Description
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder characterised by motor, cognitive, and psychiatric disturbances. It is caused by an expanded CAG trinucleotide repeat in the HTT gene, leading to the production of mutant huntingtin protein.
Pathogenesis
HD is caused by an expanded CAG trinucleotide repeat (>35 repeats) in exon 1 of the HTT gene on chromosome 4p16.3. This results in the synthesis of an abnormally long polyglutamine tract in the huntingtin protein, inducing protein misfolding and aggregation, disrupting numerous cellular functions. Neuronal degeneration primarily affects the striatum (caudate nucleus and putamen), followed by the cerebral cortex.
Epidemiology, Risk Factors & Associations
HD typically presents in middle age (30-50 years), although juvenile and late-onset forms also exist. It has a worldwide prevalence of approximately 5-10 cases per 100,000 people, with increased frequency in people of Western European descent. As an autosomal dominant condition, offspring of an affected individual have a 50% chance of inheriting the mutated gene.
Clinical Features
HD classically presents with a triad of clinical features:
- Motor symptoms: Choreiform movements (involuntary, rapid, jerky), dystonia, and later bradykinesia and rigidity.
- Cognitive decline: Initially presents as subtle changes in executive function, progressing to dementia.
- Psychiatric symptoms: Depression, irritability, apathy, and psychosis.
Complications
Complications include falls, aspiration pneumonia, malnutrition, and suicide.
Pathological Features
Histopathology
- Gross examination of the brain reveals atrophy of the caudate nucleus and putamen, with ex vacuo dilatation of the frontal horns of the lateral ventricles.
- Microscopically, there’s neuronal loss, astrocytosis, and intranuclear inclusions within neurons.
Genetics
- Genetic testing confirms the diagnosis, demonstrating an expanded CAG repeat in the HTT gene.
Radiological Features
General Features
- Pogressive atrophy of the striatum (caudate nucleus and putamen), with secondary enlargement of the frontal horns of the lateral ventricles.
MRI
- T1: Decreased volume of the caudate nucleus and putamen with resultant enlargement of the anterior horns of the lateral ventricles.
- T2/FLAIR: Striatal atrophy.
Diagnosis
Diagnosis is based on clinical features, family history, and genetic testing confirming CAG repeat expansion in the HTT gene.
Differential Diagnosis
- Wilson disease: Affects younger individuals, associated with Kayser-Fleischer rings and elevated copper levels.
- Chorea acanthocytosis: Associated with acanthocytes on blood smear and lip-licking.
- Drug-induced chorea: History of medication use (e.g., antipsychotics, antiemetics).
Management
Management is symptomatic and supportive, typically involving a multidisciplinary team. Tetrabenazine may help control chorea. Physical therapy can aid mobility, and psychological support is critical given the psychiatric manifestations and genetic implications.