What are the causes of chorea?

Causes of Chorea

Primary Genetic Causes

Huntington's disease is the most common cause of adult-onset chorea, resulting from CAG repeat expansions (≥40 repeats) in the huntingtin gene on chromosome 4p16.3, with 100% specificity for diagnosis. 1, 2, 3

• Benign hereditary chorea is caused by NKX2-1/TITF1 gene mutations on chromosome 14q13.3, typically presenting in childhood with non-progressive chorea 1, 2
• Paroxysmal kinesigenic dyskinesia (PKD) is primarily caused by PRRT2 gene mutations with 60-90% penetrance, manifesting as brief episodes of chorea triggered by sudden voluntary movements 1
• Huntington disease-like syndromes (HDL1-3), spinocerebellar ataxias (types 1,3, and 17), neuroacanthocytosis, dentatorubro-pallidoluysian atrophy (DRPLA), and inherited prion disease represent important genetic phenocopies 4
• Ataxia-telangiectasia presents with cerebellar ataxia, choreoathetosis, oculomotor apraxia, immunodeficiency, and elevated alpha-fetoprotein levels 2
• Wilson's disease must be excluded via serum ceruloplasmin measurement, particularly in younger patients with chorea 2

Autoimmune and Inflammatory Causes

Sydenham's chorea accounts for approximately 96% of acute-onset chorea cases in children, associated with Group A Streptococcal infection, and can be unilateral in 30% of cases. 1, 2

• Common associated features include behavioral changes (46%), dysarthria (67%), gait disturbance (51%), and deteriorating handwriting (29%) 2
• Carditis is the most frequent concurrent major Jones criterion, occurring in 44% of Sydenham's chorea cases 2
• Documenting recent streptococcal infection can be difficult due to the long latent period (weeks to months) between infection and chorea onset; elevated antistreptolysin O, anti-deoxyribonuclease B, or positive streptozyme support diagnosis 2
• Systemic lupus erythematosus and antiphospholipid syndrome are important autoimmune causes requiring exclusion 2, 4
• Anti-NMDAR receptor encephalitis should be considered in younger children with acute chorea 5

Metabolic and Endocrine Causes

Essential metabolic screening includes thyroid function tests, serum calcium, phosphorus, parathyroid hormone, blood glucose, and serum ceruloplasmin to identify treatable causes. 1, 2

• Hyperthyroidism, hypoparathyroidism, and hypoglycemia are reversible metabolic causes requiring prompt identification and correction 1, 2
• Kernicterus (bilirubin encephalopathy) can cause choreoathetosis in neonates 2
• Polycythemia rubra vera is a rare hematologic cause of chorea 4

Vascular Causes

Acute cerebral infarction involving the contralateral hemisphere, basal ganglia, thalamus, or corpus callosum can produce hemichorea or generalized chorea. 1

• Vascular chorea typically presents acutely with corresponding neuroimaging findings on brain MRI 2

Drug-Induced Causes

Neuroleptics are the most common drug-induced cause, producing tardive dyskinesia after prolonged exposure; discontinuing the offending agent and periodic monitoring of patients on long-term neuroleptics is essential. 1, 2

• Drug-induced chorea can also occur during treatment of neuropsychiatric conditions, making it challenging to distinguish from underlying neurodegenerative disease 6

Structural and Perinatal Causes

Dyskinetic cerebral palsy should be considered in younger children with chronic chorea, particularly with history of perinatal hypoxic-ischemic injury 5

Pregnancy-Related Causes

Chorea gravidarum occurs during pregnancy and may represent unmasking of underlying genetic susceptibility or autoimmune mechanisms 4

Infectious Causes

HIV/AIDS can cause chorea through direct CNS involvement or opportunistic infections affecting the basal ganglia 4

Dialysis-Related Causes

In hemodialysis patients treated for 12-24 months or longer, elevated plasma aluminum levels (150-350 µg/L for dialysis encephalopathy; 400-1,000 µg/L for acute neurotoxicity) can cause motor disturbances including chorea-like movements. 2

• Severe hyperkalemia or metabolic acidosis in hemodialysis patients warrants continuous ECG monitoring due to arrhythmia risk 2

Diagnostic Approach Algorithm

Brain MRI without contrast is the optimal initial imaging modality to identify structural lesions, vascular abnormalities, basal ganglia changes, and neurodegenerative patterns. 1, 2, 3

For suspected Huntington's disease, genetic testing for CAG repeat expansion provides definitive diagnosis with 100% specificity when ≥40 repeats are present, but mandatory genetic counseling must precede testing. 3

Neuroimaging in Sydenham's chorea (performed in 58% of cases) typically does not contribute to diagnosis and should be restricted to atypical presentations. 2

Critical Pitfalls to Avoid

• Do not miss treatable causes: Wilson's disease, thyroid dysfunction, calcium-phosphate abnormalities, glucose disturbances, and autoimmune conditions require immediate identification 2
• Do not use high-dose deferoxamine (20-40 mg/kg) in patients with substantial aluminum loading without extreme caution, as it can precipitate fatal acute aluminum neurotoxicity 2
• Do not overlook that approximately 30% of Sydenham's chorea presents as hemichorea, which can mimic stroke or structural lesions 2
• Do not forget that juvenile Huntington's disease (onset <20 years, ~5% of cases) presents with rigidity and spasticity rather than chorea, often with CAG repeats >55 3
• Patients with ataxia-telangiectasia must avoid ionizing radiation and x-rays due to increased radiosensitivity 2