What is the diagnostic approach for an adult with a family history of Huntington disease presenting with progressive motor dysfunction, cognitive decline, and psychiatric symptoms?

Diagnosis of Huntington Disease

Genetic testing for CAG repeat expansion in the huntingtin (HTT) gene on chromosome 4p16.3 is the definitive diagnostic test for Huntington disease, with ≥40 CAG repeats confirming the diagnosis and providing 100% specificity. 1, 2

Diagnostic Algorithm

Step 1: Clinical Assessment

When evaluating a patient with suspected HD presenting with the classic triad of progressive motor dysfunction (chorea), cognitive decline, and psychiatric symptoms, proceed directly to genetic testing rather than relying on clinical diagnosis alone. 1

Key clinical features to document:

• Motor symptoms: Involuntary, flowing, non-stereotyped choreiform movements that can be temporarily suppressed by conscious effort (distinguishing feature from other movement disorders) 3
• Cognitive symptoms: Progressive decline in attention, executive function, and visuospatial abilities 2
• Psychiatric symptoms: Depression, mood disturbances, behavioral changes, or suicidal ideation (present in up to 35% of patients) 2, 4
• Family history: Autosomal dominant inheritance pattern with affected parent 1
• Age of onset: Typically 35-45 years; juvenile onset (<20 years) presents with rigidity and spasticity rather than chorea 1, 2

Step 2: Mandatory Genetic Counseling

Before ordering genetic testing, patients must undergo genetic counseling. 1, 2 This is non-negotiable given the autosomal dominant inheritance with complete penetrance and the devastating implications of a positive result. 1

Step 3: Genetic Testing (Definitive Diagnosis)

Order CAG repeat analysis of the HTT gene. 1, 2

Interpretation of results:

• ≥40 CAG repeats: Confirms HD diagnosis with 100% specificity and full penetrance 1, 2
• 36-39 CAG repeats: Variable penetrance; may or may not develop disease 1
• 27-35 CAG repeats: Not associated with HD phenotype but may be mutable and expand in offspring 1
• ≤26 CAG repeats: Never associated with HD; excludes diagnosis 1

Special consideration for juvenile HD: CAG repeats often exceed 55 in patients with onset before age 20 years. 2

Step 4: Neuroimaging (Supportive, Not Diagnostic)

MRI brain without IV contrast is the optimal imaging modality, though it may be normal early in the disease course. 1, 2

Order MRI for two purposes:

1. To exclude other causes of chorea (cerebrovascular disease, infectious, autoimmune, metabolic disorders) 1, 2
2. To document characteristic HD findings in established disease 1, 2

Expected MRI findings in established HD:

• Progressive marked atrophy of the neostriatum, particularly the caudate nucleus head 1, 2
• Enlargement of frontal horns of lateral ventricles 1, 2
• Abnormal T2 signal in the caudate and putamen 1, 2
• T1-weighted imaging typically normal initially, with volume loss noted later 1

Important caveat: Do not delay genetic testing waiting for MRI abnormalities to appear, as imaging is often normal early in disease. 1, 2

Step 5: Exclude Alternative Diagnoses

Consider and rule out other causes of chorea before attributing symptoms to HD: 1, 3

• Cerebrovascular disease 1
• Systemic lupus erythematosus 3
• Wilson's disease 3
• Drug-induced chorea (neuroleptics, stimulants, anticonvulsants) 1, 3
• Infectious etiologies 1
• Autoimmune conditions 1
• Metabolic disorders 1

Critical Pitfalls to Avoid

Do not diagnose HD based on clinical presentation alone. Even with classic symptoms and family history, genetic confirmation is mandatory as phenocopies (clinically diagnosed cases without the genetic mutation) do exist. 5

Do not order genetic testing without pre-test genetic counseling. This violates established standards and fails to prepare patients for the psychological impact of a positive result, including increased suicide risk. 1, 4

Do not use CT as the primary imaging modality. CT has limited soft-tissue characterization compared to MRI and is not preferred for suspected HD. 1

Do not order FDG-PET, MR spectroscopy, or functional MRI for initial diagnostic evaluation. There is insufficient evidence supporting these modalities for diagnosis, though FDG-PET may show early neostriatal hypometabolism in known gene carriers. 1

Do not assume normal imaging excludes HD. Structural brain changes lag behind symptom onset, and genetic testing remains the gold standard regardless of imaging findings. 1, 2

Asymptomatic At-Risk Individuals

For asymptomatic adults with family history requesting predictive testing, use a multidisciplinary protocol modeled after Huntington Disease Society of America guidelines: 1

• Multiple pre-test genetic counseling sessions with patient-selected support person present 1
• Neurologic evaluation 1
• Psychiatric evaluation to assess for depression or suicidal ideation 1
• Post-test disclosure counseling 1

Do not perform genetic testing in children or adolescents. Given the lack of disease-modifying therapy and the adult onset of symptoms, pediatric testing provides no medical benefit and poses significant psychological harm. 1