Background
Huntington disease (HD) is an incurable, adult-onset, autosomal dominant inherited disorder associated with cell loss within a specific subset of neurons in the basal ganglia and cortex. HD is named after George Huntington, the physician who described it as hereditary chorea in 1872. [1] Characteristic features of HD include involuntary movements, dementia, and behavioral changes. [2]
Etiology
Huntington disease (HD) results from selective neuronal dysfunction and loss in the striatum, cortex, and other brain regions, driven by multiple interacting mechanisms: excitotoxicity, oxidative stress, impaired energy metabolism, and apoptosis.
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Excitotoxicity: Overactivation of glutamate receptors, particularly NMDA receptors, may contribute to neuronal death. Experimental models using NMDA agonists (eg, quinolinic acid) replicate HD-like striatal lesions.
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Oxidative stress: Excess reactive oxygen species, linked to mitochondrial dysfunction or excitotoxicity, can trigger neuronal injury. Antioxidant treatments reduce excitotoxic damage in animal models.
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Impaired energy metabolism: HD is associated with mitochondrial dysfunction, decreased activity of respiratory chain complexes (especially complex II), and elevated lactate in the brain and CSF.
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Apoptosis: Some neurons in HD brains show features suggestive of apoptosis, though definitive morphological evidence is limited. Expanded polyglutamine repeats may interfere with key survival proteins (eg, CBP), and caspase-mediated cleavage of mutant huntingtin, especially by caspase-6, appears to contribute to neurodegeneration in animal models. [3, 4]
Pathophysiology
The hallmark neuropathology of Huntington disease (HD) is atrophy of the neostriatum (caudate nucleus and putamen), with selective neuronal loss and astrogliosis. Neuronal loss also occurs in deep cortical layers. Other regions (eg, globus pallidus, thalamus, subthalamic nucleus, substantia nigra, cerebellum) show variable atrophy depending on pathologic grade. [1]
Striatal pathology is graded 0–4 based on gross atrophy, neuronal loss, and gliosis: [5]
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Grade 0: Normal gross and microscopic appearance despite clinical HD [6]
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Grade 1: Microscopic changes only
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Grade 2: Visible striatal atrophy; caudate remains convex
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Grade 3: More severe atrophy; caudate is flat
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Grade 4: Most severe; caudate is concave
HD is caused by a CAG trinucleotide expansion in the huntingtin gene, which encodes a polyglutamine tract in the huntingtin protein. [7] The function of huntingtin is unclear, but it associates with various cytoplasmic organelles.
Mutant huntingtin fragments form nuclear inclusions in human HD brains and in models of the disease. [8] Initially thought to be toxic, [9] inclusions may not be necessary for neuronal death, which appears to be driven more by nuclear translocation of mutant fragments. [3] Caspase inhibition studies found no link between reduced aggregation and improved cell survival. [4] Inclusions are rare in striatal neurons (which degenerate) and more common in spared interneurons.
The TRACK-HD study showed progressive brain atrophy in premanifest and early HD, including grey- and white-matter loss and caudate atrophy, even before clinical onset. Atrophy correlated with decline in total functional capacity, cognitive and motor function, and oculomotor performance. [10]
Epidemiology
The prevalence of Huntington disease (HD) in the United States is estimated at about 7 per 100,000. [11] Prevalence varies worldwide due to founder effects:
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Lake Maracaibo, Venezuela: 700 per 100,000 [12]
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Mauritius: 46 per 100,000
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Tasmania: 17.4 per 100,000 [13]
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Most of Europe: 1.63–9.95 per 100,000
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Finland and Japan: <1 per 100,000 [14]
Mean age of onset is 35–44 years, but the range spans from childhood to over age 80. Juvenile (< 10 years) and late-onset (> 70 years) cases are rare. Venezuelan kindreds have a younger mean onset (34.35 years) than Americans (37.47) or Canadians (40.36), likely due to genetic and environmental modifiers.
Prognosis
Huntington disease (HD) is progressive and ultimately fatal, typically due to intercurrent illness. Mean age at death is 51–57 years, with disease duration averaging 19 years. Most patients live 10–25 years after symptom onset. Pneumonia and cardiovascular disease are the leading causes of death. [15]
Juvenile HD (onset < 20 years) accounts for 5–10% of cases and is usually inherited from the father. Paternal transmission is associated with anticipation, due to CAG repeat expansion during spermatogenesis. Longer CAG repeat lengths correlate with earlier onset, especially in juvenile cases.
The CAG repeat length is the primary determinant of age at onset, though other genetic and environmental factors contribute to variability. The US-Venezuela Collaborative Research Project has studied these influences in a large HD kindred since 1979. [5]
HD is a fully autosomal dominant disorder. Homozygotes for the HD mutation show no major phenotypic differences from heterozygotes. [6]
