Huntington's Disease — Causes, Symptoms, Genetic Testing & Treatment Guide — Symptoms, Causes & Treatment | MyMedicPlus

Huntington's disease (HD, formerly Huntington's chorea) is a fatal autosomal dominant neurodegenerative disorder caused by an expanded CAG (cytosine-adenine-guanine) trinucleotide repeat in exon 1 of the HTT gene on chromosome 4p16.3, encoding an abnormally long polyglutamine tract in the huntingtin protein. Normal alleles have 10-26 CAG repeats; 36 or more repeats are pathogenic (full penetrance above 40 repeats; reduced penetrance 36-39 repeats). Affected individuals have a 50% chance of passing the mutation to each child. The expanded huntingtin protein undergoes aberrant cleavage, forming toxic fragments that aggregate in neuronal nuclei, causing selective neurodegeneration — predominantly of medium spiny neurons in the striatum (caudate nucleus and putamen) and the cerebral cortex. Progressive neuronal death in the striatum and cortex produces the characteristic triad of motor dysfunction (especially chorea), cognitive decline, and neuropsychiatric disturbances. HD is invariably progressive and fatal; mean age of onset is 30-50 years, with mean survival of 15-20 years from symptom onset. Juvenile HD (onset below age 20 — associated with longer CAG repeat lengths: above 55 repeats) accounts for 5-10% of cases and presents differently, with more rigidity, bradykinesia, seizures, and rapidly progressive dementia.

Huntington's disease is caused exclusively by the CAG repeat expansion mutation in HTT — there are no alternative genetic causes or environmental triggers. The mutation is fully penetrant above 40 repeats (all individuals with 40+ repeats will develop HD if they live long enough), with a clear correlation between repeat length and age of onset (longer repeats — earlier onset). Repeat lengths of 36-39 are associated with reduced penetrance (some, but not all, carriers will develop HD in their lifetime). Paternal transmission leads to significant 'anticipation' — the repeat may expand in the germline, meaning children of affected fathers often have longer repeats and earlier disease onset than their parent. This is particularly marked with paternal transmission (CAG repeats are less stable in spermatogenesis). The expanded huntingtin protein gains a toxic function through aberrant protein-protein interactions, mitochondrial dysfunction, transcriptional dysregulation, synaptic failure, and impaired axonal transport. Mutant HTT protein aggregates in neuronal intranuclear inclusions, though whether aggregates themselves are toxic or protective remains debated. The striatum (caudate and putamen) is disproportionately vulnerable — medium spiny neurons expressing enkephalin (indirect pathway) are preferentially lost early.

HD presents with a characteristic clinical triad — the relative contribution of each domain varies between individuals and stage of disease. Motor symptoms: chorea — involuntary, irregular, dance-like movements of the limbs, trunk, and face — is the most recognisable feature (the name 'chorea' from the Greek word for dance); early chorea is often subtle (finger tapping, facial grimacing, weight shifting); as disease progresses, chorea may diminish and be replaced by increasing rigidity (akinetic-rigid state) and dystonia. Dysarthria (slurred speech), dysphagia (swallowing difficulties — leading cause of aspiration pneumonia, a major cause of death), gait imbalance, falls, oculomotor abnormalities (abnormal saccades — one of the earliest neurological signs). Cognitive symptoms: executive dysfunction (planning, organising, multi-tasking) is often the earliest cognitive feature; slowed information processing; impaired working memory; progressive dementia with relative preservation of naming and language until late stages (HD dementia is subcortical in character — contrasting with Alzheimer's cortical dementia). Psychiatric/neuropsychiatric symptoms (often precede motor signs by years): depression (lifetime prevalence 30-40% in HD); irritability and aggression; apathy (distinct from depression — prominent feature in HD); anxiety; obsessive-compulsive symptoms; psychosis (10-15% at some stage); and personality changes. Suicide risk: significantly elevated (4-5x general population risk) — most frequent in early-diagnosed, presymptomatic carriers and early manifest HD.

Definitive diagnosis of Huntington's disease requires molecular genetic testing — PCR-based sizing of CAG repeats in the HTT gene from a blood sample. A result of 40 or more CAG repeats in an individual with compatible symptoms confirms the diagnosis. Diagnostic genetic testing (symptomatic individual): straightforward clinical and ethical process — should be accompanied by genetic counselling. Predictive genetic testing (at-risk asymptomatic individual — parent or sibling known to carry the mutation): requires careful pre-test counselling (minimum 2-3 sessions over several weeks), psychological assessment, and post-test support — guided by international HD Society guidelines (HDSA, European Huntington's Disease Network). A positive predictive result is life-changing; approximately 20-25% of at-risk individuals choose to be tested. Prenatal and preimplantation genetic testing (PGD) allows couples where one partner carries the HD mutation to conceive unaffected children. Clinical assessment: Unified Huntington's Disease Rating Scale (UHDRS) measures motor function, cognition, behaviour, and functional capacity. MRI brain: characteristic bilateral caudate nucleus atrophy (reduced caudate volume — increases the bicaudate ratio) and cortical atrophy in established disease, though early HD may show subtle or no visible changes. PET and fMRI studies show striatal hypometabolism prior to atrophy — used in research, not routine clinical diagnosis. CSF biomarkers: neurofilament light chain (NfL) and mutant huntingtin protein in CSF/blood are established research biomarkers of HD progression and are used in clinical trials.

No disease-modifying treatment is currently available that slows HD neurodegeneration, though multiple mechanisms are under active clinical investigation. Chorea management: tetrabenazine (Xenazine) — vesicular monoamine transporter 2 (VMAT2) inhibitor, reduces chorea by depleting presynaptic dopamine; FDA-approved for HD chorea; major side effects are depression, parkinsonism, and sedation; contraindicated in severe depression. Deutetrabenazine (Austedo) — a deuterium-modified tetrabenazine with improved pharmacokinetics — also FDA-approved for HD chorea with a potentially better side effect profile. Valbenazine is also approved. Antipsychotics (haloperidol, olanzapine, quetiapine): second-line for chorea (reduce dopaminergic transmission) — also used for psychosis, aggression, and irritability. Psychiatric symptom management: antidepressants (SSRIs — sertraline, fluoxetine — preferred) for depression and anxiety; citalopram, sertraline for OCD symptoms; mood stabilisers for mood lability and impulsivity; antipsychotics for psychosis. Multidisciplinary care: specialist HD neurologist; speech and language therapist (dysphagia management — texture-modified diets, PEG tube timing decisions — critical for maintaining nutrition and preventing aspiration pneumonia); physiotherapist (gait, falls prevention, exercise — aerobic exercise may slow cognitive decline); occupational therapist (adaptive equipment, daily living aids); dietitian (high-calorie needs due to chorea — many HD patients require 4,000+ calories/day). Emerging and experimental therapies: antisense oligonucleotides (ASOs) targeting mutant HTT mRNA (tominersen — phase III GENERATION HD1 trial terminated 2021 due to dose-related adverse outcomes; next-generation selective ASOs targeting only the mutant allele in development); RNA interference (siRNA) approaches delivered via convection-enhanced delivery; small molecules targeting kinase pathways, mitochondrial function, and neuroinflammation.

Huntington's disease causes a relentless progression of neurological, psychiatric, and systemic complications. Motor complications: chorea progresses to a rigid-akinetic syndrome in advanced disease — eventually patients are bedridden and unable to walk; falls and injury from uncontrolled choreic movements are common in the middle stages, leading to fractures and traumatic brain injury. Dysphagia and aspiration: impaired swallowing from chorea and progressive bulbar dysfunction leads to aspiration pneumonia — the leading direct cause of death in HD (accounting for approximately 30% of deaths); timing of percutaneous endoscopic gastrostomy (PEG) feeding is a major clinical and ethical decision. Nutritional compromise: the hyperkinetic state of HD massively increases caloric expenditure (up to 4,000–5,000 kcal/day) and weight loss is progressive despite adequate intake; weight loss predicts faster disease progression. Psychiatric complications: depression affects 30–40% of HD patients; anxiety, irritability, and apathy are nearly universal; obsessive-compulsive behaviours and psychosis occur; suicide risk is elevated 4–7-fold compared with the general population — highest in pre-manifest and early manifest HD. Cognitive decline progresses to dementia, with loss of capacity to make medical decisions and participate in clinical trials. Social and care complications: HD destroys the ability to work, manage finances, and maintain relationships — total ADL dependence is reached within 10–15 years of motor onset, placing enormous burden on family carers and requiring residential care in later stages.

Huntington's disease cannot be prevented in at-risk individuals who have inherited the mutation, as it is 100% genetically determined. However, reproductive technologies offer at-risk couples meaningful options. Preimplantation genetic testing (PGT-M — preimplantation genetic testing for monogenic disorders): in vitro fertilisation (IVF) with embryo biopsy and genetic testing of embryos before transfer — only HD mutation-negative embryos are selected for implantation. 'Non-disclosure testing' (also called exclusion testing) uses short tandem repeat (STR) markers to select embryos that have not inherited the at-risk allele from the HD parent, without revealing the parent's own HD status. Prenatal testing: chorionic villus sampling (CVS) at 11-13 weeks or amniocentesis at 15-18 weeks can identify whether a foetus has inherited the HD mutation. All these options require genetic counselling before proceeding. Genetic counselling is strongly recommended for all at-risk individuals — not just those seeking testing — to help understand the genetics, inheritance patterns, testing options, psychological implications, and family planning choices. HD support organisations (Huntington's Disease Association, HDSA) provide essential patient and carer support, including advice on disclosure, legal implications, and clinical trial opportunities.

See a neurologist or specialist HD clinic if: you are at risk of Huntington's disease (parent or sibling with confirmed HD) and are experiencing new neurological, cognitive, or psychiatric symptoms — even subtle ones; you wish to discuss predictive genetic testing or reproductive options; or if a family member receives a new diagnosis of HD. Do not delay — early diagnosis allows proactive planning, access to clinical trials, specialist multidisciplinary care, and important life decisions (insurance, career, family planning) to be made while cognition is intact. Urgent psychiatric assessment is required for: significant depression or suicidal ideation in any person at risk of or diagnosed with HD (suicide risk is elevated throughout the HD journey); and severe aggression or psychosis. The genetic counselling process for predictive testing takes several weeks by design — contact a specialist HD genetics service to begin this process. Anyone with an unexpected involuntary movement disorder (chorea), psychiatric symptoms with a family history of similar neurological or psychiatric symptoms, or a parent who died with dementia should discuss HD genetic testing with their doctor.