40. Huntington's disease - etiology, pathogenesis, clinical manifestations.

Huntington's disease – etiology, pathogenesis, and clinical manifestations

Huntington’s disease (HD) is a progressive, autosomal dominant neurodegenerative disorder, characterized by motor dysfunction (chorea), cognitive decline, and psychiatric disturbances.

Etiology (Causes)

Genetic basis

• Autosomal dominant inheritance.
• Caused by mutation in the HTT gene (huntingtin gene) on chromosome 4p.
• Mutation: CAG trinucleotide repeat expansion (codes for glutamine) → polyglutamine tract in huntingtin protein.
• Normal range: <35 repeats.
• Disease range: ≥36 repeats (usually >40).

Anticipation

• Disease tends to present earlier and more severely in successive generations (especially when paternally inherited).
• Due to further expansion of CAG repeats during spermatogenesis.

Pathogenesis

1. 1 Mutant huntingtin protein

• Abnormally long polyglutamine tract → misfolding and aggregation of huntingtin protein.
• Interferes with multiple cellular processes:
• Transcriptional regulation.
• Mitochondrial function.
• Proteasomal degradation.

1. 2 Neuronal degeneration

• Selective loss of medium spiny GABAergic neurons in the striatum (especially caudate nucleus and putamen).
• Progressive striatal atrophy → enlarged lateral ventricles on imaging.

1. 3 Imbalance in basal ganglia circuits

• Loss of inhibitory (GABAergic) output from striatum → excessive thalamocortical stimulation → hyperkinetic movements (chorea).

Clinical Manifestations

Onset

• Usually between 30–50 years (adult-onset most common).

Motor symptoms

• Chorea: involuntary, irregular, dance-like movements (hallmark feature).
• Athetosis: slow, writhing movements.
• Dystonia.
• Impaired voluntary movements → clumsiness, poor coordination, gait instability.
• Later stages: bradykinesia, rigidity → resembles Parkinsonism.

Cognitive symptoms

• Progressive dementia.
• Problems with attention and executive functions.
• Slowed thinking ("bradyphrenia").

Psychiatric symptoms

• Depression (very common, may precede motor signs).
• Irritability, aggression.
• Anxiety.
• Psychosis or obsessive-compulsive behaviors in some cases.
• Increased risk of suicide.

Other features

• Weight loss despite adequate intake.
• Dysarthria and dysphagia in advanced stages.

Course and prognosis

• Progressive deterioration over 10–25 years.
• Terminal stages: severe motor disability, cognitive decline, cachexia.
• Death usually from complications (e.g., infections, aspiration pneumonia).