A 52-year-old woman from Mumbai presents with involuntary choreiform movements of the limbs, emotional lability, and cognitive decline. Family history reveals her mother died of a similar illness at age 55. Which investigation is most appropriate to confirm the diagnosis and assess the extent of striatal neurodegeneration?

Explanation

## Investigation of Choice for Huntington Disease Diagnosis **Key Point:** Genetic testing for HTT (huntingtin) gene CAG repeat expansion is the gold standard and most specific confirmatory test for Huntington disease. It provides definitive diagnosis, predicts disease onset, and guides genetic counseling. ### Why Genetic Testing? **High-Yield:** Huntington disease is an autosomal dominant disorder caused by abnormal CAG trinucleotide repeat expansion in the HTT gene on chromosome 4. Normal individuals have 6–35 CAG repeats; pathogenic expansions have ≥40 repeats. The number of repeats correlates inversely with age of onset (anticipation phenomenon). **Clinical Pearl:** Genetic testing is the only investigation that provides: 1. **Definitive diagnosis** — confirms the molecular basis of the disease 2. **Prognostic information** — CAG repeat count predicts age of symptom onset 3. **Genetic counseling** — each child of an affected parent has 50% risk of inheriting the mutation ### Basal Ganglia Circuit Pathology in Huntington Disease The huntingtin protein accumulates in the striatum (particularly affecting medium spiny neurons of the indirect pathway), leading to: - **Selective neuronal loss** in the caudate nucleus and putamen - **Disruption of the indirect (inhibitory) pathway** — reduced inhibition of globus pallidus externus - **Net result:** Excessive thalamic output → hyperkinetic movement disorder (chorea) This contrasts with Parkinson disease, where the direct pathway is affected, causing hypokinesia. ### Structural vs. Functional vs. Genetic Investigations | Investigation | Findings in HD | Role | Limitation | | --- | --- | --- | --- | | **Genetic testing (HTT CAG)** | ≥40 repeats | **Gold standard for diagnosis** | Requires informed consent; may have psychological impact | | **MRI brain** | Striatal atrophy (caudate > putamen), ventricular enlargement | Supports diagnosis; shows disease progression | Atrophy may be absent in early disease; not diagnostic alone | | **fMRI** | Reduced activation in striatum during motor tasks | Research tool; assesses functional reserve | Not diagnostic; expensive; not routine clinical use | | **Serum ceruloplasmin** | Normal in HD | Excludes Wilson disease (copper metabolism disorder) | Wilson disease is a differential diagnosis mimic | **Mnemonic:** **CHEAT** for Huntington disease investigations: - **C**AG repeat expansion (genetic testing) — definitive - **H**yperkinetic movement (clinical feature) - **E**xcessive thalamic output (circuit mechanism) - **A**trophy of striatum (MRI finding) - **T**rinucleotide repeat disorder (molecular basis) ### Why Other Options Are Suboptimal **MRI brain (Option 1):** While volumetric analysis shows striatal atrophy in symptomatic HD, atrophy may be absent or minimal in early disease. MRI is supportive but not diagnostic; genetic testing is required for confirmation. **Serum ceruloplasmin (Option 2):** This test excludes Wilson disease (another cause of movement disorder with striatal pathology), but it does not diagnose Huntington disease. It is a differential diagnosis tool, not a confirmatory test for HD. **fMRI (Option 4):** Functional imaging may show reduced striatal activation during motor tasks, but it is a research tool with no diagnostic utility. It does not provide the definitive molecular diagnosis that genetic testing provides. **Tip:** In a patient with clinical features of Huntington disease (chorea + cognitive decline + positive family history), genetic testing is the next best investigation because it provides definitive diagnosis and prognostic information. Structural imaging (MRI) is complementary but should not delay genetic testing. [cite:Harrison 21e Ch 430]