Huntington's disease

Signs and symptoms of Huntington's disease most commonly become noticeable between the ages of 30 and 50 years, but they can begin at any age When developed in an early stage, it is known as juvenile Huntington's disease. In 50% of cases, the psychiatric symptoms appear first. Disease progression is often described in early stages, middle stages and late stages with an earlier prodromal phase. Almost everyone with HD eventually exhibits similar physical symptoms, but the onset, progression, and extent of cognitive and behavioral symptoms vary significantly between individuals. The most characteristic initial physical symptoms are jerky, random and uncontrollable movements called chorea. 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. Psychomotor functions become increasingly impaired, such that any action that requires muscle control is affected. When muscle control is affected, such as with rigidity or muscle contractures, it 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. and weight loss are also associated symptoms, and difficulty eating may cause weight loss and malnutrition. 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. Other common psychiatric disorders could include obsessive–compulsive disorder, mania, insomnia and bipolar disorder. Difficulties in recognizing other people's negative expressions have also been observed. ==Genetics==

Huntington's disease is a trinucleotide repeat disorder caused by trinucleotide repeat expansion in the first exon of the huntingtin gene (HTT), which encodes the huntingtin protein (HTT). The number of repeats varies in length between individuals and may change length between generations. When the length of this repeated section exceeds a certain threshold, it produces mutant huntingtin protein (mHTT). In turn, mHTT has toxic gains and losses of function which negatively impact cell function and lead to disease. The Huntington's disease mutation is genetically dominant and almost fully penetrant; a single mutant HTT allele from either parent is sufficient to cause the disease. Typically, people have fewer than 36 repeats in the polyQ region, which results in the normal production and cytoplasmic localization of the huntingtin. Inheritance 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. Trinucleotide CAG repeats numbering over 28 are unstable during replication, and this instability increases with the number of repeats present. Rarely is Huntington's disease caused by a new mutation, where neither parent has over 36 CAG repeats. 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%. 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. ==Mechanisms==

Huntingtin protein (HTT) interacts with over 100 other proteins, and appears to have multiple functions. The behavior of the mutated protein (mHTT) is not completely understood, but it is toxic to certain cell types, particularly brain cells. Early damage is most evident in the 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. In 2025, scientists affiliated with Harvard and MIT published a study examining the mechanism behind the onset of symptoms. They found that the length of the repeated trinucleotide sequence increases with age due to accumulated errors in DNA mismatch repair processes after transcription, and that this becomes toxic once the sequence expands beyond 150 repeats. Huntingtin function HTT is expressed in all cells, with the highest concentrations found in the brain and testes, and moderate amounts in the liver, heart, and lungs. Although its full range of functions is not yet understood, HTT interacts with proteins involved in transcription, cell signaling, and intracellular transport. HTT also plays a protective role in mature neurons: it regulates the production of brain-derived neurotrophic factor, supports synaptic vesicular transport and synaptic transmission, controls neuronal gene transcription, and prevents programmed cell death by inhibiting apoptotic enzymes such as caspases. Cellular changes (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. In its mutant (polyglutamine expanded) form, the protein is more prone to cleavage that creates shorter fragments containing the polyglutamine expansion. These aggregates share the same fundamental cross-beta amyloid architecture seen in other protein deposition diseases. Over time, the aggregates accumulate to form inclusion bodies within cells, ultimately interfering with neuronal function. Mutant huntingtin protein has been found to play a key role in mitochondrial dysfunction. The impairment of mitochondrial electron transport can result in higher levels of oxidative stress and release of reactive oxygen species. 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. Macroscopic changes made up of the caudate nucleus and the putamen. Initially, damage to the brain is regionally specific with the dorsal striatum in the subcortical basal ganglia being primarily affected, followed later by cortical involvement in all areas. Other areas of the basal ganglia affected include the substantia nigra; cortical involvement includes 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. HD also causes an abnormal increase in astrocytes and activation of the brain's immune cells, microglia. 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 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). 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. Autopsied brains of those who had Huntington's disease also have been found to have incredibly reduced amounts of CBP. 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. ==Diagnosis==

Diagnosis of the onset of HD can be made following the appearance of physical symptoms specific to the disease. A physical examination, sometimes combined with a psychological examination, can determine whether the onset of the disease has begun. 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. Cutoffs are given as follows: • At 40 or more CAG repeats, full penetrance allele (FPA) exists. 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. 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 it has no treatment. 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. Counseling and guidelines on the use of genetic testing for HD have become models for other genetic disorders, such as autosomal dominant cerebellar ataxia. Presymptomatic testing for HD has also influenced testing for other illnesses with genetic variants such as polycystic kidney disease, familial Alzheimer's disease and breast cancer. 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. Prenatal testing Obtaining a prenatal diagnosis for an embryo or fetus in the womb is also possible, using fetal genetic material acquired through chorionic villus sampling. An amniocentesis can be performed if the pregnancy is further along, within 14–18 weeks. This procedure looks at the amniotic fluid surrounding the baby for indicators of the HD mutation. This, too, can be paired with exclusion testing to avoid disclosure of parental genotype. Prenatal testing can be done when parents have been diagnosed with HD, when they have had genetic testing showing the expansion of the HTT gene, or when they have a 50% chance of inheriting the disease. The parents can be counseled on their options, which include termination of pregnancy, and on the difficulties of a child with the identified gene. 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. ==Management==

Treatments are available to reduce the severity of some HD symptoms. For many of these treatments, evidence to confirm their effectiveness in treating symptoms of HD specifically are incomplete. As the disease progresses, the ability to care for oneself declines, and carefully managed multidisciplinary caregiving becomes increasingly necessary. Assessment and management by speech-language pathologists with experience in Huntington's disease is recommended. Goals of early 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. For long-term independent management, the therapist may develop home exercise programs for appropriate people. Palliative care may also improve quality of life for people with HD by treating the symptoms and psychological stress of having a progressive degenerative disease. Medications , an approved compound for the management of chorea in HD Tetrabenazine was approved in 2000 for treatment of chorea in Huntington's disease in the EU, and in 2008 in the US. Although other drugs had been used "off label", tetrabenazine was the first approved treatment for Huntington's disease in the US. The compound has been known since the 1950s. In 2017, deutetrabenazine, a heavier form of tetrabenazine medication for the treatment of chorea in HD, was approved by the FDA. This is marketed as Austedo. Valbenazine (Ingrezza) was also approved by the FDA for the treatment of Huntington's disease chorea in 2023. Tetrabenazine, deutetrabenazine, and valbenazine are all vesicular monoamine transporter 2 (VMAT2) inhibitors, which work by depleting dopamine in the brain, lessening involuntary movements. These are the only drugs that have been approved specifically for Huntington's disease (namely the chorea associated with it). Other drugs that help to reduce chorea include antipsychotics and benzodiazepines. Amantadine has also been used to treat chorea, but there is limited evidence for its safety and efficacy. Psychiatric symptoms can be treated with medications similar to those used in the general population. 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. Also covered is information concerning family planning choices, care management, and other considerations. ==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. Individuals with more than sixty repeats often develop the disease before age 20, while those with fewer than 40 repeats may remain asymptomatic. The remaining variation is due to environmental factors and other genes that influence the mechanism of the disease. Most life-threatening complications result from muscle coordination, and to a lesser extent, behavioral changes induced by declining cognitive function. The largest risk is pneumonia, which causes death in one third of those with HD. As the ability to synchronize movements deteriorates, difficulty clearing the lungs, and an increased risk of aspirating food or drink both increase the risk of contracting pneumonia. The second-greatest risk is heart disease, which causes almost a quarter of fatalities of those with HD. 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. 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. ==Epidemiology==

The late onset of Huntington's disease means it does not usually affect reproduction. but varies greatly geographically as a result of ethnicity, local migration and past immigration patterns. Additionally, some localized areas have a much higher prevalence than their regional average. Other areas of high localization have been found in Tasmania and specific regions of Scotland, Wales and Sweden. Some of these carriers have been traced back hundreds of years using genealogical studies. 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. Finland, as well, has a low incidence of only 2.2 per 100,000 people. 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. ==History==

described the disorder in his first paper, "On Chorea", at the age of 22. 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 Charles Oscar Waters (1816–1892), published in the first edition of Robley Dunglison's Practice of Medicine in 1842. Waters described "a form of chorea, vulgarly called magrums", including accurate descriptions of the chorea, its progression, and the strong heredity of the disease. In 1846 Charles Rollin Gorman (1817–1879) observed how higher prevalence seemed to occur in localized regions. (1830–1906) also produced an early description in 1860. 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. 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." 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. Jelliffe's research roused the interest of his college friend, Charles Davenport, who commissioned Elizabeth Muncey to produce the first field study on the East Coast of the United States of families with HD and to construct their pedigrees. Davenport used this information to document the variable age of onset and range of symptoms of HD; he claimed that most cases of HD in the US could be traced back to a handful of individuals. The claim that the earliest progenitors had been established and eugenic bias of Muncey's, Davenport's, and Vessie's work contributed to misunderstandings and prejudice about HD. This idea has not been proven through scientific research. Researchers have found contrary evidence; for instance, the community of the family studied by George Huntington openly accommodated those who exhibited symptoms of HD. Sabin's three brothers 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. The study had focused on the populations of two isolated Venezuelan villages, Barranquitas and Lagunetas, where there was an unusually high prevalence of HD, and involved over 18,000 people, mostly from a single extended family, and resulted in making HD the first autosomal disease locus found using genetic linkage analysis. Among other innovations, the project developed DNA-marking methods which were an important step in making the Human Genome Project possible. 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. Modeling 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. Doctors are working toward rekindling these networks because the people who have contributed to the science of HD 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. ==Society and culture==

Ethics Genetic testing for Huntington's disease has raised several ethical issues, which include defining how mature an individual should be before being considered eligible for testing, ensuring the confidentiality of results, and deciding whether companies should be allowed to use test results for decisions on employment, life insurance or other financial matters. There was controversy when Charles Davenport proposed in 1910 that compulsory sterilization and immigration control be used for people with certain diseases, including HD, as part of the eugenics movement. In vitro fertilization has some issues regarding its use of embryos. Some HD research has ethical issues due to its use of animal testing and embryonic stem cells. The development of an accurate diagnostic test for HD 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. 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. 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. 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. 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). ==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. Research is conducted using in vitro methods, genetically modified animals, (also called transgenic 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. Research is being conducted using many approaches to either prevent HD or slow its progression. The CHDI Foundation funds research initiatives providing many publications. 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. CHDI was formerly known as the High Q Foundation. In 2006, it spent $50 million on Huntington's disease research. Reducing huntingtin production 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. The safety of RNA interference and allele-specific oligonucleotide (ASO) methods of gene silencing have been demonstrated in mice and macaques. Allele-specific silencing approaches attempt to target mHTT while leaving wild-type HTT untouched by leveraging polymorphisms present on only the mutant allele. The first gene silencing trial in humans with HD 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 HD 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. A phase 3 trial of this compound, renamed tominersen and sponsored by Roche Pharmaceuticals, began in 2019 but was halted in 2021 after the safety monitoring board concluded that the risk-benefit balance was unfavourable. A huntingtin-lowering gene therapy trial run by Dutch pharmaceutical company uniQure Biopharma began in 2019, and several trials of orally administered huntingtin-lowering splicing modulator compounds have been announced; of these, votoplam is through Phase 2 trial in 2025. 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. In 2025, researchers at University College London reported preliminary results from AMT-130, a phase 1/2 uniQure huntingtin-lowering gene therapy clinical trial, that showed a 75% slowing of disease progression over three years; the full study data has not yet been released peer-reviewed nor published. AMT-130 is a gene therapy utilising adeno-associated virus serotype 5 (AAV5) vector carrying an artificial micro-RNA to silence the gene leading to a lowering of huntingtin protein expression. The therapy is delivered directly into the deep brain structures of the caudate nucleus and putamen via an MRI guided neurosurgical procedure. 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. As mHTT (and many other protein aggregates) may be degraded by autophagy, increasing the rate of autophagy has the potential to reduce levels of mHTT and thereby ameliorate disease. Pharmacological and genetic inducers of autophagy have been tested in a variety of HD models; many have been shown to reduce mHtt levels and decrease toxicity in mice. Stem cells are also used to study HD in the laboratory. Ferroptosis Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. ALOX5-mediated ferroptosis acts as a cell death pathway upon oxidative stress in HD. Inhibitors of ferroptosis are protective in models of degenerative brain disorders, including Parkinson's, Huntington's, and Alzheimer's diseases. Compounds trialed that have failed to prevent or slow the progression of HD include remacemide, coenzyme Q10, riluzole, creatine, minocycline, ethyl-EPA, phenylbutyrate and dimebon. ==See also==