HD is a repeat expansion disorder. According to the packet, it results from a CAG repeat expansion in the HTT gene, which ClinGen classifies as definitive and which is located on chromosome 4. Normal alleles contain fewer than 27 CAG repeats, and alleles with 40 or more repeats are fully penetrant. GeneReviews classifies alleles of 26 or fewer repeats as normal, 27 to 35 as intermediate, 36 to 39 as reduced-penetrance HD-causing, and 40 or more as full-penetrance. Asymptomatic individuals with 36 to 39 repeats are described as common, and these alleles show greater variability in age of onset. GeneReviews describes individuals with intermediate alleles as not typically at risk of manifestations, though germline instability in the CAG tract may lead to a child with an allele in the HD-causing range; paternally inherited intermediate alleles are more prone to expansion. The packet describes anticipation, meaning earlier onset in successive generations, especially with paternal transmission. Inheritance is autosomal dominant. GeneReviews reports that most individuals diagnosed with HD have an affected parent, and that a sibling of a proband has a 50% risk of inheriting the expansion when a parent carries a full-penetrance allele. The packet's curated data state that approximately 8% of cases arise de novo through expansion of intermediate alleles.

According to the packet, diagnostic methods include molecular genetic testing for CAG repeat length, clinical evaluation of motor, cognitive, and psychiatric features, and brain MRI, which may show caudate atrophy. GeneReviews lists clinical findings that raise suspicion, including progressive motor disability featuring chorea, cognitive decline, and personality or psychiatric changes such as depression, together with neuroimaging findings of progressive striatal atrophy of the caudate and putamen, lateral ventricle enlargement, and gray and white matter atrophy. Family history consistent with autosomal dominant inheritance supports the suspicion, though GeneReviews states that absence of a known family history does not preclude the diagnosis. GeneReviews describes the diagnosis as established in a proband with a heterozygous CAG trinucleotide repeat expansion in HTT identified by molecular genetic testing, using targeted analysis of repeat number. It notes that fragment analysis does not account for variation in the repeat region, so loss of a CAA interruption can lead to underestimated repeat length and a false negative result or incorrect diagnostic category. The differential diagnosis includes conditions such as dentatorubral-pallidoluysian atrophy, spinocerebellar ataxias, and Huntington disease-like 2. No newborn-screening status is recorded in the packet.

GeneReviews states that there is no cure for HD and that pharmacologic therapy is limited to symptomatic treatment, with supportive care aimed at quality of life, function, and reducing complications. The packet lists foundational therapies of tetrabenazine or deutetrabenazine for chorea, psychiatric medications for depression, anxiety, and behavioral symptoms, physical therapy for mobility and balance, speech therapy for dysarthria and swallowing difficulties, and nutritional support for weight maintenance. FDA records in the packet show the following products with active market status: tetrabenazine (Xenazine, 2008), deutetrabenazine (Austedo, 2017), and valbenazine (Ingrezza, 2017, and Ingrezza Sprinkle, 2024). GeneReviews notes that medications for chorea are prone to significant side effects, including depression, sedation, nausea, restlessness, headache, neutropenia, and tardive dyskinesia, and that persons with mild-to-moderate chorea may be better assisted by nonpharmacologic therapies. It lists other medication classes used for specific manifestations, including neuroleptics, antidepressants, mood stabilizers, and antispasmodics. Nonpharmacologic approaches in GeneReviews include physical, occupational, and speech-language therapy, swallowing assessment, dietitian input, psychotherapy, and social work support, with HD support organizations described as valuable. Specialist types listed in the packet include neurologists, psychiatrists, genetic counselors, therapists, and social workers. GeneReviews also describes ongoing surveillance of motor, cognitive, functional, and behavioral features using the Unified Huntington Disease Rating Scale.

The packet does not certify life expectancy or survival data for HD. GeneReviews describes HD as a progressive disorder whose course moves from premanifest through manifest stages, classified as early, moderate, and advanced by total functional capacity. The Huntington Disease Integrated Staging System is described as a framework covering the full course from birth through clinical motor diagnosis. GeneReviews reports that full-penetrance alleles are associated with development of HD with increased certainty assuming a normal life span, whereas reduced-penetrance alleles may not lead to manifestations.

The packet lists ClinicalTrials.gov records across drug therapy, gene therapy, medical devices, and other interventions. Examples include a phase 3 study of votoplam sponsored by Novartis (NCT07326709, recruiting), a phase 3 pridopidine study sponsored by Prilenia (NCT07609108, recruiting), a phase 1 study of ALN-HTT02 sponsored by Alnylam Pharmaceuticals (NCT06585449, recruiting), a phase 2 tominersen study (GENERATION HD2) sponsored by Hoffmann-La Roche in prodromal and early manifest HD (NCT05686551, active, not recruiting), and a University of Rochester study of digital measures for clinical trial endpoints (NCT07010705, recruiting). GeneReviews lists therapies in clinical trials with mechanisms that include HTT-targeting RNAi and siRNA approaches, an AAV-delivered miRNA construct (AMT-130), pridopidine, and cell replacement therapy, and refers to the Huntington's Disease Research Pipeline maintained by the Huntington's Disease Society of America. The packet's research directions include HTT-lowering therapies, gene editing, and neuroprotective strategies. Orphan designations are listed for many investigational products; designation does not indicate approval. Listed patient organizations include the Huntington's Disease Society of America, the Huntington Society of Canada, and the Huntington's Disease Youth Organization, which is noted as having a registry.