Harvey's Garden

Huntington disease

3 min read

Epidemiology

  • Peak incidence
    • ∼ 40 years of age (symptom onset usually between 20 and 50 years of age)
    • One of the most common hereditary diseases of the brain

Etiology

  • Increased number of CAG repeats (trinucleotide or triplet repeat expansion) in the huntingtin gene on chromosome 4 (most likely due to DNA polymerase dysfunction) results in the expression of an altered huntingtin protein.
    • Huntingtin is physiologically expressed throughout the CNS, but its exact function is not known.
  • Autosomal dominant
  • Anticipation: increase in the number of CAG repeats in subsequent generations
    • In genetics, the term “anticipation” refers to the increasing severity and/or increasingly earlier manifestation of a disease from generation to generation. This phenomenon is observed in HD.

Pathophysiology

Tip

  • Leads to atrophy of the caudate and putamen (striatum).
  • Neurotransmitter changes: ↓ GABA, ↓ ACh, ↑ Dopamine.

Molecular and cellular changes lead to neuronal loss and gliosis in the striatum (particularly in the caudate nucleus)

  • Early stages: only the indirect pathway is affected → increased dopaminergic transmission → excess cortical activity → hyperkinetic/choreatic movements
  • Later stages: both pathways are affected, which, together with additional factors → overall decrease of excitatory thalamic transmission to the cortex → hypokinetic/akinetic symptoms
  • Neuronal injury and death is caused by overactivation of N-methyl-D-aspartate (NMDA) receptors through excessive glutamate stimulation (glutamate-induced excitotoxicity), which leads to:
    • Alteration of GABAergic neurotransmission → decreased GABA in the brain
    • Dysfunction of cholinergic transmission (early stage) and loss of cholinergic neurons (late stage) → decreased acetylcholine (Ach) in the brain

Mnemonic

Clinical features

  • Initial stages
    • Movement dysfunction
      • Chorea: involuntary, sudden, irregular, nonrepetitive, arrhythmic movements of the limbs, neck, head, and/or face
      • Athetosis: involuntary, writhing movements, particularly of the hands and fingers
  • Advanced stages
    • Movement dysfunction
      • Hypokinetic motor symptoms: dystonia, rigidity, bradykinesia
      • Akinetic mutism: inability to move or speak
      • Motor impersistence: inability to sustain simple voluntary acts (e.g., tongue protrusion)
      • Dysarthria and dysphagia
    • Cognitive decline, psychiatric symptoms, and behavioral changes (these symptoms may mimic substance use)
      • Dementia (particularly executive dysfunction)
      • Major depressive disorder (possibly including suicidal tendencies)
      • Schizophrenia-like psychosis (∼ 10% of cases)
        • Paranoid delusions (most common), delusions of infidelity
        • Auditory hallucinations
      • Aggression

Tip

Chorea characterizes the early stages of the disease while hypokinetic/akinetic symptoms may dominate later on. Dementia, depression, and behavioral disorders are common in advanced stages.

Diagnostics

  • Genetic testing (e.g. polymerase chain reaction)
  • CT/MRI: atrophy of the striatum, most pronounced in the caudate nucleus with consequent enlargement of ventricles (ex vacuo ventriculomegaly)

Differential diagnostics

Ballismus

Tip

  • Differentiation: Ballismus vs. Huntington
    • Movement Character:
      • Ballismus: Violent, flailing, large amplitude. Proximal muscles.
      • Huntington: Chorea (jerky, “dance-like”), low amplitude. Distal muscles/face.
    • Lesion Location:
      • Ballismus: Subthalamic Nucleus.
      • Huntington: Caudate Nucleus.
    • Onset:
      • Ballismus: Acute (usually 2° to Lacunar Stroke).
      • Huntington: Gradual (Neurodegenerative, age 20–50).
  • Definition & Clinical Presentation
    • Characterized by large-amplitude, violent, flailing movements of the limbs.
    • Involves proximal musculature (shoulders, hips), distinguishing it from chorea (distal, dance-like).
    • Most commonly presents unilaterally as Hemiballismus.
  • Lesion Localization
    • Contralateral Subthalamic Nucleus (STN).
  • Etiology
    • Most common: Lacunar Stroke (ischemic infarction) usually secondary to long-standing hypertension.
    • Other causes: Non-ketotic hyperglycemia (HHNK), neoplasms, HIV, SLE.
  • Pathophysiology (Basal Ganglia Circuitry)
    • Normal Circuit: STN stimulates the Globus Pallidus internus (GPi) GPi inhibits the Thalamus.
    • Lesion Circuit: Damage to STN excitation of GPi inhibition of Thalamus.
    • Result: Unopposed thalamic output to the motor cortex Hyperkinetic movement.
  • Treatment
    • Dopamine Antagonists: High-potency antipsychotics (e.g., Haloperidol) allow for movement suppression.
    • Depleting agents: Tetrabenazine.
    • Prognosis: Often self-limited; may resolve spontaneously over weeks/months.

Treatment

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