Huntington disease
Description
- Autosomal dominant neurodegenerative disease - chorea + cognitive decline + neuropsychiatric disturbance
- Progressive striatal (caudate > putamen) medium spiny neurone loss
- The clinical triad is motor, cognitive and psychiatric - and the psychiatric features usually come first
Motor phenotype
- Chorea - brief, non-stereotyped, flowing, unpredictable involuntary movements; incorporated into semi-purposeful movement (parakinesia)
- Motor impersistence - inability to sustain tongue protrusion or grip ("milkmaid grip")
- Saccadic abnormalities - slow, hypometric saccades with head thrusts; impaired initiation (often the earliest motor sign)
- Later: dystonia, bradykinesia, rigidity replace chorea; dysarthria, dysphagia, gait ataxia
- Westphal variant - juvenile-onset (<20 yrs), akinetic-rigid rather than choreiform, with seizures, cerebellar signs and rapid decline; almost always paternally transmitted
Epidemiology
- Prevalence ~5-10 per 100,000 in populations of European ancestry; much lower in Japanese, Chinese and African populations
- Mean age of onset 35-45 yrs; range 2-80
- M=F
- Juvenile (<20 yrs) ~5-10%; late-onset (>60) ~10-25%, usually milder with smaller repeats
Aetiopathogenesis
Genetics
- *Expanded CAG trinucleotide repeat in HTT (huntingtin), chromosome 4p16.3* -> expanded polyglutamine tract
- Autosomal dominant, essentially complete penetrance above the threshold
| CAG repeats | Meaning |
|---|---|
| <=26 | Normal |
| 27-35 | Intermediate - not affected, but unstable in transmission -> offspring at risk |
| 36-39 | Reduced/variable penetrance - may or may not develop disease, often late |
| >=40 | Full penetrance - disease certain if lifespan permits |
- Repeat length inversely correlates with age of onset (explains ~50-70% of the variance - not enough to predict onset for an individual)
- Anticipation - repeat expands in successive generations -> earlier and more severe disease
- *Predominantly with PATERNAL transmission* - spermatogenesis shows far greater repeat instability and expansion than oogenesis or somatic tissue
- Hence juvenile HD is almost always inherited from the father
- Somatic instability in striatal neurones (driven by DNA mismatch repair genes MSH3, FAN1) is now understood as the main modifier of onset - and the target of the current therapeutic pipeline
Mechanism
- Mutant huntingtin -> toxic gain of function + loss of normal wild-type function
- -> nuclear inclusions, transcriptional dysregulation (CREB-binding protein, REST/NRSF), mitochondrial dysfunction, impaired axonal transport, dec BDNF to the striatum
- Selective loss of GABAergic medium spiny neurones of the striatum
- Indirect pathway lost first -> disinhibition of the thalamus -> chorea
- Direct pathway loss later -> akinetic-rigid phase
- Cortical atrophy follows
Diagnosis
Clinical
- Motor - chorea, motor impersistence, oculomotor abnormalities, later parkinsonism and dystonia
- Cognitive - a subcortical/frontal-executive dementia
- Impaired emotional recognition (especially anger and disgust - present years before diagnosis)
- Slowed processing speed
- Visuospatial and executive dysfunction
- Memory storage is relatively preserved early; retrieval and organisation are not. Insight is often retained - which is its own cruelty
- Psychiatric - frequently the presenting complaint, years before motor onset (see Associations)
- Family history - absent in up to 8% (non-paternity, adoption, late-onset or undiagnosed parent, new expansion from an intermediate allele). Its absence does not exclude HD
Investigation of chorea - the framework
- Detailed history: family history across 3 generations, drug history, sexual health, systemic symptoms
- *Genetic testing for CAG repeat expansion in HTT* - the definitive test (>=36 repeats is disease-causing**)
- Exclude the mimics:
| Cause | Clue |
|---|---|
| Drug-induced | Levodopa, antipsychotics (tardive), anticonvulsants, oral contraceptive, cocaine, amphetamine |
| Sydenham chorea | Clinical diagnosis; post-streptococcal, supported by carditis; ASOT, echocardiogram |
| Wilson disease | Low serum caeruloplasmin, high 24-h urinary copper, KF rings, deranged LFTs, age <50 |
| SLE / antiphospholipid syndrome | ANA, dsDNA, lupus anticoagulant, anticardiolipin |
| Thyrotoxicosis | TFTs |
| Polycythaemia, hypo/hyperglycaemia, hypocalcaemia | FBE, BSL, calcium |
| HIV, neurosyphilis | Serology |
| Neuroacanthocytosis | Blood film for acanthocytes, high CK, orofacial dystonia with tongue/lip biting |
| HD phenocopies | C9orf72, HDL2 (African ancestry), SCA17, DRPLA, benign hereditary chorea (NKX2-1, with hypothyroidism and lung disease) |
| Vascular | Hemichorea from a contralateral subthalamic/basal ganglia lesion |
Imaging
- MRI: caudate head atrophy -> "boxcar" ventricles, inc frontal horn/caudate ratio; putaminal atrophy
- Normal early - imaging does not exclude HD, and is not needed if genetics are positive
Predictive testing - a formal protocol, not a blood test
- Pre-test genetic counselling, psychiatric/suicide risk assessment, a support person, and a separate results appointment are mandatory
- Never test an asymptomatic minor; never test without the individual's own informed request
- Discuss insurance, employment and reproductive implications before testing
- Reproductive options: prenatal testing, preimplantation genetic diagnosis (avoids disclosing the parent's own status), donor gametes
- Only ~5-20% of at-risk people choose to be tested
Management
No disease-modifying therapy exists. Everything below is symptomatic, and the multidisciplinary team does more than any drug.
A. Chorea
- Treat only if functionally disabling or causing injury/weight loss - many patients are less troubled by chorea than their family is
- VMAT2 inhibitors - first-line
| Agent | Notes |
|---|---|
| Tetrabenazine | The agent available in Australia. Depression and suicidality - a boxed warning; parkinsonism, sedation, akathisia; CYP2D6 metaboliser status affects dosing |
| Deutetrabenazine | Deuterated - longer half-life, twice-daily, better tolerated |
| Valbenazine | Once daily, single active metabolite; preferred where psychiatric comorbidity is prominent |
- Second-line: atypical antipsychotics - olanzapine, risperidone, tiapride
- Preferred where there is coexisting psychosis, agitation or weight loss (appetite stimulation is an advantage here)
- Amantadine and riluzole have weak and inconsistent evidence
- Withdraw or reduce anything that worsens chorea before adding drugs
B. Psychiatric - the highest-yield target
- Depression - SSRI (doubles as treatment for irritability and OCD features); screen for suicidality at every visit
- Irritability/aggression - SSRI first, then antipsychotic; behavioural and environmental strategies before drugs
- Apathy - rarely drug-responsive; structure, routine and activity scheduling; avoid sedating agents
- Psychosis - atypical antipsychotic
- OCD/perseveration - SSRI, clomipramine
- *Do not treat apathy as depression - and do not treat irritability with benzodiazepines*
C. Cognitive
- No agent works - cholinesterase inhibitors and memantine are ineffective
- Environmental structure, written cues, single-step instructions, routine
- Early advance care planning and enduring guardianship while capacity is retained
D. Multidisciplinary and supportive
- Dysphagia - speech pathology review, texture modification; aspiration pneumonia is the commonest cause of death
- Discuss PEG early, as part of advance care planning
- Weight loss - high-calorie diet; a rising energy requirement is intrinsic to the disease, not just chorea; weigh at every visit
- Physiotherapy and OT - falls prevention, home modification, wheelchair seating
- Social work - Centrelink/NDIS, driving cessation, employment, carer support
- Genetic counselling for the whole family
- Predictive suicide risk peaks at two points: around predictive testing and around loss of independence
- Palliative care involvement well before the terminal phase
E. Emerging
- Antisense oligonucleotides and huntingtin-lowering therapy (tominersen, AMT-130) remain investigational - tominersen failed at high dose and is being re-trialled in younger, earlier patients
- Pridopidine - fast-tracked but not approved
- Somatic instability modifiers (MSH3) are the current target of interest
Associations
Neuropsychiatric features - prevalence
- Apathy ~28% (the feature that correlates best with functional decline)
- Depression ~13%, irritability ~13%, OCD symptoms ~13%
- Psychosis ~1% - uncommon but disabling
- Suicide risk 2-7x the general population; ideation in up to 20%
- Also: disinhibition, sexual disinhibition, aggression, substance misuse
Systemic
- Weight loss and cachexia despite adequate intake
- Sleep disturbance - circadian phase advance, insomnia, reduced sleep efficiency
- Testicular atrophy, osteoporosis, glucose intolerance/diabetes
- Cardiac autonomic dysfunction
Related repeat expansion phenocopies
- C9orf72 expansion, HDL2 (junctophilin-3, African ancestry), SCA17, DRPLA, neuroferritinopathy, chorea-acanthocytosis
Natural history & complications
- Median survival 15-20 years from motor onset; juvenile-onset is faster (~10 years)
- Progression is relentless and roughly linear - measured with the UHDRS Total Functional Capacity score
- Phase sequence: prodromal (psychiatric, subtle cognitive and oculomotor change) -> chorea-dominant -> akinetic-rigid, mute, immobile
- Chorea often diminishes late - deterioration continues regardless
Causes of death
- Aspiration pneumonia (commonest)
- Suicide - the second commonest; risk highest around predictive testing and at loss of independence
- Cachexia, falls and trauma, cardiovascular disease
Monitor
- UHDRS motor, TFC and cognitive scores; weight at every visit
- Depression and suicidality at every visit
- Swallow safety, falls, capacity, carer strain
- Tetrabenazine: depression, parkinsonism, QT
- Family: predictive testing needs, reproductive counselling, at-risk relatives
Complications
- Dysphagia -> aspiration and malnutrition
- Falls, fractures, pressure injury, contracture
- Incontinence, immobility
- Carer burden and family breakdown; children in a household with an affected parent, themselves at 50% risk
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