Huntington's disease

Source: Wikipedia, the free encyclopedia.

Huntington's disease
Other namesHuntington's chorea
Supportive care[2]
MedicationTetrabenazine[3]
Prognosis15–20 years from onset of symptoms[4]
Frequency4–15 in 100,000 (European descent)[1]
Named afterGeorge Huntington

Huntington's disease (HD), also known as Huntington's chorea, is an incurable

gait often follow.[2] It is also a basal ganglia disease causing a hyperkinetic movement disorder known as chorea.[10][11] As the disease advances, uncoordinated, involuntary body movements of chorea become more apparent.[1] Physical abilities gradually worsen until coordinated movement becomes difficult and the person is unable to talk.[1][2] Mental abilities generally decline into dementia, depression, apathy, and impulsivity at times.[9][12][3] The specific symptoms vary somewhat between people.[1] Symptoms usually begin between 30 and 50 years of age, and can start at any age but are usually seen around the age of 40.[12][9][3][4] The disease may develop earlier in each successive generation.[1] About eight percent of cases start before the age of 20 years, and are known as juvenile HD, which typically present with the slow movement symptoms of Parkinson's disease rather than those of chorea.[3]

HD is typically

CAG repeats of cytosine-adenine-guanine (known as a trinucleotide repeat expansion) in the gene coding for the huntingtin protein results in an abnormal mutant protein (mHtt), which gradually damages brain cells through a number of possible mechanisms.[8][13] The mutant protein is dominant, so having one parent who is a carrier of the trait is sufficient to trigger the disease in their children. Diagnosis is by genetic testing, which can be carried out at any time, regardless of whether or not symptoms are present.[5] This fact raises several ethical debates: the age at which an individual is considered mature enough to choose testing; whether parents have the right to have their children tested; and managing confidentiality and disclosure of test results.[2]

No cure for HD is known, and full-time care is required in the later stages.

heart disease, and physical injury from falls reduce life expectancy; although fatal aspiration pneumonia is commonly cited as the ultimate cause of death for those with the condition.[14][12][3] Suicide is the cause of death in about 9% of cases.[3] Death typically occurs 15–20 years from when the disease was first detected.[4]

The earliest known description of the disease was in 1841 by American physician Charles Oscar Waters.[15] The condition was described in further detail in 1872 by American physician George Huntington.[15] The genetic basis was discovered in 1993 by an international collaborative effort led by the Hereditary Disease Foundation.[16][17] Research and support organizations began forming in the late 1960s to increase public awareness, provide support for individuals and their families and promote research.[17][18] Research directions include determining the exact mechanism of the disease, improving animal models to aid with research, testing of medications and their delivery to treat symptoms or slow the progression of the disease, and studying procedures such as stem-cell therapy with the goal of replacing damaged or lost neurons.[16]

Signs and symptoms

triad of motor, cognitive, and psychiatric symptoms.[19] When developed in an early stage, it is known as juvenile Huntington's disease.[20] In 50% of cases, the psychiatric symptoms appear first.[19] Their progression is often described in early stages, middle stages, and late stages with an earlier prodromal phase.[2] In the early stages, subtle personality changes, problems in cognition and physical skills, irritability, and mood swings occur, all of which may go unnoticed,[21][22] and these usually precede the motor symptoms.[23] Almost everyone with HD eventually exhibits similar physical symptoms, but the onset, progression, and extent of cognitive and behavioral symptoms vary significantly between individuals.[24][25]

The most characteristic initial physical symptoms are jerky, random, and uncontrollable movements called chorea.[10] Many people are not aware of their involuntary movements, or impeded by them.[1] Chorea may be initially exhibited as general restlessness, small unintentionally initiated or uncompleted motions, lack of coordination, or slowed saccadic eye movements.[26] These minor motor abnormalities usually precede more obvious signs of motor dysfunction by at least three years.[27] The clear appearance of symptoms such as rigidity, writhing motions, or abnormal posturing appear as the disorder progresses.[26] These are signs that the system in the brain that is responsible for movement has been affected.[28] Psychomotor functions become increasingly impaired, such that any action that requires muscle control is affected. When muscle control is affected such as rigidity or muscle contracture this is known as dystonia. Dystonia is a neurological hyperkinetic movement disorder that results in twisting or repetitive movements, that may resemble a tremor. Common consequences are physical instability, abnormal facial expression, and difficulties chewing, swallowing, and speaking.[26] Sleep disturbances and weight loss are also associated symptoms.[29] Eating difficulties commonly cause weight loss and may lead to malnutrition.[30][31] Weight loss is common in people with Huntington's disease, and it progresses with the disease. Juvenile HD generally progresses at a faster rate with greater cognitive decline, and chorea is exhibited briefly, if at all; the Westphal variant of slowness of movement, rigidity, and tremors is more typical in juvenile HD, as are seizures.[26][29]

Cognitive abilities are progressively impaired and tend to generally decline into

abstract thinking, rule acquisition, initiation of appropriate actions, and inhibition of inappropriate actions. Different cognitive impairments include difficulty focusing on tasks, lack of flexibility, a lack of impulse, a lack of awareness of one's own behaviors and abilities and difficulty learning or processing new information. 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.[28]

Reported

psychiatric disorders between 33 and 76%.[32] For many with the disease and their families, these symptoms are among the most distressing aspects of the disease, often affecting daily functioning and constituting reason for institutionalization.[32] Early behavioral changes in HD result in an increased risk of suicide.[10] Often, individuals have reduced awareness of chorea, cognitive, and emotional impairments.[33]

Mutant huntingtin is expressed throughout the body and associated with abnormalities in peripheral tissues that are directly caused by such expression outside the brain. These abnormalities include

impaired glucose tolerance, weight loss, osteoporosis, and testicular atrophy.[34]

Genetics

Everyone has two copies of the

transcript 15). Part of this gene is a repeated section called a trinucleotide repeat expansion – a short repeat, which varies in length between individuals, and may change length between generations. If the repeat is present in a healthy gene, a dynamic mutation may increase the repeat count and result in a defective gene. When the length of this repeated section reaches a certain threshold, it produces an altered form of the protein, called mutant huntingtin protein (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 almost fully penetrant; mutation of either of a person's HTT alleles causes the disease. It is not inherited according to sex, but by the length of the repeated section of the gene; hence its severity can be influenced by the sex of the affected parent.[26]

Genetic mutation

HD is one of several

codon) for the amino acid glutamine, so a series of them results in the production of a chain of glutamine known as a polyglutamine tract (or polyQ tract), and the repeated part of the gene, the polyQ region.[35]

Graphic showing at top normal range of repeats, and disease-causing range of repeats.
Classification of trinucleotide repeats, and resulting disease status, depending on the number of CAG repeats[26]
Repeat count Classification Disease status Risk to offspring
<27 Normal Will not be affected None
27–35 Intermediate Will not be affected Elevated, but <50%
36–39 Reduced Penetrance May or may not be affected 50%
40+ Full penetrance Will be affected 50%

Generally, people have fewer than 36 repeated glutamines in the polyQ region, which results in the production of the

neurons. Regions of the brain have differing amounts and reliance on these types of neurons and are affected accordingly.[26] Generally, the number of CAG repeats is related to how much this process is affected, and accounts for about 60% of the variation of the age of the onset of symptoms. The remaining variation is attributed to the environment and other genes that modify the mechanism of HD.[26] About 36 to 39 repeats result in a reduced-penetrance form of the disease, with a much later onset and slower progression of symptoms. In some cases, the onset may be so late that symptoms are never noticed.[26] With very large repeat counts (more than 60), HD onset can occur below the age of 20, known as juvenile HD. Juvenile HD is typically of the Westphal variant that is characterized by slowness of movement, rigidity, and tremors. This accounts for about 7% of HD carriers.[36][37]

Inheritance

autosomal dominant
fashion. The probability of each offspring inheriting an affected gene is 50%. Inheritance is independent of sex, and the phenotype does not skip generations.

Huntington's disease has

autosomal dominant inheritance, meaning that an affected individual typically inherits one copy of the gene with an expanded trinucleotide repeat (the mutant allele) from an affected parent.[26] Since the penetrance of the mutation is very high, those who have a mutated copy of the gene will have the disease. In this type of inheritance pattern, each offspring of an affected individual has a 50% risk of inheriting the mutant allele, so are affected with the disorder (see figure). This probability is sex-independent.[38] Sex-dependent or sex-linked genes are traits that are found on the X or Y chromosomes.[39]

Trinucleotide CAG repeats numbering over 28 are unstable during replication, and this instability increases with the number of repeats present.[26] This usually leads to new expansions as generations pass (dynamic mutations) instead of reproducing an exact copy of the trinucleotide repeat.[26] 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" (36–40), may pass on a copy of the gene with an increase in the number of repeats that produces fully penetrant HD.[26] The earlier age of onset and greater severity of disease in successive generations due to increases in the number of repeats is known as genetic anticipation.[1] Instability is greater in spermatogenesis than oogenesis;[26] maternally inherited alleles are usually of a similar repeat length, whereas paternally inherited ones have a higher chance of increasing in length.[26][40] Rarely is Huntington's disease caused by a new mutation, where neither parent has over 36 CAG repeats.[41]

In the rare situations where both parents have an expanded HD gene, the risk increases to 75%, and when either parent has two expanded copies, the risk is 100% (all children will be affected). Individuals with

both genes affected are rare. For some time, HD was thought to be the only disease for which possession of a second mutated gene did not affect symptoms and progression,[42] but it has since been found that it can affect the phenotype and the rate of progression.[26][43]

Mechanisms

Huntingtin protein interacts with over 100 other proteins, and appears to have multiple functions.

subcortical basal ganglia, initially in the striatum, but as the disease progresses, other areas of the brain are also affected, including regions of the cerebral cortex. Early symptoms are attributable to functions of the striatum and its cortical connections—namely control over movement, mood, and higher cognitive function.[26] DNA methylation also appears to be changed in HD.[45]

Huntingtin function

See also: Huntingtin § Function

Htt is

toxic gain-of-function of mHtt in the body.[26]

Cellular changes

inclusion body (stained orange) caused by HD, image width 250 μm

The toxic action of mHtt may manifest and produce the HD pathology through multiple cellular changes.

protein deposition diseases .[50] Over time, the aggregates accumulate to form inclusion bodies within cells, ultimately interfering with neuronal function.[13][48] Inclusion bodies have been found in both the cell nucleus and cytoplasm.[48] 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.[48]

Several pathways by which mHtt may cause cell death have been identified. These include 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 glutamine on nerve cells; impairment of energy production within cells; and effects on the expression of genes.[13][51]

Mutant huntingtin protein has been found to play a key role in

mitochondrial electron transport can result in higher levels of oxidative stress and release of reactive oxygen species.[52]

Glutamine is known to be

excitotoxic when present in large amounts, that can cause damage to numerous cellular structures. Excessive glutamine is not found in HD, but the interactions of the altered huntingtin protein with numerous proteins in neurons lead to an increased vulnerability to glutamine. The increased vulnerability is thought to result in excitotoxic effects from normal glutamine levels.[13]

Macroscopic changes

See also: Basal ganglia disease
dorsal striatum made up of the caudate nucleus and the putamen
.

Initially, damage to the brain is regionally specific with the

cortical layers 3, 5, and 6; also evident is involvement of the hippocampus, Purkinje cells in the cerebellum, lateral tuberal nuclei of the hypothalamus and parts of the thalamus.[26] These areas are affected according to their structure and the types of neurons they contain, reducing in size as they lose cells.[26] Striatal medium spiny neurons are the most vulnerable, particularly ones with projections towards the external globus pallidus, with interneurons and spiny cells projecting to the internal globus pallidus being less affected.[26][55] HD also causes an abnormal increase in astrocytes and activation of the brain's immune cells, microglia.[56]

The basal ganglia play a key role in movement and behavior control. Their functions are not fully understood, but theories propose that they are part of the cognitive

executive system[28] and the motor circuit.[57] The basal ganglia ordinarily inhibit a large number of circuits that generate specific movements. To initiate a particular movement, the cerebral cortex sends a signal to the basal ganglia that causes the inhibition to be released. Damage to the basal ganglia can cause the release or reinstatement of the inhibitions to be erratic and uncontrolled, which results in an awkward start to the motion or motions to be unintentionally initiated or in a motion to be halted before or beyond its intended completion. The accumulating damage to this area causes the characteristic erratic movements associated with HD known as chorea, a dyskinesia.[57] Because of the basal ganglia's inability to inhibit movements, individuals affected by it inevitably experience a reduced ability to produce speech and swallow foods and liquids (dysphagia).[58]

Transcriptional dysregulation

CREB-binding protein (CBP), a transcriptional coregulator, is essential for cell function because as a coactivator at a significant number of promoters, it activates the transcription of genes for survival pathways.[51] CBP contains an acetyltransferase domain to which HTT binds through its polyglutamine-containing domain.[59] Autopsied brains of those who had Huntington's disease also have been found to have incredibly reduced amounts of CBP.[60] In addition, when CBP is overexpressed, polyglutamine-induced death is diminished, further demonstrating that CBP plays an important role in Huntington's disease and neurons in general.[51]

Diagnosis

Diagnosis of the onset of HD can be made following the appearance of physical symptoms specific to the disease.[26] Genetic testing can be used to confirm a physical diagnosis if no family history of HD exists. Even before the onset of symptoms, genetic testing can confirm if an individual or embryo carries an expanded copy of the trinucleotide repeat (CAG) in the HTT gene that causes the disease. Genetic counseling is available to provide advice and guidance throughout the testing procedure and on the implications of a confirmed diagnosis. These implications include the impact on an individual's psychology, career, family-planning decisions, relatives, and relationships. Despite the availability of pre-symptomatic testing, only 5% of those at risk of inheriting HD choose to do so.[26]

Clinical

brain scan of a patient with HD, showing atrophy of the heads of the caudate nuclei, enlargement of the frontal horns of the lateral ventricles (hydrocephalus ex vacuo), and generalized cortical atrophy[61]

A

psychological examination, can determine whether the onset of the disease has begun.[26] 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. Cognitive or behavioral symptoms are rarely the first symptoms diagnosed; they are usually only recognized in hindsight or when they develop further. How far the disease has progressed can be measured using the unified Huntington's disease rating scale, which provides an overall rating system based on motor, behavioral, cognitive, and functional assessments.[62][63] Medical imaging, such as a CT scan or MRI scan, can show atrophy of the caudate nuclei early in the disease, as seen in the illustration to the right, but these changes are not, by themselves, diagnostic of HD. Cerebral atrophy can be seen in the advanced stages of the disease. Functional neuroimaging techniques, such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), can show changes in brain activity before the onset of physical symptoms, but they are experimental tools and are not used clinically.[26]

Predictive genetic testing

Because HD follows an autosomal dominant pattern of inheritance, a strong motivation exists for individuals who are at risk of inheriting it to seek a diagnosis. The genetic test for HD consists of a blood test, which counts the numbers of CAG repeats in each of the HTT alleles.

Cutoffs
are given as follows:

  • At 40 or more CAG repeats, full
    positive test" or "positive result" generally refers to this case. A positive result is not considered a diagnosis, since it may be obtained decades before the symptoms begin. However, a negative test means that the individual does not carry the expanded copy of the gene and will not develop HD.[26] The test will tell a person who originally had a 50% chance of inheriting the disease if their risk goes up to 100% or is eliminated. Persons who test positive for the disease will develop HD sometime within their lifetimes, provided they live long enough for the disease to appear.[26]
  • At 36 to 39 repeats, incomplete or reduced penetrance allele (RPA) may cause symptoms, usually later in the adult life.[65] The maximum risk is 60% that a person with an RPA will be symptomatic at age 65, and 70% at 75.[65]
  • At 27 to 35 repeats, intermediate allele (IA), or large normal allele, is not associated with symptomatic disease in the tested individual, but may expand upon further inheritance to give symptoms in offspring.[65]
  • With 26 or fewer repeats, the result is not associated with HD.[65]

Testing before the onset of symptoms is a life-changing event and a very personal decision.[26] The main reason given for choosing to test for HD is to aid in career and family decisions.[26] Predictive testing for Huntington's disease has been available via linkage analysis (which requires testing multiple family members) since 1986 and via direct mutation analysis since 1993.[66] At that time, surveys indicated that 50–70% of at-risk individuals would have been interested in receiving testing, but since predictive testing has been offered far fewer choose to be tested.[67] Over 95% of individuals at risk of inheriting HD do not proceed with testing, mostly because it has no treatment.[26] A key issue is the anxiety an individual experiences about not knowing whether they will eventually develop HD, compared to the impact of a positive result.[26] Irrespective of the result, stress levels are lower two years after being tested, but the risk of suicide is increased after a positive test result.[26] Individuals found to have not inherited the disorder may experience survivor guilt about family members who are affected.[26] Other factors taken into account when considering testing include the possibility of discrimination and the implications of a positive result, which usually means a parent has an affected gene and that the individual's siblings will be at risk of inheriting it.[26] In one study, genetic discrimination was found in 46% of individuals at risk for Huntington's disease. It occurred at higher rates within personal relationships than health insurance or employment relations.[68] 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.[69] Because of the implications of this test, patients who wish to undergo testing must complete three counseling sessions which provide information about Huntington's.[70]

Counseling and guidelines on the use of genetic testing for HD have become models for other genetic disorders, such as autosomal dominant

polycystic kidney disease, familial Alzheimer's disease and breast cancer.[71] The European Molecular Genetics Quality Network have published yearly external quality assessment scheme for molecular genetic testing for this disease and have developed best practice guidelines for genetic testing for HD to assist in testing and reporting of results.[73]

Preimplantation genetic diagnosis

Embryos produced using in vitro fertilization may be genetically tested for HD using preimplantation genetic diagnosis. This technique, where one or two cells are extracted from a typically 4- to 8-cell embryo and then tested for the genetic abnormality, can then be used to ensure embryos affected with HD genes are not implanted, so any offspring will not inherit the disease. Some forms of preimplantation genetic diagnosis—non-disclosure or exclusion testing—allow at-risk people to have HD-free offspring without revealing their own parental genotype, giving no information about whether they themselves are destined to develop HD. In exclusion testing, the embryo's DNA is compared with that of the parents and grandparents to avoid inheritance of the chromosomal region containing the HD gene from the affected grandparent. In nondisclosure testing, only disease-free embryos are replaced in the uterus while the parental genotype and hence parental risk for HD are never disclosed.[74][75]

Prenatal testing

Obtaining a

termination of pregnancy, and on the difficulties of a child with the identified gene.[77][78]

In addition, in at-risk pregnancies due to an affected male partner, noninvasive prenatal diagnosis can be performed by analyzing cell-free fetal DNA in a blood sample taken from the mother (via venipuncture) between six and 12 weeks of pregnancy.[65] It has no procedure-related risk of miscarriage.[65]

Differential diagnosis

About 99% of HD diagnoses based on the typical symptoms and a

chorea acanthocytosis and pantothenate kinase-associated neurodegeneration. One X-linked disorder of this type is McLeod syndrome.[79]

Management

Illustration from a case report in 1977 of a person with Huntington's disease

Treatments are available to reduce the severity of some HD symptoms.

speech therapy.[26]

Therapy

Weight loss and problems in eating due to

speech-language pathologists with experience in Huntington's disease is recommended.[26]

People with Huntington's disease may see a

rehabilitation interventions are prevention of loss of function. Participation in rehabilitation programs during the early to middle stage of the disease may be beneficial as it translates into long-term maintenance of motor and functional performance. Rehabilitation during the late stage aims to compensate for motor and functional losses.[84] For long-term independent management, the therapist may develop home exercise programs for appropriate people.[85]

Additionally, an increasing number of people with HD are turning to palliative care, which aims to improve quality of life through the treatment of the symptoms and stress of serious illness, in addition to their other treatments.[86]

Medications

diagram showing 19 carbon, 27 hydrogen, 3 oxygen and 1 nitrogen atom bonded together
Chemical structure of tetrabenazine, an approved compound for the management of chorea in HD

off label", tetrabenazine was the first approved treatment for Huntington's disease in the U.S. The compound has been known since the 1950s. An alternative to tetrabenazine is amantadine but there is limited evidence for its safety and efficacy.[88]

Other drugs that help to reduce chorea include

valproic acid.[22] Tentative evidence has found ethyl eicosapentaenoic acid to improve motor symptoms at one year.[89] In 2017, deutetrabenazine, a heavier form of tetrabenazine medication for the treatment of chorea in HD, was approved by the FDA.[90]
This is marketed as Austedo.

Psychiatric symptoms can be treated with medications similar to those used in the general population.[26][81] Selective serotonin reuptake inhibitors and mirtazapine have been recommended for depression, while atypical antipsychotics are recommended for psychosis and behavioral problems.[81] Specialist neuropsychiatric input is recommended since people may require long-term treatment with multiple medications in combination.[26]

Plant-based medications

There has been a number of alternative therapies experimented in ayurvedic medicine with plant-based products, although none have provided good evidence of efficacy. A recent study showed that the stromal processing peptidase (SPP), a synthetic enzyme found in plant chloroplasts, prevented the aggregation of proteins associated with Huntington's disease.[91] However, repeat studies and clinical validation are needed to confirm its true therapeutic potential.

Education

The families of individuals, and society at large, who have inherited or are at risk of inheriting HD have generations of experience of HD but may be unaware of recent breakthroughs in understanding the disease, and of the availability of genetic testing. Genetic counseling benefits these individuals by updating their knowledge, seeking to dispel any unfounded beliefs that they may have, and helping them consider their future options and plans. The Patient Education Program for Huntington's Disease has been created to help educate family members, caretakers, and those diagnosed with Huntington's disease.[92] Also covered is information concerning family planning choices, care management, and other considerations.[26][93]

Prognosis

The length of the trinucleotide repeat accounts for 60% of the variation of the age of symptoms onset and their rate of progress. A longer repeat results in an earlier age of onset and a faster progression of symptoms.[26][94] Individuals with more than sixty repeats often develop the disease before age 20, while those with fewer than 40 repeats may remain asymptomatic.[95] The remaining variation is due to environmental factors and other genes that influence the mechanism of the disease.[26]

Life expectancy in HD is generally around 10 to 30 years following the onset of visible symptoms.

heart disease, which causes almost a quarter of fatalities of those with HD.[96] Suicide is the third greatest cause of fatalities, with 7.3% of those with HD taking their own lives and up to 27% attempting to do so. To what extent suicidal thoughts are influenced by behavioral symptoms is unclear, as they signify a desire to avoid the later stages of the disease.[97][98][99] Suicide is the greatest risk of this disease before the diagnosis is made and in the middle stages of development throughout the disease. Other associated risks include choking; due to the inability to swallow, physical injury from falls, and malnutrition.[96][20]

Epidemiology

The late onset of Huntington's disease means it does not usually affect reproduction.

geographic isolation.[99][104] Some of these carriers have been traced back hundreds of years using genealogical studies.[99] Genetic haplotypes can also give clues for the geographic variations of prevalence.[99][105] Iceland, on the contrary, has a rather low prevalence of 1 per 100,000, despite the fact that Icelanders as a people are descended from the early Germanic tribes of Scandinavia which also gave rise to the Swedes; all cases with the exception of one going back nearly two centuries having derived from the offspring of a couple living early in the 19th century.[106] Finland, as well, has a low incidence of only 2.2 per 100,000 people.[107]

Until the discovery of a genetic test, statistics could only include

clinical diagnosis based on physical symptoms and a family history of HD, excluding those who died of other causes before diagnosis. These cases can now be included in statistics; and, as the test becomes more widely available, estimates of the prevalence and incidence of the disorder are likely to increase.[99][108]

History

On the right is a young man, dressed in suit and tie, sporting a moustache and tuft of hair on the chin; on the left is the top half of a medical journal titled 'Medical and Surgical Reporter'
In 1872, George Huntington described the disorder in his first paper "On Chorea" at the age of 22.[109]

In centuries past, various kinds of chorea were at times called by names such as Saint Vitus' dance, with little or no understanding of their cause or type in each case.

The first definite mention of HD was in a letter by

Setesdalen, a secluded mountain valley in Norway, the high prevalence of dementia was associated with a pattern of jerking movement disorders that ran in families.[114]

The first thorough description of the disease was by George Huntington in 1872. Examining the combined medical history of several generations of a family exhibiting similar symptoms, he realized their conditions must be linked; he presented his detailed and accurate definition of the disease as his first paper. Huntington described the exact pattern of inheritance of autosomal dominant disease years before the rediscovery by scientists of Mendelian inheritance.

Of its hereditary nature. When either or both the parents have shown manifestations of the disease ... one or more of the offspring almost invariably suffer from the disease ... But if by any chance these children go through life without it, the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the disease.[109][115]

Sir William Osler was interested in the disorder and chorea in general, and was impressed with Huntington's paper, stating, "In the history of medicine, there are few instances in which a disease has been more accurately, more graphically or more briefly described."[116][111][117] Osler's continued interest in HD, combined with his influence in the field of medicine, helped to rapidly spread awareness and knowledge of the disorder throughout the medical community.[111] Great interest was shown by scientists in Europe, including Louis Théophile Joseph Landouzy, Désiré-Magloire Bourneville, Camillo Golgi, and Joseph Jules Dejerine, and until the end of the century, much of the research into HD was European in origin.[111] By the end of the 19th century, research and reports on HD had been published in many countries and the disease was recognized as a worldwide condition.[111]

During the rediscovery of Mendelian inheritance at the turn of the 20th century, HD was used tentatively as an example of autosomal dominant inheritance.

eugenic bias of Muncey's, Davenport's, and Vessie's work contributed to misunderstandings and prejudice about HD.[113] Muncey and Davenport also popularized the idea that in the past, some with HD may have been thought to be possessed by spirits or victims of witchcraft, and were sometimes shunned or exiled by society.[122][123] This idea has not been proven. Researchers have found contrary evidence; for instance, the community of the family studied by George Huntington openly accommodated those who exhibited symptoms of HD.[113][122]

The search for the cause of this condition was enhanced considerably in 1968, when the

psychoanalyst based in Los Angeles, California, whose wife Leonore Sabin had been diagnosed earlier that year with Huntington's disease.[124]
The three brothers of Wexler's wife also had this disease.

The foundation was involved in the recruitment of more than 100 scientists in the US-Venezuela Huntington's Disease Collaborative Project, which over a 10-year period from 1979, worked to locate the genetic cause.

autosomal disease locus found using genetic linkage analysis.[126][127] Among other innovations, the project developed DNA-marking methods which were an important step in making the Human Genome Project possible.[125]

In the same time, key discoveries concerning the mechanisms of the disorder were being made, including the findings by Anita Harding's research group on the effects of the gene's length.[128]

Modelling the disease in various types of animals, such as the

transgenic mouse developed in 1996, enabled larger-scale experiments. As these animals have faster metabolisms and much shorter lifespans than humans results from experiments are received sooner, speeding research. The 1997 discovery that mHtt fragments misfold led to the discovery of the nuclear inclusions they cause. These advances have led to increasingly extensive research into the proteins involved with the disease, potential drug treatments, care methods, and the gene itself.[111][129]

The networks of care and support that had developed in Venezuela and Colombia during the research projects there in the 1970s through 2000s were eventually eroded by various forces, such as the ongoing crisis in Venezuela and the death of a lead researcher in Colombia (Jorge Daza Barriga).[130] Doctors are working toward rekindling these networks because the people who have contributed to the science of Huntington's disease by participating in these studies deserve adequate follow-up care; societies elsewhere in the world who benefit from the scientific advances thus achieved owe at least that much to those who participated in the research.[130]

The condition was formerly called Huntington's chorea, but this term has been replaced by Huntington's disease because not all patients develop chorea and due to the importance of cognitive and behavioral problems.[131]

Society and culture

See also:
List of Huntington's disease media depictions

Ethics

See also: In vitro fertilisation § Ethics, and Stem cell controversy

embryonic stem cells.[133][134]

The development of an accurate diagnostic test for Huntington's disease has caused social, legal, and ethical concerns over access to and use of a person's results.[135][136] Many guidelines and testing procedures have strict procedures for disclosure and confidentiality to allow individuals to decide when and how to receive their results and also to whom the results are made available.[26] Insurance companies and businesses are faced with the question of whether to use genetic test results when assessing an individual, such as for life insurance or employment. The United Kingdom's insurance companies agreed with the Department of Health and Social Care that until 2017 customers would not need to disclose predictive genetics tests to them, but this agreement explicitly excluded the government-approved test for Huntington's when writing policies with a value over £500,000.[137][138] As with other untreatable genetic conditions with a later onset, it is ethically questionable to perform presymptomatic testing on a child or adolescent since there would be no medical benefit for that individual. There is consensus for testing only individuals who are considered cognitively mature, although there is a counter-argument that parents have a right to make the decision on their child's behalf. With the lack of effective treatment, testing a person under legal age who is not judged to be competent is considered unethical in most cases.[49][139][140]

There are ethical concerns related to

prenatal genetic testing or preimplantation genetic diagnosis to ensure a child is not born with a given disease.[141] For example, prenatal testing raises the issue of selective abortion, a choice considered unacceptable by some.[141] As it is a dominant disease, there are difficulties in situations in which a parent does not want to know his or her own diagnosis. This would require parts of the process to be kept secret from the parent.[141]

Support organizations

A black-and-white photograph taken indoors of Woody Guthrie wearing pinstripe trousers, a tartan shirt with the top button undone, and a cap. He sits playing a six-string acoustic guitar, which is supported on one knee, and he appears to be singing. 'This Machine Kills Fascists' is written in all capital letters on a rectangular sticker, which is fixed onto the guitar.
The death of Woody Guthrie led to the foundation of the Committee to Combat Huntington's Disease

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 illnesses by coordinating and supporting research.[17] The foundation and Wexler's daughter, Nancy Wexler, were key parts of the research team in Venezuela which discovered the HD gene.[17]

At roughly the same time as the HDF formed, Marjorie Guthrie helped to found the committee to Combat Huntington's Disease (now the Huntington's Disease Society of America), after her husband, folk singer-songwriter Woody Guthrie died from complications of HD.[18]

Since then, support and research organizations have formed in many countries around the world and have helped to increase public awareness of HD. A number of these collaborate in umbrella organizations, like the International Huntington Association and the European HD network.[142] Many support organizations hold an annual HD awareness event, some of which have been endorsed by their respective governments. For example, 6 June is designated "National Huntington's Disease Awareness Day" by the US Senate.[143] Many organizations exist to support and inform those affected by HD, including the Huntington's Disease Association in the UK. The largest funder of research is provided by the Cure Huntington's Disease Initiative Foundation (CHDI).[144]

Research directions

Research into the mechanism of HD is focused on identifying the functioning of Htt, how mHtt differs or interferes with it, and the brain pathology that the disease produces.

neurodegeneration and HD-like symptoms.[129]

Research is being conducted using many approaches to either prevent Huntington's disease or slow its progression.

phosphodiesterase inhibitors.[146][147]

The CHDI Foundation funds a great many research initiatives providing many publications.[148] The CHDI foundation is the largest funder of Huntington's disease research globally and aims to find and develop drugs that will slow the progression of HD.[144][149] CHDI was formerly known as the High Q Foundation. In 2006, it spent $50 million on Huntington's disease research.[144] CHDI collaborates with many academic and commercial laboratories globally and engages in oversight and management of research projects as well as funding.[150]

Reducing huntingtin production

Gene splicing techniques are being looked at to try to repair a genome with the erroneous gene that causes HD, using tools such as CRISPR/Cas9.[147]

Increasing huntingtin clearance

Another strategy to reduce the level of mutant huntingtin is to increase the rate at which cells are able to clear it.[162] As mHtt (and many other protein aggregates) are degraded by autophagy, increasing the rate of autophagy has the potential to reduce levels of mHtt and thereby ameliorate disease.[163] Pharmacological and genetic inducers of autophagy have been tested in a variety of Huntington's disease models; many have been shown to reduce mHtt levels and decrease toxicity.[162]

Improving cell survival

Among the approaches aimed at improving cell survival in the presence of mutant huntingtin are correction of

synapses.[151]

Neuronal replacement

Stem-cell therapy is used to replace damaged neurons by transplantation of stem cells into affected regions of the brain. Experiments in animal models (rats and mice only) have yielded positive results.[164]

Whatever their future therapeutic potential, stem cells are already a valuable tool for studying Huntington's disease in the laboratory.[165]

Ferroptosis

ALOX5-mediated ferroptosis acts as a cell death pathway upon oxidative stress in Huntington's disease.[166]
Inhibitors of ferroptosis are protective in models of degenerative brain disorders, including Parkinson's, Huntington's, and Alzheimer's Diseases.[166]

Clinical trials

In 2020, there were 197

dimebon.[168]

See also

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External links

Retrieved from "https://en.wikipedia.org/w/index.php?title=Huntington%27s_disease&oldid=1227397506"