vania-janet/multiturn-rag-retrieval-data huggingface dataset:
Huntington's disease
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 , but it has since been found that it can affect the phenotype and the rate of progression .
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 . The foundation and Wexler 's daughter , Nancy Wexler , were key parts of the research team in Venezuela which discovered the HD gene .
Huntington's disease
The late onset of Huntington 's disease means it does not usually affect reproduction . The worldwide prevalence of HD is 5 -- 10 cases per 100,000 persons , but varies greatly geographically as a result of ethnicity , local migration and past immigration patterns . Prevalence 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 , and is lower in the rest of the world ; e.g. , one per million people of Asian and African descent . A 2013 epidemiological study of the prevalence of Huntington 's disease in the UK between 1990 and 2010 found that the average prevalence for the UK was 12.3 per 100,000 . Additionally , some localized areas have a much higher prevalence than their regional average . One of the highest incidences is in the isolated populations of the Lake Maracaibo region of Venezuela , where HD affects up to 700 per 100,000 persons . Other areas of high localization have been found in Tasmania and specific regions of Scotland , Wales and Sweden . Increased prevalence in some cases occurs due to a local founder effect , a historical migration of carriers into an area of geographic isolation . Some of these carriers have been traced back hundreds of years using genealogical studies . Genetic haplotypes can also give clues for the geographic variations of prevalence . Iceland , on the contrary , has a rather low prevalence of 1 per 100,000 , despite the fact that Icelanders as a people are descended of 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 . Finland , as well , has a low incidence of only 2.2 per 100,000 people .
Huntington's disease
The search for the cause of this condition was enhanced considerably in 1968 , when the Hereditary Disease Foundation ( HDF ) was created by Milton Wexler , a psychoanalyst based in Los Angeles , California , whose wife Leonore Sabin had been diagnosed earlier that year with Huntington 's disease . The three brothers of Wexler 's wife also suffered from this disease . The foundation was involved in the recruitment of over 100 scientists in the Huntington 's Disease Collaborative Research Project who over a 10 - year period worked to locate the responsible gene .
Huntington's disease
All humans have two copies of the Huntingtin gene ( HTT ) , which codes for the protein Huntingtin ( HTT ) . The gene is also called HD and IT15 , which stands for ' interesting transcript 15 ' . Part of this gene is a repeated section called a trinucleotide 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 the length of the repeated section of the gene and hence its severity can be influenced by the sex of the affected parent .
Huntington's disease
Cognitive abilities are progressively impaired . Especially affected are executive functions , which include planning , cognitive flexibility , abstract thinking , rule acquisition , initiation of appropriate actions , and inhibition of inappropriate actions . 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 . Cognitive problems tend to worsen over time , ultimately leading to dementia . This pattern of deficits has been called a subcortical dementia syndrome to distinguish it from the typical effects of cortical dementias e.g. Alzheimer 's disease .
Huntington's disease
HD is one of several trinucleotide repeat disorders which are caused by the length of a repeated section of a gene exceeding a normal range . The HTT gene is located on the short arm of chromosome 4 at 4p16. 3 . HTT contains a sequence of three DNA bases -- cytosine - adenine - guanine ( CAG ) -- repeated multiple times ( i.e. ... CAGCAGCAG ... ) , known as a trinucleotide repeat . CAG is the 3 - letter genetic code ( 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 .
Huntington's disease
Testing before the onset of symptoms is a life - changing event and a very personal decision . The main reason given for choosing testing for HD is to aid in career and family decisions . Before 1993 there was not an available test for individuals to learn if they carried the Huntington 's gene . 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 . Over 95 % of individuals at risk of inheriting HD do not proceed with testing , mostly because there is no treatment . 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 . Irrespective of the result , stress levels have been found to be lower two years after being tested , but the risk of suicide is increased after a positive test result . Individuals found to have not inherited the disorder may experience survivor guilt with regard to family members who are affected . 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 . 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 . 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 . Because of the implications of this test , patients who wish to undergo testing must complete three counseling sessions which provide information about Huntington 's .
Huntington's disease
Reported neuropsychiatric manifestations are anxiety , depression , a reduced display of emotions ( blunted affect ) , egocentrism , aggression , and compulsive behavior , the latter of which can cause or worsen addictions , including alcoholism , gambling , and hypersexuality . Difficulties in recognizing other people 's negative expressions have also been observed . The prevalence of these symptoms is highly variable between studies , with estimated rates for lifetime prevalence of psychiatric disorders between 33 % and 76 % . For many sufferers and their families , these symptoms are among the most distressing aspects of the disease , often affecting daily functioning and constituting reason for institutionalization . Suicidal thoughts and suicide attempts are more common than in the general population . Often individuals have reduced awareness of chorea , cognitive and emotional impairments .
Huntington's disease
Trinucleotide CAG repeats over 28 are unstable during replication , and this instability increases with the number of repeats present . This usually leads to new expansions as generations pass ( dynamic mutations ) instead of reproducing an exact copy of the trinucleotide repeat . 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 . Such increases in the number of repeats ( and hence earlier age of onset and severity of disease ) in successive generations is known as genetic anticipation . Instability is greater in spermatogenesis than oogenesis ; maternally inherited alleles are usually of a similar repeat length , whereas paternally inherited ones have a higher chance of increasing in length . It is rare for Huntington 's disease to be caused by a new mutation , where neither parent has over 36 CAG repeats .
Huntington's disease
Thanks to the HDF , the ongoing US - Venezuela Huntington 's Disease Collaborative Research Project was started in 1979 , and reported a major breakthrough in 1983 with the discovery of the approximate location of a causal gene . This was the result of an extensive study focusing on the populations of two isolated Venezuelan villages , Barranquitas and Lagunetas , where there was an unusually high prevalence of the disease . It involved over 18,000 people -- mostly from a single extended family .
Huntington's disease
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 . 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 . Financial institutions 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 have agreed that until 2017 they will not use genetic information when writing insurance policies under GB £ 500,000 , but Huntington 's is explicitly excluded from this agreement . As with other untreatable genetic conditions with a later onset , it is ethically questionable to perform pre-symptomatic testing on a child or adolescent , as 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 an effective treatment , testing a person under legal age who is not judged to be competent is considered unethical in most cases .
Huntington's disease
Generally , people have fewer than 36 repeated glutamines in the polyQ region which results in production of the cytoplasmic protein Huntingtin . However , a sequence of 36 or more glutamines results in the production of a protein which has different characteristics . This altered form , called mutant huntingtin ( mHTT ) , increases the decay rate of certain types of neurons . Regions of the brain have differing amounts and reliance on these types of neurons , and are affected accordingly . 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 environment and other genes that modify the mechanism of HD . 36 -- 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 . With very large repeat counts , HD has full penetrance and 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 .
Huntington's disease
There are ethical concerns related to prenatal genetic testing or preimplantation genetic diagnosis to ensure a child is not born with a given disease . For example , prenatal testing raises the issue of selective abortion , a choice considered unacceptable by some . 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 .
Huntington's disease
Among other innovations , the project developed DNA - marking methods which were an important step in making the Human Genome Project possible . In 1993 , the research group isolated the precise causal gene at 4p16. 3 , making this the first autosomal disease locus found using genetic linkage analysis .
Huntington's disease
Research into the mechanism of HD has focused on identifying the functioning of HTT , how mHTT differs or interferes with it , and the brain pathology that the disease produces . Research is conducted using in vitro methods , animal models and human volunteers . Animal models are critical for understanding the fundamental mechanisms causing the disease and for supporting the early stages of drug development . Animals with chemically induced brain injury exhibit HD - like symptoms and were initially used , but they did not mimic the progressive features of the disease . The identification of the causative gene has enabled the development of many transgenic animal models including nematode worms , Drosophila fruit flies , mice , rats , sheep , pigs and monkeys that express mutant huntingtin and develop progressive neurodegeneration and HD - like symptoms .
Huntington's disease
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 .
Huntington's disease
Gene silencing aims to reduce the production of the mutant protein , since HD is caused by a single dominant gene encoding a toxic protein . Gene silencing experiments in mouse models have shown that when the expression of mHTT is reduced , symptoms improve . Safety of non-allele specific RNAi and ASO gene silencing has now been demonstrated in mice and the large , human - like brains of primates . Allele - specific silencing attempts to silence mutant HTT while leaving wild - type HTT untouched . One way of accomplishing this is to identify polymorphisms present on only one allele and produce gene silencing drugs that target polymorphisms in only the mutant allele . The first ' gene silencing ' trial involving human HD patients began in 2015 , testing the safety of IONIS - HTTRx , produced by Ionis Pharmaceuticals and led by UCL Institute of Neurology . Mutant huntingtin was detected and quantified for the first time in cerebrospinal fluid from Huntington 's disease mutation - carriers in 2015 using a novel ' single - molecule counting ' immunoassay , providing a direct way to assess whether huntingtin - lowering treatments are achieving the desired effect . Similarly , 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 .
Huntington's disease
Embryos produced using in vitro fertilization may be genetically tested for HD using preimplantation genetic diagnosis ( PGD ) . 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 , and therefore 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 embryos ' 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 non-disclosure testing , only disease - free embryos are replaced in the uterus while the parental genotype and hence parental risk for HD are never disclosed .
Huntington's disease
Symptoms of Huntington 's disease most commonly become noticeable between the ages of 35 and 44 years , but they can begin at any age from infancy to old age . In the early stages , there are subtle changes in personality , cognition , and physical skills . The physical symptoms are usually the first to be noticed , as cognitive and behavioral symptoms are generally not severe enough to be recognized on their own at the earlier stages . Almost everyone with Huntington 's disease eventually exhibits similar physical symptoms , but the onset , progression and extent of cognitive and behavioral symptoms vary significantly between individuals .
Huntington's disease
A physical examination , sometimes combined with a psychological examination , can determine whether the onset of the disease has begun . 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 . Medical imaging , such as computerized tomography ( CT ) and magnetic resonance imaging ( MRI ) , 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 .
Huntington's disease
The largest funder of Huntington 's disease research globally , in terms of financial expenditure , is the CHDI Foundation , a US non-profit biomedical foundation that aims to `` rapidly discover and develop drugs that delay or slow Huntington 's disease '' . CHDI was formerly known as the High Q Foundation . In 2006 , it spent $50 million on Huntington 's disease research . CHDI collaborates with many academic and commercial laboratories globally and engages in oversight and management of research projects as well as funding . Many organizations exist to support and inform those affected by HD .
Huntington's disease
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 .
Huntington's disease
40 or more CAG repeats : full penetrance allele ( FPA ) . A `` 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 . The test will tell a person who originally had a 50 percent chance of inheriting the disease if their risk goes up to 100 percent or is eliminated . A person who tests positive for the disease will develop HD sometime within their lifetime , provided he or she lives long enough for the disease to appear . 36 to 39 repeats : incomplete or reduced penetrance allele ( RPA ) . It may cause symptoms , usually later in the adult life . There is a maximum risk of 60 % that a person with an RPA will be symptomatic at the age of 65 years , and a 70 % risk of being symptomatic at the age of 75 years . 27 to 35 repeats : intermediate allele ( IA ) , or large normal allele . It is not associated with symptomatic disease in the tested individual , but may expand upon further inheritance to give symptoms in offspring . 26 or fewer repeats : Not associated with HD .
Huntington's disease
The most characteristic initial physical symptoms are jerky , random , and uncontrollable movements called chorea . Chorea may be initially exhibited as general restlessness , small unintentionally initiated or uncompleted motions , lack of coordination , or slowed saccadic eye movements . These minor motor abnormalities usually precede more obvious signs of motor dysfunction by at least three years . The clear appearance of symptoms such as rigidity , writhing motions or abnormal posturing appear as the disorder progresses . These are signs that the system in the brain that is responsible for movement has been affected . Psychomotor functions become increasingly impaired , such that any action that requires muscle control is affected . Common consequences are physical instability , abnormal facial expression , and difficulties chewing , swallowing , and speaking . Eating difficulties commonly cause weight loss and may lead to malnutrition . Sleep disturbances are also associated symptoms . 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 . Seizures are also a common symptom of this form of HD .
Huntington's disease
HD affects the whole brain , but certain areas are more vulnerable than others . The most prominent early effects are in a part of the basal ganglia called the neostriatum , which is composed of the caudate nucleus and putamen . Other areas affected include the substantia nigra , layers 3 , 5 and 6 of the cerebral cortex , the hippocampus , purkinje cells in the cerebellum , lateral tuberal nuclei of the hypothalamus and parts of the thalamus . These areas are affected according to their structure and the types of neurons they contain , reducing in size as they lose cells . Striatal spiny neurons are the most vulnerable , particularly ones with projections towards the external globus pallidus , with interneurons and spiny cells projecting to the internal pallidum being less affected . HD also causes an abnormal increase in astrocytes and activation of the brain 's immune cells , microglia .