• Clinical science

Huntington disease

Abstract

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 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 19 years.

Epidemiology

  • Sex: =
  • Peak incidence: 40 years of age
  • HD is one of the most common hereditary diseases of the brain.

References:[1][2]

Epidemiological data refers to the US, unless otherwise specified.

Etiology

  • Increased number of CAG repeats in the huntingtin gene on chromosome 4 (most likely due to DNA polymerase malfunction) → expression of an altered huntingtin protein
    • 10 to 35 repeats → physiologic
    • 36 to 39 repeats → intermediate form
    • 40 or more repeats → development of HD is almost certain
  • Huntingtin is physiologically expressed throughout the CNS, but it's exact function is not known.
  • Inheritance

References:[3]

Pathophysiology

  • 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
    • Involvement of direct cytotoxic effects
    • Disturbance of metabolic and signaling pathways on multiple levels (e.g., activation of proteases, disturbance of axonal transport) by the mutated huntingtin proteins (or even by protein fractions)
    • Mutated huntingtin proteins tend to aggregate, although the pathologic relevance of this phenomenon is not clear.
  • 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).
      • 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.
      • 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, causes an overall decrease of excitatory thalamic transmission to the cortex → hypokinetic/akinetic symptoms


References:[4][3][5]

Clinical features

  • Initial stages
    • Movement dysfunction
      • Chorea (involuntary, irregular, nonrepetitive, arrhythmic movements of the limbs, neck, head, and/or face)
      • Oculomotor disorders (e.g., reduced velocity in optokinetic nystagmus, hypometric saccades)
    • Hyperreflexia
    • Sensory deficits
    • Autonomic symptoms (hyperhidrosis, urinary incontinence)
  • 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 and behavioral changes
      • Dementia (particularly executive dysfunction)
      • Depression (possibly including suicidal tendencies)
      • Apathy
      • Anxiety
      • Aggression and psychosis
    • Cachexia (due to dysphagia and high energy consumption)
  • Atypical symptoms

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!
References:[4][6][7][8]

Diagnostics

References:[4][6]

Differential diagnoses

Chhorea (involuntary, irregular, nonrepetitive and arrhythmic movements) and/or athetosis (involuntary, writhing movements particularly of the hands and fingers) may occur in all of the presented diseases. Only common distinguishing signs and symptoms are listed below.

Differential diagnosis of choreoathetoid movement disorders

Epidemiology & etiology Signs & symptoms Diagnostics

Huntington disease

  • Motor symptoms
    • Motor impersistence
    • Dystonia
    • Dysphagia
  • Neuropsychiatric symptoms (e.g., inappropriate laughing/crying, psychosis, akinetic mutism)
  • Genetic testing (→ CAG repeats)
  • CT/MRI (→ brain atrophy)

Sydenham's chorea

  • Motor symptoms
    • Muscle weakness
    • Motor impersistence
  • Neuropsychiatric symptoms (e.g., inappropriate laughing/crying, obsessive-compulsive behavior)
  • Atypical symptoms: fever, fatigue, malaise

Wilson's disease

  • Usually younger or middle-aged men or women
  • Genetic (mutations in hepatic copper transport protein ATP7B)
  • Laboratory (e.g., ceruloplasmin, liver enzymes)
  • Abdominal imaging (→ hepatomegaly and/or splenomegaly)
  • Liver biopsy (if other diagnostics are inconclusive)

Creutzfeldt-Jakob disease

  • Very rare
  • Infectious (prion particles)
  • Rapid progression
  • Motor symptoms
    • Myoclonus
    • Hypokinesia
    • Ataxia, nystagmus
  • Neuropsychiatric symptoms (e.g., sensory disturbances, mutism, sleep disorders)
  • EEG (e.g., periodic sharp wave complexes during illness)
  • Laboratory (e.g., 14-3-3 protein in CSF)
  • MRI (→ abnormalities in caudate nucleus and/or putamen)

Systemic lupus erythematosus (SLE)

  • Most commonly affects women of childbearing age
  • Chronic inflammatory, possibly autoimmune (exact cause unknown)
  • Motor symptoms
  • Neuropsychiatric symptoms (e.g., confusion, coma)
  • Fatigue, fever, myalgia, weight change
  • Arthritis, arthralgia
  • Cardiovascular, pulmonary and/or renal disorders (e.g., vasculitis, pleural effusion)
  • Hair loss, photosensitive skin lesions, rash, oral/nasopharyngeal ulcers

Drug-induced chorea

  • Twisting movements of the tongue and of the fingers
  • Lip smacking, chewing movements
  • Ballistic limb movements, foot tapping
  • Postural abnormalities
  • Laboratory (toxicology screen)


Other types of choreoathetoid movement disorders:

  • Chorea gravidarum
  • Senile chorea
  • Benign hereditary chorea
  • Neuroacanthocytosis chorea

References:[9][10][11][6][12][13][14][15][16]

The differential diagnoses listed here are not exhaustive.

Treatment

No causal therapy is available!

References:[4][17]

Prognosis

  • Progressive
  • Mean duration of illness: approximately 19 years
  • Cause of death: often respiratory insufficiency or aspiration pneumonia

References:[17][18][19]