Huntington Disease — Causes, Symptoms, Diagnosis & Treatment Guide — Symptoms, Causes & Treatment | MyMedicPlus

Huntington disease (HD) is a fatal, hereditary neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HTT gene encoding the huntingtin protein, leading to progressive striatal and cortical neuronal death. It manifests as a triad of movement disorder (chorea), cognitive decline, and psychiatric disturbances. Onset typically occurs between ages 30 and 50. HD follows autosomal dominant inheritance — each child of an affected parent has a 50% chance of inheriting the mutation. Approximately 30,000 people in the USA have HD, with 200,000 at risk. Currently no disease-modifying therapy exists. The expanded polyglutamine (polyQ) tract in mutant huntingtin protein confers toxic gain-of-function properties that disrupt mitochondrial function, axonal transport, synaptic transmission, and transcriptional regulation, causing selective vulnerability of striatal medium spiny neurons. Research into gene-silencing strategies — particularly antisense oligonucleotides and RNA interference targeting mutant huntingtin — represents the most promising avenue toward disease-modifying treatment.

HD is caused by expansion of a CAG trinucleotide repeat in exon 1 of the HTT gene on chromosome 4. Normal HTT alleles contain fewer than 26 CAG repeats; HD is caused by 40 or more repeats. Intermediate alleles (27–39 repeats) have reduced penetrance. Repeat length inversely correlates with age of onset — juvenile HD (below 20 years) occurs with very large repeat expansions (above 60). Anticipation — increasing repeat length in successive generations — can cause earlier-onset disease in offspring, especially with paternal transmission. Approximately 30% of cases arise de novo with no known family history. The CAG repeat encodes a polyglutamine (polyQ) stretch in the huntingtin protein; expansions above 36 repeats result in abnormal protein folding, intranuclear inclusion body formation, and progressive neuronal dysfunction.

HD presents with insidious onset of a clinical triad: motor (chorea — involuntary, irregular dance-like movements; dystonia; dysarthria; dysphagia; gait instability), cognitive (executive dysfunction, memory impairment, progressive dementia), and psychiatric (depression in 40%, anxiety, irritability, apathy, obsessive-compulsive features, psychosis in 10%). Prodromal mood and cognitive changes may precede motor symptoms by years. Falls and aspiration pneumonia from dysphagia become major hazards in advanced disease. Death typically occurs 15–20 years after motor symptom onset, commonly from pneumonia, falls, or cardiovascular complications. Dysphagia (difficulty swallowing) develops in most HD patients with advancing disease and is clinically significant — aspiration of food and liquid into the airway leads to aspiration pneumonia, the most common immediate cause of death in Huntington disease, necessitating regular speech and language therapy assessment and dietary modification.

HD is definitively diagnosed by genetic testing demonstrating 40 or more CAG repeats in the HTT gene. Clinical diagnosis is made in the context of a positive family history, characteristic triad of motor, cognitive, and psychiatric features. Brain MRI shows characteristic caudate nucleus atrophy and cortical atrophy in established disease. Neuropsychological testing documents cognitive decline severity. Predictive genetic testing in asymptomatic at-risk individuals is available but requires extensive pre- and post-test genetic counseling given the life-altering implications of a positive result in a currently healthy person. Pre-symptomatic genetic testing in at-risk individuals follows a strict international protocol requiring multiple pre-test counselling sessions, psychological assessment, independent clinical geneticist input, and planned post-test disclosure appointments regardless of result — reflecting the profound psychological impact of a positive predictive result in a disease currently lacking disease-modifying therapy.

No disease-modifying treatment currently exists for HD. Symptomatic management targets each domain. Chorea: tetrabenazine (VMAT2 inhibitor, first HD-specific approved drug) or deutetrabenazine (better tolerated) reduce involuntary movements; antipsychotics (olanzapine, haloperidol) also reduce chorea. Psychiatric symptoms: SSRIs for depression and anxiety; antipsychotics for psychosis; mood stabilizers for emotional dysregulation. Multidisciplinary care including physiotherapy, speech therapy for dysphagia management, occupational therapy, dietetics, and social work is essential throughout the disease course. Speech-language therapy is critical for managing dysarthria and dysphagia — modified diet textures and thickened liquids reduce aspiration pneumonia risk, the most common cause of death in advanced HD. Percutaneous endoscopic gastrostomy (PEG) tube feeding is considered when oral intake becomes inadequate to maintain nutrition. Physiotherapy maintains balance and mobility, reducing fall risk and prolonging independent ambulation. Advance care planning — including resuscitation preferences, gastrostomy decisions, and hospice care — should be completed early while the patient retains full decision-making capacity.

Progressive dysphagia leads to aspiration pneumonia — the most common cause of death in HD. Falls with serious injuries are common as gait and balance deteriorate. Weight loss despite adequate intake is universal and worsens with disease progression, requiring high-calorie diet supplementation or eventually PEG tube feeding. Dementia renders patients fully dependent on caregivers in advanced stages. Suicide risk is elevated — particularly in the period following a positive predictive genetic test and in the early symptomatic phase. Caregiver burnout is a major concern given the prolonged, progressive, and ultimately fatal nature of the illness.

HD cannot currently be prevented in gene carriers, but antisense oligonucleotide therapies targeting mutant huntingtin mRNA are in advanced clinical trials and may slow or halt disease progression. Preimplantation genetic diagnosis (PGD) during IVF allows conception of unaffected embryos for at-risk couples. Predictive genetic testing allows at-risk individuals to make informed life decisions — family planning, career, finances, and anticipatory care planning. Exercise may slow cognitive and motor decline; maintain aerobic fitness and engage in cognitively stimulating activities. Join an HD specialist center or clinical trial for access to emerging therapies.

Consult your GP for neurological referral if you have a family history of Huntington disease and are noticing new involuntary movements, personality or mood changes, memory difficulties, or problems with coordination — even subtle early symptoms warrant specialist HD assessment. If you are at risk of HD and wish to consider predictive genetic testing, request a referral to a genetics service or HD specialist clinic — predictive testing requires comprehensive pre-test and post-test counselling under a multidisciplinary protocol and should not be done through direct-to-consumer genetic tests. Seek emergency care for: acute psychiatric crisis (severe depression or suicidal ideation — HD patients have significantly elevated suicide risk), falls causing significant injury, aspiration pneumonia (choking on food in advanced disease), or sudden new neurological symptoms. Connect with an HD specialist multidisciplinary centre (neurologist, psychiatrist, speech therapist, physiotherapist, social worker) as early as possible after diagnosis — comprehensive specialist care significantly improves quality of life at every stage. Contact the Huntington's Disease Association (UK) or HDSA (US) for specialist centre referral and family support.