A 58-year-old man from Mumbai presents with involuntary jerky movements of his limbs and face that worsen with emotional stress and improve with voluntary movement. He has a family history of similar illness in his father and paternal uncle. Genetic testing confirms a CAG trinucleotide repeat expansion. On examination, he shows hyperkinetic movements and mild cognitive decline. What is the most appropriate immediate management strategy?

Explanation

## Clinical Diagnosis **Key Point:** The presentation—involuntary choreiform movements, family history of autosomal dominant inheritance, CAG repeat expansion, and emotional exacerbation—is diagnostic of **Huntington disease (HD)**. ## Basal Ganglia Pathophysiology in Huntington Disease ```mermaid flowchart TD A[Huntington Disease: CAG repeat expansion]:::outcome --> B[Selective loss of medium spiny neurons<br/>in striatum]:::urgent B --> C[Preferential loss of GABA neurons<br/>in indirect pathway]:::urgent C --> D[Indirect pathway hypoactive<br/>Direct pathway relatively overactive]:::urgent D --> E[Reduced inhibition of thalamus<br/>Excessive facilitatory output]:::urgent E --> F[Hyperkinetic movements: chorea]:::urgent G[Contrast: Parkinson Disease]:::outcome --> H[Loss of dopamine]:::outcome H --> I[Direct pathway hypoactive<br/>Indirect pathway overactive]:::outcome I --> J[Hypokinetic: bradykinesia, rigidity]:::outcome ``` **High-Yield:** HD and PD represent **opposite imbalances** in basal ganglia circuits: - **HD**: Loss of indirect pathway GABA neurons → unopposed direct pathway activity → **chorea** (hyperkinesia) - **PD**: Loss of dopamine → indirect pathway overactivity → **bradykinesia** (hypokinesia) ## Pharmacotherapy for Huntington Disease | Agent | Mechanism | Role in HD | Notes | |-------|-----------|-----------|-------| | **Tetrabenazine / Deutetrabenazine** | VMAT2 inhibitor; depletes presynaptic monoamines (dopamine, serotonin, norepinephrine) | **First-line** for chorea | Reduces involuntary movements; FDA-approved for HD | | **Levodopa** | Dopamine precursor | **Contraindicated** | Worsens chorea by enhancing dopaminergic tone in already overactive direct pathway | | **Haloperidol** | D2 dopamine antagonist | Older option; now avoided | Side effects (tardive dyskinesia, parkinsonism) limit use; tetrabenazine preferred | | **Selective serotonin reuptake inhibitors (SSRIs)** | Serotonin reuptake inhibition | Adjunct for mood, anxiety, depression | Common comorbidities in HD | **Clinical Pearl:** Tetrabenazine works by blocking the vesicular monoamine transporter (VMAT2), preventing reuptake of dopamine into synaptic vesicles. This depletes presynaptic monoamine pools and reduces involuntary movements without blocking postsynaptic receptors, avoiding the tardive dyskinesia risk of antipsychotics. **Key Point:** Deutetrabenazine is a longer-acting analog of tetrabenazine with improved pharmacokinetics and once-daily dosing, making it increasingly preferred. **Warning:** Levodopa is a common trap in HD questions. Unlike PD, HD requires **reduction** of dopaminergic tone, not enhancement. Levodopa will **worsen** chorea. ## Recommended Next Step Initiate **tetrabenazine 12.5 mg daily** (or deutetrabenazine 6 mg daily), titrated gradually to suppress involuntary movements. Concurrent cognitive and psychiatric support (neuropsychology, counseling, SSRIs for mood) should be arranged. Genetic counseling for family members is essential.