Huntington's disease

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Huntington's disease
Classification and external resources
Medium spiny neurons (yellow) with nuclear inclusions, which occur as part of the disease process, stained orange
ICD-10	G10., F02.2
ICD-9	333.4, 294.1
OMIM	143100
DiseasesDB	6060
MedlinePlus	000770
eMedicine	article/1150165  article/792600 article/289706
MeSH	D006816

Huntington's disease, also known as Huntington disease, Huntington's chorea, chorea major, sometimes abbreviated as HD, is the most common genetic cause of the pattern of repetitive abnormal movements called chorea.^[1][2] It is a neurodegenerative disorder named after the American physician George Huntington who accurately described it in 1872, and has no current cure.^[3][4] HD prevalence, per country, is up to 7 people in 100,000 (in populations of Western European inheritance), but can be much higher in localized regions.^[1] Physical symptoms of the disorder can begin at any age, although the mean is 35 to 44 years of age.^[5] Less commonly, onset is before age 20, and the condition, classified as juvenile HD (also known as akinetic-rigid HD or Westphal variant HD), progresses faster with slightly different symptoms.^[6] In 1993 genetic testing was made possible with the discovery of a single causal gene, the first non-sex-linked dominant disease gene to be found.^[7] Consequently counseling for HD had to be developed and became a model for other genetically dominant disorders.^[8] The test can be performed before the onset of symptoms, at any age—even pre-birth,^[1] which has raised various ethical issues and heated debates.^[9]

The disease runs strongly in families: it is inherited dominantly, so the offspring of an affected person have a 50% risk of suffering it, and an individual will often experience several generations of family members suffer from the disease in their lifetime.^[1] The exact way HD affects an individual varies, even between family members, but there is a characteristic progression.^[10] The earliest symptoms are a general lack of coordination and an unsteady gait. As the disease advances uncoordinated, jerky body movements become more apparent, as does a decline in mental abilities and behavioral and psychiatric problems.^[1] Physical abilities are gradually impeded. Mental abilities generally decline into dementia, requiring full-time care in the later stages of the disease.^[1] Although the disorder itself is not fatal, complications reduce life expectancy to around twenty years after onset of symptoms.^[1]

The mechanism of the disease is not fully understood, but a number of factors have been identified.^[1] A mutation in the Huntingtin gene causes the production of an abnormal form of the protein huntingtin, which in turn produces cellular and anatomical changes in the brain.^[11] There is no cure for HD, although there are treatments to relieve some of its symptoms.^[1]

Since the late 1960s and the formation of the Hereditary Disease Foundation by Dr. Milton Wexler and the Committee to Combat Huntington's Disease by Marjorie Guthrie, both spouses of HD sufferers, lay organizations have increased in number, playing a key factor in stimulating research, increasing public awareness and providing support for families in many countries.^[12] Research directions include determining the exact mechanism of the disease, improvement of animal models to speed research, clinical trials of pharmaceuticals to treat symptoms or slow the progression of the disease, and studying procedures such as stem cell therapy with a view to repairing damage caused by the disease.^[1]

Contents 1 Signs and symptoms 2 Genetics 2.1 Genetic mutation 2.2 Inheritance 3 Mechanism 3.1 HTT function 3.2 Cellular changes due to mHTT 3.3 Macroscopic changes due to mHTT 4 Diagnosis 4.1 Clinical 4.2 Genetic 4.3 Embryonic 4.4 Differential diagnosis 5 Management 6 Prognosis 7 Epidemiology 8 History 9 Society and culture 9.1 Ethics 9.2 Support organizations 9.3 Media depictions 10 Research directions 11 References 12 External links

[edit] Signs and symptoms

Huntington's disease is a neurodegenerative disorder.^[1] Symptoms can appear at any age,^[1] but most commonly the age of onset is between 35 and 44 years.^[5] The early stage of the disease involves subtle changes in personality, cognition, or physical skills.^[1] The physical symptoms are usually the first to be noticed, as cognitive and psychiatric symptoms are generally not severe enough to be recognized on their own at this stage.^[1] Almost everyone with Huntington's disease eventually exhibits all physical symptoms, but the onset, progression and extent of cognitive and psychiatric symptoms vary significantly between individuals.^{[10] [13]}

The most characteristic initial physical symptoms are jerky, random, and uncontrollable movements called chorea.^[1] Chorea may be initially exhibited as general restlessness, small unintentionally initiated or uncompleted motions, incoordination, or slowed saccadic eye movements.^[1] These minor motor abnormalities usually precede obvious signs of motor dysfunction by at least 3 years.^[10] The clear appearance of symptoms such as rigidity, repetitive motions or abnormal posturing appear as the disorder progresses.^[1] These symptoms are regarded as the onset stage of the disease, and gradually become the dominant physical symptoms.^[1] These are signs that the brain's psychomotor function is affected; this is the system that achieves a desired movement by using perceptual and spatial skills to send messages to the muscles.^[14] Psychomotor functions are increasingly impaired, such that any action that requires muscle control is affected, resulting in physical instability, abnormal facial expression, and difficulties chewing, swallowing and speaking.^[1] Eating difficulties commonly cause weight loss and may lead to malnutrition.^[15][16] Sleep disturbances are also associated symptoms.^[17] Juvenile HD differs from these symptoms, in that it generally progresses faster and chorea is exhibited briefly, if at all, with rigidity being the dominant symptom. Additionally, Seizures are a common symptom of this form of HD.^[1]

Reported prevalences of behavioral and psychiatric symptoms in HD^[18]

Depressed mood	33–69%
Anxiety	34–61%
Irritability	38–73%
Apathy	34–76%
Obsessive and compulsive	10–52%
Psychotic	3–11%

Cognitive abilities are impaired progressively.^[14] Especially affected are executive functions which include planning, cognitive flexibility, abstract thinking, rule acquisition, initiating appropriate actions and inhibiting inappropriate actions.^[14] As the disease progresses, memory deficits tend to appear. Reported impairments 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.^[14] Cognitive problems tend to worsen over time, leading ultimately to dementia.^[14] This pattern of deficits has been called a "subcortical dementia" syndrome to separate it from the typical effects of "cortical dementias" such as Alzheimer's disease.^[14]

Possible neuropsychiatric manifestations are 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.^[18] Difficulties in recognizing other people's negative expressions have also been observed.^[14] Prevalence of these symptoms is also highly variable between studies, with estimated rates for lifetime prevalence of psychiatric disorders between 33% and 76%.^[18] For many sufferers and their families these symptoms are among the most distressing aspects of the disease, heavily affecting daily functioning and often constituting reason for institutionalisation.^[18] Suicidal thoughts and suicide attempts are more common than in the general population.^[1]

[edit] Genetics

All humans have the Huntingtin gene, which provides the genetic code to produce the protein huntingtin, abbreviated to HTT. Part of this gene is a repeated section called a trinucleotide repeat, which varies in length between individuals and may change length between generations. When the length of this repeated section reaches a certain threshold, it produces an altered form of the protein, called mutant huntingtin protein or mHTT. The differing functions of these proteins are the cause of pathological changes which in turn cause the disease symptoms. The Huntington's disease mutation is genetically dominant, and the gene is not on a sex-linked chromosome; however, the scale of the changes in length can depend on the gender of the parent it is inherited from.^[1]

[edit] Genetic mutation

HD is one of several trinucleotide repeat disorders, caused by the length of a repeated section of a gene exceeding a normal range.^[1] HTT is located on the short arm of chromosome 4.^[1] HTT contains a sequence of three DNA bases—cytosine-adenine-guanine (CAG)—repeated multiple times (i.e. ...CAGCAGCAG...), known as a trinucleotide repeat.^[1] 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 a polyglutamine or polyQ tract, and the repeated part of the gene, the PolyQ region.^[19]

Classification of the trinucleotide repeat and the disease status of the person depending on the number of CAG repeats^[1]

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

Generally, people have less than 27 repeated glutamines in the polyQ.^[1] A polyQ region containing fewer than 36 glutamines results in production of the cytoplasmic protein Huntingtin.^[1] However, a sequence of 36 or more glutamines results in the production of a protein which has different characteristics.^[1] This altered form, called mHTT (mutant HTT), increases the decay rate of medium spiny neurons, affecting regions of the brain according to their reliance on them for normal functioning.^[1] 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.^[1] For example, 36–39 repeats result in much later onset and slower progression of symptoms than the mean, such that individuals may die of other causes before they manifest symptoms; this is termed "reduced penetrance".^[1] With very large repeat counts, HD can occur under the age of 20, when it is then referred to as juvenile HD, akinetic-rigid, or Westphal variant HD. This accounts for about 7% of HD carriers.^[6]

[edit] 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.^[1] 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). This probability is sex-independent.

Trinucleotide CAG repeats over 28 are unstable during replication and this instability increases with the number of repeats present.^[1] This usually leads to new expansions as generations pass (dynamic mutations) instead of reproducing an exact copy of the trinucleotide repeat.^[1] This causes 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.^[1] Such increase in the number of repeats (and hence earlier age of onset and severity of disease) in successive generations is known as genetic anticipation.^[1] Maternally inherited alleles are usually of a similar repeat length, whereas paternally inherited ones have a higher chance of increasing in length; therefore the anticipation phenomenon occurs only when the person transmitting HD is a male.^[1][20] This occurs because instability is greater in spermatogenesis than oogenesis.^[1] It is rare for Huntington's disease to be caused by a new mutation, where neither parent have over 36 CAG repeats.^[21]

Homozygous individuals, with two affected genes, are very rare except in large consanguineous families.^[22] For some time HD was thought to be the only disease for which homozygosity did not affect the expression of the disease,^[23] but it has since been found that it can affect the phenotype and the rate of progression.^[1][22] In identical twins their age of onset typically varies by years and clinical phenotypes can also differ.^[22]

[edit] Mechanism

The HTT protein interacts with over 100 other proteins, and appears to have multiple biological functions.^[24] The mutated mHTT protein behaves differently in ways that are not completely understood, and is toxic to certain types of cells. The brain is greatly affected, with damage initially in the striatum, and then later, as the disease progresses, in other brain areas as well. As the damage accumulates, symptoms associated with the functions of these brain areas appear, usually starting with symptoms that affect the planning and modulation of movement, which are the main functions of the striatum.^[1]

[edit] HTT function

HTT is expressed in all mammalian cells (including human), but the highest concentrations are found in the brain and testes; and moderate amounts in the liver, heart, and lungs.^[1] The function of HTT in humans is unclear: proteins it interacts with are involved in transcription, cell signaling and intracellular transporting.^[1][25] Its function in animal models is better known.^[26] In these models HTT has been shown to be important for development as its absence is related to embryonic death. It also acts as an anti-apoptotic agent preventing programmed cell death; controls the production of brain derived neurotrophic factor, a protein which protects neurons and regulates the neurogenesis of new ones; facilitates vesicular transport and synaptic transmission; and controls neuronal gene transcription.^[26] If HTT expression is increased, brain cell survival is improved and the effects of mHTT are reduced, whereas when HTT expression is reduced, the resulting characteristics are more typical of the presence of mHTT ^[26] In humans the disruption of the normal gene does not cause the disease.^[1] It is currently concluded that the disease is not caused by inadequate production of HTT, but by a gain of toxic function of mHTT.^[1]

[edit] Cellular changes due to mHTT

There are multiple cellular changes through which the toxic function of mHTT may manifest and produce the HD pathology.^[11] During the biological process of posttranslational modification of mHTT, cleavage of the protein can leave behind shorter fragments constituted of parts of the polyglutamine expansion.^[11] These fragments can then misfold and coalesce, in a process called protein aggregation, to form inclusion bodies within cells.^[11] Inclusion bodies have been found in both the nucleus and the cytoplasm of the cell.^[11] Inclusion bodies in cells of the brain are one of the earliest pathological changes, and some experiments have found that they can be toxic for the cell, but other experiments have shown that they may form as part of the body's defense mechanism and help protect cells.^[11] Several pathways by which mHTT may cause cell death have been identified, including effects on chaperone proteins, which help fold proteins and remove misfolded ones; interactions with caspases which play a role in the process of removing cells; the toxic effects of glutamate on nerve cells; impairment of energy production within cells; and effects on the expression of genes. A 2009 study shed new light on this question, by showing that the cytotoxic effects of mHTT are strongly enhanced by interactions with a protein called Rhes, which is expressed mainly in the striatum.^[27] Rhes was found to induce sumoylation of mHTT, which causes the protein clumps to disaggregate—studies in cell culture showed that the clumps were much less toxic than the disaggregated form.^[27]

[edit] Macroscopic changes due to mHTT

HD affects specific areas of the brain. The most prominent early effects are in a part of the basal ganglia called the striatum, which is composed of the caudate nucleus and putamen.^[1] Other areas affected include the substantia nigra, layers 3, 5 and 6 of the cerebral cortex, hippocampus, purkinje cells in the cerebellum, lateral tuberal nuclei of the hypothalamus and parts of the thalamus.^[1] These areas are affected according to their structure and the types of neurons they contain, reducing in size as they lose cells.^[1] Striatal spiny neurons are the most vulnerable, particularly ones with projections towards the external globus pallidus; interneurons and spiny cells projecting to the internal pallidum are less affected.^[1][28] HD also causes an abnormal increase in astrocytes.^[29]

The basal ganglia—the part of the brain most prominently affected in HD—play a key role in movement and behavior control. Their functions are not fully understood, but current theories propose that they are part of the cognitive executive system,^[14] and the motor circuit.^[1][30] Regarding motor function the basal ganglia ordinarily inhibit a large number of circuits that generate specific movements. To activate a particular motor behavior, the cerebral cortex sends a signal to the basal ganglia that causes the inhibition to be released. In HD, damage to the basal ganglia causes behaviors to be released in an erratic and uncontrollable way, or to be terminated before they have been completed.^[1][30] Depending on the precise distribution of damage, the intrusive behaviors may consist of complex patterns such as walking motions, simple movements such as twitching a limb, or many other combinations of motor elements.

[edit] Diagnosis

With the appearance of symptoms HD can be diagnosed clinically.^[1] Genetic testing can confirm if an individual carries an expanded copy of the gene, even before onset of symptoms, and can also be used for embryonic testing. Although the initial motivation for having a pre-symptomatic test is strong, the considered implications and relevance of having a confirmed diagnosis mean that less than 5% of individuals choose to do so.^[1]

[edit] Clinical

A physical, sometimes combined with a psychological examination can determine whether onset of the disease has begun.^[1] Excessive unintentional movements of any part of the body are often the reason for seeking medical consultation. If these are abrupt and have random timing and distribution, they suggest a diagnosis of HD. Rarely, cognitive or psychiatric symptoms may be the first diagnosed, but they are usually only recognized in hindsight or when they further develop. How far the disease has progressed can be measured using the Unified Huntington's disease rating scale (UHDRS), which provides an overall rating system based on motor, behavioral, cognitive, and functional assessments, but is primarily used for clinical trials.^[31][32] Functional neuroimaging techniques such as fMRI or PET can show changes in brain activity before symptom onset, but are rarely used. Other methods such as computerized tomography (CT) or magnetic resonance imaging (MRI) only show a visible volume reduction in the striatum in advanced stages.^[1]

[edit] Genetic

Because a child of a parent with HD has a 50% chance of inheriting the condition, there is a strong motivation to resolve the uncertainty. The genetic test for HD consists of a blood test which counts the numbers of CAG repeats in each of the HTT alleles.^[33] A positive result is not considered a diagnosis, since it may be obtained decades before onset of symptoms, however, a negative test means that the individual does not carry the expanded copy of the gene and will not develop HD.

A pre-symptomatic test is a life-changing event and a very personal decision.^[1] The main reason given for choosing testing for HD is to aid in career and family decisions; conversely, most individuals at-risk do not proceed with testing because there is no treatment.^[1] A key issue is the anxiety an individual experiences about not knowing whether they will some day develop HD, compared to the impact of a positive result.^[1] Irrespective of the result, stress levels have been found to be lower two years after being tested,^[1] but the risk of suicide is increased after a disease confirmation.^[1] Individuals found to have not inherited the disorder may experience survivor guilt with regard to family members who are affected.^[1] The possibility of discrimination and the implications of a positive result (which reveals a parent is carrying an affected gene and that siblings are at risk of inheriting it) are other factors taken into account when testing is being considered.^[1] Disclosure and confidentiality are emphasized, as individuals have the right to decide when and how to reveal their results.^[1] Genetic counseling in HD can provide information, advice and support for initial decision-making, and then, if chosen, throughout all stages of the testing process; ^[34] and has become a model for counselling in other dominant disorders.^{[8] [35]}

Guidelines on the use of genetic testing have been proposed with the aims of informing candidates of the implications for them and their relatives, excluding children and those with suicide risk, providing resources for support, and ensuring confidentiality.^[1][36]

[edit] Embryonic

Preimplantation genetic diagnosis can be used after in vitro fertilisation to choose an embryo that does not carry the affected gene is implanted and will therefore not be at risk of HD. It is possible to obtain a prenatal diagnosis for an embryo in the womb, which gives individuals who are not opposed to abortion the option of ensuring the disease will not be inherited.^[37]

[edit] Differential diagnosis

In a person with typical symptoms, and a family history of the disease, diagnosis is not usually complicated.^[1] Of all the genetic disorders that cause chorea, ninety percent are attributable to HD, while most of the remainder are collectively labeled HD-like (HDL).^[2] Genetic testing for HD confirms if the remaining ten percent of causes should be considered.^[1] The causes of most of these HDL diseases are unknown, but those that are have been found to be caused by mutations in the prion protein gene (HDL1), the junctophilin 3 gene (HDL2), a recessively inherited HTT gene (HDL3 — only found in one family and poorly understood), and the gene encoding the TATA box-binding protein (HDL4/SCA17).^[2]

[edit] Management

There is no cure for HD; available treatments offer relatively small symptomatic benefit and remain palliative in nature.^[1] As HD gradually renders people incapable of tending to their own needs, caregiving essentially is the treatment and must be carefully managed over the course of the disease.^[1]

Tetrabenazine, an orphan drug, is useful in the reduction of chorea,^[1] and was approved in 2008 for this use in the US.^[38] Other drugs that help to reduce it include neuroleptics and benzodiazepines.^[5] Compounds such as amantadine or remacemide are still under investigation but have shown preliminary positive results.^[1] Hypokinesia and rigidity can be treated with antiparkinsonians and myoclonic hyperkinesia with valproic acid.^[5]

Psychiatric symptoms can be treated with medications similar to those used in the general population.^[1] Selective serotonin reuptake inhibitors and mirtazapine for depression, and atypical antipsychotic drugs for psychosis and behavioural problems have been recommended, however more studies on the efficacy of these and other treatments are needed.^[39] Patients, their families, and individuals at risk of having HD may benefit from counselling.^[1]

Although there are relatively few studies of rehabilitation for HD 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.^[40] A multidisciplinary approach may be important to limit disability.^[41]

Nutrition management is important. Weight loss and eating difficulties due to dysphagia, as well as difficulty getting food into the mouth due to lack of muscle coordination are common as the disease advances.^[1] Thickening agents can be added to liquids as thicker fluids are easier and safer to swallow.^[1] Reminding the patient to eat slowly and to take smaller pieces of food into the mouth may also be of use to prevent choking.^[1] If eating becomes too hazardous or uncomfortable, the option of using a percutaneous endoscopic gastrostomy is available. This is a feeding tube, permanently attached through the abdomen into the stomach, which reduces the chance of aspirating food and provides better nutritional management.^[42]

[edit] Prognosis

The age of onset decreases, and the rate of progression of symptoms increases, with the number of CAG repeats.^[43] However there is a variation in age of onset for any given CAG repeat length: only 60% of the variation in age of onset is explained by the number of CAG repeats, with genes and environment also being important.^[1] Individuals with greater than approximately 60 CAG repeats often develop juvenile Huntington's disease.^[44]

The life expectancy is around 20 years following diagnosis.^[1] Mortality is not caused by Huntington’s disease directly, but by associated complications. The largest risk is pneumonia, which is the cause of one third of deaths. The risk of pneumonia increases as the ability to synchronise movements to clear the lungs is compromised and sometimes caused as a result of aspiration of food or drink. The other leading cause of death is heart disease, which causes almost a quarter of fatalities. Other associated risks include choking, physical injury from falls and malnutrition.^[1] Suicide is an associated risk, with increased suicide rates of up to 7.3%, and attempted suicides of up to 27%.^[45][46] Survival expectancy is similar in all regions independent of their economic development and the accessibility of treatment.^[1]

[edit] Epidemiology

HD is autosomal dominant. Because of the late age of symptom onset, it does not usually affect reproduction.^[1] The prevalence varies greatly geographically as a result of ethnicity, local migration and past immigration patterns; however it is similar for men and women. The rate of occurrence is highest in peoples of Western European descent, averaging around 7 per 100,000 people, but is relatively lower in the rest of the world, e.g. 1 per 1,000,000 people of Asian and African descent.^[1] Additionally, some localized areas have a much higher prevalence than their regional average.^[1] An example is in the isolated populations of the Lake Maracaibo region of Venezuela, which have prevalences of up to 700 per 100,000 and were studied to locate the marker for the gene.^[1][47] Other areas of high localization have been found in Tasmania and specific regions of Scotland, Wales and Sweden.^[48] Increased prevalence in some cases occurs according to a local founder effect; a historical migration of carriers into an area of geographic isolation.^[48][49] Some of these carriers have been traced back hundreds of years using genealogical studies.^[48] Genetic haplotypes can also give clues for the geographic variations of prevalence.^[48][50]

Since the discovery of a genetic test that can be used pre-symptomatically, estimates of the prevalence and incidence of the disorder are likely to increase. Without the test, only individuals displaying physical symptoms and a family history 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.^[48][51]

[edit] History

Until the 19th century Huntington's disease was grouped with numerous movement disorders, and as with many of these disorders, people with the condition may have been persecuted as witches or thought to be possessed by spirits, and shunned or exiled by society.^[52] For example a woman, named Elizabeth Knap, was judged in the Salem witch trials although she probably suffered from HD.^[53][54] Not all communties were so ignorant however, as the family that was cause for George Huntington's description were accepted by their local community, working all their lives until physically unable.^[55]

The first definite description of HD was in a letter by Charles Oscar Waters, published in the first edition of Robley Dunglison's Practice of Medicine in 1842. Waters described 'a form of chorea, vulgarly called magrums', this included accurate descriptions of the chorea, it's progression, and also highlighted the strong heredity of the disease^[56] In 1846 Charles Gorman observed how prevalence seemed to occur in localized regions.^[56] Both Gorman and Waters were students of Dungison at Jefferson Medical College.^[55] Independently, Johan Christian Lund also produced an early description in 1860.^[56] He specifically noted that in Setesdalen, a rather secluded area, there was a high prevalence of dementia associated with a pattern of jerking movement disorders that ran in families.^[57] The first widely recognized description was by George Huntington in 1872. Huntington was a third generation physician on Long Island. Examining the combined medical history of several generations of a family exhibiting similar symptoms, he realized their conditions must be linked and presented his detailed and accurate definition of the disease as his first paper.^[3][58] Sir William Osler was interested in the disorder and chorea in general, and was impressed with Huntington's paper, even wishing to reassess the family involved a decade later.^[56] Osler's interest in HD combined with his influence in medicine circles helped to spread knowledge of the disorder rapidly.^[56]

As Mendelian inheritance was being rediscovered at the turn of the century, HD was used tentatively as an example of autosomal dominant inheritence.^[56] Charles Davenport in 1911 made major contributions to early understanding of the disease, proving that it was indeed autosomal dominant, and proceeding to document most of the inheritance variabilities like age of onset. He also described the range of psychiatric and physical symptoms, providing much of the framework for following research.^[56] Davenport's interested was created by his college friend Smith Ely Jelliffe, who was intrigued by the strong inheritance pattern of the disease.^[55] Jellife collected information from across New York State and published several articles regarding the genealogy of HD in New England.^[59] This work was expanded upon in 1932 by P. R. Vessie, who traced about a thousand people with HD back to two brothers who left England in 1630, bound for Boston.^[60]

Research into the disorder continued progressively, and was given a major boost in 1983 when the US–Venezuela Huntington's Disease Collaborative Research Project discovered the approximate location of a causal gene.^[49] This was the result of an extensive study begun in 1979, focusing on the populations of isolated Venezuelan villages of Barranquitas and Lagunetas, where there was an unusually high prevalence of the disease. Among other innovations, the project developed DNA marking methods which were an important step in making the Human Genome Project possible.^[61] In 1993 the research group isolated the precise gene at 4p16.3;^[62] making this the first autosomal disease locus to be found using genetic linkage analysis.^[63] In the same time frame key discoveries concerning the mechanisms of the disorder were being made—for example, the finding by Anita Harding's research group that the length of the gene affected disease severity.^[64]

A transgenic mouse that could be made to exhibit HD, the R6 line, was developed in 1996. This enabled larger scale testing, and as the mouse's metabolism is faster and lifespan shorter, results could be obtained more quickly.^[65][66] These advancements, and the 1997 discovery that mHTT fragments misfold, led to the discovery of nuclear inclusions,^[67] which in turn led to increasingly extensive research into the interactions of HTT, mHTT, and mHTT fragments, potential drug treatments, care methods, and the gene itself.^[56][68][69]

[edit] Society and culture

[edit] Ethics

Huntington's disease has tested society's ethics in various ways. HD was one of the targets of the eugenics movement, in which Charles Davenport proposed in 1910 that compulsory sterilization and immigration control be used for people with certain diseases, including HD.^[70] 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.^[71][72] Financial institutions and businesses are faced with the question of whether to use results when assessing an individual, such as for life insurance or employment. Some countries' organizations have agreed not to use this information.^[73] As with other genetic conditions with later onset and no treatment, it is ethically questionable to perform pre-symptomatic testing for a child or adolescent.^[9][74][75] There are opponents against permitting testing until individuals are cognitively mature, and defenders of the parents' right to make the decision; with much greater acceptance of the former position.^[9][74][75] Testing a person under legal age who is not judged as competent is considered unethical in most cases.^[9][74][75] The balance of opinion would change with an effective treatment.^[9][74][75] Abortion after prenatal genetic testing with positive results and preimplantation genetic diagnosis in order to ensure that the disorder is not passed on are not free of ethical concerns.^[76] Finally, research with embryonic stem cells is controversial in any disease.^[77]

[edit] Support organizations

In 1968, after experiencing HD in his wife's family, Dr. Milton Wexler was inspired to start the Hereditary Disease Foundation (HDF); with the aim of curing genetic illness by coordinating and supporting research.^[12] The foundation; and especially his daughter, Nancy S. Wexler, were a key part of the research team in Venezuela which discovered the HD gene.^[12] Nancy Wexler is the current president of the Foundation.^[12] At the same time, Woody Guthrie's wife, Marjorie, had helped to found the Committee to Combat Huntington's Disease (now the Huntington's Disease Society of America), after his death from HD complications.^[78][78] Since then, lay organizations have been formed in many countries around the world and have helped to increase the awareness on HD. A number of these collaborate in larger organizations, like the International Huntington Association and the EuroHD network.^[79] Many support organizations hold an annual HD awareness event - some of which have been endorsed by their respective governments. For example, June 6 is designated "National Huntington's Disease Awareness Day" by the US senate.^[80]

[edit] Media depictions

The earliest references to HD in the popular media are made in Arlo Guthrie's 1969 film Alice's Restaurant^[81] and Jacqueline Susann's 1966 novel Valley of the Dolls. As awareness of HD has increased, so has the number of depictions in books, films and TV series, such as ER,^[82] Private Practice,^[83] Everwood,^[84] All Saints,^[85] House,^[86] and Steven T. Seagle's It's a Bird.^[87]

[edit] Research directions

Research into the mechanism has focused on identifying the functioning of HTT, how mHTT differs or interferes with it and the brain pathology that the disease produces.^[11] Most research is conducted in animals. Appropriate animal models are critical for understanding the fundamental mechanisms causing the disease and for supporting the early stages of drug development.^[1] Mice and monkeys, chemically induced to exhibit HD like symptoms were initially used,^[1][88][89] but they did not mimic the progressive features of the disease. Since the Huntingtin gene was identified, transgenic animals (mice,^[1][90][91] Drosophila fruit flies,^[1][92] and more recently monkeys^[93]) exhibiting HD-like syndromes can be generated by inserting a CAG repeat expansion into the gene. Nematode worms also provide a valuable model when the gene is expressed.^[1][94]

Genetically engineered intracellular antibody fragments called intrabodies have shown therapeutic results preventing larval and pupal mortality in drosophila models. Their mechanism of action was an inhibition of mHTT aggregation.^[1][95][96] As HD has been conclusively linked to a single gene, gene silencing is potentially possible. Researchers have investigated using gene knockdown of mHTT in mice as a potential treatment.^[1][97][98] Stem cell therapy is the replacement of damaged neurons by transplantation of stem cells into affected regions of the brain. Experiments have yielded some positive results in animal models and preliminary human clinical trials.^[99] All of these advances are at their first stages and there are important practical difficulties for the use of such techniques in humans.^[1][99]

Different drugs have also been reported to produce benefits in animals; some of them are being tested on humans in clinical trials at different stages of development.^[1] Examples of substances that have shown promise in initial experiments include creatine, coenzyme Q10 or the antibiotic minocycline.^[1]

[edit] References

[edit] External links

• DMOZ HD links directory at the Open Directory Project.
• 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

v • d • e WHO ICD-10 mental and behavioral 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, Elopement, Sundowning, Wandering) · Delirium · Post-concussion syndrome · Organic brain syndrome Psychoactive substance alcohol (acute alcohol intoxication, drunkenness, alcohol dependence, alcoholic hallucinosis, Alcohol withdrawal, delirium tremens, Korsakoff's syndrome, alcohol abuse) · opioids (opioid overdose, opioid dependency) · sedative/hypnotic (benzodiazepine overdose, benzodiazepine dependence, benzodiazepine withdrawal) · cocaine (cocaine dependence) · general (Intoxication/Drug overdose, Drug abuse, Physical dependence, Rebound effect, Withdrawal) Schizophrenia, schizotypal and delusional Psychosis (Schizoaffective disorder, Schizophreniform disorder, Brief reactive psychosis) · Schizophrenia (Disorganized schizophrenia, Delusional disorder, Folie à deux) · Personality disorder (Schizotypal personality disorder) Mood (affective) Mania · Bipolar disorder (Bipolar I, Bipolar II, Cyclothymia) · Depression (Major depressive disorder, Dysthymia, Seasonal affective disorder) Neurotic, stress-related and somatoform Anxiety disorder/ adjustment disorder phobic anxiety disorders: Agoraphobia · Social anxiety/Social phobia (Anthropophobia) · Specific phobia (Claustrophobia) Panic disorder/Panic attack · Generalized anxiety disorder · OCD · stress (Acute stress reaction, PTSD) Somatoform disorder Somatization disorder · Body dysmorphic disorder · Hypochondriasis · Nosophobia · Da Costa's syndrome · Psychalgia · Conversion disorder (Ganser syndrome, Globus pharyngis) · Neurasthenia Dissociative disorder Dissociative identity disorder · Psychogenic amnesia Physiological/physical behavioral Eating disorder Anorexia nervosa · Bulimia nervosa · Rumination syndrome Sleep disorder Dyssomnia (Hypersomnia, Insomnia) · Parasomnia (REM behavior disorder, Night terror) · Nightmare Sexual dysfunction Erectile dysfunction · Premature ejaculation · Vaginismus · Dyspareunia · Hypersexuality · Female sexual arousal disorder Postnatal Postpartum depression · Postnatal psychosis Adult personality and behavior Personality disorder · Impulse control disorder (Kleptomania, Trichotillomania, Pyromania) · Factitious disorder (Munchausen syndrome) · Ego-dystonic sexual orientation · Paraphilia (Voyeurism, Fetishism) Mental disorders diagnosed in childhood Mental retardation X-Linked mental retardation 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 · Rett syndrome · Asperger syndrome Behavioral and emotional ADHD · Conduct disorder (ODD) · emotional disorder (Separation anxiety disorder) · social functioning (Selective mutism, RAD, DAD) · Tic disorder (Tourette syndrome) · Speech (Stuttering, Cluttering) · Stereotypic movement disorder

v • d • e Pathology of the nervous system, primarily CNS (G00–G47, 320–349) Brain/ encephalopathy Inflammatory Encephalitis (Viral encephalitis, Herpesviral encephalitis) · Cavernous sinus thrombosis · Brain abscess (Amoebic) Degenerative Extrapyramidal and movement disorders Basal ganglia disease: Parkinsonism (Parkinson's disease, Postencephalitic parkinsonism)  · Neuroleptic malignant syndrome  · Pantothenate kinase-associated neurodegeneration · Progressive supranuclear palsy · Striatonigral degeneration · Hemiballismus · Huntington's disease · Olivopontocerebellar atrophy Dyskinesia: Dystonia (Spasmodic torticollis, Meige's, Blepharospasm) · Chorea (Choreoathetosis)  · Myoclonus (Myoclonic epilepsy) Essential tremor  · Restless legs  · Stiff person Dementia Alzheimer's (Early-onset)  · Frontotemporal dementia/Frontotemporal lobar degeneration (Pick's, Dementia with Lewy bodies) · Multi-infarct dementia Mitochondrial disease Leigh's Demyelinating autoimmune (Multiple sclerosis, Neuromyelitis optica, Schilder's disease) · hereditary (Adrenoleukodystrophy, Alexander, Canavan, Krabbe, ML, Pelizaeus-Merzbacher, VWM, MFC, CAMFAK syndrome) · Central pontine myelinolysis · Marchiafava-Bignami disease  · Alpers' Episodic/ paroxysmal Seizure/epilepsy Focal  · Generalised  · Status epilepticus  · Myoclonic epilepsy Headache Migraine (Familial hemiplegic)  · Cluster  · Vascular  · Tension Vascular Transient ischemic attack (Amaurosis fugax, Transient global amnesia) Cerebrovascular disease  · Stroke (MCA, ACA, PCA, Foville's, Millard-Gubler, Lateral medullary, Weber's, Lacunar stroke) Sleep disorders Insomnia  · Hypersomnia  · Sleep apnea (Obstructive, Ondine's curse)  · Narcolepsy  · Cataplexy  · Kleine-Levin  · Circadian rhythm sleep  · Delayed sleep phase  · Advanced sleep phase CSF Intracranial hypertension (Hydrocephalus/Normal pressure, Idiopathic intracranial hypertension) · Cerebral edema · Intracranial hypotension Other Brain herniation · Reye's  · Hepatic encephalopathy  · Toxic encephalopathy Spinal cord/ myelopathy Inflammatory Myelitis: Poliomyelitis · Demyelinating disease (Transverse myelitis) · Tropical spastic paraparesis Other Syringomyelia · Syringobulbia · Morvan's syndrome · Vascular myelopathy (Foix-Alajouanine syndrome) · Spinal cord compression Both/either Inflammatory Encephalomyelitis (Acute disseminated) Meningitis/Arachnoiditis: Bacterial (Tuberculous, Haemophilus, Pneumococcal) · Viral (Herpesviral) · Fungal (Cryptococcal) · Aseptic (Drug-induced) Meningoencephalitis Systemic atrophies SA Friedreich's ataxia · Ataxia telangiectasia MND UMN only: PLS · PP · HSP LMN only: PMA · PBP (Fazio-Londe, Infantile progressive bulbar palsy) · SMA (SMN-linked, Kennedy disease, SMAX2, DSMA1) both: ALS see also congenital, tumors

v • d • e Non-Mendelian inheritance: anticipation Trinucleotide repeat disorders Polyglutamine (PolyQ) Dentatorubral-pallidoluysian atrophy · Huntington's disease  · Kennedy disease · Spinocerebellar ataxia 1, 2, 3, 6, 7, 17 (Machado-Joseph disease) Non-Polyglutamine Fragile X syndrome · Friedreich's ataxia · Myotonic dystrophy type 1 · Spinocerebellar ataxia 8, 12 Four nucleotides Myotonic dystrophy type 2