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

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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.

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Pathophysiology

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

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Clinical features

• Initial stages
  • Movement dysfunction
    • Chorea: involuntary, sudden, irregular, nonrepetitive, arrhythmic movements of the limbs, neck, head, and/or faceNeurological examination - AMBOSS
    • 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.

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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

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Ballismus

• Epidemiology & etiology
  • Rare disorder typically affecting elderly diabetic patients
  • Hemorrhagic or ischemic stroke
  • Nonketotic hyperglycemia
  • Brain metastases
  • Infectious (e.g., HIV)
• Signs & symptoms
  • Involuntary, proximal, violent, and large-amplitude movements of one or both extremities (e.g., kicking, wild flailing)
  • Typically unilateral (hemiballismus), due to contralateral lesion (e.g., lacunar stroke) of the subthalamic nucleus
    • Damage to the subthalamic nucleus can decrease excitation of the globus pallidus internus, thereby reducing inhibition of the thalamus.

Treatment

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