- Clinical science
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.
- Sex: ♂ = ♀
- Peak incidence: ∼ 40 years of age
- HD is one of the most common hereditary diseases of the brain.
Epidemiological data refers to the US, unless otherwise specified.
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 its exact function is not known.
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.
- 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
- 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)
- Sensory deficits
- Autonomic symptoms (hyperhidrosis, urinary incontinence)
- Movement dysfunction
- Movement dysfunction
Cognitive decline and behavioral changes
- Dementia (particularly executive dysfunction)
- Depression (possibly including suicidal tendencies)
- 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!
Chorea (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.
|Epidemiology & etiology||Signs & symptoms||Diagnostics|
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Other types of choreoathetoid movement disorders:
- Chorea gravidarum
- Senile chorea
- Benign hereditary chorea
- Neuroacanthocytosis chorea
The differential diagnoses listed here are not exhaustive.
No causal therapy is available!
- Ongoing physiotherapeutic, ergotherapeutic, and logotherapeutic care
- Psychotherapy (if needed)
- Consultation of specially trained counselors (if genetic diagnostics are employed)
- Medical therapy
- Mean duration of illness: approximately 19 years
- Cause of death: often respiratory insufficiency or aspiration pneumonia