What are the diagnosis and management strategies for Huntington's chorea?

Huntington's Chorea: Diagnosis and Management

Diagnosis

Genetic testing for CAG repeat expansion in the huntingtin gene on chromosome 4p16.3 is the definitive diagnostic test for Huntington's disease (HD), with ≥40 CAG repeats confirming the diagnosis and providing 100% specificity. 1

Genetic Testing Approach

• CAG repeat interpretation: 1

  • ≥40 repeats: Fully penetrant, confirms HD diagnosis
  • 36-39 repeats: Variable penetrance, associated with both affected and unaffected individuals
  • 27-35 repeats: Rare, not convincingly associated with HD phenotype but may be mutable
  • ≤26 repeats: Never associated with HD phenotype

• Genetic counseling is mandatory before testing, particularly given the autosomal dominant inheritance with complete penetrance for alleles ≥40 repeats 1

• Pre-manifest diagnosis should only be performed by multidisciplinary teams in healthy at-risk adults who specifically request testing 2

Imaging Evaluation

MRI brain without IV contrast is the optimal initial imaging modality, though it may be normal early in disease course. 1, 3

• MRI findings in established HD: Progressive marked atrophy of the neostriatum, particularly the caudate nucleus head with enlargement of frontal horns of lateral ventricles, and abnormal T2 signal (hyperintensity or hypointensity) in the caudate and putamen 1

• CT head is not preferred due to limited soft-tissue characterization, though it may exclude other etiologies of chorea such as cerebrovascular disease or acute infectious/inflammatory processes 1

• FDG-PET/CT has insufficient evidence for initial evaluation, though it may demonstrate early neostriatal hypometabolism in known gene carriers before structural changes appear 1

Differential Diagnosis Considerations

The diagnostic workup must consider other causes of chorea beyond HD, including: 1

• Cerebrovascular disease
• Infectious etiologies
• Autoimmune conditions (systemic lupus erythematosus, antiphospholipid syndrome)
• Metabolic disorders
• Drug-induced syndromes
• Other genetic neurodegenerative disorders

Management

Pharmacological Treatment for Chorea

Tetrabenazine, a VMAT2 inhibitor, is FDA-approved for treating chorea in HD and demonstrated a statistically significant 3.5-unit reduction in Total Chorea Score compared to placebo. 4

Tetrabenazine Dosing Protocol 4

Initial dosing (up to 50 mg/day):

• Start at 12.5 mg once daily in the morning
• After 1 week, increase to 25 mg/day (12.5 mg twice daily)
• Titrate slowly at weekly intervals by 12.5 mg increments
• Doses of 37.5-50 mg/day should be given three times daily
• Maximum single dose: 25 mg

Dosing above 50 mg/day:

• Requires CYP2D6 genotyping to determine if patient is a poor metabolizer (PM) or extensive metabolizer (EM) 4
• For extensive/intermediate metabolizers: Continue weekly titration by 12.5 mg increments
• Maximum daily dose: 100 mg (given three times daily)
• Maximum single dose: 37.5 mg

Critical Safety Considerations

BLACK BOX WARNING: Tetrabenazine increases risk of depression and suicidality in HD patients. 4

• Contraindicated in: Actively suicidal patients and those with untreated or inadequately treated depression 4
• Close monitoring required for emergence or worsening of depression, suicidality, or unusual behavioral changes 4
• Exercise particular caution in patients with history of depression or prior suicide attempts, which are already increased in HD 4

If adverse reactions occur (akathisia, restlessness, parkinsonism, depression, insomnia, anxiety, sedation): Stop titration and reduce dose; consider withdrawing treatment or initiating specific treatment (e.g., antidepressants) if reactions persist 4

Alternative Pharmacological Approaches

• For autoimmune-related chorea: Antiplatelet and/or anticoagulation therapy for antiphospholipid antibody syndrome 3
• For SLE-related chorea: Glucocorticoids alone or combined with immunosuppressive therapy (azathioprine, cyclophosphamide) 3
• For refractory autoimmune cases: Pulse IV methylprednisolone with IV cyclophosphamide 3

Non-Pharmacological Management

• Speech therapy is beneficial for orofacial chorea affecting speech and swallowing 3, 5
• Occupational therapy assists with activities of daily living impacted by choreiform movements 3, 5

Clinical Course and Prognosis

• Average age of onset: 35-45 years 1
• Disease progression: Symptoms progress to death within 15-20 years of onset 1
• Juvenile HD (onset <20 years): Occurs in ~5% of cases, presents with rigidity, spasticity, and intellectual decline rather than chorea; CAG repeats often exceed 55 1, 2
• Most common cause of death: Pneumonia, followed by suicide 2

Important Clinical Pitfalls

• Imaging may be normal early in disease course, so negative MRI does not exclude HD—proceed with genetic testing if clinical suspicion remains 1
• Real-world treatment patterns show only 36.1% of patients with chorea receive indicated medications, with approximately half of treated patients receiving off-label alternatives instead of VMAT2 inhibitors 6
• Tetrabenazine effects are reversible—chorea scores returned to baseline 1 week after discontinuation in clinical trials 4
• Functional capacity may decline despite chorea improvement with tetrabenazine, as demonstrated by decrements in activities of daily living scores 4