Autosomal dominant CAG trinucleotide repeat disorder producing chorea, psychiatric symptoms, and progressive cognitive decline.
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Risk factors
- Affected parent (autosomal dominant inheritance; 50% risk to each offspring)
- Paternal transmission predisposes to anticipation — earlier onset and longer repeat in next generation
- CAG repeat length: ≥40 fully penetrant; 36-39 reduced penetrance; 27-35 intermediate (no disease but risk of expansion); ≤26 normal
Pathophysiology
Expanded CAG repeats produce mutant huntingtin protein with an elongated polyglutamine tract that misfolds, aggregates, and causes selective neuronal degeneration. Medium spiny GABAergic neurons of the striatum are preferentially lost, particularly those projecting to the lateral globus pallidus (indirect pathway), producing disinhibition of thalamocortical drive and chorea. Cortical neurodegeneration contributes to cognitive decline.
Clinical presentation
Symptoms
- Movement: chorea (early), dystonia, bradykinesia, dysarthria, dysphagia, gait impairment; rigidity in juvenile or late disease
- Psychiatric (often the first complaint): depression, irritability, apathy, anxiety, obsessive-compulsive features, psychosis; elevated suicide risk
- Cognitive: subcortical dementia with executive dysfunction, impaired attention, and slowed processing — memory relatively preserved until later
- Weight loss despite adequate caloric intake
Signs / physical exam
- Chorea — involuntary, brief, irregular, dance-like movements that flit from one body part to another
- Motor impersistence ('milkmaid grip' — inability to maintain sustained tongue protrusion or hand grip)
- Abnormal saccades — slow and hypometric, often the earliest motor sign
- Oculomotor apraxia (head thrust to initiate gaze)
- Hyperreflexia and gait instability
Classic findings
Adult with new chorea + family history of dementia or movement disorder + early personality change.
Differential diagnosis
- Sydenham chorea — Post-streptococcal, children/young adults, self-limited, jerking movements with hypotonia, anti-streptolysin O
- Wilson disease — Young adult with movement disorder + hepatic dysfunction, Kayser-Fleischer rings, low ceruloplasmin, high 24-h urinary copper
- Drug-induced chorea — Levodopa, neuroleptics (tardive), stimulants, cocaine, oral contraceptives, antiepileptics
- Neuroacanthocytosis — Chorea + acanthocytes on smear + elevated CK + self-mutilation behaviors
- Benign hereditary chorea — Childhood onset, non-progressive, TITF1 mutation
- C9orf72 expansion — Can produce HD phenocopy with motor and behavioral features
- SLE / antiphospholipid syndrome — Chorea in young woman with autoimmune features
Diagnostic workup
Diagnostic criteria
Clinical motor signs + positive genetic test (CAG ≥36, fully penetrant ≥40).
Labs
- Genetic testing for CAG repeat number in HTT (diagnostic and predictive)
- Pre-test and post-test counseling are mandatory for presymptomatic testing
- Rule out mimics: ceruloplasmin and 24-h urine copper, peripheral smear for acanthocytes, anti-streptolysin O, ANA/lupus serologies, TFTs
Imaging
- MRI brain — caudate atrophy with enlarged frontal horns of lateral ventricles ('boxcar ventricles'); later cortical atrophy
- FDG-PET shows striatal hypometabolism preceding atrophy
Treatment
First-line
- Tetrabenazine or deutetrabenazine — VMAT2 inhibitors that deplete presynaptic dopamine; reduce chorea. Monitor for depression/suicidality, parkinsonism, QT prolongation
- Valbenazine — newer VMAT2 inhibitor with similar efficacy and arguably better tolerability
- Atypical antipsychotics (olanzapine, risperidone, quetiapine, aripiprazole) — useful when chorea coexists with psychosis or aggression
- SSRIs (sertraline, citalopram, escitalopram) for depression and irritability
- Speech and swallow therapy; PT/OT; nutrition counseling for caloric intake
Juvenile-onset (Westphal)
- Rigidity and dystonia predominate over chorea — VMAT2 inhibitors often unhelpful
- Levodopa or dopamine agonists may help rigidity
- Seizure management with standard AEDs
Genetic counseling
- Presymptomatic testing reserved for adults with mature decision-making capacity after multidisciplinary counseling
- Prenatal and preimplantation genetic diagnosis available
- Address insurance and confidentiality concerns
Second-line / adjunct
- Amantadine for chorea (limited evidence)
- Botulinum toxin for focal dystonia
- Hospice/palliative care in advanced disease
Complications
- Aspiration pneumonia — most common cause of death
- Falls and traumatic injury
- Severe weight loss / malnutrition
- Suicide (substantially elevated risk, particularly around the time of genetic diagnosis and loss of independence)
- Loss of capacity for ADLs and need for institutional care
PANCE pearls
- VMAT2 inhibitors can precipitate or worsen depression and suicidality — screen psychiatric status at every visit.
- Anticipation is more pronounced with paternal inheritance — sons of an affected father may present earlier.
- Slow saccades and motor impersistence appear before frank chorea — examine eye movements and ask the patient to stick out the tongue.
- Avoid antidopaminergic agents for non-essential nausea/sedation when atypical agents are available — they can worsen parkinsonism in late disease.
- Caudate atrophy on MRI is a late finding; normal imaging does not exclude HD when CAG repeat is positive.
References
- AAN 2012 — Armstrong MJ, Miyasaki JM. Evidence-based guideline: Pharmacologic treatment of chorea in Huntington disease. Neurology 2012;79:597-603.
- EHDN — European Huntington's Disease Network guidelines on genetic testing (Mac Leod et al., Clin Genet 2013).
- TETRA-HD — Huntington Study Group. Tetrabenazine as antichorea therapy in Huntington disease. Neurology 2006;66:366-372.
- First-HD — Huntington Study Group. Effect of deutetrabenazine on chorea among patients with HD. JAMA 2016;316:40-50.
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