Changes: Huntington's disease

**Huntington's disease**
ICD-10	G10, F022
ICD-9	333.4, 294.1
OMIM	143100
DiseasesDB	6060
MedlinePlus	[1]
eMedicine	/
MeSH	{{{MeshNumber}}}

Revision as of 00:25, 29 August 2014

Clinical: Approaches · Group therapy · Techniques · Types of problem · Areas of specialism · Taxonomies · Therapeutic issues · Modes of delivery · Model translation project · Personal experiences ·

georgehuntington.jpg|

Huntington's disease, also called Huntington's chorea, chorea major, or HD, is a genetic neurological disorder^[1] characterized after onset by uncoordinated, jerky body movements and a decline in some mental abilities. These characteristics vary per individual, physical ones less so, but the differing decline in mental abilities can lead to a number of potential behavioral problems. The disorder itself isn't fatal, but as symptoms progress, complications reducing life expectancy increase.^[2] Research of HD has increased greatly in the last few decades, but its exact mechanism is unknown, so symptoms are managed individually.^[3] Globally, up to 7 people in 100,000 have the disorder, although there are localized regions with a higher incidence.^[4] Onset of physical symptoms occurs gradually and can begin at any age, although it is statistically most common in a person's mid-forties (with a 30 year spread). If onset is before age twenty, the condition is classified as juvenile HD.^[5]

The disorder is named after George Huntington, an American physician who published a remarkably accurate description in 1872.^[6] In 1983 a marker for the altered DNA causing the disease was found,^[7] followed a decade later by discovery of a single, causal, gene.^[8] As it was caused by a single gene, an accurate genetic test for HD was developed; this was one of the first inherited genetic disorders for which such a test was possible. Due to the availability of this test, and similar characteristics with other neurological disorders, the amount of HD research has increased greatly in recent years.^[9]

Classification

Huntington's disease is one of several trinucleotide repeat disorders, caused by the length of a repeated section of a gene exceeding the normal range. The huntingtin gene (HTT) normally provides the information to produce Huntingtin protein, but when affected, produces mutant Huntingtin (mHTT) instead.^[10]

Signs and symptoms

Physical symptoms are usually the first to cause problems and to be noticed, but at this point they are usually accompanied by unrecognized cognitive and psychiatric ones. Almost everyone with Huntington's disease eventually exhibits all physical symptoms, but cognitive and psychiatric symptoms can vary significantly between individuals.^[2]

The most characteristic physical symptoms are jerky, random, and uncontrollable movements called chorea. In a few cases, very slow movement and stiffness (called bradykinesia and dystonia) occur instead, and often become more prominent than the chorea as the disorder progresses. Abnormal movements are initially exhibited as general lack of coordination, an unsteady gait and slurring of speech, but, as the disease progresses, any function that requires muscle control is affected, causing physical instability, abnormal facial expression, and difficulties chewing and swallowing. Eating difficulties commonly cause weight loss and may lead to malnutrition.^[11]^[12] Associated symptoms involve sleep cycle disturbances, including insomnia and Rapid eye movement sleep alterations.^[13]^[14] Juvenile HD generally progresses faster, is more likely to exhibit rigidity and bradykinesia, instead of chorea, and commonly includes seizures.^[2]

Select cognitive abilities are impaired progressively. Especially affected are executive functions which include planning, cognitive flexibility, abstract thinking, rule acquisition, initiating appropriate actions and inhibiting inappropriate actions.^[15] Psychomotor function, controlling muscles, perception and spatial skills, is also affected.^[15] As the disease progresses, memory deficits tend to appear. Memory impairments reported range from short-term memory deficits to long-term memory difficulties, including deficits in episodic (Memory of one's life), procedural (Memory of the body of how to perform an activity) and working memory.^[15]

Psychiatric symptoms vary far more than cognitive and physical ones, and may include anxiety, depression, a reduced display of emotions (blunted affect), egocentrism, aggression, and compulsive behavior, which can cause, or worsen addictions, including alcoholism and gambling, or hypersexuality.^[16]^[17] Difficulties in recognizing other people's negative expressions has also been observed.^[15]^[18]

Genetics

See also: Trinucleotide repeat disorders

The Huntingtin gene (HTT) is located on the short arm of chromosome 4 (4p16.3). HTT contains a sequence of three DNA bases—cytosine-adenine-guanine (CAG)—repeated multiple times (i.e. ...CAGCAGCAG...) on its 5' end, known as a trinucleotide repeat. CAG is the genetic code for the amino acid glutamine, so a series of them results in the production of a chain of glutamine known as polyglutamine or polyQ tract, and the repeated part of the gene, the PolyQ region.^[19]

Repeat count	Classification	Disease status
<27	Normal	Unaffected
27–35	Intermediate	Unaffected
36–39	Reduced Penetrance	+/- Affected
>39	Full Penetrance	Affected

A polyQ region containing fewer than 36 glutamines results in production of the cytoplasmic protein called huntingtin (Htt). Generally, people have less than 27 repeated glutamines, however, a sequence of 36 or more glutamines, results in the production of form of Htt which has different characteristics. This altered form, called mutant Htt or more commonly mHtt, increases the rate of neuronal decay in certain types of neurons, affecting regions of the brain with a higher proportion or dependency on them. Generally, the number of CAG repeats is related to how much this process is affected, and correlates with age at onset and the rate of progression of symptoms.^[10] For example, 36–39 repeats result in much later onset and slower progression of symptoms than the mean, such that some individuals may die of other causes before they even manifest symptoms of Huntington disease, this is termed "reduced penetrance".^[20] With very large repeat counts, HD can occur under the age of 20 years, when it is then referred to as juvenile HD, akinetic-rigid, or Westphal variant HD and accounts for about 7 percent of HD carriers.^[5]

Inheritance

File:Autosomal Dominant Pedigree Chart2.svg

HD is inherited in an autosomal dominant fashion. Each successive generation is given a roman numeral I, II, or III. Note that the probability of the offspring of an affected individual being affected (red) themselves is 50%, however if they receive the affected parent's normal allele, they and all of their offspring are unaffected (blue). Transmission from an affected father to an affected son rules out X-linked inheritance.

Huntington's disease is inherited autosomal dominantly, meaning that an affected individual typically inherits a copy of the gene with an expanded trinucleotide repeat (the mutant allele) from an affected parent. In this type of inheritance pattern, each offspring of an affected individual has a 50% chance of inheriting the mutant allele and therefore being affected with the disorder (see figure). It is extremely rare for Huntington's disease to be caused by a de novo mutation,^[21]^[22] however, the inheritance of HD is more complex due to potential dynamic mutations, where DNA replication does not produce an exact copy of the trinucleotide repeat. This can cause the number of repeats to change in successive generations, such that an unaffected parent with an "intermediate" number of repeats (28-35), or "reduced penetrance" (36-39), may pass on a copy of the gene with an increase in the number of repeats that produces fully penetrant HD.^[23] These new mutations have occurred in less than 10 percent of people with HD, but explain the origins of the disorder.^[24] Maternally inherited alleles are usually of a similar repeat length, whereas paternally inherited ones seem to have a higher chance of increasing in length.^[25] Increases in the number of repeats (and hence earlier age of onset and severity of disease) in successive generations is known as genetic anticipation.

Homozygous individuals, who have two affected genes, are very rare except in large consanguineous families. While HD seemed to be the first disease for which homozygotes did not differ in clinical expression or course from typical heterozygotes,^[26] more recent analysis suggests that homozygosity affects the phenotype and the rate of disease progression but does not alter the age of onset, suggesting that the mechanisms for these factors differ.^[27]

Mechanism

See also: Huntingtin protein

Like all proteins, Htt and mHtt are translated, perform or affect biological functions, and are then marked by ubiquitin to be degraded by proteasomes, but their exact roles are unknown. Research has focused on identifying the functioning of Htt, how mHtt differs or interferes with it, including its influence in programmed cell death, and the proteopathy of remnants of mHtt left after degradation.^[1]

Function

Although the function of the Huntingtin protein is unclear, some hypotheses have been drawn from observations. In mouse models, Htt is essential for development and survival.^[28] In "knockin" mice, the extended CAG repeat portion of the gene is all that is needed to cause disease.^[29] The protein has no sequence homology with other proteins and is highly expressed in neurons and testes.^[30] Experiments have shown Htt acts as a transcription factor in upregulating the expression of Brain Derived Neurotrophic Factor (BDNF), a protein which protects neurons and regulates the neurogenesis of new ones, whereas mHtt suppresses this transcription regulatory function of Huntingtin and hence underexpression of BDNF, which leads to progressive atrophy of select areas of the brain.^[31]^[32]^[33]^[34]From immunohistochemistry, electron microscopy, subcellular fractionation studies of the molecule, it has been found that Huntingtin is primarily associated with vesicles and microtubules.^[35]^[36].These indicate a functional role in cytoskeletal anchoring or transport of mitochondria. The Htt protein is involved in vesicle trafficking as it interacts with HIT1, a clathrin binding protein, to mediate endocytosis, the absorption of materials into a cell.^[37]^[38] Initial studies show carriers of the expanded repeat may have better than average immune systems, with higher levels of Interleukin 6 and tumor suppressor protein p53.^[39]^[40]

Degradation

In the first step of degradation, both Htt and mHtt are cleaved by caspase-3, which removes the protein's amino end (the N-terminal).^[41] Caspase-2 then further breaks down the amino terminal fragment (which includes the CAG repeat) of Htt, but cannot process all of the mHtt protein.^[42] In transgenic mice, the caspase-6 enzyme has been shown to be involved in cleaving the Htt protein, as mice made resistant to this enzyme did not suffer neurodegeneration.^[43]The uncleaved pieces of mHtt, left in the cell, called N-fragments, and are able to affect genetic transcription.^[44] Specifically, mHtt binds with TAF_II130, a coactivator to CREB dependent transcription.^[45] The mHtt protein also interacts with the transcription factor protein SP₁, preventing it from binding to DNA.^[46]

Neuronal intranuclear inclusions containing the huntingtin and ubiquitin proteins have been found in both humans and mice with HD,^[47]^[48]. Such inclusions are most prevalent in cortical pyramidal neurons, less so in striatal medium-sized spiny neurons and almost entirely absent in most other regions.^[47]^[49]^[50] These inclusions consist mainly of the amino terminal end of mHtt (CAG repeat), and are found in both the cytoplasm and nucleus of neurons,^[51] however their presence does not correlate with cell death, and may even act as a protective mechanism to the cell.^[52]^[53] Thus, mHtt acts in the nucleus but does not cause apoptosis through protein aggregation.^[54]

Pathophysiology

HD causes astrogliosis^[55] and loss of medium spiny neurons^[56]^[57] Areas of the brain are affected according to their structure and the types of neurons they contain, reducing in size as they cumulatively lose cells. The areas affected are mainly in the striatum, but also the frontal and temporal cortices.^[58] The striatum's subthalamic nuclei send control signals to the globus pallidus, which initiates and modulates motion. The weaker signals from subthalamic nuclei thus cause reduced initiation and modulation of movement, resulting in the characteristic movements of the disorder.^[59]

Although studies are mainly focused on physiopathology of the brain, some look at how Huntington's disease appears to affect other physiological functions. One study in humans highlighted a systemic, early hypermetabolic state and a lower level of branched chain amino acids in the plasma as the disease progresses, which is hypothesised to be caused by the brain's use of these.^{[How to reference and link to summary or text]}^[60]

Diagnosis

Further information: Genetic testing

A physical and/or psychological examination can determine whether initial symptoms are evident. Abnormal movements are often the symptoms that cause initial impetus to seek medical consultation and lead to diagnosis; however, the disease may begin with cognitive or pyschiatric symptoms, which are not always recognized except in hindsight, or if they develop further. Pre-symptomatic testing is possible using a blood test which counts the numbers of CAG repeats in each of the HTT alleles,^[61] although a positive result is not considered a diagnosis, since it may be obtained decades before onset of symptoms. A negative blood test means that the individual does not carry the expanded copy of the gene. A full pathological diagnosis can only be established by a neurological examination's findings and/or demonstration of cell loss in the areas affected by HD, supported by a cranial CT or MRI scan findings.^[62]

A pre-symptomatic test is a life-changing event and a very personal decision. The personal ramifications to an at-risk individual and lack of cure for the disease necessitate several counseling sessions to ensure that they are prepared for either result before it is given.^[63] In England, Scotland, Northern Ireland, Australia, Canada and New Zealand, unless a person under eighteen years of age is considered to be Gillick competent, testing is not considered ethical - unless they show significant symptoms, or are sexually active.^[64] Many organizations and lay groups strongly endorse these restrictions in their testing protocol.

Embryonic screening is also possible, giving affected or at-risk individuals the option of ensuring their children will not inherit the disease. It is possible for women who would consider abortion of an affected fetus to test an embryo in the womb (prenatal diagnosis). Other techniques, such as preimplantation genetic diagnosis in the setting of in vitro fertilisation, can be used to ensure that the newborn is unaffected.^[65]

Management

Treatments for cognitive and psychological symptoms include antidepressants and sedatives, and low doses of antipsychotics.^[66] There is limited evidence for specific treatments aimed at controlling the chorea and other movement abnormalities, although tetrabenazine has been shown to reduce the severity of the chorea;^[67] it was approved in 2008 specifically for this indication.^[3]

Nutrition management is an important part of treatment; most people in the later stages of the disease need more calories than average to maintain body weight.^[68] Thickening agent can be added to drinks as swallowing becomes more difficult, as thicker fluids are easier and safer to swallow. The option of using a percutaneous endoscopic gastrostomy (i.e., a feeding tube into the stomach) is available when eating becomes too hazardous or uncomfortable. A "stomach PEG" greatly reduces the chances of aspiration of food, which can lead to aspiration pneumonia,and also increases the amount of nutrients and calories that can be ingested, aiding the body's natural defenses.^[69]

Although there are relatively few studies of rehabilitation for HD, its general effectiveness when conducted by a team of specialists has been clearly demonstrated in other pathologies such as stroke,^[70] or head trauma.^[71] As for any patient with neurologic deficits, a multidisciplinary approach is key to limiting and overcoming disability.^[72] There is some evidence for the usefulness of physical therapy and speech therapy but more rigorous studies are needed for health authorities to endorse them.^[73]

Prognosis

The age of onset decreases, and the rate of progression of symptoms increase, with the number of CAG repeats. Individuals with greater than approximately 60 CAG repeats often develop juvenile Huntington's disease.^[74]^[75] There is a variation in age of onset for any given CAG repeat length, particularly within the intermediate range (40–50 CAGs). For example, a repeat length of 40 CAGs leads to an onset ranging from 40 to 70 years of age in one study. This variation means that, although algorithms have been proposed for predicting the age of onset, in practice, it can not be predicted confidently.^[76]^[77]

The life expectancy is around 15 to 20 years following the onset of characteristic manifestations of the disorder.^[78] Mortality is not caused by Huntington’s disease directly, but by associated complications; these include pneumonia (which causes one third of fatalities), heart failure (although heart disease, cerebrovascular disease and atherosclerosis show no increase), choking, malnutrition and physical injury.^[79] Suicide is an associated risk, with increased suicide rates of up to 7.3 percent, and attempted suicides of up to 27 percent.^[80]^[81]^[2]

Epidemiology

As HD is autosomal dominant, and does not usually affect reproduction, areas of increased prevalence occur according to historical migration of carriers, some of which can be traced back thousands of years using genetic haplotypes.^[82] Since the discovery of a genetic test that can also be used pre-symptomatically, estimates of the incidence of the disorder are likely to increase. Without the test, only individuals displaying physical symptoms or neurologically examined cases were diagnosed, excluding any who died of other causes before symptoms or diagnosis occurred. These cases can now be included in statistics as the test becomes more widely available and estimates have shown the incidence of HD could be two to three times higher when these results are included.^[83]

The prevalence varies greatly according to geographical location, both by ethnicity and local migration; The highest occurrence is in peoples of Western Europe descent, averaging between 3 to 7 per 100,000 people, but is relatively lower in the rest of the world, e.g. 1 per 1,000,000 of Asian and African descent.^[4] Some localised areas have a much higher prevalence than their geographical average, for example the isolated populations of the Lake Maracaibo region of Venezuela (where the marker for the gene was discovered), have an extremely high prevalence of up to 700 per 100,000,^[84] leading to the conclusion that one of their initial founders must have been a carrier of the gene. This is known as the local founder effect.^[7]

History

In the first part of the twentieth century and earlier, many people with HD were misdiagnosed as suffering from alcoholism or manic depression. Previously mortality due to starvation or dehydration was a major risk.

Middle Ages: People with the condition were probably persecuted as being witches or as being possessed by spirits, and were shunned, exiled or worse. Some speculate that the "witches" in the Salem Witch Trials in 1692 had HD.^[85]^[86]
1860: One of the early medical descriptions of HD was made in 1860 by a Norwegian district physician, Johan Christian Lund. He noted that in Setesdalen, a remote and rather secluded area, there was a high prevalence of dementia associated with a pattern of jerking movement disorders that tended to run in families. This is the reason for the disease being commonly referred to as Setesdalsrykkja (Setesdalen=the location, rykkja=jerking movements) in Norwegian.^[87]
1872: George Huntington was the third generation of a family medical practice in Long Island. With their combined experience of several generations of a family with the same symptoms, he realized their conditions were linked and set about describing it. A year after leaving medical school, in 1872, he presented his accurate definition of the disease to a medical society in Middleport, Ohio.^[6]^[88]
c. 1902: Smith Ely Jelliffe (1866–1945) began studying the history of HD sufferers in New England and published several articles over the next few decades.^[89]
1932: P. R. Vessie expanded Jelliffe and Tilney's work, tracing about a thousand people with HD back to two brothers and their families who left Bures in Suffolk, England bound for Boston, MA in 1630.^[90]
File:Hdpubmedarticleschart.png
1979: The US-Venezuela Huntington's Disease Collaborative Research Project began an extensive study which formed the basis for the gene to be discovered. This was conducted in the small, isolated Venezuelan fishing villages of Barranquitas and Lagunetas, where families have a high prevalence of the disease.^[91]
1983: James Gusella, David Housman, P. Michael Conneally, Nancy Wexler, and their colleagues find the general location of the gene, using DNA marking methods for the first time—an important first step toward the Human Genome Project.^[7]
1992: Anita Harding, et al. find that trinucleotide repeats affect disease severity.^[92]
1993: The Huntington's Disease Collaborative Research Group isolates the precise gene at 4p16.3.^[93]
1996: A transgenic mouse (the R6 line) was created that could be made to exhibit HD, greatly advancing how much experimentation can be achieved.^[94]^[95]
1997: DiFiglia M, Sapp E, Chase KO, et al., discover that mHtt fragments misfold, leading to the formation of nuclear inclusions.^[47]
The full record of research is extensive.^[2]^[96]^[97]

Society and culture

See also: List of Huntington's disease media depictions

As public awareness has increased, HD has been depicted increasingly in numerous books, films and TV series. Early works were Arlo Guthrie's 1969 film Alice's Restaurant^[98] and Jacqueline Susann's 1966 American novel Valley of the Dolls; more recent references were made in ER,^[99] Private Practice,^[100] Everwood,^[101] All Saints,^[102] and House.^[103] Steven T. Seagle's 2004 graphic novel "It's a Bird" discusses Huntington's disease and the effects on his family.^[104] Many support organizations hold an annual HD awareness event, and some have been endorsed by their respective governments, for example, June 6 is designated "National Huntington's Disease Awareness Day" by the USA senate, and the UK HDA holds an awareness campaign in the third week of June.^[105]

Social impact

The development of an accurate diagnostic test for Huntington's disease has caused social, legal, and ethical concerns over access and use of a person's results^[106]^[107] There have been guidelines created by the IHA and WFN for the use of genetic testing in HD, but many governments and institutions, although agreeing not to genetically discriminate against an individual, have not reached a consensus.^[108] As for the individual, the decision to undergo a presymptomatic test, thereby learning whether they will inherit the disorder, is a complicated one. Genetic counseling is designed to provide information, advice and support for a person to decide, and then throughout all stages of the testing process, if so chosen.^[63]

One of the key issues is the level of anxiety that an individual experiences about "not knowing" whether they will some day develop HD, compared to the psychological impact that might occur if the test indicates that one will eventually succumb to the disease. In contrast individuals found to have inherited the normal allele may experience Survivor guilt with regard to their affected family members.^[109] Some individuals choose not to undergo testing due to concerns about prejudice in areas such as insurability, employment and financial matters. An important ethical consideration is the testing of asymptomatic minors. As with other genetic conditions with later onset for which no treatment is available, it is ethically questionable to perform presymptomatic testing for a child or individual who has not made a mature, informed decision for themselves.^[110] Such information may cause psychological harm, jeopardize that individual's employment or ability to obtain health and life insurance. For this reason, presymptomatic testing in minors is a controversial area, with arguments in favor of permitting testing only when the individual is mature enough to provide assent versus minimizing medical paternalism in favor of parental preferences.^[111]^[112]^[113]^[64] The balance of opinion would change drastically if an effective treatment was discovered.

Genetic testing may infer information about relatives who do not want it. Testing a descendant of a undiagnosed parent has implications to other family members, since a positive result automatically reveals the parent as carrying the affected gene, and siblings (and especially identical twins) as being 'at risk' of also inheriting it.^[114] This emphasizes the importance of disclosure, as individuals have to decide when and how to reveal the information to their children and other family members. For those at risk, or known to carry a mutant allele, there can be the consideration of prenatal genetic testing and preimplantation genetic diagnosis in order to ensure that the disorder is not passed on.^[115]

Huntington's disease has tested society's ethics in various ways. HD was one of the targets of the eugenics movement, in which American scientist Charles Davenport proposed in 1910 that compulsory sterilization and immigration control be used for people with certain diseases, including HD.^[116] Since the development of genetic testing for HD, financial institutions and businesses are also faced with the question of whether to use results when assessing an individual, e.g. for life insurance or employment. Some countries' organizations have already agreed not to use this information.^[117] Recent passage of the Genetic Information Nondiscrimination Act (GINA) in the United States prevents health insurance companies from denying coverage or charging higher premiums for individuals with predisposition to genetic disease.^{[How to reference and link to summary or text]}

Organizations

1967: Woody Guthrie's wife, Marjorie, helped found the Committee to Combat Huntington's Disease, after his death from HD complications. This eventually became the Huntington's Disease Society of America.^[118] Since then, lay organizations have been formed in many countries around the world.
1968: After experiencing HD in his wife's family Dr. Milton Wexler was inspired to start the Hereditary Disease Foundation (HDF). Professor Nancy S. Wexler, Dr. Wexler's daughter, was in the research team in Venezuela and is now president of the HDF.
1974: The first international meeting took place when the founders of the Canadian HD Society (Ralph Walker) and of the British HD Society (Mauveen Jones) attended the annual meeting of the American HD Society.
1977: Second meeting organized by the Dutch Huntington Society the "Vereniging van Huntington", representatives of six countries were present.
1979: International Huntington Association (IHA) formed during international meeting in Oxford, England organized by HDA of England.
1981–2001: Biennial meetings held by IHA which became the World Congress on HD.
2003: The first World Congress on Huntington's Disease was held in Toronto.^[119] This is a biennial meeting for associations and researchers to share ideas and research, which is held on odd-number years. The Euro-HD Network^[120] was started as part of the Huntington Project,^[121] funded by the High-Q Foundation.^[122]

Research directions

Appropriate animal models are critical for understanding the fundamental mechanisms causing the disease and for supporting the early stages of drug development. Neurochemically induced mice or monkeys were first available,^[123]^[124] but they did not mimic the progressive features of the disease. After the HD gene was discovered, transgenic animals exhibiting HD were generated by inserting a CAG repeat expansion into their genome, these were of mice (strain R6/2),^[125]^[126]), Drosophila fruit flies,^[127] and more recently monkeys.^[128] Expression without insertion of a DNA repeat in nematode worms also produced a valuable model.^[129]

Intrabody therapy

Genetically engineered intracellular antibody fragments called intrabodies have shown therapeutic results, by inhibiting mHtt aggregation, in drosophila models. This was achieved using an intrabody called C4 sFv, a single chain variable fragment which binds to the end of mHtt within a cell.^[130]^[131] This therapy prevented larval and pupal mortality (without therapy 77% died) and delayed neurodegeneration in the adult, significantly increasing their lifespan.^[132] Intrabody therapy shows promise as a tool for drug discovery, and as a potential therapy for HD and other neurodegenerative disorders caused by protein mis-folding or abnormal protein interactions.^[133]^[134]

Gene silencing

As HD has been conclusively linked to a single gene, gene silencing is potentially possible. Researchers have investigated using gene knockdown of mHTT as a potential treatment. Using a mouse model, siRNA therapy achieved a 60 percent reduction in expression of the mHTT and progression of the disease was stalled.^[135] However, this study used the human form of the mHTT protein in the mouse, and was therefore only able to directly target the mHTT, leaving endogenous, wild-type mouse Htt gene expression unaffected. From a practical standpoint, it would be difficult in humans to use siRNA to target the mutant form while leaving the normal copy unaffected. The precise function of HTT is unknown, but in mice, complete deletion of the Htt gene is lethal.^[28] Thus, using RNA interference to treat HD could have unexpected effects unless knock-down of the normal HTT protein can be avoided. Other issues include problems delivering the siRNA to the appropriate target tissue, off-target effects of siRNA, and toxicity from shRNA over-expression.^[136] Another study showed that mouse models already in late stages of the disease recovered motor function after expression of mHTT was stopped.^[137]

Stem cell implants

Main article: Stem cell treatments

Stem cell therapy is the replacement of damaged neurons by transplantation of stem cells (or possibly neural stem cells—a type of somatic [adult] stem cell) into affected regions of the brain. Hypothetically, embryonic stem cells can be differentiated into neuronal precursors in vitro, and transplanted into damaged areas of the brain to generate replacement neurons, if enough damaged neurons can be replaced and develop the correct synaptic connectivity, symptoms could be alleviated. This treatment would not prevent further neuronal damage, so it would have to be an ongoing treatment. Experiments have yielded some positive results in animal models, but remains highly speculative and has not been tested in clinical trials.^[138]

Pharmacological

As of August 2008, several trials of various compounds are in development or ongoing,^[139] a few at the point of testing on larger numbers of people, known as phase III of clinical trials. Substances that have shown promise in initial experiments include dopamine receptor blockers, select dopamine antagonists, such as tetrabenazine, creatine, CoQ10, the antibiotic Minocycline, antioxidant-containing foods and nutrients, and antidepressants, including selective serotonin reuptake inhibitors such as sertraline, fluoxetine, and paroxetine.^[140]^[3]

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Bibliography

Conomy, John P., M.D., J.D Dr. George Huntington and the Disease Bearing His Name. URL accessed on 2008-08-15.
OMIM 143100
OMIM 606438
Stevenson, Charles S. (April 1934). A Biography of George Huntington, M.D. Bulletin of the Institute of the History of Medicine II (2).

External links

DMOZ HD links directory at the Open Directory Project.

Professional and research

Huntington Project - worldwide umbrella organization for the clinical research efforts for HD.
Huntington Study Group
Huntington's Disease Research - Research abstracts on HD.
Huntington's Disease Outreach Project for Education, at Stanford (HOPES) - A layperson's guide to HD
Worldwide Education and Awareness for Movement Disorders - HD section
University College London Huntington's Disease Research
TRACK-HD, an international observational study of HD
University California and San Francisco Memory and Aging Center - HD Info

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This page uses Creative Commons Licensed content from Wikipedia (view authors).

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[21] Myers et al. (1993). De novo expansion of a (CAG)n repeat in sporadic Huntington's disease. Nature Genetics 5: 168–173.

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[pmid9063751-23] Chong SS, Almqvist E, Telenius H, et al (February 1997). Contribution of DNA sequence and CAG size to mutation frequencies of intermediate alleles for Huntington disease: evidence from single sperm analyses. Hum. Mol. Genet. 6 (2): 301–9.

[24] García-Planells J, Burguera JA, Solís P, et al. (May 2005). Ancient origin of the CAG expansion causing Huntington disease in a Spanish population. Hum. Mutat. 25 (5): 453–9.

[25] RM Ridley, CD Frith, TJ Crow and PM Conneally (1988). Anticipation in Huntington's disease is inherited through the male line but may originate in the female. Journal of Medical Genetics 25: 589–595.

[pmid2881213-26] Wexler NS, Young AB, Tanzi RE, et al. (1987). Homozygotes for Huntington's disease. Nature 326 (6109): 194–197.

[27] Squitieri F, Gellera C, Cannella M, Mariotti C, Cislaghi G, Rubinsztein DC, Almqvist EW, Turner D, Bachoud-Lévi AC, Simpson SA, Delatycki M, Maglione V, Hayden MR, Donato SD (2003). Homozygosity for CAG mutation in Huntington disease is associated with a more severe clinical course. Brain 126 (4): 946–955.

[Nasir-28] 28.0 ^28.1 Nasir J, Floresco S, et al (1995). Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes. Cell 81: 811–823.

[29] Murphy KP, Carter RJ, Lione LA, et al. (2000). Abnormal synaptic plasticity and impaired spatial cognition in mice transgenic for exon 1 of the human Huntington's disease mutation. J. Neurosci. 20 (13): 5115–23.

[Cattaneo-30] Cattaneo E, Zuccato C, Tartari M (December 2005). Normal huntingtin function: an alternative approach to Huntington's disease. Nature Reviews Neuroscience 6: 919–930.

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v·d·e WHO ICD-10 mental and behavioural disorders (F · 290–319)
Neurological/ symptomatic	Dementia (Alzheimer's disease, multi-infarct dementia, Pick's disease, Creutzfeldt-Jakob disease, Huntington's disease, Parkinson's disease, AIDS dementia complex, Frontotemporal dementia) · Delirium · Post-concussion syndrome
Psychoactive substance	alcohol (drunkenness, alcohol dependence, delirium tremens, Korsakoff's syndrome, alcohol abuse) · opiods (opioid dependency) · sedative/hypnotic (benzodiazepine withdrawal) · cocaine (cocaine dependence) · general (Intoxication, Drug abuse, Physical dependence, Withdrawal)
Psychotic disorder	Schizophrenia (disorganized schizophrenia) · Schizotypal personality disorder · Delusional disorder · Folie à deux · Schizoaffective disorder
Mood (affective)	Mania · Bipolar disorder · Clinical depression · Cyclothymia · Dysthymia
Neurotic, stress-related and somatoform	Anxiety disorder (Agoraphobia, Panic disorder, Panic attack, Generalized anxiety disorder, Social anxiety) · OCD · Acute stress reaction · PTSD · Adjustment disorder · Conversion disorder (Ganser syndrome) · Somatoform disorder (Somatization disorder, \Body dysmorphic disorder, Hypochondriasis, Nosophobia, Da Costa's syndrome, Psychalgia) · Neurasthenia
Physiological/ physical behavioural	Eating disorder (anorexia nervosa, bulimia nervosa) · Sleep disorder (dyssomnia, insomnia, hypersomnia, parasomnia, night terror, nightmare) · Sexual dysfunction (erectile dysfunction, premature ejaculation, vaginismus, dyspareunia, hypersexuality) · Postnatal depression
Adult personality and behaviour	Personality disorder · Passive-aggressive behavior · Kleptomania · Trichotillomania · Voyeurism · Factitious disorder · Munchausen syndrome · Ego-dystonic sexual orientation
Intellectual disability	Intellectual disability
Psychological development (developmental disorder)	Specific: speech and language (expressive language disorder, aphasia, expressive aphasia, receptive aphasia, Landau-Kleffner syndrome, lisp) · Scholastic skills (dyslexia, dysgraphia, Gerstmann syndrome) · Motor function (developmental dyspraxia) · Pervasive: Autism/Asperger syndrome · Rett syndrome
Behavioural and emotional, childhood and adolescence onset	ADHD · Conduct disorder · Oppositional defiant disorder · Separation anxiety disorder · Selective mutism · Reactive attachment disorder · Tic disorder · Tourette syndrome · Speech (stuttering · cluttering)

@@ Line 1: / Line 1: @@
+{{ClinPsy}}
-{{DiseaseDisorder infobox |
- Name = Huntington's disease |
+{{Infobox Disease |
- ICD10 = {{ICD10|G|10||g|10}} |
+  Name           = Huntington&#39;s disease |
- ICD9 = {{ICD9|333.4}} |
- Image = georgehuntington.jpg |
+  Image          = georgehuntington.jpg  |
- Caption = [[George Huntington]], wrote a paper describing the disease in 1872. |
+  Caption        = [[George Huntington]]'s 1872 paper described the disorder. |
+  DiseasesDB     = 6060 |
- OMIM = 143100 |
+  ICD10          = {{ICD10|G|10||g|10}}, {{ICD10|F|02|2|f|00}} |
- OMIM_mult = |
+  ICD9           = {{ICD9|333.4}}, {{ICD9|294.1}}  |
+  ICDO           = |
+  OMIM           = 143100  |
+  MedlinePlus    = |
+  eMedicineSubj  = |
+  eMedicineTopic = |
+  MeshID         = D006816 |
 }}
+'''Huntington's disease''', also called '''Huntington's [[Chorea (disease)|chorea]]''', '''chorea major''', or '''HD''', is a [[genetics|genetic]] [[Neurodegenerative disease|neurological disorder]]<ref name="Imariso">{{cite journal |author=Imarisio S, Carmichael J, Korolchuk V, ''et al'' |title=Huntington's disease: from pathology and genetics to potential therapies |journal=Biochem. J. |volume=412 |issue=2 |pages=191–209 |year=2008 |month=June |pmid=18466116 |doi=10.1042/BJ20071619 |url=}}</ref> characterized after onset by uncoordinated, jerky body movements and a decline in some mental abilities. These characteristics vary per individual, physical ones less so, but the differing decline in mental abilities can lead to a number of potential behavioral problems. The disorder itself  isn't fatal, but as symptoms progress, complications reducing [[life expectancy]] increase.<ref name="Huntington1">{{cite book| author= Gillian Bates, Peter Harper, and Lesley Jones| title=Huntington's Disease - Third Edition| publisher=Oxford University Press| location=Oxford| year=2002| isbn=0-19-851060-8}}</ref>
-{{DiseaseDisorder infobox |
+Research of HD has increased greatly in the last few decades, but its exact mechanism is unknown, so symptoms are managed individually.<ref name="pmid16842168">{{cite journal |author=Bonelli RM, Wenning GK |title=Pharmacological management of Huntington's disease: An evidence-based review |journal=Curr. Pharm. Des. |volume=12 |issue=21 |pages=2701–20 |year=2006 |pmid=16842168 |doi= 10.2174/138161206777698693|url=http://www.bentham-direct.org/pages/content.php?CPD/2006/00000012/00000021/0010B.SGM}}</ref> Globally, up to 7 people in 100,000 have the disorder, although there are localized regions with a higher incidence.<ref name="OMIM">{{cite web|title=Huntington's Disease|author=NCBI OMIM|url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=OMIM&dopt=Detailed&tmpl=dispomimTemplate&list_uids=143100#143100_POPULATION_GENETICS' |accessdate=2008-05-22}}</ref> Onset of physical symptoms occurs gradually and can begin at any age, although it is statistically most common in a person's mid-forties (with a 30 year spread). If onset is before age twenty, the condition is classified as '''juvenile HD'''.<ref name="juvenilehd">{{cite journal |author=Nance MA, Myers RH |title=Juvenile onset Huntington's disease--clinical and research perspectives |journal=Ment Retard Dev Disabil Res Rev |volume=7 |issue=3 |pages=153–7 |year=2001 |pmid=11553930 |doi=10.1002/mrdd.1022}}</ref>
- Name = Dementia in Huntington's disease |
- ICD10 = {{ICD10|F|02|2|f|00}} |
+The disorder is named after [[George Huntington]], an American physician who published a remarkably accurate description in 1872.<ref name="onchorea">{{cite journal| last=Huntington |first= G.| title=On Chorea|url=http://en.wikisource.org/wiki/On_Chorea| journal=Medical and Surgical Reporter of Philadelphia| volume=26| issue=15| date=1872-04-13| pages=317–321}}</ref> In 1983 a marker for the altered DNA causing the disease was found,<ref name="dnamarker">{{cite journal |author=Gusella JF, Wexler NS, Conneally PM, ''et al.'' |title=A polymorphic DNA marker genetically linked to Huntington's disease |journal=Nature |volume=306 |issue=5940 |pages=234–8 |year=1983 |pmid=6316146| doi = 10.1038/306234a0 <!--Retrieved from CrossRef by DOI bot-->|url= }}</ref> followed a decade later by discovery of a single, causal, gene.<ref>{{cite journal |author= Macdonald, M|title=A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group |journal=Cell |volume=72 |issue=6 |pages=971–83 |year=1993 |month=March |pmid=8458085 |doi=10.1016/0092-8674(93)90585-E |url=}}</ref> As it was caused by a single gene, an accurate genetic test for HD was developed; this was one of the first inherited [[genetic disorder]]s for which such a test was possible. Due to the availability of this test, and similar characteristics with other neurological disorders, the amount of HD research has increased greatly in recent years.<ref name="lancetseminar">{{cite journal |author=Walker FO |title=Huntington's disease |journal=[[Lancet]] |volume=369 |issue=9557 |pages=218–28 |year=2007 |month=January |pmid=17240289 |doi=10.1016/S0140-6736(07)60111-1 |url=}}</ref>
- ICD9 = {{ICD9|294.1}} |
-}}
-{{Main|Psychological aspects of Huntington's disease}}
-'''Huntington's disease''' ('''HD'''), also known as '''Huntington disease''' and previously as '''Huntington's chorea''' and '''chorea maior''', is a [[Rare disease|rare]] inherited [[neurological disorder]] affecting up to 8 people per 100,000. It takes its name from the Ohio physician [[George Huntington]] who described it precisely in [[1872]] in his first medical paper. HD has been heavily researched in the last few decades and it is one of the first inherited genetic disorders for which an accurate test can be performed.
-HD is caused by a tri[[nucleotide]] repeat expansion in the [[Huntingtin]] ('''Htt''') gene, and is one of several '''[[trinucleotide repeat disorders|polyglutamine (or PolyQ) diseases]]'''. This produces an extended form of the '''mutant Huntingtin''' protein ('''mHtt'''), which causes cell death in selective areas of the brain. HD's most obvious symptoms are abnormal body movements called [[Chorea (disease)|chorea]], but also affects a number of mental abilities.
+== Classification ==
-HD has a broad distribution of age of onset of physical symptoms, but is usually between 40 and 50 years old. If the age of onset is below 20 years then it is known as Juvenile HD. Like all genetic disorders there is currently no cure, but some symptoms can be managed with medication and appropriate care.
+<!-- Note: Huntingtin is the proper spelling for the gene and protein. -->
+Huntington's disease is one of several [[trinucleotide repeat disorders]], caused by the length of a repeated section of a gene exceeding the normal range. The [[huntingtin]] [[gene]] (HTT) normally provides the information to produce [[Huntingtin protein]], but when affected, produces mutant Huntingtin (mHTT) instead.<ref name="kieburtz"> {{cite journal |author=Kieburtz K, MacDonald M, Shih C, ''et al.'' |title=Trinucleotide repeat length and the progression of illness in Huntington's disease |journal=J. Med. Genet. |volume=31 |issue=11 |pages=872–4 |year=1994 |pmid=7853373 |doi=}}</ref>
 == Signs and symptoms ==
+Physical symptoms are usually the first to cause problems and to be noticed, but at this point they are usually accompanied by unrecognized [[cognition|cognitive]] and [[psychiatry|psychiatric]] ones. Almost everyone with Huntington's disease eventually exhibits all physical symptoms, but cognitive and psychiatric symptoms can vary significantly between individuals.<ref name="Huntington1"/>
-There is no sudden loss of abilities or exhibition of symptoms, but there is a progressive decline, and some symptoms may disappear as the disease progresses. Physical signs are usually the first noticed, but it is unknown how long before this that cognition and psychiatric condition are affected. Physical symptoms are almost always shown, cognitive symptoms are exhibited differently from person to person, and psychiatric problems may not be evident at all. The list of possible symptoms are:
+The most characteristic physical symptoms are jerky, random, and uncontrollable movements called [[Chorea (disease)|chorea]]. In a few cases, very slow movement and stiffness (called [[bradykinesia]] and [[dystonia]]) occur instead, and often become more prominent than the chorea as the disorder progresses. Abnormal movements are initially exhibited as general lack of coordination, an unsteady [[gait (human)|gait]] and slurring of speech, but, as the disease progresses, any function that requires muscle control is affected, causing physical instability, abnormal [[facial expression]], and difficulties chewing and [[Dysphagia|swallowing]]. Eating difficulties commonly cause weight loss and may lead to [[malnutrition]].<ref>{{cite journal |author=Gaba AM, Zhang K, Marder K, Moskowitz CB, Werner P, Boozer CN |title=Energy balance in early-stage Huntington disease |journal=Am. J. Clin. Nutr. |volume=81 |issue=6 |pages=1335–41 |year=2005 |pmid=15941884 |doi=}}</ref><ref>{{cite web |url=http://www.hdac.org/caregiving/pdf/Caregiver_Handbook.pdf |format=PDF |title=  Booklet by the Huntington Society of Canada|accessdate=2008-08-10 |work= Caregiver's Handbook for Advanced-Stage Huntington Disease.|publisher=HD Society of Canada |date=2007-04-11 }}</ref> Associated symptoms involve [[Circadian rhythm|sleep cycle]] disturbances, including [[insomnia]] and [[Rapid eye movement sleep]] alterations.<ref name="pmid15634777">{{cite journal |author=Morton AJ, Wood NI, Hastings MH,  ''et al.''|title=Disintegration of the sleep-wake cycle and circadian timing in Huntington's disease |journal=J. Neurosci. |volume=25 |issue=1 |pages=157–63 |year=2005 |month=January |pmid=15634777 |doi=10.1523/JNEUROSCI.3842-04.2005 |url=http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=15634777}}</ref><ref>{{cite journal |author=Arnulf I, Nielsen J, Lohmann E,  ''et al.'' |title=Rapid eye movement sleep disturbances in Huntington disease |journal=Arch Neurol |volume=65 |issue=4 |pages=482–488 |year=2008 | month=April |pmid=18413470 |doi=10.1001/archneur.65.4.482}}</ref> Juvenile HD generally progresses faster, is more likely to exhibit rigidity and bradykinesia, instead of chorea, and commonly includes [[seizure]]s.<ref name="Huntington1"/>
+Select cognitive abilities are impaired progressively. Especially affected are [[executive system|executive functions]] which include planning, cognitive flexibility, [[abstract thinking]], rule acquisition, initiating appropriate actions and inhibiting inappropriate actions.<ref name="pmid16496032">{{cite journal
-=== Physical ===
+|author=Montoya A, Price BH, Menear M, Lepage M
-Most people with HD eventually exhibit chorea, which is jerky, random, uncontrollable, rapid movements, although some exhibit very slow movement and stiffness ([[bradykinesia]], [[dystonia]]). Typically, the abnormal movements begin at the extremities and then later progress. This is exhibited as a general lack of coordination and involuntary movements causing an unsteady [[gait]], loss of facial expression (called "masks in movement") and synchronising muscles to speak,chew and swallow (which can lead to weight loss if the diet  doesn't have enough calories).
+|title=Brain imaging and cognitive dysfunctions in Huntington's disease
+|journal=J Psychiatry Neurosci
+|volume=31
+|issue=1
+|pages=21–9
+|year=2006
+|month=January
+|pmid=16496032
+|pmc=1325063
+|doi=
+|url=http://www.cma.ca/multimedia/staticContent/HTML/N0/l2/jpn/vol-31/issue-1/pdf/pg21.pdf
+|format=PDF}}</ref> [[Psychomotor retardation|Psychomotor]] function, controlling [[muscle]]s, [[perceptual|perception]] and [[spatial]] skills, is also affected.<ref name="pmid16496032"/> As the disease progresses, memory deficits tend to appear. [[Memory]] impairments reported range from [[short-term memory]] deficits to [[long-term memory]] difficulties, including deficits in [[episodic memory|episodic]] (Memory of one's life), [[procedural memory|procedural]] (Memory of the body of how to perform an activity) and [[working memory]].<ref name="pmid16496032"/>
+Psychiatric symptoms vary far more than cognitive and physical ones, and may include [[anxiety]], [[Clinical depression|depression]], a reduced display of emotions ([[blunted affect]]), [[egocentrism]], [[aggression]], and [[compulsive behavior]], which can cause, or worsen [[addictions]], including [[alcoholism]] and [[gambling]], or [[hypersexuality]].<ref name="pmid1305630">{{cite journal |author=Sandyk R |title=L-tryptophan in neuropsychiatric disorders: A review |journal=Int. J. Neurosci. |volume=67 |issue=1-4 |pages=127–44 |year=1992 |pmid=1305630 |doi= |url=}}</ref><ref name="pmid18070848">{{cite journal |author=van Duijn E, Kingma EM, van der Mast RC |title=Psychopathology in verified Huntington's disease gene carriers |journal=J Neuropsychiatry Clin Neurosci |volume=19 |issue=4 |pages=441–8 |year=2007 |pmid=18070848 |doi=10.1176/appi.neuropsych.19.4.441 |url=}}</ref> Difficulties in recognizing other people's negative expressions has also been observed.<ref name="pmid16496032"/><ref name="pmid17584778">{{cite journal |author=Johnson SA, Stout JC, Solomon AC, ''et al.'' |title=Beyond disgust: Impaired recognition of negative emotions prior to diagnosis in Huntington's disease |journal=Brain |volume=130 |issue=Pt 7 |pages=1732–44 |year=2007 |pmid=17584778 |doi=10.1093/brain/awm107}}</ref>
-=== Cognitive ===
-Some selective areas of cognitive ability are impaired, whereas others remain intact. Areas affected are:
-*[[Executive system|Executive function]] - planning, cognitive flexibility, abstract thinking, rule acquisition, initiating appropriate actions and inhibiting inappropriate actions.
-*[[Psychomotor retardation|Psychomotor]] function - slowing of thought processes to control muscles
-*[[Language]] abilities are not impaired but actual speech is.
-*[[Perceptual]] and [[spatial]] skills of self and surrounding environment.
-*[[Memory]] - ability to select correct method of remembering new information, but not actual memory itself.
-*Learning new [[skills]] is affected - depending on which parts of the brain the skill requires.
-=== Psychiatric ===
+==Genetics==
+{{see also|Trinucleotide repeat disorders}}
-These vary more than cognitive and physical symptoms. Possible conditions may be:
+<!-- Please note that although the disorder is spelt huntington, the associated gene and protein are correctly spelt huntingtin -->
-*[[Blunted affect|Blunting]] - reduced display of emotions
+The [[Huntingtin| Huntingtin gene]] (''HTT'') is located on the [[Locus (genetics)|short arm]] of [[chromosome 4 (human)|chromosome 4]] (4p16.3).  ''HTT''  contains a sequence of three [[DNA]] [[nucleobase|bases]]—[[cytosine]]-[[adenine]]-[[guanine]] ([[Codon|CAG]])—repeated multiple times (i.e. ...CAGCAGCAG...) on its [[Directionality (molecular biology)|5' end]], known as a [[Trinucleotide repeat disorders|trinucleotide repeat]]. CAG is the [[genetic code]] for the [[amino acid]] [[glutamine]], so a series of them results in the production of a chain of glutamine known as [[polyglutamine tract|polyglutamine or polyQ tract]], and the repeated part of the gene, the ''PolyQ region''.<ref>{{cite journal |author=Katsuno M, Banno H, Suzuki K, ''et al.'' |title=Molecular genetics and biomarkers of polyglutamine diseases |journal=Curr. Mol. Med. |volume=8 |issue=3 |pages=221–34 |year=2008 |month=May |pmid=18473821 |doi= 10.2174/156652408784221298|url=http://www.bentham-direct.org/pages/content.php?CMM/2008/00000008/00000003/0005M.SGM}}</ref>
-*[[Egocentrism]]
+{| class="wikitable" style="float:right; margin-left:15px; text-align:center"
-*[[Anxiety]]
+|-
-*[[Clinical depression|Depression]]
+! Repeat count
-*[[Aggression (psychology)|Aggression]]
+! Classification
-*[[Compulsion]]s, which can often lead to [[addictions]] such as [[alcoholism]] and [[gambling]]
+! Disease status
-*[[Hypersexuality]]
+|-
+| <27
+| Normal
+| Unaffected
+|-
+| 27–35
+| Intermediate
+| Unaffected
+|-
+| 36–39
+| Reduced Penetrance
+| +/- Affected
+|-
+| >39
+| Full Penetrance
+| Affected
+|}
+A polyQ region containing fewer than 36 glutamines results in production of the [[cytoplasmic]] [[protein]] called [[huntingtin protein|huntingtin]] (Htt). Generally, people have less than 27 repeated glutamines, however, a sequence of 36 or more glutamines, results in the production of form of Htt which has different characteristics. This altered form, called mutant Htt or more commonly ''mHtt'', increases the rate of neuronal decay in certain types of neurons, affecting regions of the brain with a higher proportion or dependency on them. Generally, the number of CAG repeats is related to how much this process is affected, and correlates with age at onset and the rate of progression of symptoms.<ref name="kieburtz"/>  For example, 36–39 repeats result in much later onset and slower progression of symptoms than the mean, such that some individuals may die of other causes before they even manifest symptoms of Huntington disease, this is termed "reduced [[penetrance]]".<ref>{{cite journal |author=Chong SS, Almqvist E, Telenius H, ''et al.'' |title=Contribution of DNA sequence and CAG size to mutation frequencies of intermediate alleles for Huntington disease: Evidence from single sperm analyses |journal=Hum. Mol. Genet. |volume=6 |issue=2 |pages=301–9 |year=1997 |month=February |pmid=9063751 |doi= 10.1093/hmg/6.2.147|url=http://hmg.oxfordjournals.org/cgi/reprint/6/2/301 | format=PDF}}</ref> With very large repeat counts, HD can occur under the age of 20 years, when it is then referred to as juvenile HD, akinetic-rigid, or Westphal variant HD and accounts for about 7 percent of HD carriers.<ref name="juvenilehd"/>
-== Causes ==
-{{see also|HD (gene)}}
+===Inheritance===
-[[Image:Autosomal Dominant Pedigree Chart.svg|thumb|right|HD is inherited in an [[autosomal dominant]] fashion.]]
+[[Image:Autosomal Dominant Pedigree Chart2.svg|thumb|270px|right|HD is inherited in an [[autosomal dominant]] fashion.  Each successive generation is given a roman numeral I, II, or III.  Note that the probability of the offspring of an affected individual being affected (red) themselves is 50%, however if they receive the affected parent's normal allele, they and all of their offspring are unaffected (blue). Transmission from an affected father to an affected son rules out X-linked inheritance.]]
-The [[gene]] involved in HD, called the [[HD (gene)|HD gene]], is located on the short arm of [[chromosome 4 (human)|chromosome 4]] (4p16.3). The end of the HD gene has a sequence of three [[DNA]] bases, cytosine-adenine-guanosine (CAG), that is repeated multiple times (i.e. ...CAGCAGCAG...), this is called a [[Trinucleotide repeat disorders|trinucleotide repeat]]. CAG is the DNA coding for the [[amino acid]] [[glutamine]].
+Huntington's disease is inherited [[autosomal dominant]]ly, meaning that an affected individual typically inherits a copy of the gene with an expanded trinucleotide repeat (the mutant [[allele]]) from an affected parent. In this type of inheritance pattern, each offspring of an affected individual has a 50% chance of inheriting the mutant allele and therefore being affected with the disorder (see figure). It is extremely rare for Huntington's disease to be caused by a [[de novo mutation]],<ref>{{cite journal| author=Myers ''et al.''| title=De novo expansion of a (CAG)n repeat in sporadic Huntington's disease| journal=Nature Genetics| year=1993| volume=5| pages=168–173| url=http://www.nature.com/ng/journal/v5/n2/abs/ng1093-168.html| doi=10.1038/ng1093-168}}</ref><ref>{{cite journal| author=Sánchez A, Milà M, Castellví-Bel S, Rosich M, Jiménez D, Badenas C, Estivill X.| title=Maternal transmission in sporadic Huntington's disease| journal=J Neurol Neurosurg Psychiatry| year=1997| volume=62| issue=5| pages=535–537| pmc=486880| pmid=9153618}}</ref> however, the inheritance of HD is more complex due to potential [[dynamic mutation]]s, where [[DNA replication]] does not produce an exact copy of the trinucleotide repeat. This can cause the number of repeats to change in successive generations, such that an unaffected parent with an "intermediate" number of repeats (28-35), or "reduced penetrance" (36-39), may pass on a copy of the gene with an increase in the number of repeats that produces fully penetrant HD.<ref name="pmid9063751">{{cite journal |author=Chong SS, Almqvist E, Telenius H, ''et al'' |title=Contribution of DNA sequence and CAG size to mutation frequencies of intermediate alleles for Huntington disease: evidence from single sperm analyses |journal=[[Hum. Mol. Genet.]] |volume=6 |issue=2 |pages=301–9 |year=1997 |month=February |pmid=9063751 |doi= 10.1093/hmg/6.2.147|url=http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=9063751}}</ref> These new mutations have occurred in less than 10 percent of people with HD, but explain the origins of the disorder.<ref>{{cite journal |author=García-Planells J, Burguera JA, Solís P, ''et al.'' |title=Ancient origin of the CAG expansion causing Huntington disease in a Spanish population |journal=Hum. Mutat. |volume=25 |issue=5 |pages=453–9 |year=2005 |month=May |pmid=15832309 |doi=10.1002/humu.20167}}</ref> Maternally inherited alleles are usually of a similar repeat length, whereas paternally inherited ones seem to have a higher chance of increasing in length.<ref>{{cite journal| author=RM Ridley, CD Frith, TJ Crow and PM Conneally| title=Anticipation in Huntington's disease is inherited through the male line but may originate in the female| journal=Journal of Medical Genetics| year=1988| volume=25| pages=589–595| url=http://jmg.bmjjournals.com/cgi/content/abstract/25/9/589| pmid=2972838}}</ref> Increases in the number of repeats (and hence earlier age of onset and severity of disease) in successive generations is known as genetic [[anticipation (genetics)|anticipation]].
-The gene's coding is used to produce a 348&nbsp;[[kDa]] [[cytoplasmic]] [[protein]] called [[huntingtin]] ('''Htt''').
-Htt has a characteristic sequence of fewer than 40 [[glutamine]] [[amino acid]] residues in the normal form, more than this and a mutated form of Htt that causes the disease, '''mHtt''', is produced. The severity of the disease is generally proportional to the number of extra residues. The continuous aggregation of the mHtt [[molecule]]s in [[neuron]]al cells causes them to die off in selected regions of the brain.
+[[Homozygous]] individuals, who have two affected genes, are very rare except in large [[Consanguinity|consanguineous]] families. While HD seemed to be the first disease for which homozygotes did not differ in clinical expression or course from typical [[heterozygote]]s,<ref name="pmid2881213">{{cite journal |author=Wexler NS, Young AB, Tanzi RE, ''et al.'' |title=Homozygotes for Huntington's disease |journal=Nature |volume=326 |issue=6109 |pages=194–197 |year=1987 |pmid=2881213 |doi=10.1038/326194a0}}</ref> more recent analysis suggests that homozygosity affects the [[phenotype]] and the rate of disease progression but does not alter the age of onset, suggesting that the mechanisms for these factors differ.<ref>{{cite journal |author=Squitieri F, Gellera C, Cannella M, Mariotti C, Cislaghi G, Rubinsztein DC, Almqvist EW, Turner D, Bachoud-Lévi AC, Simpson SA, Delatycki M, Maglione V, Hayden MR, Donato SD |title=Homozygosity for CAG mutation in Huntington disease is associated with a more severe clinical course |journal=Brain |volume=126 |issue=4 |pages=946–955 |year=2003 |pmid=12615650| url=http://brain.oxfordjournals.org/cgi/content/full/126/4/946 |doi=10.1093/brain/awg077}}</ref>
-HD is inherited in an [[autosomal dominant]] fashion. That is, a recipient of the gene only needs one [[allele]] from one parent, to inherit the disease. More often, genetic diseases are autosomal [[recessive]], meaning that they need two alleles, one from each parent, to inherit the disease. The dominant nature of HD increases the chance of the disease occurring in offspring. A heterozygous parent has a 50% chance of passing on the gene to each child (For recessive traits, both parents must carry the allele for the same probability).
+==Mechanism==
-When the gene has more than 35 copies of the repeated trinucleotide sequence, the [[DNA replication]] process becomes unstable and the number of repeats can change in successive generations. If the gene is inherited from the mother the count is usually similar, but tends to increase if inherited from the father.<ref>{{cite journal| author=RM Ridley, CD Frith, TJ Crow and PM Conneally| title=Anticipation in Huntington's disease is inherited through the male line but may originate in the female| journal=Journal of Medical Genetics| year=1988| volume=25| pages=589-595| url=http://jmg.bmjjournals.com/cgi/content/abstract/25/9/589}}</ref>
+{{see also|Huntingtin protein}}
-Because of the progressive increase in length of the repeats, the disease tends to increase in severity and have an earlier onset in successive generations. This is known as [[anticipation (genetics)|anticipation]].
+Like all proteins, Htt and mHtt are [[Translation (biology)|translated]], perform or affect [[biology|biological]] functions, and are then marked by [[ubiquitin]] to be degraded by [[proteasome]]s, but their exact roles are unknown. Research has focused on identifying the functioning of Htt, how mHtt differs or interferes with it, including its influence in [[apoptosis|programmed cell death]], and the [[proteopathy]] of remnants of mHtt left after degradation.<ref name="Imariso"/>
+===Function===
-About 10 percent of HD cases occur in people under the age of 20 years. This is referred to as Juvenile HD, "akinetic-rigid", or "Westphal variant" HD.
+Although the function of the Huntingtin protein is unclear, some hypotheses have been drawn from observations. In mouse models, Htt is essential for development and survival.<ref name="Nasir">{{ cite journal | author=Nasir J, Floresco S, et al | title=Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes | journal =Cell  | volume = 81 | pages=811–823 | year=1995 | doi=10.1016/0092-8674(95)90542-1 | pmid=7774020}}</ref> In "knockin" mice, the extended CAG repeat portion of the gene is all that is needed to cause disease.<ref>{{cite journal |author=Murphy KP, Carter RJ, Lione LA, ''et al.'' |title=Abnormal synaptic plasticity and impaired spatial cognition in mice transgenic for exon 1 of the human Huntington's disease mutation |journal=J. Neurosci. |volume=20 |issue=13 |pages=5115–23 |year=2000 |pmid=10864968 |doi=}}</ref> The protein has no sequence [[homology]] with other proteins and is highly expressed in neurons and testes.<ref name="Cattaneo">{{cite journal | author=Cattaneo E, Zuccato C, Tartari M | title=Normal huntingtin function: an alternative approach to Huntington's disease | journal = Nature Reviews Neuroscience | volume = 6 | pages= 919–930 | year=2005 | month=December | doi=10.1038/nrn1806}}</ref> Experiments have shown Htt acts as a [[transcription factor]] in upregulating the expression of [[BDNF|Brain Derived Neurotrophic Factor (BDNF)]], a protein which protects neurons and regulates the [[neurogenesis]] of new ones, whereas mHtt suppresses this [[Transcription (genetics)|transcription]] regulatory function of Huntingtin and hence underexpression of BDNF, which leads to progressive atrophy of select areas of the brain.<ref name="Zuccato">{{cite journal | author=Zuccato C, Ciammola A, Rigamonti D, Leavitt BR, Goffredo D, et al | title=Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease | journal=Science | date=2001-07-20 | volume = 293| issue=5529 | pages=445–6 | doi=10.1126/science.1063429 | pmid=11463904}}</ref><ref>{{cite journal |author=Canals JM, Pineda JR, Torres-Peraza JF, ''et al.'' |title=Brain-derived neurotrophic factor regulates the onset and severity of motor dysfunction associated with enkephalinergic neuronal degeneration in Huntington's disease |journal=J. Neurosci. |volume=24 |issue=35 |pages=7727–39 |year=2004 |pmid=15342740 |doi=10.1523/JNEUROSCI.1197-04.2004}}</ref><ref>{{cite journal |author=Sawa A, Nagata E, Sutcliffe S, ''et al.'' |title=Huntingtin is cleaved by caspases in the cytoplasm and translocated to the nucleus via perinuclear sites in Huntington's disease patient lymphoblasts |journal=Neurobiol. Dis. |volume=20 |issue=2 |pages=267–74 |year=2005 |pmid=15890517 |doi=10.1016/j.nbd.2005.02.013}}</ref><ref name="pmid17959817">{{cite journal |author=Strand AD, Baquet ZC, Aragaki AK, ''et al.'' |title=Expression profiling of Huntington's disease models suggests that brain-derived neurotrophic factor depletion plays a major role in striatal degeneration |journal=[[Journal of Neuroscience|J. Neurosci.]] |volume=27 |issue=43 |pages=11758–68 |year=2007 |month=October |pmid=17959817 |doi=10.1523/JNEUROSCI.2461-07.2007 |url=http://www.jneurosci.org/cgi/content/full/27/43/11758}}</ref>From [[immunohistochemistry]], [[electron microscopy]], [[subcellular fractionation]] studies of the molecule, it has been found that Huntingtin is primarily associated with [[vesicles]] and [[microtubules]].<ref name="Hoffner">{{cite journal | author=Hoffner G, Kahlem P, Djian P | title=Perinuclear localization of huntingtin as a consequence of its binding to microtubules through an interaction with β-tubulin: relevance to Huntington's disease | journal= J Cell Sci | volume=115 | pages=941–948 |year=2002 |month=March |pmid=11870213 |doi= |url=http://jcs.biologists.org/cgi/pmidlookup?view=long&pmid=11870213}}</ref><ref name="DiFiglia">{{cite journal | author=DiFiglia M, et al. | title = Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons | journal=Neuron | volume=14 | pages = 1075–1081 | year=1995 | doi = 10.1016/0896-6273(95)90346-1}}</ref>.These indicate a functional role in [[cytoskeletal]] anchoring or transport of [[mitochondria]]. The Htt protein is involved in [[vesicle (biology)|vesicle]] trafficking as it interacts with HIT1, a [[clathrin]] binding protein, to mediate [[endocytosis]], the absorption of materials into a cell.<ref>{{cite journal |author=Velier J, Kim M, Schwarz C, ''et al.'' |title=Wild-type and mutant huntingtins function in vesicle trafficking in the secretory and endocytic pathways |journal=Exp. Neurol. |volume=152 |issue=1 |pages=34–40 |year=1998 |pmid=9682010 |doi=10.1006/exnr.1998.6832}}</ref><ref>{{cite journal |author=Waelter S, Scherzinger E, Hasenbank R, ''et al.'' |title=The huntingtin interacting protein HIP1 is a clathrin and alpha-adaptin-binding protein involved in receptor-mediated endocytosis |journal=Hum. Mol. Genet. |volume=10 |issue=17 |pages=1807–17 |year=2001 |pmid=11532990| doi = 10.1093/hmg/10.17.1807 }}</ref> Initial studies show carriers of the expanded repeat may have better than average [[immune system]]s, with higher levels of [[Interleukin 6]] and tumor suppressor [[p53 (protein)|protein p53]].<ref name=pmid18625748> {{cite journal|author=Björkqvist M, Wild EJ, Thiele J, ''et al.''|title=A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington's disease|journal=J. Exp. Med.|volume=205|issue=8|pages=1869–77|year=2008|month=August|pmid=18625748|doi=10.1084/jem.20080178|url=http://www.jem.org/cgi/pmidlookup?view=long&pmid=18625748}}</ref><ref>{{ cite journal |author=Eskenazi BR,Wilson-Rich NS, Starks PT|journal=Med. Hypotheses|volume=69|issue=6|pages=1183–9|year=2007|pmid=17689877|doi=10.1016/j.mehy.2007.02.046|url= |title=A Darwinian approach to Huntington’s disease: Subtle health benefits of a neurological disorder}} </ref>
-==Mechanism==
+===Degradation===
+In the first step of degradation, both Htt and mHtt are cleaved by [[caspase|caspase-3]], which removes the protein's amino end (the [[N-terminus|N-terminal]]).<ref>{{cite journal |author=Kim YJ, Yi Y, Sapp E, ''et al.'' |title=Caspase 3-cleaved N-terminal fragments of wild-type and mutant huntingtin are present in normal and Huntington's disease brains, associate with membranes, and undergo calpain-dependent proteolysis |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=98 |issue=22 |pages=12784–9 |year=2001 |pmid=11675509 |doi=10.1073/pnas.221451398}}</ref> Caspase-2 then further breaks down the amino terminal fragment (which includes the CAG repeat) of Htt, but cannot process all of the mHtt protein.<ref>{{cite journal |author=Hermel E, Gafni J, Propp SS, ''et al.'' |title=Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington's disease |journal=Cell Death Differ. |volume=11 |issue=4 |pages=424–38 |year=2004 |pmid=14713958 |doi=10.1038/sj.cdd.4401358}}</ref> In transgenic mice, the [[Caspase|caspase-6]] enzyme has been shown to be involved in cleaving the Htt protein, as mice made resistant to this enzyme did not suffer neurodegeneration.<ref name="pmid16777606">{{cite journal |author=Graham RK, Deng Y, Slow EJ, ''et al.'' |title=Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin |journal=Cell |volume=125 |issue=6 |pages=1179–91 |year=2006 |pmid=16777606 |doi=10.1016/j.cell.2006.04.026}}</ref>The uncleaved pieces of mHtt, left in the cell, called N-fragments, and are able to affect genetic [[Transcription (genetics)|transcription]].<ref>{{cite journal |author=Freiman RN, Tjian R |title=Neurodegeneration. A glutamine-rich trail leads to transcription factors |journal=Science |volume=296 |issue=5576 |pages=2149–50 |year=2002 |pmid=12077389 |doi=10.1126/science.1073845}}</ref> Specifically, mHtt binds with [[TAF4|TAF<sub>II</sub>130]], a coactivator to [[CREB]] dependent transcription.<ref>{{cite journal |author=Bae BI, Xu H, Igarashi S, ''et al.'' |title=p53 mediates cellular dysfunction and behavioral abnormalities in Huntington's disease |journal=Neuron |volume=47 |issue=1 |pages=29–41 |year=2005 |pmid=15996546 |doi=10.1016/j.neuron.2005.06.005}}</ref> The mHtt protein also interacts with the [[transcription factor]] protein [[Sp1|SP<sub>1</sub>]], preventing it from binding to [[DNA]].<ref>{{cite journal |author=Dunah AW, Jeong H, Griffin A, ''et al.'' |title=Sp1 and TAFII130 transcriptional activity disrupted in early Huntington's disease |journal=Science |volume=296 |issue=5576 |pages=2238–43 |year=2002 |pmid=11988536 |doi=10.1126/science.1072613}}</ref>
-{{see also|Huntingtin}}
-Although the full function of Htt is unknown, it acts as a transcription factor in upregulating the expression of [[Brain-derived neurotrophic factor]] (BDNF). With mHtt, there is supression of this transcription regulatory function of Htt and hence underexpression of BDNF.
-Various studies have shown possible links between low levels of BDNF and conditions such as [[clinical depression]], [[Obsessive-compulsive disorder]] and [[dementia]], although it is still not known whether these levels represent a cause or a symptom.
+Neuronal intranuclear inclusions containing the huntingtin and ubiquitin proteins have been found in both humans and mice with HD,<ref name="pmid9302293">{{cite journal |author=DiFiglia M, Sapp E, Chase KO, ''et al.'' |title=Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain |journal=Science |volume=277 |issue=5334 |pages=1990–3 |year=1997 |pmid=9302293 |doi=10.1126/science.277.5334.1990}}</ref><ref>{{cite journal |author=Davies SW, Turmaine M, Cozens BA, ''et al.'' |title=Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation |journal=Cell |volume=90 |issue=3 |pages=537–48 |year=1997 |pmid=9267033| doi = 10.1016/S0092-8674(00)80513-9 <!--Retrieved from CrossRef by DOI bot-->}}</ref>. Such inclusions are most prevalent in [[Pyramidal cell|cortical pyramidal neurons]], less so in [[Medium spiny neuron|striatal medium-sized spiny neurons]] and almost entirely absent in most other regions.<ref name="pmid9302293"/><ref>{{cite journal |author=Gutekunst CA, Li SH, Yi H, ''et al.'' |title=Nuclear and neuropil aggregates in Huntington's disease: Relationship to neuropathology |journal=J. Neurosci. |volume=19 |issue=7 |pages=2522–34 |year=1999 |pmid=10087066 |doi=}}</ref><ref>{{cite journal |author=Sieradzan KA, Mechan AO, Jones L,  ''et al.'' |title=Huntington's disease intranuclear inclusions contain truncated, ubiquitinated huntingtin protein |journal=Exp. Neurol. |volume=156 |issue=1 |pages=92–9 |year=1999 |pmid=10192780 |doi=10.1006/exnr.1998.7005}}</ref> These inclusions consist mainly of the amino terminal end of mHtt (CAG repeat), and are found in both the [[cytoplasm]] and [[Cell nucleus|nucleus]] of neurons,<ref>{{cite journal |author=Cooper JK, Schilling G, Peters MF, ''et al.'' |title=Truncated N-terminal fragments of huntingtin with expanded glutamine repeats form nuclear and cytoplasmic aggregates in cell culture |journal=Hum. Mol. Genet. |volume=7 |issue=5 |pages=783–90 |year=1998 |pmid=9536081| doi = 10.1093/hmg/7.5.783 <!--Retrieved from CrossRef by DOI bot-->}}</ref> however their presence does not correlate with cell death, and may even act as a protective mechanism to the cell.<ref>{{cite journal |author=Fusco FR, Chen Q, Lamoreaux WJ, ''et al.'' |title=Cellular localization of huntingtin in striatal and cortical neurons in rats: Lack of correlation with neuronal vulnerability in Huntington's disease |journal=J. Neurosci. |volume=19 |issue=4 |pages=1189–202 |year=1999 |pmid=9952397 |doi=}}</ref><ref>{{cite journal | author=Arrasate M, Mitra S, Schweitzer ES, Segal MR, Finkbeiner S | title=Inclusion body formation reduces levels of mutant Huntingtin and the risk of neuronal death | journal=Nature | year=2004 | pages=805–810 | volume=431 | pmid=15483602}}</ref> Thus, mHtt acts in the nucleus but does not cause apoptosis through [[protein aggregation]].<ref>{{cite journal |author=Saudou F, Finkbeiner S, Devys D, Greenberg ME |title=Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions |journal=Cell |volume=95 |issue=1 |pages=55–66 |year=1998 |pmid=9778247| doi = 10.1016/S0092-8674(00)81782-1 <!--Retrieved from CrossRef by DOI bot-->}}</ref>
-The continuous aggregation of the mHtt molecules in [[neuron]]al cells causes [[apoptosis|cell death]], especially in the [[frontal lobe]]s and the [[basal ganglia]] (mainly in the [[caudate nucleus]]). Degeneration of the [[striatum]] (a part of the brain consisting of the [[caudate nucleus]] and the [[putamen]]) can be found. There is also neuronal loss and [[astrogliosis]], as well as loss of medium spiny neurons, a [[Gamma-aminobutyric acid|GABAergic]] (the chief inhibitory neurotransmitter in the [[vertebrate]] [[central nervous system]]) result. Intranuclear inclusions that stain for [[ubiquitin]] and Htt can be seen, as well as Htt in [[cortex|cortical]] [[neurite]]s.
+===Pathophysiology===
-It is suspected that the [[cross-link]]ing of Htt results in aggregates which are toxic, and can lead to dysfunction of the [[proteasome]] system. This [[mitochondrion|mitochondrial]] dysfunction can lead to [[excitotoxicity]] and [[oxidative stress]].
+HD causes [[astrogliosis]]<ref name="pmid17965655">{{cite journal |author=Lobsiger CS, Cleveland DW |title=Glial cells as intrinsic components of non-cell-autonomous neurodegenerative disease |journal=Nat. Neurosci. |volume=10 |issue=11 |pages=1355–60 |year=2007 |month=November |pmid=17965655 |doi=10.1038/nn1988}}</ref> and loss of medium spiny neurons<ref>{{cite book  | author = Purves D, Augustine GA, Fitzpatrick D, Hall W, LaMantia A-S, McNamara JO, Williams SM | editor = Dale Purves | title = Neuroscience  | origyear = 2001  | url = http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=neurosci.TOC&depth=2  | edition = 2nd edition  | publisher = Sinauer Associates  | location = Sunderland, MA  | isbn = 0-87893-742-0  | chapter = Modulation of Movement by the Basal Ganglia - Circuits within the Basal Ganglia System | chapterurl = http://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=Huntington's%20disease&rid=neurosci.section.1251}}</ref><ref name="pmid18279698">{{cite journal |author=Estrada Sánchez AM, Mejía-Toiber J, Massieu L |title=Excitotoxic neuronal death and the pathogenesis of Huntington's disease |journal=Arch. Med. Res. |volume=39 |issue=3 |pages=265–76 |year=2008 |month=April |pmid=18279698 |doi=10.1016/j.arcmed.2007.11.011 |url=http://linkinghub.elsevier.com/retrieve/pii/S0188-4409(07)00412-2}}</ref> Areas of the brain are affected according to their structure and the types of neurons they contain, reducing in size as they cumulatively lose cells. The areas affected are mainly in the [[striatum]], but also the [[Frontal lobe|frontal]] and [[Temporal lobe|temporal]] cortices.<ref>{{cite book  | author = Purves D, Augustine GA, Fitzpatrick D, Hall W, LaMantia A-S, McNamara JO, Williams SM  | editor = Dale Purves  | title = Neuroscience | origyear = 2001  | url = http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=neurosci.TOC&depth=2  | edition = 2nd edition  | publisher = Sinauer Associates  | location = Sunderland, MA  | isbn = 0-87893-742-0  | chapter = Modulation of Movement by the Basal Ganglia - Box A. Huntington's Disease  | chapterurl = http://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=Huntington's%20disease&rid=neurosci.box.1240}}</ref> The striatum's [[subthalamic nucleus|subthalamic nuclei]] send control signals to the [[globus pallidus]], which initiates and modulates motion. The weaker signals from subthalamic nuclei thus cause reduced initiation and modulation of movement, resulting in the characteristic movements of the disorder.<ref name="pmid10923984">{{cite journal |author=Crossman AR |title=Functional anatomy of movement disorders |journal=J. Anat. |volume=196 ( Pt 4) |issue= |pages=519–25 |year=2000 |month=May |pmid=10923984 |pmc=1468094 |doi=10.1046/j.1469-7580.2000.19640519.x |url=http://www3.interscience.wiley.com/cgi-bin/fulltext/119004203/PDFSTART | format=PDF}}</ref>
-The exact link between CAG repeats that produce mHtt and mitochondrial failure is unknown. There is evidence that aggregates may trap critical enzymes that are involved in energy metabolism.{{citation needed}}
-Some think that the cause of [[apoptosis|cell death]] is the splitting of the [[lysosome]] so that the hydrolytic enzymes within it are released. {{citation needed}}This will cause the cell membrane to split and the cell to die.
+Although studies are mainly focused on physiopathology of the brain, some look at how Huntington's disease appears to affect other physiological functions. One study in humans highlighted a systemic, early hypermetabolic state and a lower level of [[branched chain amino acids]] in the plasma as the disease progresses, which is hypothesised to be caused by the brain's use of these.{{Fact|date=August 2008}}<ref>{{cite journal |author=Mochel F, Charles P, Seguin F, Barritault J, Coussieu C, Perin L, Le Bouc Y, Gervais C, Carcelain G, Vassault A, Feingold J, Rabier D, Durr A |title=Early energy deficit in Huntington disease: Identification of a plasma biomarker traceable during disease progression |journal=PLoS ONE |volume=2 |issue=7 |pages= e647|year=2007 |pmid=17653274 |pmc=1919424 |doi=10.1371/journal.pone.0000647 |url=}}</ref>
-While theories as to how the mutation brings about disease remain diverse and speculative, researchers have identified many specific subcellular abnormalities associated with mHtt, as well as unusual properties of the protein in vitro. Just as one example, in 2002, [[Max Perutz]], ''et al'' discovered that the glutamine residues form a [[nanotube]] in vitro, and the mutated forms are long enough in principle to pierce [[cell membrane]]s.<ref>{{cite journal| author=Perutz, M.F., J.T. Finch, J. Berriman, and A. Lesk| year=2002| title=Amyloid fibers are water-filled nanotubes| journal=Proceedings of the National Academy of Sciences| volume=99 | pages=5591-5595}}</ref>
-In the June 16, 2006 issue of ''[[Cell (journal)|Cell]]'', scientists at the [[University of British Columbia]] (UBC) and [[Merck & Co.|Merck Labs]] presented findings that the neurodegeneration caused by mHtt is related to the [[Caspase|caspase-6]] enzyme cleaving the Htt protein.  Transgenic mice that have caspase-6 resistant Htt did not show effects of HD.<ref>{{cite journal| author=Graham, RK, Y Deng, EJ Slow, B Haigh, N Bissada, G Lu, J Pearson, J Shehadeh, L Bertram, Z Murphy, SC Warby, CN Doty, S Roy, CL Wellington, BR Leavitt, LA Raymond, DW Nicholson, MR Hayden| title=Cleavage at the Caspase-6 site is required for neuronal dysfunction and degeneration due to mutant Huntingtin| journal=[[Cell (journal)|Cell]] | date=2006-06-16 | volume=125| pages=1179-1191}}</ref>  The researchers found "substantial support for the hypothesis that cleavage at the caspase-6 site in mhtt represents a crucial rate-limiting event in the pathogenesis of HD.... Our study highlights the importance of preventing cleavage of htt at this site and also reinforces the importance of modulating excitotoxicity as a potential therapeutic approach for HD." In essence, scientists have managed to prevent the appearance of HD in genetically modified mice. Dr. Marian DiFiglia, a world-renowned HD researcher and neurobiologist at Harvard University, called this find "very important" and "extremely intriguing".<ref>{{cite web| title=Canadian Researchers cure Huntington's disease in mice| url=http://bodyandhealth.canada.com/channel_health_news_details.asp?news_id=10154&news_channel_id=11&channel_id=11|author=S. Ubelacker| accessdate=2006-07-16}}</ref>
 == Diagnosis ==
-To determine if someone has the initial symptoms, a physical and/or psychological examination is required. The uncontrollable movements are often the symptoms which cause initial alarm and lead to diagnosis; however, the disease may begin with cognitive or emotional symptoms, which are not always recognized.
+{{see|Genetic testing}}
-Every child of a person with HD has a fifty percent chance of inheriting the gene and the disease.  [[wiktionary:pre-symptomatic|Pre-symptomatic]] testing is possible by means of a [[Genetic testing|blood test]] which counts the number of repetitions in the gene. A negative blood test means that the individual does not carry the gene, will never develop symptoms, and cannot pass it on to children. A positive blood test means that the individual does carry the gene, will develop the disease, and has a 50% chance of passing it on to children, assuming he or she lives long enough to do so. A pre-symptomatic positive blood test is not considered a diagnosis, because it may be decades before onset.
+A physical and/or [[psychological examination]] can determine whether initial symptoms are evident. Abnormal movements are often the symptoms that cause initial impetus to seek medical consultation and lead to diagnosis; however, the disease may begin with cognitive or pyschiatric symptoms, which are not always recognized except in hindsight, or if they develop further. [[wiktionary:pre-symptomatic|Pre-symptomatic]] testing is possible using a [[Genetic testing|blood test]] which counts the numbers of CAG repeats in each of the HTT alleles,<ref name="pmid15717026">{{cite journal |author=Myers RH |title=Huntington's disease genetics |journal=NeuroRx |volume=1 |issue=2 |pages=255–62 |year=2004 |month=April |pmid=15717026 |pmc=534940 |doi= 10.1602/neurorx.1.2.255|url=}}</ref> although a positive result is not considered a diagnosis, since it may be obtained decades before onset of symptoms. A negative blood test means that the individual does not carry the expanded copy of the gene. A full pathological diagnosis can only be established by a neurological examination's findings and/or demonstration of cell loss in the areas affected by HD, supported by a cranial [[Computed axial tomography|CT]] or [[magnetic resonance imaging|MRI]] scan findings.<ref name="pmid6234475">{{cite journal |author=Stober T, Wussow W, Schimrigk K |title=Bicaudate diameter--the most specific and simple CT parameter in the diagnosis of Huntington's disease |journal=Neuroradiology |volume=26 |issue=1 |pages=25–8 |year=1984 |pmid=6234475 |doi=10.1007/BF00328198}}</ref>
+A pre-symptomatic test is a life-changing event and a very personal decision. The personal ramifications to an at-risk individual and lack of cure for the disease necessitate several counseling sessions to ensure that they are prepared for either result before it is given.<ref name="geneticcounselling">{{cite journal |author=Burson CM, Markey KR |title=Genetic counseling issues in predictive genetic testing for familial adult-onset neurologic diseases |journal=Semin Pediatr Neurol |volume=8 |issue=3 |pages=177–86 |year=2001 |month=September |pmid=11575847 |doi= 10.1053/spen.2001.26451|url=}}</ref>  In England, Scotland, Northern Ireland, Australia, Canada and New Zealand, unless a person under eighteen years of age is considered to be [[Gillick competence|Gillick competent]], testing is not considered ethical - unless they show significant symptoms, or are sexually active.<ref name="minorstesting">{{cite journal |author=Borry P, Goffin T, Nys H, Dierickx K |title=Predictive genetic testing in minors for adult-onset genetic diseases |journal=[[Mt. Sinai J. Med.]] |volume=75 |issue=3 |pages=287–296 |year=2008 |month=August |pmid=18704981 |doi=10.1002/msj.20038}}</ref> Many organizations and lay groups strongly endorse these restrictions in their testing protocol.
-Because of the ramifications on the life of an at-risk individual, with no cure for the disease and no proven way of slowing it, several counseling sessions are usually required before the blood test.  Unless a child shows significant symptoms of the juvenile form, children under eighteen cannot be tested. The members of the [[Huntington's Disease Society of America]] strongly encourage these restrictions in their testing protocol.  A pre-symptomatic test is a life-changing event and a very personal decision.  For those living in America, there is a list of testing centers available on the HDSA homepage.<ref>[http://www.hdsa.org/site/PageServer?pagename=testing_centers www.hdsa.org]</ref>
+Embryonic screening is also possible, giving affected or at-risk individuals the option of ensuring their children will not inherit the disease. It is possible for women who would consider abortion of an affected fetus to test an embryo in the womb ([[prenatal diagnosis]]). Other techniques, such as [[preimplantation genetic diagnosis]] in the setting of [[in vitro fertilisation]], can be used to ensure that the newborn is unaffected.<ref name="pmid15758612">{{cite journal |author=Kuliev A, Verlinsky Y |title=Preimplantation diagnosis: A realistic option for assisted reproduction and genetic practice |journal=Curr. Opin. Obstet. Gynecol. |volume=17 |issue=2 |pages=179–83 |year=2005 |month=April |pmid=15758612 |doi= |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=1040-872X&volume=17&issue=2&spage=179}}</ref>
-[[In vitro fertilisation]] and embryonic genetic screening are also possible, enabling gene-positive or at-risk individuals the option of making sure their children will be clear of the disease. Expense and the ethical considerations of abortion are potential drawbacks to these procedures.
-The full pathological diagnosis is established by neurological examination findings and/or demonstration of cell loss, especially in the caudate nucleus, supported by a cranial [[Computed axial tomography|CT]] or [[MRI]] scan findings.
 == Management ==
+Treatments for cognitive and psychological symptoms include [[antidepressant]]s and sedatives, and low doses of [[antipsychotic]]s.<ref>{{cite web |url=http://www.nhsdirect.nhs.uk/articles/article.aspx?articleId=199&sectionId=149 |title= UK NHS guide to Huntington's medications|accessdate=2008-08-10 |work= |publisher=NHS |date= }} </ref> There is limited evidence for specific treatments aimed at controlling the chorea and other movement abnormalities, although [[tetrabenazine]] has been shown to reduce the severity of the chorea;<ref name="pmid16476934">{{cite journal |author= |title=Tetrabenazine as antichorea therapy in Huntington disease: a randomized controlled trial |journal=Neurology |volume=66 |issue=3 |pages=366–72 |year=2006 |month=February |pmid=16476934 |doi=10.1212/01.wnl.0000198586.85250.13 |url=http://www.neurology.org/cgi/pmidlookup?view=long&pmid=16476934}}</ref>  it was approved in 2008 specifically for this indication.<ref name="pmid16842168">{{cite web |url=http://www.fda.gov/bbs/topics/NEWS/2008/NEW01874.html |title=FDA Approves First Drug for Treatment of Chorea in Huntington’s Disease |accessdate=2008-08-10 |work=FDA Approves First Drug for Treatment of Chorea in Huntington’s Disease |publisher=U.S. Food and Drug Administration |date=August 15, 2008}}</ref>
-There is no treatment to fully stop the progression of the disease, but symptoms can be reduced or alleviated through the use of correct medication and care methods.
+Nutrition management is an important part of treatment; most people in the later stages of the disease need more [[calories]] than average to maintain body weight.<ref>{{cite web |url=http://www.hdsa.org/site/PageServer?pagename=family_guide_nutrition |title=Family Guide Series - Nutrition and Huntington's Disease |publisher=Huntington's Disease Society of America Publications  |author=Gaba, Anna  |date=    |accessdate=2008-04-02}}</ref> [[Thickening agent]] can be added to drinks as swallowing becomes more difficult, as thicker fluids are easier and safer to swallow. The option of using a [[percutaneous endoscopic gastrostomy]] (i.e., a feeding tube into the stomach) is available when eating becomes too hazardous or uncomfortable. A "stomach PEG"  greatly reduces the chances of aspiration of food, which can lead to [[aspiration pneumonia]],and also increases the amount of nutrients and calories that can be ingested, aiding the body's natural defenses.<ref name="pmid18390785">{{cite journal |author=Panagiotakis PH, DiSario JA, Hilden K, Ogara M, Fang JC |title=DPEJ tube placement prevents aspiration pneumonia in high-risk patients |journal=Nutr Clin Pract |volume=23 |issue=2 |pages=172–5 |year=2008 |pmid=18390785 |doi=10.1177/0884533608314537 |url=http://ncp.sagepub.com/cgi/pmidlookup?view=long&pmid=18390785}}</ref>
-=== Medication ===
-There are treatments available to help control the [[chorea]], although these may have the side effect of aggravating [[bradykinesia]] or [[dystonia]].
+Although there are relatively few studies of [[rehabilitation]] for HD, its general effectiveness when conducted by a team of specialists has been clearly demonstrated in other pathologies such as [[stroke]],<ref name="pmid10796318">{{cite journal |author= |title=Organised inpatient (stroke unit) care for stroke. Stroke Unit Trialists' Collaboration |journal=[[Cochrane Database Syst Rev]] |volume= |issue=2 |pages=CD000197 |year=2000 |pmid=10796318 |doi=10.1002/14651858.CD000197}}</ref> or [[head trauma]].<ref name="pmid16034923">{{cite journal |author=Turner-Stokes L, Disler PB, Nair A, Wade DT |title=Multi-disciplinary rehabilitation for acquired brain injury in adults of working age |journal=[[Cochrane Database Syst Rev]] |volume= |issue=3 |pages=CD004170 |year=2005 |pmid=16034923 |doi=10.1002/14651858.CD004170.pub2}}</ref> As for any patient with neurologic deficits, a [[multidisciplinary]] approach is key to limiting and overcoming disability.<ref name="pmid17702702">{{cite journal |author=Zinzi P, Salmaso D, De Grandis R, ''et al'' |title=Effects of an intensive rehabilitation programme on patients with Huntington's disease: a pilot study |journal=[[Clin Rehabil]] |volume=21 |issue=7 |pages=603–13 |year=2007 |month=July |pmid=17702702 |doi=10.1177/0269215507075495 |url=http://cre.sagepub.com/cgi/pmidlookup?view=long&pmid=17702702}}</ref> There is some evidence for the usefulness of [[physical therapy]] and [[speech therapy]] but more rigorous studies are needed for health authorities to endorse them.<ref name="pmid12645441">{{cite journal |author=Bilney B, Morris ME, Perry A |title=Effectiveness of physiotherapy, occupational therapy, and speech pathology for people with Huntington's disease: a systematic review |journal=[[Neurorehabil Neural Repair]] |volume=17 |issue=1 |pages=12–24 |year=2003 |month=March |pmid=12645441 |doi= 10.1177/0888439002250448|url=http://nnr.sagepub.com/cgi/pmidlookup?view=long&pmid=12645441}}</ref>
-Other standard treatments to alleviate emotional symptoms include the use of [[antidepressant]]s and sedatives, with [[antipsychotic]]s (in low doses) for psychotic symptoms. Care needs to be taken with antipsychotic usage as people suffering psychotic symptoms of organic origin are often more sensitive to the side effects of these drugs.
-=== Nutrition ===
+== Prognosis ==
+The age of onset decreases, and the rate of progression of symptoms increase, with the number of CAG repeats. Individuals with greater than approximately 60 CAG repeats often develop juvenile Huntington's disease.<ref>{{cite journal |author=Harper PS |title=Huntington's disease: A clinical, genetic and molecular model for polyglutamine repeat disorders |journal=Philos. Trans. R. Soc. Lond., B, Biol. Sci. |volume=354 |issue=1386 |pages=957–61 |year=1999 |pmid=10434293 |doi=10.1098/rstb.1999.0446}}</ref><ref>{{cite journal |author=Andrew SE, Goldberg YP, Kremer B, ''et al.'' |title=The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease |journal=Nat. Genet. |volume=4 |issue=4 |pages=398–403 |year=1993 |pmid=8401589 |doi=10.1038/ng0893-398}}</ref> There is a variation in age of onset for any given CAG repeat length, particularly within the intermediate range (40–50 CAGs). For example, a repeat length of 40 CAGs leads to an onset ranging from 40 to 70 years of age in one study. This variation means that, although [[algorithm]]s have been proposed for predicting the age of onset, in practice, it can not be predicted confidently.<ref>{{cite journal |author=Rubinsztein DC, Leggo J, Chiano M, ''et al.'' |title=Genotypes at the GluR6 kainate receptor locus are associated with variation in the age of onset of Huntington disease |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=94 |issue=8 |pages=3872–6 |year=1997 |pmid=9108071| doi = 10.1073/pnas.94.8.3872 <!--Retrieved from CrossRef by DOI bot-->}}</ref><ref name="pmid2973230">{{cite journal |author=Adams P, Falek A, Arnold J |title=Huntington disease in Georgia: Age at onset |journal=Am. J. Hum. Genet. |volume=43 |issue=5 |pages=695–704 |year=1988 |pmid=2973230 |doi=}}</ref>
-Nutrition is an important part of treatment; most HD sufferers need two to three times the [[calories]] than the average person to maintain body weight, so a [[nutritionist]]'s advice is needed (average daily intake is approximately 2000 calories for women and 2500 for children and men).
+The life expectancy is around 15 to 20 years following the onset of characteristic manifestations of the disorder.<ref>{{cite journal |author=Roos RA, Hermans J, Vegter-van der Vlis M, ''et al.'' |title=Duration of illness in Huntington's disease is not related to age at onset |journal=J. Neurol. Neurosurg. Psychiatr. |volume=56 |issue=1 |pages=98–100 |year=1993 |pmid=8429330 |doi=}}</ref>  Mortality is not caused by Huntington’s disease directly, but by associated complications; these include [[pneumonia]] (which causes one third of fatalities), [[heart failure]] (although [[heart disease]], [[stroke|cerebrovascular disease]] and [[atherosclerosis]] show no increase), choking, malnutrition and physical injury.<ref>{{cite journal |author=Lanska DJ, Lanska MJ, Lavine L, Schoenberg BS |title=Conditions associated with Huntington's disease at death. A case-control study |journal=Arch. Neurol. |volume=45 |issue=8 |pages=878–80 |year=1988 |pmid=2969233 |doi=}}</ref> [[Suicide]] is an associated risk, with increased suicide rates of up to 7.3 percent, and attempted suicides of up to 27 percent.<ref>{{cite journal |author=Di Maio L, Squitieri F, Napolitano G, ''et al.'' |title=Suicide risk in Huntington's disease |journal=J. Med. Genet. |volume=30 |issue=4 |pages=293–5 |year=1993 |pmid=8487273 |doi=}}</ref><ref>{{cite journal |author=Schoenfeld M, Myers RH, Cupples LA, ''et al.'' |title=Increased rate of [[suicide]] among patients with Huntington's disease |journal=J. Neurol. Neurosurg. Psychiatr. |volume=47 |issue=12 |pages=1283–7 |year=1984 |pmid=6239910 |doi=}}</ref><ref name="Huntington1"/>
-[[Speech therapy]] can help by improving speech and swallowing methods. This advice should be sought early on, as the ability to learn is reduced as the disease progresses.
+== Epidemiology ==
-To aid swallowing thickener can be added to drinks. When swallowing becomes hazardous the option of using a [[Percutaneous endoscopic gastrostomy|stomach PEG]] for intake of nutrients is often chosen, this reduces the chances of pnuemonia due to aspiration of food and increases the amount of nutrients that can be given.
+As HD is autosomal dominant, and does not usually affect reproduction, areas of increased prevalence occur according to historical migration of carriers, some of which can be traced back thousands of years using genetic [[haplotypes]].<ref>{{cite journal |author=Squitieri F, Andrew SE, Goldberg YP, ''et al.'' |title=DNA haplotype analysis of Huntington disease reveals clues to the origins and mechanisms of CAG expansion and reasons for geographic variations of prevalence |journal=Hum. Mol. Genet. |volume=3 |issue=12 |pages=2103–14 |year=1994 |month=December |pmid=7881406 | doi = 10.1093/hmg/3.12.2103 <!--Retrieved from CrossRef by DOI bot-->|url=http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=7881406}}</ref> Since the discovery of a genetic test that can also be used pre-symptomatically, estimates of the incidence of the disorder are likely to increase. Without the  test, only individuals displaying physical symptoms or neurologically examined cases were diagnosed, excluding any who died of other causes before symptoms or diagnosis occurred. These cases can now be included in statistics as the test becomes more widely available and estimates have shown the [[incidence (epidemiology)|incidence]] of HD could be two to three times higher when these results are included.<ref name="pmid11595021">{{cite journal |author=Almqvist EW, Elterman DS, MacLeod PM, Hayden MR |title=High incidence rate and absent family histories in one quarter of patients newly diagnosed with Huntington disease in British Columbia |journal=Clin. Genet. |volume=60 |issue=3 |pages=198–205 |year=2001 |month=September |pmid=11595021 |doi= 10.1034/j.1399-0004.2001.600305.x|url=http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=0009-9163&date=2001&volume=60&issue=3&spage=198}}</ref>
+The [[prevalence]] varies greatly according to geographical location, both by ethnicity and local migration; The highest occurrence is in peoples of Western Europe descent, averaging between 3 to 7 per 100,000 people, but is relatively lower in the rest of the world, e.g. 1 per 1,000,000 of Asian and African descent.<ref name="OMIM"/> Some localised areas have a much higher prevalence than their geographical average, for example the isolated populations of the [[Lake Maracaibo]] region of Venezuela (where the marker for the gene was discovered), have an extremely high prevalence of up to 700 per 100,000,<ref>
-[[Eicosapentaenoic acid|EPA]], an Omega-III fatty acid, slows and possibly reverses the progression of the disease. It is currently in FDA clinical trial, as Miraxion© (LAX-101), for prescription use. Clinical trials utilize 2&nbsp;grams per day of EPA. In the United States, it is available over the counter in lower concentrations in Omega-III and fish oil supplements.
+{{cite journal |author= Avila-Giron R.|title= Medical and Social Aspects of Huntington's chorea in the state of Zulia, Venezuela |journal=Advances in Neurology |volume=1 |pages=261–6 |year=1973 |month= |pmid=|pmc= |doi= |url=}}</ref> leading to the conclusion that one of their initial founders must have been a carrier of the gene. This is known as the local [[founder effect]].<ref name="dnamarker"/>
+== History ==
-A [[Calorie restriction|calorie restrictive]] diet delays the onset of symptoms in HD mice.<ref>Fasting Forestalls Huntington's Disease in Mice [http://www.friendsoffreedom.org/print.php?sid=1377 on friendsoffreedom.org]</ref>
+In the first part of the twentieth century and earlier, many people with HD were misdiagnosed as suffering from alcoholism or manic depression. Previously mortality due to starvation or dehydration was a major risk.
+*[[Middle Ages]]: People with the condition were probably persecuted as being [[Witch-hunt|witches]] or as being possessed by spirits, and were [[shunning|shunned]], [[exile]]d or worse. Some speculate that the "witches" in the [[Salem Witch Trials]] in 1692 had HD.<ref>{{cite web |url=http://www.stanford.edu/group/hopes/sttools/print/p_r_timeline.pdf |format=PDF |title= The brief history of HD|accessdate=2008-08-10 |work=The HOPES Timeline - A Brief History of Huntington's Disease |publisher= standford hopes|date=2005-04-05}} </ref><ref>{{cite journal |author=Okun MS |title=Huntington's disease: what we learned from the original essay |journal=[[Neurologist]] |volume=9 |issue=4 |pages=175–9 |year=2003 |month=July |pmid=12864927 |doi=10.1097/01.nrl.0000080952.78533.1f |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=1074-7931&volume=9&issue=4&spage=175}}</ref>
-=== Potential Treatments ===
+*1860: One of the early medical descriptions of HD was made in 1860 by a [[Norway|Norwegian]] district physician, [[Johan Christian Lund]]. He noted that in [[Setesdalen]], a remote and rather secluded area, there was a high prevalence of [[dementia]] associated with a pattern of jerking [[movement disorder]]s that tended to run in families. This is the reason for the disease being commonly referred to as ''Setesdalsrykkja'' (Setesdalen=the location, rykkja=jerking movements) in [[Norwegian language|Norwegian]].<ref>{{Citation | last=Lund | first=Johan Christian | title= Chorea Sti Viti i Sætersdalen. Uddrag af Distriktslæge J. C. Lunds Medicinalberetning for 1860| journal=Beretning om Sundhedstilstanden | location =Norway  | volume= | issue= | year=1860 | pages=137–138 | url= }}</ref>
-Trials and research are conducted on [[Drosophila melanogaster|Drosophila fruit flies]] and mice that have been [[Genetically modified organism|genetically modified]] to exhibit HD, before moving on to human trials.
+*1872: [[George Huntington]] was the third generation of a family medical practice in [[Long Island]]. With their combined experience of several generations of a family with the same symptoms, he realized their conditions were linked and set about describing it. A year after leaving medical school, in 1872, he presented his accurate definition of the disease to a medical society in [[Middleport, Ohio|Middleport]], [[Ohio]].<ref name="onchorea"/><ref>{{cite journal |author=Lanska DJ |title=George Huntington (1850-1916) and hereditary chorea |journal=[[J Hist Neurosci]] |volume=9 |issue=1 |pages=76–89 |year=2000 |month=April |pmid=11232352 |doi= 10.1076/0964-704X(200004)9:1;1-2;FT076|url= }}</ref>
+*c. 1902: [[Smith Ely Jelliffe]] (1866–1945) began studying the history of HD sufferers in [[New England]] and published several articles over the next few decades.<ref>{{cite journal |author=Jelliffe SE, Muncey EB, Davenport CB |title=Huntington's Chorea: A Study in Heredity |journal=The Journal of Nervous and Mental Disease |volume=40|issue=12 |pages=796 |year=1913|doi= |url=http://scholar.google.co.uk/scholar?hl=en&lr=&q=info:s7u8s5gzl6oJ:scholar.google.com/&output=viewport&pg=1|issn=}}</ref>
+*1932: P. R. Vessie expanded Jelliffe and Tilney's work, tracing about a thousand people with HD back to two brothers and their families who left Bures in [[Suffolk]], [[England]] bound for [[Boston]], [[MA]] in 1630.<ref>{{Citation | last=Vessie | first=P.R. | title=On the transmission of Huntington's chorea for 300 years – the Bures family group | journal=Nervous and Mental Disease | location = Baltimore | volume=76 | issue=6 | year=1932 | pages=553–573 | url=http://scholar.google.co.uk/scholar?hl=en&lr=&q=info:12mCk4CjFKAJ:scholar.google.com/&output=viewport&pg=1 }}</ref><br/>[[Image:Hdpubmedarticleschart.png|250px|right]]
+*1979: The US-[[Venezuela]] Huntington's Disease Collaborative Research Project began an extensive study which formed the basis for the gene to be discovered. This was conducted in the small, isolated Venezuelan fishing villages of Barranquitas and Lagunetas, where families have a high prevalence of the disease.<ref>{{cite web |url=http://www.hdfoundation.org/html/venezuela_huntington.php |title=THE VENEZUELA HUNTINGTON'S DISEASE PROJECT |accessdate=2008-09-08 |work=Hereditary Disease Foundation website|publisher=Hereditary Disease Foundation |year=2008 }}</ref>
+*1983: James Gusella, David Housman, P. Michael Conneally, Nancy Wexler, and their colleagues find the general location of the gene, using DNA marking methods for the first time—an important first step toward the [[Human Genome Project]].<ref name="dnamarker"/>
+*1992: [[Anita Harding]], ''et al.'' find that trinucleotide repeats affect disease severity.<ref name="pmid1303283">{{cite journal |author=La Spada AR, Roling DB, Harding AE, ''et al.'' |title=Meiotic stability and genotype-phenotype correlation of the trinucleotide repeat in X-linked spinal and bulbar muscular atrophy |journal=Nat. Genet. |volume=2 |issue=4 |pages=301–4 |year=1992 |pmid=1303283 |doi=10.1038/ng1292-301}}</ref>
+*1993: The Huntington's Disease Collaborative Research Group isolates the precise gene at 4p16.3.<ref name="pmid8458085">{{cite journal |author= Macdonald, M|title=A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group |journal=[[Cell (journal)|Cell]] |volume=72 |issue=6 |pages=971–83 |year=1993 |month=March |pmid=8458085 |doi= 10.1016/0092-8674(93)90585-E|url=http://linkinghub.elsevier.com/retrieve/pii/0092-8674(93)90585-E}}</ref>
+*1996: A [[transgenic]] mouse ([[the R6 line]]) was created that could be made to exhibit HD, greatly advancing how much experimentation can be achieved.<ref name="transgenmodels">{{cite journal |author=Sathasivam K, Hobbs C, Mangiarini L, ''et al'' |title=Transgenic models of Huntington's disease |journal=[[Philos. Trans. R. Soc. Lond., B, Biol. Sci.]] |volume=354 |issue=1386 |pages=963–9 |year=1999 |month=June |pmid=10434294 |pmc=1692600 |doi=10.1098/rstb.1999.0447 |url=http://journals.royalsociety.org/openurl.asp?genre=article&issn=0962-8436&volume=354&issue=1386&spage=963}}</ref><ref name="pmid16389308">{{cite journal |author=Li JY, Popovic N, Brundin P |title=The use of the R6 transgenic mouse models of Huntington's disease in attempts to develop novel therapeutic strategies |journal=[[NeuroRx]] |volume=2 |issue=3 |pages=447–64 |year=2005 |month=July |pmid=16389308 |pmc=1144488 |doi= 10.1602/neurorx.2.3.447|url= }}</ref>
+*1997: DiFiglia M, Sapp E, Chase KO, et al., discover that mHtt fragments [[Protein folding|misfold]], leading to the formation of [[Inclusion bodies|nuclear inclusions]].<ref name="pmid9302293"/>
+*The full record of research is extensive.<ref name="Huntington1"/><ref>{{cite web |url=http://www.hdfoundation.org/achievements.php |title=Achievements of Hereditary Disease Foundation|accessdate=2008-08-10 |work=Achievements of Hereditary Disease Foundation |publisher=Hereditary Disease Foundation |date= }}</ref><ref>{{cite web |url=http://www.hda.org.uk/charity/research.html |title= HDA research news—medical research into treatment & prevention on hda.org.uk|accessdate=2008-08-10 |work= |publisher= |date= }}</ref>
+==Society and culture==
-Research is reviewed on various websites for HD sufferers and their families, including the Huntington's Disease Lighthouse, Hereditary Disease Foundation, and Stanford HOPES websites. Primary research can be found by searching the National Library of Medicine's PubMed. Clinical trials of various treatments are ongoing, or yet to be initiated,for example the US registar of trials has 9 that are recruiting volunteers.<ref>[http://clinicaltrials.gov/ct/gui/action/FindCondition?ui=D006816 clinicaltrials.gov]</ref>
+{{seealso|List of Huntington's disease media depictions}}
+As public awareness has increased, HD has been depicted increasingly in numerous books, films and TV series. Early works were [[Arlo Guthrie]]'s 1969 film ''[[Alice's Restaurant (film)|Alice's Restaurant]]''<ref>{{cite web|url=http://www.imdb.com/title/tt0064002/|title=Alice's Restaurant |publisher=IMDB |accessdate=2008-08-30}}</ref> and [[Jacqueline Susann]]'s 1966 American novel ''[[Valley of the Dolls]]''; more recent references were made in [[ER (TV series)|ER]],<ref>{{cite web|url=http://www.imdb.com/title/tt0108757/|title=ER (1994) |publisher=IMDB |accessdate=2008-08-30}}</ref> [[Private Practice]],<ref>{{cite web|url=http://www.imdb.com/title/tt0972412/|title=Private Practice (2007) |publisher=IMDB |accessdate=2008-08-30}}</ref> [[Everwood]],<ref>{{cite web|url=http://www.imdb.com/title/tt0318883/|title=Everwood (2002) |publisher=IMDB |accessdate=2008-08-30}}</ref> [[All Saints (TV series)|All Saints]],<ref>{{cite web|url=http://www.imdb.com/title/tt0163924/|title=All Saints (1998) |publisher=IMDB |accessdate=2008-08-30}}</ref> and [[House (TV series)|House]].<ref>{{cite web|url=http://www.imdb.com/title/tt1134258/|title=House M.D.|publisher=IMDB |accessdate=2008-08-30}}</ref> Steven T. Seagle's 2004 graphic novel "[[It's a Bird]]" discusses Huntington's disease and the effects on his family.<ref>{{cite book |title= It's a Bird|last= Seagle|first= Steven T.|authorlink= |coauthors= Teddy Kristiansen|year= 2004 |publisher=Vertigo|location=New York |isbn=978-1401203115 |pages=123 |url=http://www.worldcat.org/oclc/55071368?tab=details#tabs }}</ref> Many support organizations hold an annual HD awareness event, and some have been endorsed by their respective governments, for example, [[June 6]] is designated "National Huntington's Disease Awareness Day" by the USA senate, and the UK HDA holds an awareness campaign in the third week of June.<ref>{{cite web |url=http://www.hdsa.org/static/resolutionhdprint.pdf |format=PDF |title= US Senate s. resolution 531|accessdate=2008-08-10 |work=S. Res. 531 |publisher=US Senate|date=2008-04-06 }}</ref>
-==== Gene silencing ====
+=== Social impact ===
+The development of an accurate diagnostic test for Huntington's disease has caused social, legal, and ethical concerns over access and use of a person's results<ref>{{cite journal |author=Chapman MA |title=Predictive testing for adult-onset genetic disease: ethical and legal implications of the use of linkage analysis for Huntington disease |journal=Am. J. Hum. Genet. |volume=47 |issue=1 |pages=1–3 |year=1990 |month=July |pmid=2140926 |pmc=1683745 |doi= |url=}}</ref><ref>{{cite journal |author=Huggins M, Bloch M, Kanani S, ''et al'' |title=Ethical and legal dilemmas arising during predictive testing for adult-onset disease: the experience of Huntington disease |journal=Am. J. Hum. Genet. |volume=47 |issue=1 |pages=4–12 |year=1990 |month=July |pmid=1971997 |pmc=1683755 |doi= |url=}}</ref> There have been guidelines created by the IHA and WFN for the use of genetic testing in HD, but many governments and institutions, although agreeing not to genetically discriminate against an individual, have not reached a consensus.<ref>{{cite journal |author= |title=Guidelines for the molecular genetics predictive test in Huntington's disease. International Huntington Association (IHA) and the World Federation of Neurology (WFN) Research Group on Huntington's Chorea |journal=Neurology |volume=44 |issue=8 |pages=1533–6 |year=1994 |month=August |pmid=8058167 |doi= |url=}}</ref> As for the individual, the decision to undergo a presymptomatic test, thereby learning whether they will inherit the disorder, is a complicated one. [[Genetic counseling]] is designed to provide information, advice and support for a person to decide, and then throughout all stages of the testing process, if so chosen.<ref name="geneticcounselling"/>
-The most hopeful prospective treatment currently studied is based on [[gene silencing]].  Since HD is caused by expression of a single gene, silencing of the gene could theoretically halt the progression of the disease.  One study with a mouse model of HD treated with [[siRNA]] therapy achieved 60% [[knockdown]] in expression of the defective gene.  Progression of the disease halted.<ref>{{cite web| title=Huntington's Disease Overview| url=http://www.sirna.com/wt/page/neurology |author=Sirna Therapeutics| accessdate=2006-07-16}}</ref>  Additional research shows full recovery of motor function in late stage Tet/HD94 mice after addition of [[doxycycline]].<ref>{{cite journal| author=Miguel Díaz-Hernández, Jesús Torres-Peraza, Alejandro Salvatori-Abarca, María A. Morán, Pilar Gómez-Ramos, Jordi Alberch, and José J. Lucas| title=Full Motor Recovery Despite Striatal Neuron Loss and Formation of Irreversible Amyloid-Like Inclusions in a Conditional Mouse Model of Huntington's Disease| journal=The Journal of Neuroscience| date=October 19, 2005| volume=25| issue=42| pages=9773-9781| url=http://www.jneurosci.org/cgi/content/abstract/25/42/9773| accessdate=2006-07-16}} </ref>
+One of the key issues is the level of anxiety that an individual experiences about "not knowing" whether they will some day develop HD, compared to the psychological impact that might occur if the test indicates that one will eventually succumb to the disease. In contrast individuals found to have inherited the normal allele may experience [[Survivor guilt]] with regard to their affected family members.<ref>{{cite journal |author=Tibben A, Vegter-van der Vlis M, Skraastad MI, ''et al'' |title=DNA-testing for Huntington's disease in The Netherlands: a retrospective study on psychosocial effects |journal=Am. J. Med. Genet. |volume=44 |issue=1 |pages=94–9 |year=1992 |month=September |pmid=1387764 |doi=10.1002/ajmg.1320440122 |url=}}</ref>  Some individuals choose not to undergo testing due to concerns about prejudice in areas such as [[health insurance|insurability]], employment and financial matters. An important ethical consideration is the testing of asymptomatic minors. As with other genetic conditions with later onset for which no treatment is available, it is ethically questionable to perform presymptomatic testing for a child or individual who has not made a mature, informed decision for themselves.<ref>{{cite journal |author=Bloch M, Hayden MR |title=Opinion: predictive testing for Huntington disease in childhood: challenges and implications |journal=Am. J. Hum. Genet. |volume=46 |issue=1 |pages=1–4 |year=1990 |month=January |pmid=2136787 |pmc=1683548 |doi= |url=}}</ref> Such information may cause psychological harm, jeopardize that individual's employment or ability to obtain health and [[life insurance]]. For this reason, presymptomatic testing in minors is a controversial area, with arguments in favor of permitting testing only when the individual is mature enough to provide assent versus minimizing medical paternalism in favor of parental preferences.<ref>{{cite journal |author=Binedell J, Soldan JR, Scourfield J, Harper PS |title=Huntington's disease predictive testing: the case for an assessment approach to requests from adolescents |journal=J. Med. Genet. |volume=33 |issue=11 |pages=912–8 |year=1996 |month=November |pmid=8950670 |pmc=1050784 |doi= |url=}}</ref><ref>{{cite journal |author=Wertz DC, Fanos JH, Reilly PR |title=Genetic testing for children and adolescents. Who decides? |journal=JAMA |volume=272 |issue=11 |pages=875–81 |year=1994 |month=September |pmid=8078166 |doi= 10.1001/jama.272.11.875|url=}}</ref><ref>{{cite journal |author=Hoffmann DE, Wulfsberg EA |title=Testing children for genetic predispositions: is it in their best interest? |journal=J Law Med Ethics |volume=23 |issue=4 |pages=331–44 |year=1995 |pmid=8715053 |doi= 10.1111/j.1748-720X.1995.tb01375.x|url=}}</ref><ref name="minorstesting"/> The balance of opinion would change drastically if an effective treatment was discovered.
-==== Others ====
-Other agents and measures that have shown promise in initial experiments include [[dopamine]] receptor blockers, [[creatine]], [[CoQ10]], the antibiotic [[Minocycline]], [[Trehalose]], exercise, antioxidant-containing foods and nutrients, a simple sugar called [[trehalose]] can alleviate HD symptoms in genetically modified mice. antidepressants (notably, but not exclusively, selective serotonin reuptake inhibitors [[SSRI]]s, such as sertraline, fluoxetine, and paroxetine) and select [[Dopamine]] antagonists, such as [[Tetrabenazine]].
+Genetic testing may infer information about relatives who do not want it. Testing a descendant of a undiagnosed parent has implications to other family members, since a positive result automatically reveals the parent as carrying the affected gene, and siblings (and especially [[identical twin]]s) as being  'at risk' of also inheriting it.<ref>{{cite journal |author=Gómez-Esteban JC, Lezcano E, Zarranz JJ, ''et al'' |title=Monozygotic twins suffering from Huntington's disease show different cognitive and behavioral symptoms |journal=Eur. Neurol. |volume=57 |issue=1 |pages=26–30 |year=2007 |pmid=17108691 |doi=10.1159/000097006 |url=http://content.karger.com/produktedb/produkte.asp?typ=fulltext&file=ENE2007057001026}}</ref> This emphasizes the importance of disclosure, as individuals have to decide when and how to reveal the information to their children and other family members. For those at risk, or known to carry a mutant allele, there can be the consideration of [[prenatal diagnosis|prenatal genetic testing]] and [[preimplantation genetic diagnosis]] in order to ensure that the disorder is not passed on.<ref name="pmid15732064">{{cite journal |author=Kuliev A, Verlinsky Y |title=Place of preimplantation diagnosis in genetic practice |journal=Am. J. Med. Genet. A |volume=134A |issue=1 |pages=105–10 |year=2005 |month=April |pmid=15732064 |doi=10.1002/ajmg.a.30635}}</ref>
-Pig cell implants in HD trial: Living Cell Technologies in New Zealand has attempted trials with positive results in primates, but is yet to conduct a human trial.<ref>[http://www.worldhealth.net/p/pig-cell-implants-in-huntingtons-trial-2005-08-19.html World health Article]</ref>
+Huntington's disease has tested society's ethics in various ways.  HD was one of the targets of the [[eugenics]] movement, in which [[United States|American]] scientist [[Charles Davenport]] proposed in 1910 that compulsory [[sterilization]] and [[immigration]] control be used for people with certain diseases, including HD.<ref>{{cite journal |author=Davenport CB |title=Huntington's chorea in relation to heredity and eugenics |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=1 |issue=5 |pages=283–5 |year=1915 |month=May |pmid=16575999 |pmc=1090803 |doi= 10.1073/pnas.1.5.283|url=}}</ref> Since the development of genetic testing for HD, financial institutions and businesses are also faced with the question of whether to use results when assessing an individual, e.g. for life insurance or employment.  Some countries' organizations have already agreed not to use this information.<ref>{{cite web |url=http://news.bbc.co.uk/1/hi/business/7452909.stm |title= BBC article: Genetic data banned for insurers|accessdate=2008-08-10 |work= |publisher=BBC |date=2008-06-13 }} </ref> Recent passage of the [[Genetic Information Nondiscrimination Act]] (GINA) in the United States prevents health insurance companies from denying coverage or charging higher premiums for individuals with predisposition to genetic disease.{{Fact|date=August 2008}}
-The [[Folding@home]] project is the second largest distributed processing project on the internet It models protein folding and HD is listed amongst the potential benefactors of its results.
-== Prognosis ==
+=== Organizations ===
+*1967: [[Woody Guthrie]]'s wife, [[Marjorie Guthrie|Marjorie]], helped found the Committee to Combat Huntington's Disease, after his death from HD complications. This eventually became the [[Huntington's Disease Society of America]].<ref>{{cite web |url=http://www.hdsa.org/ Huntington's Disease Society of America |title=HDSA|accessdate=2008-08-10 |work=http://www.hdsa.org/ Huntington's Disease Society of America website|publisher=HDSA |date= }}</ref> Since then, lay organizations have been formed in many countries around the world.
-Onset of HD seems to be correlated to the number of CAG repeats a person has in their HD gene. Generally, the higher the number of repeats the sooner onset is.<ref>[http://hdlighthouse.org/abouthd/cag/updates/0029cagvonset.shtml The Huntington Disease lighthouse.org]</ref>  The number of repeats may change slightly with each successive generation, so that the age of onset may vary as well. Symptoms of Huntington’s disease usually become noticeable in the mid 30s to mid 40s.
+*1968: After experiencing HD in his wife's family Dr. Milton Wexler was inspired to start the [[Hereditary Disease Foundation]] (HDF). Professor Nancy S. Wexler, Dr. Wexler's daughter, was in the research team in [[Venezuela]] and is now president of the HDF.
+*1974: The first international meeting took place when the founders of the Canadian HD Society (Ralph Walker) and of the British HD Society (Mauveen Jones) attended the annual meeting of the American HD Society.
+*1977: Second meeting organized by the [[Netherlands|Dutch]] Huntington Society the "Vereniging van Huntington", representatives of six countries were present.
+*1979: International Huntington Association (IHA) formed during international meeting in [[Oxford, England|Oxford]], [[England]] organized by HDA of England.
+*1981–2001: Biennial meetings held by IHA which became the World Congress on HD.
+*2003: The first World Congress on Huntington's Disease was held in [[Toronto]].<ref>{{cite web |url=http://www.worldcongress-hd.net/ World Congress on Huntington's Disease |title= World Congress on Huntington's Disease website |accessdate=2008-08-10 |work= |publisher= |date= }}</ref> This is a biennial meeting for associations and researchers to share ideas and research, which is held on odd-number years. The Euro-HD Network<ref>{{cite web |url=http://www.euro-hd.net/ Euro-HD Network |title= Euro-HD website|accessdate=2008-08-10 |work= |publisher= |date= }}</ref> was started as part of the Huntington Project,<ref>{{cite web |url=http://www.huntingtonproject.org/ Huntington Project |title= Huntington Porject website|accessdate=2008-08-10 |work= |publisher= |date= }}</ref> funded by the High-Q Foundation.<ref>{{cite web |url=http://www.highqfoundation.org/ High-Q Foundation |title=HighQ foundation website |accessdate=2008-08-10 |work=HighQ |publisher= |date= }}</ref>
+==Research directions==
-Juvenile HD has an age of onset anywhere between infancy and 20 years of age. The symptoms of juvenile HD are different from those of adult-onset HD in that they generally progress faster and are more likely to exhibit rigidity and [[bradykinesia]] (very slow movement) instead of chorea.
+Appropriate animal models are critical for understanding the fundamental mechanisms causing the disease and for supporting the early stages of [[drug development]]. Neurochemically induced mice or monkeys were first available,<ref>{{cite journal |author=Beal MF, Kowall NW, Ellison DW, Mazurek MF, Swartz KJ, Martin JB |title=Replication of the neurochemical characteristics of Huntington's disease by quinolinic acid |journal=Nature |volume= 321|issue=321 | year=1986 |month= |pages=168–71 |pmid=2422561 |doi=10.1038/321168a0}}</ref><ref>{{cite journal |author=Brouillet E, Hantraye P, Ferrante RJ, Dolan R, Leroy-Willig A, Kowall NW, Beal MF |title=Chronic mitochondrial energy impairment produces selective striatal degeneration and abnormal choreiform movements in primates |journal=Proc Natl Acad Sci USA |volume=92 |issue= | year=1995 |month= |pages=7105–7109 |pmid= 7624378|doi=10.1073/pnas.92.15.7105}}</ref> but they did not mimic the progressive features of the disease. After the HD gene was discovered, [[transgenic animal]]s exhibiting HD were generated by inserting a CAG repeat expansion into their genome, these were of mice (strain R6/2),<ref>{{cite journal |author=Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, Hetherington C, Lawton M, Trottier Y, Lehrach H, Davies SW, Bates GP |title=Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological genotype in transgenic mice |journal=Cell |volume=87 |issue=3 | year=1996 |month=November |pages=493–506 |pmid=8898202 |doi=10.1016/S0092-8674(00)81369-0}}</ref><ref>{{cite journal |author=Carter RJ, Lione LA, Humby T, Mangiarini L, Mahal A, Bates GP, Dunnett SB, and Morton AJ |title=Characterization of Progressive Motor Deficits in Mice Transgenic for the Human Huntington's Disease Mutation |journal=The Journal of Neuroscience |volume=19 |issue=8 | year=1999 |month=April |pages=3248–3257 |pmid= 10191337| url=http://www.jneurosci.org/cgi/content/full/19/8/3248}}</ref>), ''[[Drosophila melanogaster|Drosophila]]'' fruit flies,<ref>{{cite journal |author=Marsh JL, Pallos J and Thompson LM |title=Fly models of Huntington's disease |journal=Human Molecular Genetics |volume=12 |issue=2 | year=2003 |month= |pages=187–193 |pmid= 12925571|doi=10.1093/hmg/ddg271| url=http://hmg.oxfordjournals.org/cgi/content/full/12/suppl_2/R187}}</ref> and more recently monkeys.<ref>
+{{cite web |url=http://www.sciencedaily.com/releases/2008/05/080518152643.htm |title=Science Daily article on HD monkey model |accessdate=2008-08-10 |work= First Transgenic Monkey Model Of Huntington's Disease Developed|publisher=ScienceDaily |date=2008-05-19}}</ref> Expression without insertion of a DNA repeat in [[nematode]] worms also produced a valuable model.<ref>{{cite journal |author=Voisine C, Varma H, Walker N, Bates EA, Stockwell BR, Hart AC |title=Identification of potential therapeutic drugs for huntington's disease using Caenorhabditis elegans |journal=PLoS ONE |volume=2 |issue=6 |pages=e504 |year=2007 |pmid=17551584 |pmc=1876812 |doi=10.1371/journal.pone.0000504 |url=http://www.plosone.org/article/info:doi/10.1371/journal.pone.0000504}}</ref>
+=== Intrabody therapy ===
-Mortality is due to infection (mostly [[pneumonia]]), injuries related to a fall, or other complications resulting from HD rather than the disease itself, and is usually 10 to 25 years after the onset of obvious symptoms.
+[[Genetic engineering|Genetically engineered]] [[intracellular]] [[antibody]] fragments called intrabodies have shown therapeutic results, by inhibiting mHtt aggregation, in drosophila models. This was achieved using an intrabody called C4 sFv, a [[single chain variable fragment]] which binds to the end of mHtt [[Intracellular|within a cell]].<ref>{{cite journal |author=Lecerf JM, Shirley TL, Zhu Q, ''et al.'' |title=Human single-chain Fv intrabodies counteract in situ huntingtin aggregation in cellular models of Huntington's disease |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=98 |issue=8 |pages=4764–9 |year=2001 |pmid=11296304 |doi=10.1073/pnas.071058398}}</ref><ref>{{cite journal |author=Miller TW, Zhou C, Gines S, ''et al.'' |title=A human single-chain Fv intrabody preferentially targets amino-terminal Huntingtin's fragments in striatal models of Huntington's disease |journal=Neurobiol. Dis. |volume=19 |issue=1-2 |pages=47–56 |year=2005 |pmid=15837560 |doi=10.1016/j.nbd.2004.11.003}}</ref> This therapy prevented [[larva]]l and [[pupa]]l mortality (without therapy 77% died) and delayed neurodegeneration in the adult, significantly increasing their lifespan.<ref>{{cite journal |author=Wolfgang WJ, Miller TW, Webster JM, ''et al.'' |title=Suppression of Huntington's disease pathology in ''Drosophila'' by human single-chain Fv antibodies |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=102 |issue=32 |pages=11563–8 |year=2005 |pmid=16061794 |doi=10.1073/pnas.0505321102}}</ref> [[Intrabody therapy]] shows promise as a tool for [[drug discovery]], and as a potential therapy for HD and other neurodegenerative disorders caused by protein mis-folding or abnormal [[protein interactions]].<ref>{{cite journal |author=Miller TW, Messer A |title=Intrabody applications in neurological disorders: Progress and future prospects |journal=Mol. Ther. |volume=12 |issue=3 |pages=394–401 |year=2005 |pmid=15964243 |doi=10.1016/j.ymthe.2005.04.003}}</ref><ref name="pmid17176119">{{cite journal |author=Messer A, McLear J |title=The therapeutic potential of intrabodies in neurologic disorders: focus on Huntington and Parkinson diseases |journal=BioDrugs |volume=20 |issue=6 |pages=327–33 |year=2006 |pmid=17176119 |doi= 10.2165/00063030-200620060-00002|url= |accessdate=2008-09-21}}</ref>
-The suicide rate amongst HD sufferers is much greater than the national average.<ref>http://www.huntington-assoc.com/Critical%20ab05.pdf]</ref>
+=== Gene silencing ===
-== Epidemiology ==
+As HD has been conclusively linked to a single gene, [[gene silencing]] is potentially possible. Researchers have investigated using [[gene knockdown]] of mHTT as a potential treatment. Using a mouse model, [[siRNA]] therapy achieved a 60 percent reduction in expression of the mHTT and progression of the disease was stalled.<ref name="pmid15811941">{{cite journal |author=Harper SQ, Staber PD, He X, ''et al.'' |title=RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=102 |issue=16 |pages=5820–5 |year=2005 |pmid=15811941 |doi=10.1073/pnas.0501507102}}</ref> However, this study used the human form of the mHTT protein in the mouse, and was therefore only able to directly target the mHTT, leaving endogenous, [[Wild type|wild-type]] mouse ''Htt'' [[gene expression]] unaffected. From a practical standpoint, it would be difficult in humans to use siRNA to target the mutant form while leaving the normal copy unaffected. The precise function of HTT is unknown, but in mice, complete deletion of the ''Htt'' gene is lethal.<ref name="Nasir"/> Thus, using [[RNA interference]] to treat HD could have unexpected effects unless knock-down of the normal HTT protein can be avoided. Other issues include problems delivering the siRNA to the appropriate target tissue, off-target effects of siRNA, and toxicity from [[Small hairpin RNA|shRNA]] over-expression.<ref>{{cite journal| author=Jodi L. McBride ''et al.'' |title=Artificial miRNAs mitigate shRNA-mediated toxicity in the brain: Implications for the therapeutic development of RNAi |journal=PNAS |volume=105 |issue=15 |pages=5868–5873 |doi=10.1073/pnas.0801775105| year=2008| pmid=18398004}}</ref> Another study showed that mouse models already in late stages of the disease recovered motor function after expression of mHTT was stopped.<ref>{{cite journal| author=Miguel Díaz-Hernández, Jesús Torres-Peraza, Alejandro Salvatori-Abarca, ''et al.''| title=Full Motor Recovery Despite Striatal Neuron Loss and Formation of Irreversible Amyloid-Like Inclusions in a Conditional Mouse Model of Huntington's Disease| journal=The Journal of Neuroscience|date=October 19, 2005| volume=25| issue=42| pages=9773–9781| doi=10.1523/JNEUROSCI.3183-05.2005| pmid=16237181}}</ref>
+=== Stem cell implants ===
-The prevalence is 5 to 8 per 100,000, varying geographically.
+{{main|Stem cell treatments}}
+Stem cell therapy is the replacement of damaged neurons by transplantation of [[stem cell]]s (or possibly neural stem cells—a type of somatic [adult] stem cell) into affected regions of the brain. Hypothetically, [[embryonic stem cell]]s can be differentiated into neuronal precursors ''in vitro'', and transplanted into damaged areas of the brain to generate replacement neurons, if enough damaged neurons can be replaced and develop the correct synaptic connectivity, symptoms could be alleviated. This treatment would not prevent further neuronal damage, so it would have to be an ongoing treatment. Experiments have yielded some positive results in animal models,  but remains highly speculative and has not been tested in clinical trials.<ref>{{cite web |url=http://www.worldhealth.net/p/pig-cell-implants-in-huntingtons-trial-2005-08-19.html |title=Pig cell implants in Huntington's trial |publisher=WorldHealth.net |accessdate=2008-05-15}}</ref>
-=== Ethical aspects ===
+=== Pharmacological ===
+As of August 2008, several trials of various compounds are in development or ongoing,<ref>{{cite web |url= http://clinicaltrials.gov/ct2/results?cond=%22Huntington+Disease%22|title= Trials for Huntington's disease at clinicaltrials.gov|accessdate=2008-08-10 |work= |publisher= |date= }}</ref> a few at the point of testing on larger numbers of people, known as [[Clinical trial#Phases|phase III]] of [[clinical trial]]s.
-HD presents individuals and families with several issues:
+Substances that have shown promise in initial experiments include [[dopamine]] receptor blockers, select [[dopamine antagonists]], such as [[tetrabenazine]], [[creatine]], [[CoQ10]], the antibiotic [[Minocycline]], antioxidant-containing foods and nutrients, and antidepressants, including [[selective serotonin reuptake inhibitor]]s  such as [[sertraline]], [[fluoxetine]], and [[paroxetine]].<ref name="pmid18482027">{{cite journal |author=Mostert JP, Koch MW, Heerings M, Heersema DJ, De Keyser J |title=Therapeutic potential of fluoxetine in neurological disorders |journal=CNS Neurosci Ther |volume=14 |issue=2 |pages=153–64 |year=2008 |pmid=18482027 |doi=10.1111/j.1527-3458.2008.00040.x |url=}}</ref><ref name="pmid16842168"/>
-* Testing for the presence of the disease
-* Whether to have children
-* Informing children with an HD positive parent that they are at risk
-* Coping with the discovery of the disease in a family member.
-* Testing of grandchildren of a sufferer has serious ethical implications if their parent declines testing, as a positive result in a grandchild's test automatically diagnoses the parent.
-* Coping with the social and personal impacts of impairment of learning new skills.
-[[Genetic counseling]] may provide perspective for those at risk of the disease. Some choose not to undergo HD testing due to numerous concerns (for example, insurability).
-For those at risk, or known to have the disease, consideration is necessary prior to having children due to the genetically dominant nature of the disease. In vitro and embryonic genetic screening now make it possible (with 99% certainty) to have an HD-free child; however, the cost of this process can easily reach tens of thousands of dollars.
-Parents and grandparents have to decide when and how to tell their children and grandchildren. The issue of disclosure also comes up when siblings are diagnosed with the disease, and especially in the case of [[identical twin]]s.  It is not unusual for entire segments of a family to become alienated as a result of such information or the withholding of it.
-Financial institutions are also faced with the question of whether to use genetic testing results when assessing an individual, e.g. for life insurance. Some countries organizations have already agreed not to use this information.
-==Cultural references==
-HD features prominently in several novels e.g.[[Ian McEwan|Ian McEwan's]] 2005 novel ''[[Saturday (novel)|Saturday]]'', where the protagonist Dr Henry Perowne diagnoses his antagonist Baxter's condition, [[Pål Johan Karlsen|Pål Johan Karlsen's]] 2002 Norwegian novel ''Daimler'', where the main character Daniel Grimsgaard is afflicted, and [[Kurt Vonnegut]]'s novel [[Galapagos]].
-The disease has also been depicted on television e.g. an episode of the BBC drama [[Waterloo Road (TV series)|Waterloo Road]] features HD.
-== History ==
-*c300 There is evidence that doctors as far back as the [[Middle Ages]] knew of this disease. It was known, amongst other conditions with abnormal movements, as St Vitus dance. [[St Vitus]] is the Christian patron saint of epileptics who was martyred in [[303]].
-*Middle ages. People with the condition were often persecuted as being [[Witch-hunt|witches]] or as being possessed by spirits, and were shunned, exiled or worse. Some speculate that the "witches" in the [[Salem Witch Trials]] in 1692 had HD.<ref>The brief history of HD [http://www.stanford.edu/group/hopes/sttools/print/p_r_timeline.pdf on stanford.edu]</ref>
-*1860 One of the early medical descriptions of HD was made in [[1860]] by a Norwegian district physician, [[Johan Christian Lund]]. He noted that in [[Setesdalen]], a remote and rather secluded area, there was a high prevalence of dementia associated with a pattern of jerking movement disorders that tended to run in families. This is the reason for the disease being commonly referred to as ''Setesdalsrykkja'' (Setesdalen=the location, rykkja=jerking movements) in [[Norwegian language|Norwegian]].
-*1872 [[George Huntington]] was one of three generations of medical practitioners in [[Long Island]]. With their combined experience of several generations of a family with the same symptoms, he realised their conditions were linked and set about describing it. A year after leaving medical school , in 1872, he presented his accurate definition of the disease to a medical society in Middleport, Ohio.
-*c1923 [[Smith Ely Jelliffe]] (1866-1945) and Frederick Tilney (1875-1938) began analyzing the history of HD sufferers in New England.
-*1932 P. R. Vessie expanded Jelliffe and Tilney's work, tracing about a thousand people with HD back to two brothers and their families who left Bures in Essex for Suffolk bound for Boston in [[1630]].
-*1979 The U.S-Venezuela Huntington's Disease Collaborative Research Project began an extensive study which gave the basis for the gene to be discovered. This was conducted in the small and isolated [[Venezuelan]] fishing village of Barranquitas. Families there have a high presence of the disease, which has proved invaluable in the research of the disease.
-*1983 Professor Wexler, James Gusella, David  Housman, P. Michael Conneally and their colleagues find the general location of the gene, using DNA marking methods for the first time - an important first step toward the [[Human Genome Project]].
-*1993 The Huntington's Disease Collaborative Research Group isolates the precise gene at 4p16.3.
-*1996 A [[transgenic]] mouse was created that could be made to exhibit HD greatly advancing how much experimentation can be achieved.
-*1997 Researchers discovered that mHtt bunches up ([[Protein folding|mis folds]]) to form [[Inclusion bodies|nuclear inclusions]].
-*2001 Christopher Ross and his team at Johns Hopkins University described how mHtt causes the death of cells.<ref>Huntington’s disease  [http://pubs.acs.org/subscribe/journals/mdd/v05/i02/html/02disease.html on pubs.acs.org]</ref>
-The full record of research is extensive.<ref>Achievements of  [http://www.hdfoundation.org/achievements.php Hereditary Disease Foundation]</ref><ref>HDA research news - medical research into treatment & prevention [http://www.hda.org.uk/charity/research.html on hda.org.uk]</ref>
-=== Relevant organizations ===
-[[Image:hdalogo2.gif|thumb|right|logo of the IHA and other HD organizations]]
-*1967 [[Woody Guthrie]]'s wife, Marjorie Guthrie, helped found the Committee to Combat Huntington's Disease, after his death whilst suffering from HD. This eventually became the Huntington's Disease Society of America.<ref>[http://www.hdsa.org Huntington's Disease Society of America]</ref> Since then, lay organizations have been formed in many countries around the world.
-*1968 After experiencing HD in his wife's family, Dr. Milton Wexler was inspired to start the Hereditary Disease Foundation (HDF). Professor [[Nancy Wexler]], Dr. Wexler's daughter, was in the research team in Venezeula and is now president of the HDF.
-*1974 the first international meeting took place when the founders of the Canadian HD Society (Ralph Walker) and of the British HD Society (Mauveen Jones) attended the annual meeting of the American HD Society
-*1977 second meeting organized by the Dutch Huntington Society the "Vereniging van Huntington", representatives of six countries were present.
-*1979 International Huntington Association (IHA) formed during international meeting in Oxford (England) organized by HDA of England.
-*1981-2001 Biennial meetings held by IHA which became the World Congress on HD.
-*2003 the first World Congress on Huntington's Disease was held in Toronto. This is a biennial meeting for associations and researchers to share ideas and research, which is held on odd-number years. The Euro-HD Network<ref>[http://www.euro-hd.net Euro-HD Network]</ref> was started as part of the Huntington Project<ref>[http://www.huntingtonproject.org Huntington Project]</ref>, funded by the High-Q Foundation<ref>[http://www.highqfoundation.org High-Q Foundation]</ref>.
 ==References==
+{{reflist|2}}
-<div class="references-small">
-<references />
-</div>
 ==Bibliography==
-*{{cite web| author=John P. Conomy, M.D., J.D.| url=http://www.lkwdpl.org/hdsa/conomy.htm| title=Dr. George Sumner Huntington and the Disease Bearing His Name}}
+*{{cite web| last= Conomy|first=John P., M.D., J.D | url=http://www.lkwdpl.org/hdsa/conomy.htm| title=  Dr. George Huntington and the Disease Bearing His Name | accessdate=2008-08-15}}
+*{{OMIM|143100|Huntington Disease}}
-* {{cite journal| author=P. R. Vessie| title=On the transmission of Huntington's chorea for 300 years – the Bures family group| journal=Journal of Nervous and Mental Disease, Baltimore| year=1932| volume=76| pages=553-573}}
+*{{OMIM|606438|Huntingtons Disease-Like 2}}
-* {{cite journal| author=G. Huntington| title=On Chorea| journal=Medical and Surgical Reporter of Philadelphia| volume=26| issue=15| date=1872-04-13| pages=317-321}}
+* {{cite journal |last= Stevenson |first= Charles S. |year= 1934 |month= April |title=A Biography of George Huntington, M.D |journal=Bulletin of the Institute of the History of Medicine |volume= II |issue= 2 | publisher =[[Johns Hopkins University]] |url= http://www.shv.ch/download/BiographyGeorgeHuntington.doc | format = Microsoft Word |accessdate= 2007-12-05|archiveurl=http://web.archive.org/web/20030310093528/http://www.shv.ch/download/BiographyGeorgeHuntington.doc|archivedate=2003-03-10}}
-* {{cite book| author=Gillian Bates, Peter Harper, Lesley Jones| title=Huntington's Disease - Third Edition| publisher=Oxford University Press| location=Oxford| year=2002| id=ISBN 0-19-851060-8}}
-* [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=143100 Article 143100 - Huntington Disease ], ''[[Online Mendelian Inheritance in Man]]'', [[Johns Hopkins University]]
-* [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=606438 Article 606438 - Huntingtons Disease-Like 2 ] ''[[Online Mendelian Inheritance in Man]]'', [[Johns Hopkins University]]
-* [http://www.shv.ch/download/BiographyGeorgeHuntington.doc ''History of Medicine Bulletin''],[[The Johns Hopkins University]], a biography of George Huntington and other relevant information.
 ==External links==
 {{wikisource|On Chorea}}
+* [http://www.dmoz.org/Health/Conditions_and_Diseases/Neurological_Disorders/Huntington's_Disease DMOZ HD links directory] at the [[Open Directory Project]].
 ===Professional and research===
 * [http://www.huntingtonproject.org/ Huntington Project] - worldwide umbrella organization for the clinical research efforts for HD.
 * [http://www.huntington-study-group.org/ Huntington Study Group]
-* [http://huntingtonsdisease.researchtoday.net Huntington's Disease Research] - Research abstracts on HD.
+* [http://huntingtonsdisease.researchtoday.net/ Huntington's Disease Research] - Research abstracts on HD.
-* [http://hopes.stanford.edu/ Huntington's Outreach Project for Education, at Stanford (HOPES)] - A layperson's guide to HD
+* [http://hopes.stanford.edu/ Huntington's Disease Outreach Project for Education, at Stanford (HOPES)] - A layperson's guide to HD
 * [http://www.wemove.org/hd/ Worldwide Education and Awareness for Movement Disorders] - HD section
-* [http://hdresearch.ucl.ac.uk University College London Huntington's Disease Research]
+* [http://hdresearch.ucl.ac.uk/ University College London Huntington's Disease Research]
+* [http://www.track-hd.net/ TRACK-HD], an international [[observational study]] of HD
+* University California and San Francisco [[Memory and aging|Memory and Aging]] Center - [http://memory.ucsf.edu/Education/Disease/hd.html HD Info]
+{{Mental and behavioural disorders}}
-===Support and advocacy===
+{{Diseases of the nervous system}}
-* [http://www.huntington-assoc.com The International Huntington Association] - coordinates HD organizations in 39 countries with contacts in others across the world.
+{{Trinucleotide repeat disorders}}
-* [http://www.hdsa.org/ Huntington's Disease Society of America]
-* [http://www.hdfoundation.org/ Hereditary Disease Foundation] - spearheaded Venezuela Collaborative Huntington's Disease Project.
-* [http://www.euro-hd.net European HD Network]
-* [http://www.thehdsc.org Huntington's Disease Support Club]
-* [http://www.ahdansw.asn.au Australian Huntington's Disease Association (NSW) Inc.]
-* [http://www.hdlighthouse.org Huntington's Disease Lighthouse] - reporting on the latest HD research and studies
-* [http://www.hda.org.uk Huntington's Disease Association UK]
-* [http://www.huntingtonliga.be Huntington Liga BE]
-* [http://www.hdac.org/ Huntington's Disease Advocacy Center] - providing HD community support through shared stories and forums
-[[Category:Eponymous diseases]]
+[[Category:Chorea]]
 [[Category:Genetic disorders]]
 [[Category:Neurological disorders]]
+<!--
+[[ca:Malaltia de Huntington]]
+[[da:Huntingtons chorea]]
 [[de:Chorea Huntington]]
 [[es:Enfermedad de Huntington]]
@@ Line 229: / Line 220: @@
 [[fr:Chorée de Huntington]]
 [[ko:헌팅턴 무도병]]
+[[id:Penyakit Huntington]]
 [[it:Morbo di Huntington]]
 [[he:מחלת הנטינגטון]]
@@ Line 235: / Line 227: @@
 [[no:Huntingtons sykdom]]
 [[pl:Pląsawica Huntingtona]]
+[[pt:Doença de Huntington]]
 [[ru:Болезнь Хантингтона]]
+[[simple:Huntington's disease]]
 [[sr:Хантингтонова хореа]]
 [[fi:Huntingtonin tauti]]
 [[sv:Huntingtons sjukdom]]
+[[tr:Huntington hastalığı]]
+[[zh:亨丁頓舞蹈症]]
+-->
 {{enWP|Huntington's disease}}

ICD-10	G 10, F 022
ICD-9	333.4, 294.1
OMIM	143100
DiseasesDB	6060
MedlinePlus	[1]
eMedicine	/
MeSH	{{{MeshNumber}}}