Huntington Disease

Summary

Huntington disease, also known as Huntington chorea, is an autosomal dominant neurodegenerative disorder caused by CAG trinucleotide repeat expansions in the Huntingtin gene on chromosome 4. This mutation causes damage to neurons, especially in the caudate nucleus of the basal ganglia, which manifests as caudate atrophy on brain imaging. Other neurotransmitter changes seen in Huntington disease include a decrease in GABA levels, an increase in dopamine levels, and a decrease in acetylcholine levels. Clinically, patients initially present with personality changes like aggression and depression, followed by onset of involuntary muscle movements, including the dance-like movements of chorea and snake-like writhing of athetosis. In the later stages of the disease, patients often experience cognitive decline and dementia. While most cases are eventually fatal, tetrabenazine can be used to reduce involuntary muscle movements to improve the quality of life.

Key Points

• Huntington Disease
  • Neurodegenerative disorder
  • Genetics
    • CAG trinucleotide repeat disorder
      • Repeat expansions in huntingtin (HTT) gene on chromosome 4
    • Inheritance is autosomal dominant
    • Exhibits genetic anticipation
      • Progressive increase in severity of illness with each successive generation of offspring
      • Trinucleotide repeats are prone to errors in replication and may expand when gene is passed from parent to offspring
  • Pathogenesis
    • Atrophy of caudate
      • Caudate nucleus atrophy is a common sign on radiographic imaging, with increased ventricular space near the anterior horns of the lateral ventricles described as “ex vacuo” ventriculomegaly
      • The putamen and other structures of the basal ganglia may also be involved
      • Damage to basal ganglia leads to hyperkinesis
      • Neuronal death via NMDA-R binding and glutamate excitotoxicity
    • Neurotransmitter Changes
      • Decreased GABA
        • Due to death of GABA-ergic neurons in striatum
        • Decrease in major inhibitory neurotransmitter thought to play a role in hyperkinesis
        • Most important neurotransmitter change
      • Increased dopamine
        • Increased dopamine activity on nigrostriatal pathway (leading to hyperkinesis) and mesolimbic pathway (leading to psychosis)
      • Decreased ACh
        • Thought to play a role in cognitive decline
  • Presentation
    • Symptoms manifest between ages 20-50
      • Often mistaken for substance abuse
    • Athetosis
      • Snake-like slow writhing movements, especially in fingers
    • Chorea
      • Sudden, jerky, purposeless movements
      • Involuntary “dance-like” movements
      • Facial grimacing and ataxia may also be seen
    • Dementia
      • Decreased memory, attention, and concentration
    • Aggression and depression
      • Personality changes are often the first signs of disease
  • Treatment
    • Tetrabenazine
      • Helps control symptoms of hyperkinesia
    • Incurable; generally leads to death
    • Suicide prevention and management of depression