Neurosurgery notes/Functional/Movement disorders/Huntington’s disease

Huntington’s disease

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Movement disorders

General

  • An autosomal dominant neurodegenerative disease
  • Characterized by
    • Choreiform movements,
    • Psychiatric symptoms,
    • Dementia and genetic expansion of the trinucleitide (CAG) repeat in the HD gene (chromosome 4p).

Numbers

  • Age range 2-85 (mean 40);
  • Incidence 2-4 per 1,000,000 per year,
  • Prevalence 5-8 per 100,000;
  • No gender predilection;

Pathology

  • Gross appearance
      • Marked atrophy of the
        • Caudate nucleus
        • Putamen
      • Ex vacuo hydrocephalus
       
      notion image
  • Histology shows striatal atrophy (caudate/putamen) due to degeneration of medium spiny neurons, and reactive gliosis.

Pathophysiology

  • Autosomal dominant trinucleotide CAG repeat expansion in huntingtin (HTT) gene on Chr 4
    • Has anticipation due to CAG repeats
      • Once expanded beyond 40 CAG repeats, the repeats are unstable and may further increase as they are passed on from one generation to the next.
    • Patients with Huntington’s disease may have from 36 to more than 100 repeats.
      • Adult onset: > 36 CAG repeats in the HTT gene
      • Juvenile onset: > 60 CAG repeats
      • 36-39 CAG repeats still may not develop signs/symptoms
      • 27-35 CAG repeats in the HTT gene do not develop Huntington’s disease
        • Are at risk of having children who will develop the disorder.
  • Interaction of mutated Huntington protein with other proteins results in neuronal death.
  • Degeneration of neurons in the putamen + caudate + cerebral cortex.
    • The preferential degeneration of the enkephalin-containing medium spiny neurons in the basal ganglia in the indirect pathway provides the basis for chorea.
    • Additional loss of substance-P containing medium spiny neurons in the direct pathway results in the development of dystonia and akinesia.
    • The region-specific pattern of loss of neurons in the cortex and basal ganglia in the affected patients could explain the phenotypic variability.
    • Loss of striatal neurons resulting in reduced levels of choline acetyltransferase, glutamic acid decarboxylase, and GABA in the striatum resulting in a relative excess of dopamine causing a hyperkinetic movement disorder with writhing and jerking movements of the limbs (chorea).

Presentation

  • Insidious onset of
    • Chorea
    • Psychiatric symptoms (irritability, depression, anxiety)
    • Cognitive impairment
  • Successive generations have expanded repeats leaded to earlier onset and more severe phenotype (anticipation).
  • Eventually fatal disease. Imaging: striatal and cortical atrophy.