Huntington Disease
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Direct answer
Huntington disease follows a CAG trinucleotide expansion of 36 or more repeats in the HTT gene: 40 and above is fully penetrant, 36-39 shows reduced penetrance, and paternal transmission drives anticipation so children present earlier than parents — juvenile (Westphal) cases usually exceed 60 repeats. Clinically it is the triad of movement disorder, subcortical-type dementia and psychiatric disturbance, typically emerging in the thirties-forties with insidious clumsiness evolving into chorea, irritability or depression preceding the motor diagnosis by years, and executive dysfunction early. Pathology is striatal: medium spiny neuron loss and caudate atrophy with neuronal intranuclear inclusions of mutant huntingtin. There is no disease-modifying therapy; tetrabenazine, deutetrabenazine or valbenazine suppress chorea, antipsychotics manage psychosis and severe behavioural disruption, and structured genetic counselling governs predictive testing in relatives.
What you must remember
- Genetic threshold ladder: 27 CAG repeats or fewer normal; 27-35 intermediate (never affected, may expand in paternal transmission); 36-39 reduced penetrance; 40 and above fully penetrant.
- Anticipation direction: expansion is paternal driven, so early-onset and juvenile disease usually arrive through affected fathers; juvenile Westphal variant (under 20 years) is akinetic-rigid with dystonia, seizures and academic decline rather than chorea.
- Pathology sequence: early loss of indirect-pathway medium spiny neurons in the caudate (chorea), later direct-pathway loss (bradykinesia and rigidity); Vonsattel grades 0-4 striatal atrophy; grossly box-car ventricles.
- Psychiatry precedes neurology: irritability, apathy, depression, obsessive-compulsive traits and rarely hyposexuality appear on average years before chorea — a favourite "which feature came first" stem.
- Chorea pharmacology: tetrabenazine and deutetrabenazine deplete vesicular dopamine (VMAT2 inhibitors) but can cause depression and parkinsonism; valbenazine is more selective; antipsychotics (risperidone, olanzapine, quetiapine) when psychosis coexists.
- Predictive testing protocol: adults only (18 and above), pre-test counselling, accompanied decision-making, right not to know, results given in person, no testing of minors for untreatable adult disease — the examinable ethics.
- Mimics to keep honest: Huntington phenocopies (SCA17, C9orf72, DRPLA), neuroacanthocytosis (bitten tongue, elevated creatine kinase, acanthocytes on blood film), Wilson disease and drug-induced chorea — a negative HTT test in a chorea-plus syndrome does not end the workup.
A family seen across two generations
A 44-year-old bank manager is brought in for "fidgeting" that colleagues noticed first. Chorea of the hands and face, impersistence of tongue protrusion, an irritable edge to the history, and slowed trail-making on cognitive screening form the clinical picture; his father died in a psychiatric facility labelled with dementia, and MRI shows caudate atrophy with box-car ventricles. HTT testing returns 44 CAG repeats, confirming the diagnosis without further tests. Management is arranged in layers: chorea that embarrasses but does not disable is left untreated; when it progresses, deutetrabenazine is started low and titrated, with mood monitored because the drug and the disease both depress. A social worker addresses employment; a Will is made while executive function allows. Then the harder consultation: his 24-year-old daughter requests "the blood test". The protocol answer is staged — counselling sessions, a support person, a set date for result disclosure, and an explicit offer of withdrawal at any point — because a positive result is untreatable information with insurance, marriage and employment consequences, particularly acute in the Indian context where predictive testing requests frequently come from the family rather than the at-risk person, and where a relative may accompany the patient asking to be tested "for the family".
Where candidates slip
Chorea is not Huntington disease until genetics says so: benign hereditary chorea, oral contraceptive-induced chorea, post-streptococcal (Sydenham) chorea with its long latency after infection, and antipsychotic withdrawal all enter differential stems. The second error is treating the gene count as prognosis arithmetic — repeat length correlates with age at onset on average but predicts little for the individual, and the CAG-age product is a research tool, not clinical guidance. Finally, juvenile Huntington presents without chorea; a rigid-dystonic child with seizures and a positive family history is Westphal until excluded.
Frequently asked questions
At what CAG repeat number does Huntington disease become fully penetrant?
Forty repeats or above; 36-39 repeats show reduced penetrance, and 27-35 are intermediate alleles that can expand paternally in the next generation.
Why does juvenile Huntington disease lack chorea?
Massive repeat expansions (often above 60) degenerate both indirect and direct pathways early, producing an akinetic-rigid Westphal variant with dystonia, seizures and cognitive decline.
Which drug class is first-line for disabling chorea?
VMAT2 inhibitors — tetrabenazine, deutetrabenazine or valbenazine — with watchful monitoring for depression, sedation and parkinsonism.
What does MRI show in established Huntington disease?
Caudate head atrophy producing box-car-shaped lateral ventricles, with proportional wider striatal and cortical loss at later stages.
What safeguards govern predictive genetic testing in an at-risk adult?
Adult-only testing after counselling, an accompanied and scheduled disclosure process, the unconditional right not to know or withdraw, and no third-party or prenatal pressure.