- Author: Fredy J Revilla, MD; Chief Editor: Selim R Benbadis, MD more...
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. Characteristic features of HD include involuntary movements, dementia, and behavioral changes.
The most striking neuropathology in HD occurs within the neostriatum, in which gross atrophy of the caudate nucleus and putamen is accompanied by selective neuronal loss and astrogliosis. Marked neuronal loss also is seen in deep layers of the cerebral cortex. Other regions, including the globus pallidus, thalamus, subthalamic nucleus, substantia nigra, and cerebellum, show varying degrees of atrophy depending on the pathologic grade.
The extent of gross striatal pathology, neuronal loss, and gliosis provides a basis for grading the severity of HD pathology (grades 0-4).
No gross striatal atrophy is observed in grades 0 and 1. Grade 0 cases have no detectable histologic neuropathology in the presence of a typical clinical picture and positive family history suggesting HD. Grade 1 cases have neuropathologic changes that can be detected microscopically but without gross atrophy. In grade 2, striatal atrophy is present, but the caudate nucleus remains convex. In grade 3, striatal atrophy is more severe, and the caudate nucleus is flat. In grade 4, striatal atrophy is most severe, and the medial surface of the caudate nucleus is concave.
The genetic basis of HD is the expansion of a cysteine-adenosine-guanine (CAG) repeat encoding a polyglutamine tract in the N-terminus of the protein product called huntingtin.
The function of huntingtin is not known. Normally, it is located in the cytoplasm. The association of huntingtin with the cytoplasmic surface of a variety of organelles, including transport vesicles, synaptic vesicles, microtubules, and mitochondria, raises the possibility of the occurrence of normal cellular interactions that might be relevant to neurodegeneration.
N-terminal fragments of mutant huntingtin accumulate and form inclusions in the cell nucleus in the brains of patients with HD, as well as in various animal and cell models of HD.
The presence of neuronal intranuclear inclusions (NIIs) initially led to the view that they are toxic and, hence, pathogenic. More recent data from striatal neuronal cultures transfected with mutant huntingtin and transgenic mice carrying the spinocerebellar ataxia-1 (SCA-1) gene (another CAG repeat disorder) suggest that NIIs may not be necessary or sufficient to cause neuronal cell death, but translocation into the nucleus is sufficient to cause neuronal cell death. Caspase inhibition in clonal striatal cells showed no correlation between the reduction of aggregates in the cells and increased survival.
Furthermore, postmortem studies reveal that NIIs are quite rare in the striata of patients with HD as compared to the cortex, and most of the aggregates within the striatum are observed in populations of interneurons that typically are spared in individuals with HD.
TRACK-HD is a prospective observational study that reported 12-month longitudinal changes in 116 pre-manifest individuals carrying the mutant Huntington gene (preHD), 114 patients with early HD, and 115 age- and sex-matched controls. Generalized and regional brain atrophy was higher in preHD and early HD than in controls. Voxel-based morphometry revealed grey-matter and white-matter atrophy, even in subjects furthest from predicted disease onset. The study showed change in the total functional capacity, a widely used measure of HD clinical severity, that was associated with both whole-brain and caudate atrophy rates. Compared to controls, deterioration in cognition and motor function was detectable in both preHD and early HD, as well as worsening in oculomotor function in early HD. Change in cognitive and motor measures were associated with whole-brain volume loss.
The selective neuronal dysfunction and subsequent loss of neurons in the striatum, cerebral cortex, and other parts of the brain can explain the clinical picture seen in cases of HD. Several mechanisms of neuronal cell death have been proposed for HD, including excitotoxicity, oxidative stress, impaired energy metabolism, and apoptosis.
Excitotoxicity refers to the neurotoxic effect of excitatory amino acids in the presence of excessive activation of postsynaptic receptors.
Intrastriatal injections of kainic acid, an agonist of a subtype of glutamate receptor, produce lesions similar to those seen in HD.
Intrastriatal injections of quinolinic acid, an N -methyl-D-aspartate (NMDA) receptor agonist, selectively affect medium-sized GABA-ergic spiny projection neurons, sparing the striatal interneurons and closely mimicking the neuropathology seen in HD.
NMDA receptors are depleted in the striata of patients with HD, suggesting a role of NMDA receptor-mediated excitotoxicity, but no correlation exists between the distribution of neuronal loss and the density of such receptors.
The theory that reduced uptake of glutamate by glial cells may play a role in the pathogenesis of HD also has been proposed.
Oxidative stress is caused by the presence of free radicals (ie, highly reactive oxygen derivatives) in large amounts. This may occur as a consequence of mitochondrial malfunction or excitotoxicity and can trigger apoptosis.
Striatal damage induced by quinolinic acid can be ameliorated by the administration of spin-trap agents, which reduce oxidative stress, providing indirect evidence for the involvement of free radicals in excitotoxic cell death.
Impaired energy metabolism
Impaired energy metabolism reduces the threshold for glutamate toxicity and can lead to activation of excitotoxic mechanisms as well as increased production of reactive oxygen species.
Nuclear magnetic resonance spectroscopy studies have shown elevated lactate levels in the basal ganglia and occipital cortex of patients with HD.
Patients with HD have an elevated lactate-pyruvate ratio in the cerebrospinal fluid.
A reduction in the activity of the respiratory chain complex II and III (and less in complex IV) of mitochondria of caudate neurons in patients with HD has been reported.
In rats, intrastriatal injections of 3-nitroproprionic acid (3-NP), an inhibitor of succinate dehydrogenase or complex II of the respiratory chain, cause dose-dependent ATP depletion, increased lactate concentration, and neuronal loss in the striatum. Systemic injections of 3-NP into rats produce a selective loss of medium spiny neurons in the striatum.
Apoptosis is the programmed cell death that is activated normally in the nervous system during embryogenesis to remove supernumerary neurons as part of natural development.
Morphological features of apoptosis have been well characterized. Oxidative stress, excitotoxicity, and partial energy failure can lead to apoptosis.
A subset of neurons and glia in the neostriata of patients with HD appears to undergo apoptosis, as shown by in situ DNA nick end labeling (TUNEL) staining, but clear morphological evidence for an apoptotic process in HD is still missing.
One theory is that expanded polyglutamine repeats cause neuronal degeneration through abnormal interactions with other proteins containing short polyglutamine tracts. Recent work suggests that polyglutamine interference with transcription of CREB binding protein (CBP), a major mediator of survival signals in mature neurons, may constitute a genetic gain of function underlying polyglutamine disorders including HD.
The role of caspases (a class of highly specific proteases) in apoptosis involves cleavage of target proteins at different sites. In humans with HD and in animal models of HD, the intracellular accumulation of N-terminal huntingtin fragments is one of the neuropathological features. Caspases, among other proteins, cleave huntingtin within the N-terminal region. To address the question of a potential in vivo neuroprotective effect of inhibition of caspases, a YAC mouse model expressing mutant huntingtin, along with selective mutations of the caspase-3 and caspase-6 cleavage sites, was studied. Selective elimination of the caspase-6, but not caspase-3, cleavage site in mutant huntingtin resulted in protection from neuronal dysfunction and neurodegeneration in vivo. These results suggest that preventing caspase-6 cleavage of huntingtin may be of therapeutic interest.
Estimates of the prevalence of HD in the United States range from 4.1-8.4 per 100,000 people. Accurate estimates of the incidence of HD are not available.
The frequency of HD in different countries varies greatly. A few isolated populations of western European origin have an unusually high prevalence of HD that appears to have resulted from a founder effect. These include the Lake Maracaibo region in Venezuela (700 per 100,000 people) , the island of Mauritius off the South African coast (46 per 100,000 people), and Tasmania (17.4 per 100,000 people). The prevalence in most European countries ranges from 1.63-9.95 per 100,000 people. The prevalence of HD in Finland and Japan is less than 1 per 100,000 people.
Age-related differences in incidence
Most studies show a mean age at onset ranging from 35-44 years. However, the range is large and varies from 2 years to older than 80 years. Onset in patients younger than 10 years and in patients older than 70 years is rare. The Venezuelan kindreds manifest an earlier mean age of onset (34.35 years) when compared with Americans (37.47 years) and Canadians (40.36 years). Modifying genes and environmental factors are thought to influence the age of onset in these different populations.
HD is a relentlessly progressive disorder, leading to disability and death, usually from an intercurrent illness.
The mean age at death in all major series ranges from 51-57 years, but the range may be broader. Duration of illness varies considerably, with a mean of approximately 19 years. Most patients survive for 10-25 years after the onset of illness. In a large study, pneumonia and cardiovascular disease were the most common primary causes of death.
Juvenile HD (ie, onset of HD in patients younger than 20 years) accounts for approximately 5-10% of all affected patients. Most patients with juvenile HD inherit the disease from their father, whereas patients with onset of the disease after age 20 years are more likely to have inherited the gene from their mother. Inheritance through the father can lead to earlier onset through succeeding generations, a phenomenon termed anticipation. This is caused by greater instability of the HD allele during spermatogenesis. CAG repeat length correlates inversely with age of onset, and the correlation is stronger when the onset of symptoms occurs earlier.
The length of the CAG repeat is the most important factor in determining age of onset of HD, although substantial variability remains after controlling for repeat length. Both genetic and environmental components account for this variability. The US-Venezuela Collaborative Research Project studied Venezuelan HD kindreds, the world's largest genetically related HD community (18,149 individuals spanning 10 generations) since 1979, collecting genetic and clinical data.
A small number of homozygotes for the HD mutation have been identified, and they seem to be phenotypically indistinguishable from heterozygotes, making HD a truly autosomal dominant disorder.
With the increasing amount of genetic/hereditary information available in HD, the question of whether patients and/or family members should be made aware of the genetic risks is becoming an increasingly important issue.
For excellent patient education resources, visit eMedicineHealth's Brain and Nervous System Center. Also, see eMedicineHealth's patient education article Huntington Disease Dementia.
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