Figure 2.

Genetic etiology and pathophysiological consequences of HD. Schematic representation of the genetic basis of HD. (a) HD is an autosomal dominant disorder caused by a CAG trinucleotide repeat expansion in the first exon of the HTT gene. (b) This expansion encodes an abnormally elongated polyglutamine (polyQ) tract in the huntingtin protein. Individuals with intermediate alleles (27–35 CAG repeats) are typically unaffected but may transmit expanded alleles into the pathogenic range during germline transmission. Some carriers of intermediate alleles can exhibit HD-like phenotypes, including motor dysfunction, cognitive decline, and behavioral disturbances. Individuals with ≥36 CAG repeats are considered mutation carriers: those with 36–39 repeats show reduced penetrance and may remain asymptomatic, whereas those with ≥40 repeats exhibit full penetrance and develop clinical HD. (c) The mutant huntingtin protein (mHTT) induces widespread cellular dysfunction, ultimately leading to neuronal degeneration, with prominent loss observed in the striatum.