is selective vulnerability of medium spiny neurons (MSNs) in the caudate nucleus and putamen (striatum). These GABAergic projection neurons degenerate through multiple mechanisms: mitochondrial dysfunction (complex II/III impairment), excitotoxicity (NMDA receptor overactivation), transcriptional dysregulation, impaired BDNF transport, and proteasome dysfunction. Striatal degeneration disrupts the indirect pathway of the basal ganglia, causing chorea (excessive involuntary movements). As disease progresses and the direct pathway also degenerates, chorea decreases while rigidity and bradykinesia increase. Anticipation occurs with paternal transmission (CAG repeats tend to expand during spermatogenesis).