Foundations · Year 1 · from Foundations
Case 1: Huntington Disease (Trinucleotide Repeat Expansion)
Clinical Image
Source: Radiopaedia - Huntington disease - CC BY-NC-SA 3.0
Case Presentation
A 42-year-old man presents with his wife who reports 2 years of progressive personality changes, involuntary movements, and cognitive decline. She describes him as increasingly irritable and impulsive, with difficulty at work. Physical examination reveals chorea (rapid, involuntary, irregular movements) affecting his face, trunk, and limbs, along with motor impersistence (inability to maintain tongue protrusion). Cognitive testing shows executive dysfunction. His father died at age 50 from "dementia" after years in a psychiatric facility. MRI brain shows bilateral caudate atrophy with enlarged frontal horns of the lateral ventricles, giving a characteristic "boxcar" appearance. Genetic testing reveals 45 CAG repeats in the HTT gene (normal <36, pathogenic >39), confirming Huntington disease. The genetic counselor explains anticipation: his father likely had fewer repeats with later onset, and any children have 50% risk of inheriting the expanded allele. The repeats tend to expand further during paternal transmission, potentially causing earlier onset in the next generation. He is referred to a movement disorder specialist for symptomatic treatment (tetrabenazine for chorea) and to psychiatric services for mood management. Presymptomatic testing is discussed for his adult children.
Key Learning Points
- Huntington disease is caused by CAG repeat expansion in HTT encoding huntingtin protein; the polyglutamine tract becomes toxic when expanded, causing selective neurodegeneration in the striatum
- Trinucleotide repeat disorders show anticipation (earlier onset in successive generations) because repeats tend to expand during DNA replication, particularly in spermatogenesis; juvenile HD is typically inherited from the father
- Genetic testing requires careful counseling because the result is predictive and there is no disease-modifying treatment; guidelines recommend testing only after age 18 with appropriate genetic counseling