Residency · Residency · Neurology

Huntington Disease and Other Choreas

Overview

Chorea is an involuntary, irregular, unpredictable movement pattern characterized by brief movements that flow randomly from one body part to another. It is distinguished from other hyperkinetic movements by its random, non-patterned quality. Huntington disease (HD) is the most common inherited cause of chorea, but the differential diagnosis is broad, encompassing genetic, autoimmune, metabolic, drug-induced, and vascular etiologies.

Huntington Disease

Genetics

HD follows autosomal dominant inheritance, caused by a CAG trinucleotide repeat expansion in the HTT gene on chromosome 4p16.3, encoding polyglutamine in the huntingtin protein. Normal alleles have fewer than 27 repeats. Intermediate (mutable normal) alleles of 27-35 repeats do not cause disease but may expand in offspring, especially through paternal transmission. Reduced penetrance alleles of 36-39 repeats may or may not produce disease in a given individual. Full penetrance alleles of 40 or more repeats will invariably cause disease if the individual lives long enough. Anticipation, the tendency for repeat length to increase in successive generations (particularly with paternal transmission), leads to earlier onset in subsequent generations. There is an inverse correlation between CAG repeat length and age of onset.

Clinical Features

Motor

Chorea is the most recognizable feature, often beginning distally and progressing to become generalized. Motor impersistence, the inability to maintain sustained contraction, manifests as "milkmaid's grip" and darting tongue movements. Dystonia becomes more prominent as disease progresses and may dominate in juvenile HD. Bradykinesia and rigidity develop in later stages, and the akinetic-rigid presentation (Westphal variant) is more common in juvenile HD. Gait instability causes falls that are a major source of morbidity. Dysarthria and dysphagia are progressive, with aspiration pneumonia being a leading cause of death. Oculomotor abnormalities include impaired saccade initiation and slowed saccades.

Cognitive

Executive dysfunction appears early and prominently, with difficulty in planning, set-shifting, and multitasking. Processing speed is slowed early in the disease. Memory retrieval is impaired more than encoding, reflecting a subcortical pattern. The condition progresses to dementia, though unlike cortical dementias, language and visuospatial function remain relatively preserved in early stages.

Psychiatric

Depression affects up to 40-50% of patients and carries a high suicide risk, particularly around the time of genetic testing and early symptomatic disease. Irritability and aggression are common and disabling for caregivers. Apathy increases with disease progression. OCD-spectrum symptoms manifest as perseveration and rigid thinking. Psychosis occurs less commonly.

Clinical Staging

The Total Functional Capacity (TFC) scale is a 13-point scale rating occupation, finances, domestic chores, activities of daily living, and care level. Stages I through V are based on TFC scores, ranging from Stage I (independent) to Stage V (total care). The Unified Huntington's Disease Rating Scale (UHDRS) provides comprehensive assessment across motor, cognitive, behavioral, and functional domains.

<image>Brain MRI showing characteristic bilateral caudate nucleus atrophy with compensatory lateral ventricle enlargement (box-car ventricles) in Huntington disease</image>

Genetic Testing and Counseling

Diagnostic testing in symptomatic patients involves CAG repeat analysis. Predictive testing in at-risk asymptomatic individuals must follow international guidelines (HDSA/IHA protocol), including mandatory pre-test genetic counseling, a waiting period between counseling and results disclosure, and psychological support before, during, and after testing. Testing of minors is not performed unless medically indicated. Prenatal testing and preimplantation genetic diagnosis are available.

Symptomatic Management of Chorea

VMAT2 inhibitors are first-line therapy. Tetrabenazine was the first FDA-approved drug for HD chorea; it requires three-times-daily dosing and CYP2D6 testing, with side effects including depression, parkinsonism, sedation, and akathisia. Deutetrabenazine is a deuterated form with a longer half-life allowing twice-daily dosing, a better tolerability profile, and no requirement for CYP2D6 testing for initial dosing. Valbenazine, FDA-approved for tardive dyskinesia, is used off-label for HD chorea. Antipsychotics (olanzapine, risperidone, haloperidol) may help chorea and psychiatric symptoms but carry risk of tardive dyskinesia. Benzodiazepines serve an adjunctive role for chorea and anxiety. Treatment is purely symptomatic and does not alter disease progression.

Management of Non-Motor Symptoms

Depression is treated with SSRIs (citalopram, sertraline) or mirtazapine, with ECT available for refractory cases. Irritability responds to SSRIs, mood stabilizers (valproate, carbamazepine), or atypical antipsychotics. Psychosis is managed with atypical antipsychotics, with quetiapine preferred. Apathy is the most treatment-resistant symptom, with limited evidence for any agent. Weight loss requires a high-calorie diet, as patients can burn more than 5000 kcal per day due to chorea.

Disease-Modifying Research

Antisense oligonucleotide (ASO) therapy with tominersen, targeting HTT mRNA, had its Phase 3 trial halted early due to worsening outcomes, but next-generation allele-selective ASOs are in development. RNA interference approaches targeting mutant HTT are under investigation. Small molecules such as branaplam and PTC518 (HTT-lowering compounds) have trials ongoing or paused. CRISPR-based gene editing approaches remain in preclinical stages.

<image>Mechanism of action of VMAT2 inhibitors showing blockade of vesicular monoamine transport leading to depletion of presynaptic dopamine</image>

Other Causes of Chorea

Sydenham Chorea

Sydenham chorea is a post-streptococcal autoimmune chorea and a major criterion for rheumatic fever. It predominantly affects children aged 5-15 and involves anti-basal ganglia antibodies. The condition is self-limited over weeks to months but may recur. Treatment includes penicillin prophylaxis, valproate or carbamazepine for chorea, and immunotherapy in severe cases.

Chorea Gravidarum

Chorea during pregnancy is often a recurrence of Sydenham chorea or unmasking of antiphospholipid syndrome. It may also occur with hormonal contraceptive use.

Autoimmune/Paraneoplastic Chorea

Antibodies associated with chorea include anti-CRMP5 (CV2), anti-Hu, anti-CASPR2, and anti-LGI1. These may be paraneoplastic (associated with small cell lung cancer or thymoma) or purely autoimmune. Bilateral chorea in an adult without family history should prompt antibody testing.

Drug-Induced Chorea

Causes include levodopa (producing dyskinesia in PD), neuroleptic withdrawal (withdrawal-emergent syndrome), oral contraceptives, phenytoin, and stimulants. Tardive dyskinesia is a distinct entity with stereotyped movements but overlaps with chorea.

Vascular Chorea

Contralateral hemichorea or hemiballismus results from subthalamic nucleus or basal ganglia stroke. Nonketotic hyperglycemic chorea-ballism produces characteristic T1 hyperintensity on MRI of the contralateral putamen. These are usually self-limited and may respond to dopamine blockers.

Other Genetic Choreas

Chorea-acanthocytosis (ChAc) is autosomal recessive (VPS13A gene) and features orofacial dystonia with tongue and lip biting, seizures, acanthocytes on peripheral smear, and elevated CK. McLeod syndrome is X-linked (XK gene) and features acanthocytosis, Kell blood group abnormalities, cardiomyopathy, and late-onset chorea. Benign hereditary chorea (DYT/CHOREA-NKX2-1) produces non-progressive chorea with thyroid disease and pulmonary problems (brain-thyroid-lung syndrome). DRPLA (dentatorubral-pallidoluysian atrophy) is a CAG repeat disorder in ATN1 causing chorea, ataxia, seizures, and dementia, more common in the Japanese population. Wilson disease must always be excluded in young patients with chorea plus dystonia.

<image>Diagnostic algorithm for the evaluation of chorea in adults showing stepwise approach from history and examination through laboratory testing, imaging, and genetic testing</image>

Hemiballismus

Hemiballismus manifests as high-amplitude, flinging proximal limb movements and represents the severe end of the chorea spectrum. It most commonly results from a contralateral subthalamic nucleus lesion, typically from stroke or hyperglycemia. Most vascular cases are self-limited over weeks to months. Treatment options include dopamine blockers (haloperidol, risperidone), tetrabenazine, or valproate.

Clinical Pearls

Motor impersistence, specifically the inability to keep the tongue protruded, is more specific for HD than chorea itself and correlates with functional decline. Always check for acanthocytes on a fresh wet-prep peripheral blood smear (not a dried Wright-stained smear), which is necessary to evaluate for neuroacanthocytosis. Juvenile HD (Westphal variant, onset before age 20) presents with rigidity, bradykinesia, seizures, and cognitive decline rather than chorea, and is often misdiagnosed. Suicide risk is highest around the time of genetic testing results and in early symptomatic disease; screening should occur at every visit. Weight loss in HD is multifactorial (hypermetabolism, dysphagia, depression, apathy) and independently predicts faster progression. CYP2D6 poor metabolizers require lower doses of tetrabenazine; genotyping is recommended before initiating therapy. Nonketotic hyperglycemic chorea can be diagnosed by the characteristic T1-bright putaminal lesion on MRI; the hyperglycemia should be corrected first.

References

• Huntington Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell. 1993;72(6):971-983.
• Frank S, Testa CM, Stamler D, et al. Effect of deutetrabenazine on chorea among patients with Huntington disease: a randomized clinical trial (First-HD). JAMA. 2016;316(1):40-50.
• Tabrizi SJ, Flower MD, Ross CA, Wild EJ. Huntington disease: new insights into molecular pathogenesis and therapeutic opportunities. Nat Rev Neurol. 2020;16(10):529-546.
• McColgan P, Tabrizi SJ. Huntington's disease: a clinical review. Eur J Neurol. 2018;25(1):24-34.
• Hermann A, Walker RH. Diagnosis and treatment of chorea syndromes. Curr Neurol Neurosci Rep. 2015;15(2):514.

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