Huntington disease

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.

• Toxic Gain of Function: Mutated huntingtin protein aggregates inside neurons, causing toxicity.
• Neuronal Death: Selective atrophy of the striatum (caudate nucleus and putamen).
  • Loss of spiny GABAergic neurons is the hallmark.
• Excitotoxicity: Potential mechanism involving excessive activation of NMDA receptors by glutamate, leading to neuronal cell death.
• Neurotransmitter Changes
  • ↓ GABA (gamma-aminobutyric acid): Loss of inhibition leads to hyperkinetic movement.
  • ↓ ACh (acetylcholine).
  • ↑ Dopamine: Relative excess contributes to chorea.

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) t

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). t
• 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) $\to$ GPi inhibits the Thalamus.
  • Lesion Circuit: Damage to STN $\to$ $\downarrow$ excitation of GPi $\to$ $\downarrow$ inhibition of Thalamus.
  • Result: Unopposed thalamic output to the motor cortex $\to$ 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

---