Huntington’s disease, a dominantly inherited neurodegenerative disorder, is

characterized by progressively worsening motor disturbances, cognitive decline and

behavioral signs and loss of neuronal cells, initially in the deep brain structures (caudate

and putamen). The singular genetic cause of the disorder is an expanded, unstable CAG

triplet repeat located in the HD gene (HTT), that encodes a stretch of polyglutamine in a

large HEAT-repeat protein (huntingtin). Deep Huntington’s disease natural history

studies, such as PHAROS, COHORT, PREDICT-HD, TRACK-HD, and ENROLL-HD,

have fueled genetic searches for the DNA sequence variants that influence the ratelimiting

steps in the decades-long disease process. Huntington’s disease modifier genes

now provide insights into the driver of the timing of onset of clinical signs and begin to

dissect the relationships between phenotypes that can be measured before and after the

onset of overt clinical signs. The genetic paradigm provides a guide for studies in other

brain disorders and the specific findings in Huntington’s disease have implications for the

pathogenesis of other triplet repeat disorders, including the notion that these should be

considered to be ‘polyglutamine diseases’.