Key Facts

Huntington disease (HD) is a devastating progressive neurodegenerative condition with autosomal dominant inheritance. Diagnosis carries profound implications for the patient and family. Predictive genetic testing is available but requires careful genetic counselling.

Epidemiology

Prevalence ~12 per 100,000 in UK/Europe (higher than previously estimated). Incidence ~0.5-1 per 100,000 per year. Mean age of onset 35-45 years. Juvenile HD (<20 years) accounts for ~5% (more rapid progression, rigidity > chorea). Equal sex distribution.

Aetiology

Expansion of CAG trinucleotide repeat in exon 1 of HTT gene (chromosome 4p16.3). Normal: <26 repeats. Full penetrance: ≥40 repeats. The number of CAG repeats correlates inversely with age of onset. Anticipation: repeat length tends to increase with paternal transmission (spermatogenesis — meiotic instability), leading to earlier onset in successive generations.

Pathophysiology

Mutant huntingtin protein (polyglutamine expansion) misfolds and aggregates → intranuclear inclusions → progressive neuronal dysfunction and death. Preferential neurodegeneration of medium spiny neurones in the caudate nucleus and putamen (striatum) → loss of inhibitory output to the globus pallidus externa → excessive thalamic inhibition → reduced cortical excitation → chorea (initially) and later rigidity/akinesia. Cortical atrophy also occurs (frontal > temporal) → cognitive decline.

Motor Features

• Chorea: involuntary, irregular, non-repetitive, flowing movements; most characteristic feature; affects face, trunk, and limbs; may be subtle early (fidgeting, clumsiness)
• Dystonia: more prominent as disease progresses
• Rigidity and akinesia: late features (replace chorea as disease advances — "Westphal variant" in juvenile HD)
• Oculomotor abnormalities: slowed saccades (early sign), gaze impersistence
• Dysarthria and dysphagia: progressive
• Gait disturbance: wide-based, dance-like

Cognitive Features

• Executive dysfunction (early): planning, multitasking, problem-solving
• Progressive subcortical dementia: memory, attention, concentration
• Eventual severe dementia

Psychiatric Features (Often Precede Motor Symptoms)

• Depression (40-50% — commonest psychiatric feature; high suicide risk)
• Irritability and aggression
• Apathy
• Psychosis (hallucinations, paranoid delusions — ~10%)
• OCD-like behaviours

Red Flags

• Chorea + cognitive decline + psychiatric symptoms + positive family history
• Juvenile onset: rigidity > chorea, seizures, rapid progression
• Suicide risk: 4× general population (especially around diagnosis and loss of independence)

Genetic Testing

• HTT gene CAG repeat count: diagnostic; ≥40 repeats = fully penetrant; 36-39 = reduced penetrance; 27-35 = intermediate (may expand in next generation)
• Predictive testing: for at-risk individuals (offspring of affected parent — 50% risk); requires genetic counselling (minimum 2 sessions), psychological assessment, and informed consent; performed in specialist genetics centres

Imaging

• MRI brain: caudate nucleus atrophy (loss of convexity of caudate heads → ex vacuo dilatation of frontal horns of lateral ventricles — "boxcar" ventricles); cortical atrophy (frontal predominant)
• CT brain: may show caudate atrophy but less sensitive than MRI

Bloods

• Copper, caeruloplasmin: exclude Wilson disease in young-onset chorea
• Blood film: acanthocytes (neuroacanthocytosis)
• TFTs: thyrotoxicosis (chorea)
• Autoantibodies: SLE, antiphospholipid syndrome

Pharmacological (Symptomatic Only)

• Chorea: tetrabenazine 12.5-100 mg/day (vesicular monoamine transporter 2 (VMAT2) inhibitor — depletes dopamine; main side effects: depression, sedation, parkinsonism); NICE recommendation
  • Alternative: sulpiride, olanzapine, risperidone (if tetrabenazine not tolerated)
  • Deutetrabenazine (modified formulation — fewer side effects; not yet widely available in UK)
• Depression: SSRIs (citalopram, sertraline) — first-line; mirtazapine if insomnia/weight loss; monitor suicide risk
• Psychosis/aggression: olanzapine, risperidone, quetiapine (low-dose atypical antipsychotics)
• OCD features: SSRIs (fluoxetine, sertraline)
• Insomnia: zopiclone, melatonin

Non-pharmacological

• MDT: neurology, psychiatry, genetic counselling, physiotherapy, occupational therapy, speech and language therapy, dietitian, social work, palliative care
• Physiotherapy: maintain mobility, prevent falls, stretching (contractures)
• Speech and language therapy: swallowing assessment (aspiration risk), communication aids
• Dietitian: weight loss is common (hypermetabolism + dysphagia); high-calorie diet, PEG feeding in advanced disease
• Psychological support: for patient and family (carers)

Genetic Counselling

• All patients and at-risk family members should be offered genetic counselling
• Predictive testing protocol: ≥2 counselling sessions, psychological assessment, informed consent, no obligation to test
• Prenatal testing and pre-implantation genetic diagnosis (PGD) available

Palliative Care

• Early involvement recommended; advance care planning
• End-of-life: aspiration pneumonia, cachexia, falls are common causes of death

Referral Criteria

• All suspected HD: specialist neurogenetics service
• Psychiatric input: depression, psychosis, suicide risk
• Palliative care: early referral for symptom management and advance planning

Mean survival 15-20 years from symptom onset. Juvenile HD has more rapid course (8-10 years). Death usually from aspiration pneumonia, cardiovascular disease, or suicide. Suicide risk is 4× general population (particularly around time of diagnosis, loss of driving, loss of independence). Chorea tends to peak then decline as rigidity/akinesia supervene. Cognitive and functional decline is relentless. There is no disease-modifying treatment (antisense oligonucleotides and gene-silencing therapies are in clinical trials — GENERATION-HD1 was discontinued but newer approaches continue).

CAG Repeat Classification

Trinucleotide Repeat Disorders (Comparison)