Clinical meaning
Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expanded CAG trinucleotide repeat in the huntingtin gene (HTT) on chromosome 4p16.3. Normal alleles contain 10-35 CAG repeats; intermediate alleles (27-35) may expand in subsequent generations; reduced penetrance alleles (36-39) may or may not cause disease; full penetrance alleles (≥40 repeats) invariably cause HD. The length of the CAG expansion inversely correlates with age of onset — longer repeats cause earlier disease (juvenile HD with >60 repeats can present before age 20 with rigidity and seizures rather than chorea). The phenomenon of genetic anticipation occurs particularly in paternal transmission: the CAG repeat can expand during spermatogenesis, leading to earlier onset and more severe disease in successive generations. The mutant huntingtin protein undergoes abnormal folding and forms intranuclear aggregates that are toxic to neurons, particularly in the caudate nucleus and putamen (striatum). Striatal medium spiny neurons (GABAergic, inhibitory) are selectively vulnerable, and their loss disrupts the basal ganglia circuitry controlling movement. Loss of indirect pathway inhibition causes the characteristic hyperkinetic movements (chorea). As disease progresses, direct pathway neurons are also affected, leading to rigidity and akinesia. Genetic testing is definitive: PCR-based assessment of CAG repeat length. Predictive testing in at-risk asymptomatic individuals follows strict guidelines: pre-test genetic counseling, psychological assessment, informed consent, waiting period, and post-test support. Testing of minors is generally discouraged unless symptoms are present.