Huntington disease

Huntington disease (HD) is a neurodegenerative movement disorder characterized by involuntary and irregular movements of the limbs, neck, head, and/or face (chorea). This autosomal-dominant inherited disease is caused by mutations (increased number of CAG trinucleotide repeats) in the huntingtin gene which eventually leads to the dysfunction of subcortical motor circuits. Symptom onset depends on the individual extent of the genetic abnormalities but usually occurs around 40 years of age. In later stages, psychiatric symptoms like dementia and depression are common. To date, no disease-modifying treatment is available. Management involves symptomatic treatment and supportive care. On average, HD leads to death within 15–20 years after symptom onset.

• Sex: ♂ = ♀
• Peak incidence ^[1]
  • ∼ 40 years of age (symptom onset usually between 20 and 50 years of age)
  • One of the most common hereditary diseases of the brain
• Peak prevalence: 3–7 per 100,000 people of Western European descent (compared to 1 per 100,000 people of Asian and African descent) ^[2]

Epidemiological data refers to the US, unless otherwise specified.

• 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.
  • 40 or more CAG repeats result in almost certain development of HD .
• Inheritance ^[3]
  • Autosomal dominant
  • Anticipation: increase in the number of CAG repeats in subsequent generations
  • Imprinting: Paternal inheritance causes more CAG triplets.

Summary

Molecular and cellular changes lead to neuronal loss and gliosis in the striatum (particularly in the caudate nucleus) and, subsequently, the thalamus and the cortex.

Pathomechanism

• Overall levels of abnormal huntingtin protein correlate with the severity of symptoms.
• The striatum normally controls movement via inhibitory outputs to the globus pallidus internus (direct pathway) and globus pallidus externus (indirect pathway). ^[4]
  • Direct pathway
    • Striatal projections inhibit the internal globus pallidus, which normally inhibits the thalamus and its excitatory projections to the cortex.
    • Activation of the direct pathway generally results in increased transmission to the cortex.
  • Indirect pathway
    • Striatal projections inhibit the external globus pallidus, which normally inhibits the subthalamic nucleus.
    • The subthalamic nucleus possesses excitatory projections to the internal globus pallidus which in turn projects to the thalamus and ultimately to the cortex.
    • Activation of the indirect pathway generally results in decreased transmission to the cortex.
• In HD, the indirect pathway is commonly affected earlier than the direct pathway. ^[3]
  • Early stages: only the indirect pathway is affected → increased dopaminergic transmission → excess cortical activity → hyperkinetic/choreatic movements ^[5]
  • 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 ^[6]

In Huntington disease, increased number of CAG repeats leads to the damage to the Caudate nucleus and results in decreased Ach and GABA.

• Initial stages
  • Movement dysfunction ^[4]
    • 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
    • Oculomotor disorders: reduced velocity in optokinetic nystagmus, hypometric saccades
  • Hyperreflexia
  • Sensory deficits
  • Autonomic symptoms: hyperhidrosis, urinary incontinence
• Advanced stages ^[7][8]
  • 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) ^[9]
    • Dementia (particularly executive dysfunction)
    • Major depressive disorder (possibly including suicidal tendencies)
    • Schizophrenia-like psychosis (∼ 10% of cases) ^[10]
      • Paranoid delusions (most common), delusions of infidelity
      • Auditory hallucinations
    • Aggression, apathy, anxiety , irritability
  • Cachexia (due to dysphagia and high energy consumption)
• Atypical symptoms
  • Gait ataxia
  • Myoclonus or seizures

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.

• Patient history
• Genetic testing (e.g. polymerase chain reaction)
• Imaging: rarely used ^[7]
  • CT/MRI: atrophy of the striatum, most pronounced in the caudate nucleus with consequent enlargement of ventricles (ex vacuo ventriculomegaly)
  • FDG-PET: disorder of glucose metabolism in the striatum (apparent early)

Chorea and/or athetosis may occur in all of the presented diseases. Only common distinguishing signs and symptoms are listed below.

The differential diagnoses listed here are not exhaustive.

General approach

• Ongoing physiotherapeutic, ergotherapeutic, and logotherapeutic care
• Psychotherapy (if needed)
• Consultation of specially trained counselors (if genetic diagnostics are employed)

Medical therapy ^[20]

• Hyperkinetic/choreatic movements
  • Monoamine‑depleting drugs (deutetrabenazine, tetrabenazine) ^[21]
  • Atypical neuroleptics (e.g., clozapine)
  • NMDA-receptor antagonists (e.g., amantadine)
• Psychosis: atypical neuroleptics (e.g., clozapine)
• Depression: SSRIs (e.g., citalopram)

There is no causal therapy available.

• Progressive ^[20]
• Mean duration of illness: approximately 15–20 years after symptom onset ^[2]
• Most common causes of death: respiratory insufficiency, aspiration pneumonia ^[22]