A 35-year-old woman from Mumbai presents with involuntary choreiform movements of the limbs, emotional lability, and cognitive decline over 6 months. Her father died at age 50 with similar symptoms. Genetic testing confirms huntingtin gene expansion (CAG repeats >40). MRI shows caudate nucleus atrophy. What is the most appropriate next step in management?

Explanation

## Clinical Context The patient presents with the classic triad of Huntington disease: chorea (involuntary movements), cognitive decline, and psychiatric symptoms. Genetic confirmation (CAG >40) and imaging evidence of caudate atrophy establish the diagnosis. The family history (father affected) confirms autosomal dominant inheritance. ## Pathophysiology of Basal Ganglia Dysfunction in Huntington Disease **Key Point:** Huntington disease involves selective degeneration of medium spiny neurons (MSNs) in the striatum, particularly those expressing the indirect pathway (enkephalin-positive neurons). This leads to relative overactivity of the indirect pathway, causing excessive thalamic inhibition and involuntary movements. ```mermaid flowchart TD A[Huntingtin protein mutation]:::outcome --> B[MSN degeneration in striatum]:::outcome B --> C{Pathway imbalance}:::decision C -->|Indirect pathway overactive| D[Excessive thalamic inhibition]:::outcome C -->|Direct pathway relatively spared| E[Unopposed inhibition]:::outcome D --> F[Chorea & involuntary movements]:::outcome E --> F F --> G[Reduce dopamine signaling]:::action G --> H[Tetrabenazine/Deutetrabenazine]:::action ``` ## Management Strategy **High-Yield:** Unlike Parkinson disease (dopamine deficiency), Huntington disease involves relative dopamine excess in the striatum due to selective loss of inhibitory MSNs. Treatment aims to reduce dopaminergic signaling, not enhance it. | Drug | Mechanism | Use in Huntington | |---|---|---| | Tetrabenazine | VMAT2 inhibitor; depletes vesicular dopamine | First-line for chorea | | Deutetrabenazine | Deuterated tetrabenazine; longer half-life | FDA-approved, improved tolerability | | Levodopa | Dopamine agonist | **Contraindicated**—worsens chorea | | Pallidotomy | Surgical ablation of globus pallidus | Rarely used; limited efficacy | **Clinical Pearl:** The caudate atrophy on MRI is pathognomonic for Huntington disease and reflects the selective vulnerability of striatal MSNs. This anatomical finding correlates with the clinical phenotype of chorea. **Mnemonic:** **VMAT** = Vesicular Monoamine Transporter. Tetrabenazine blocks VMAT2, preventing dopamine packaging into vesicles and reducing synaptic release—the opposite of what you'd do in Parkinson disease. **Tip:** In NEET PG, remember the key distinction: Parkinson disease = dopamine deficiency (give dopamine); Huntington disease = dopamine excess (block dopamine). This reversal is a high-yield trap.