Huntington Disease
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Direct answer
Huntington disease is an autosomal dominant neurodegenerative disorder caused by an expanded CAG trinucleotide repeat in the HTT gene on chromosome 4. Repeats of 40 or more give full penetrance, and the expansion grows in successive generations, producing anticipation, especially when inherited from the father. Its features are chorea, cognitive decline and psychiatric change, with caudate atrophy on MRI, and treatment is symptomatic because no disease-modifying therapy is yet established.
What you must remember
- Inheritance: autosomal dominant, with a 50 per cent risk to each child of an affected parent.
- CAG repeats: normal up to 26, intermediate from 27 to 35, reduced penetrance from 36 to 39, and full disease at 40 or more.
- Anticipation: earlier onset and worse disease in successive generations, with the largest expansions on paternal transmission.
- Juvenile form: onset before 20 years, with rigidity and bradykinesia rather than chorea, often seizures and a much larger repeat.
- Chorea: irregular, flitting involuntary movements that worsen with stress; tetrabenazine or deutetrabenazine are used, with monitoring for depression.
- Cognition and mood: executive dysfunction, apathy, irritability and depression, which may precede the movement disorder.
- Imaging: caudate and putamen atrophy on MRI, with frontal volume loss in later stages.
- Genetic testing: CAG repeat analysis with pre-test and post-test counselling; presymptomatic testing follows a formal protocol.
Working through a family with chorea
A 34-year-old woman reports irritability and falling work performance, and her mother developed involuntary movements in her late forties. On examination, she has chorea of the face and limbs with restlessness, and the family history makes Huntington disease the leading diagnosis.
- Exclude secondary causes: Thyrotoxicosis, lupus, drugs such as levodopa and antipsychotics, and pregnancy are excluded before the genetic diagnosis is accepted.
- Image the brain: MRI shows caudate atrophy in keeping with the diagnosis.
- Counsel before testing: Genetic testing is offered with formal counselling, since a positive result has consequences for relatives and for her insurance and employment.
- Treat chorea only when disabling: Tetrabenazine is started at a low dose, with ECG monitoring for QT prolongation and close review for depression and suicidality, a boxed warning for VMAT2 inhibitors.
- Advise relatives: Children of an affected parent are at 50 per cent risk, and testing of minors is not offered for adult-onset disease.
Where the genetics and the chorea get tested
Huntington questions test the repeat cut-offs, the parent-of-origin effect and the chorea differential.
- Trap: Treating a 36 to 39 repeat as certain disease. Correct: This is the reduced penetrance zone, where disease may appear late or not at all.
- Trap: Missing anticipation in juvenile cases. Correct: The parent-of-origin effect is the reason juvenile cases so often come from a father.
- Trap: Calling Sydenham chorea Huntington chorea. Correct: Sydenham chorea in children is immune-mediated after rheumatic fever and resolves, while Huntington chorea is progressive, familial and linked to caudate atrophy.
- Trap: Starting dopamine blockers first without weighing depression risk. Correct: Modern management weighs depression risk, and presymptomatic testing requires counselling and consent, not routine screening.
Frequently asked questions
Which CAG repeat length causes full penetrance in Huntington disease?
A CAG repeat of 40 or more in the HTT gene causes full penetrance in Huntington disease. Repeats of 36 to 39 show reduced penetrance, so disease may appear late or not at all, and intermediate repeats of 27 to 35 do not cause disease but can expand on transmission.
Why does Huntington disease show anticipation?
Huntington disease shows anticipation because the CAG repeat tends to expand as it is passed on, with the largest increases during paternal transmission. The result is earlier onset and more severe disease in each generation, and juvenile-onset cases are more often inherited from the father.
Which drugs control chorea in Huntington disease?
Chorea in Huntington disease is controlled with VMAT2 inhibitors such as tetrabenazine or deutetrabenazine, and antipsychotics are used when these are not tolerated. Depression and suicidality need monitoring with VMAT2 inhibitors, and treatment is started only when chorea is disabling.
How does Huntington chorea differ from Sydenham chorea?
Huntington chorea is a progressive autosomal dominant disorder with a family history, caudate atrophy and cognitive decline. Sydenham chorea is an immune-mediated complication of rheumatic fever in children, usually self-limiting, and it is supported by raised antistreptolysin O titres.