Huntington's disease

Symptoms of Huntington's disease can appear at any age,^[1] but most commonly the age of onset is between 35 and 44 years.^[2] In the early stages, there are subtle changes in personality, cognition, or physical skills.^[1] The physical symptoms are usually the first to be noticed, as cognitive and psychiatric symptoms are generally not severe enough to be recognized on their own at the earlier stages.^[1] Almost everyone with Huntington's disease eventually exhibits similar physical symptoms, but the onset, progression and extent of cognitive and psychiatric symptoms vary significantly between individuals.^[3][4]

The most characteristic initial physical symptoms are jerky, random, and uncontrollable movements called chorea.^[1] Chorea may be initially exhibited as general restlessness, small unintentionally initiated or uncompleted motions, lack of coordination, or slowed saccadic eye movements.^[1] These minor motor abnormalities usually precede more obvious signs of motor dysfunction by at least three years.^[3] The clear appearance of symptoms such as rigidity, repetitive motions or abnormal posturing appear as the disorder progresses.^[5] These are signs that the system in the brain that is responsible for movement is affected.^[6] 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.^[5] Eating difficulties commonly cause weight loss and may lead to malnutrition.^[7][8] Sleep disturbances are also associated symptoms.^[9] 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.^[5]

Cognitive abilities are impaired progressively.^[6] Especially affected are executive functions which include planning, cognitive flexibility, abstract thinking, rule acquisition, initiating appropriate actions and inhibiting inappropriate actions.^[6] 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.^[6] Cognitive problems tend to worsen over time, ultimately leading to dementia.^[6] This pattern of deficits has been called a "subcortical dementia" syndrome to separate it from the typical effects of "cortical dementias" such as Alzheimer's disease.^[6]

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.^[10] Difficulties in recognizing other people's negative expressions have also been observed.^[6] Prevalence of these symptoms is also highly variable between studies, with estimated rates for lifetime prevalence of psychiatric disorders between 33% and 76%.^[10] 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 institutionalisation.^[10] Suicidal thoughts and suicide attempts are more common than in the general population.^[1]

All humans have the Huntingtin gene (HTT), which provides the genetic code to produce the protein huntingtin (HTT). Part of this gene is a repeated section called a trinucleotide repeat, which varies in length between individuals and may change length between generations. When the length of this repeated section reaches a certain threshold, it produces an altered form of the protein, called mutant huntingtin protein (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, because either of a person's HTT genes being mutated causes the disease. It is not inherited according to gender, but the length of the repeated section of the gene, and hence its severity, can be influenced by the gender of the affected parent.^[11]

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.^[12] The HTT gene is located on the short arm of chromosome 4.^[12] HTT contains a sequence of three DNA bases—cytosine-adenine-guanine (CAG)—repeated multiple times (i.e. ...CAGCAGCAG...), known as a trinucleotide repeat.^[12] CAG is the genetic code for the amino acid glutamine, so a series of them results in the production of a chain of glutamine known as a polyglutamine tract (or polyQ tract), and the repeated part of the gene, the PolyQ region.^[13]

Generally, people have fewer than 36 repeated glutamines in the polyQ region which results in production of the cytoplasmic protein Huntingtin.^[12] However, a sequence of 36 or more glutamines results in the production of a protein which has different characteristics.^[12] This altered form, called mHTT (mutant HTT), increases the decay rate of certain types of neuron. Regions of the brain have differing amounts and reliance on these type of neurons, and are affected accordingly.^[5] 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 at onset and the rate of progression of symptoms. The remaining variation is attributed to environment and other genes that modify the mechanism of HD.^[12] 36–40 repeats result in a reduced-penetrance form of the disease, with much later onset and slower progression of symptoms, which in some cases may not even appear.^[14] 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.^[15]

Huntington's disease has autosomal dominant inheritance, meaning that an affected individual typically inherits a copy of the gene with an expanded trinucleotide repeat (the mutant allele) from an affected parent.^[1] In this type of inheritance pattern, each offspring of an affected individual has a 50% chance of inheriting the mutant allele and therefore being affected with the disorder (see figure). This probability is sex-independent.^[16]

Trinucleotide CAG repeats over 28 are unstable during replication and this instability increases with the number of repeats present.^[14] This usually leads to new expansions as generations pass (dynamic mutations) instead of reproducing an exact copy of the trinucleotide repeat.^[12] 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.^[12] 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.^[12] Instability is greater in spermatogenesis than oogenesis,^[12] so maternally inherited alleles are usually of a similar repeat length, whereas paternally inherited ones have a higher chance of increasing in length and can exhibit the anticipation phenomenon.^[12][17] It is rare for Huntington's disease to be caused by a new mutation, where neither parent have over 36 CAG repeats.^[18]

Individuals with both genes affected are rare, except in large consanguineous families.^[19] For some time HD was thought to be the only disease for which this did not affect the symptoms and progression of the disease,^[20] but it has since been found that it can affect the phenotype and the rate of progression.^[12][19] In identical twins their age of onset typically varies by years and clinical phenotypes can also differ.^[19]

The HTT protein interacts with over 100 other proteins, and appears to have multiple biological functions.^[21] The behavior of mutated mHTT protein is not completely understood, but it is toxic to certain types of cells, particularly in the brain. Damage mainly occurs in the striatum, but as the disease progresses, other areas of the brain are also significantly affected. As the damage accumulates, symptoms associated with the functions of these brain areas appear. Planning and modulating movement are the main functions of the striatum, and difficulties with these are initial symptoms.^[11]

HTT is expressed in all mammalian cells. The highest concentrations are found in the brain and testes, with moderate amounts in the liver, heart, and lungs.^[11] The function of HTT in humans is unclear. It interacts with proteins which are involved in transcription, cell signaling and intracellular transporting.^[11][22] In animals genetically modified to exhibit HD, several functions of HTT have been found.^[23] In these animals, HTT is important for embryonic development, as its absence is related to embryonic death. It also acts as an anti-apoptotic agent preventing programmed cell death and controls the production of brain-derived neurotrophic factor, a protein which protects neurons and regulates their creation during neurogenesis. HTT also facilitates vesicular transport and synaptic transmission and controls neuronal gene transcription.^[23] If HTT expression is increased, brain cell survival is improved and the effects of mHTT are reduced, whereas when HTT expression is reduced, the resulting characteristics are more typical of the presence of mHTT.^[23] In humans the disruption of the normal gene does not cause the disease.^[11] It is currently concluded that the disease is not caused by inadequate production of HTT, but by a gain of toxic function of mHTT.^[11]

There are multiple cellular changes through which the toxic function of mHTT may manifest and produce the HD pathology.^[24][25] During the biological process of posttranslational modification of mHTT, cleavage of the protein can leave behind shorter fragments constituted of parts of the polyglutamine expansion.^[24] These fragments can then misfold and coalesce, in a process called protein aggregation, to form inclusion bodies within cells.^[24] Inclusion bodies have been found in both the cell nucleus and cytoplasm.^[24] 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.^[24]

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 glutamate on nerve cells; impairment of energy production within cells; and effects on the expression of genes. The cytotoxic effects of mHTT are strongly enhanced by interactions with a protein called Rhes, which is expressed mainly in the striatum.^[26] Rhes was found to induce sumoylation of mHTT, which causes the protein clumps to disaggregate—studies in cell culture showed that the clumps were much less toxic than the disaggregated form.^[26]

HD affects specific areas of the brain. The most prominent early effects are in a part of the basal ganglia called the striatum, which is composed of the caudate nucleus and putamen.^[11] 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.^[12] These areas are affected according to their structure and the types of neurons they contain, reducing in size as they lose cells.^[12] 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.^[12][27] HD also causes an abnormal increase in astrocytes.^[28]

The basal ganglia—the part of the brain most prominently affected by HD—play a key role in movement and behavior control. Their functions are not fully understood, but current theories propose that they are part of the cognitive executive system^[6] and the motor circuit.^[29] 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 motion or motions to be unintentionally initiated, or 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.^[29]

With the appearance of symptoms HD can be diagnosed clinically.^[1] Genetic testing can confirm if an individual carries an expanded copy of the gene, even before onset of symptoms, and can also be used for embryonic testing. Genetic counseling is provided to advise and to guide an individual throughout the testing procedure and also in the consideration of the implications of having a confirmed diagnosis, on his or her pyschology and career, in family planning decisions, and on friends and family. Although the initial motivation of individuals at risk of inheriting HD for having a pre-symptomatic test is strong, upon consideration, only a minority choose to do so.^[11]

A physical examination, sometimes combined with a psychological examination, can determine whether onset of the disease has begun.^[1] Excessive unintentional movements of any part of the body are often the reason for seeking medical consultation. If these are abrupt and have random timing and distribution, they suggest a diagnosis of HD. Cognitive or psychiatric symptoms are rarely the first 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.^[31][32] Medical imaging such as computerized tomography (CT) or magnetic resonance imaging (MRI) only show a visible volume reduction in the striatum in advanced stages. Functional neuroimaging techniques such as fMRI or PET can show changes in brain activity before symptom onset.^[12]

Because a child of a parent with HD has a 50% chance of inheriting the condition, there is a strong motivation to resolve the uncertainty. The genetic test for HD consists of a blood test which counts the numbers of CAG repeats in each of the HTT alleles.^[33] A positive result is not considered a diagnosis, since it may be obtained decades before onset of symptoms. However, a negative test means that the individual does not carry the expanded copy of the gene and will not develop HD.^[12]

A pre-symptomatic test is a life-changing event and a very personal decision.^[12] The main reason given for choosing testing for HD is to aid in career and family decisions.^[12] Over 95% of individuals at risk of inheriting HD do not proceed with testing, mostly because there is no treatment.^[12] 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.^[11] Irrespective of the result, stress levels have been found to be lower two years after being tested,^[11] but the risk of suicide is increased after a positive test result.^[11] Individuals found to have not inherited the disorder may experience survivor guilt with regard to family members who are affected.^[11] The possibility of discrimination and the implications of a positive result (which reveals a parent is carrying an affected gene and that siblings are at risk of inheriting it) are other factors taken into account when testing is being considered.^[11] Disclosure and confidentiality are emphasized, as individuals have the right to decide when and how to reveal their results.^[11] Genetic counseling in HD can provide information, advice and support for initial decision-making, and then, if chosen, throughout all stages of the testing process.^[34] Counseling and guidelines on the use of genetic testing for HD have become models for other genetic disorders.^[11][35][36]

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

In a person with typical symptoms, and a family history of the disease, diagnosis is usually straightforward.^[5] Of all the genetic disorders that cause chorea, ninety percent are attributable to HD, while most of the remainder are collectively labeled HD-like (HDL).^[38] If genetic testing for HD is negative, the remaining ten percent of causes should be considered.^[5] The causes of most of these HDL diseases are unknown, but those that are have been found to be caused by mutations in the prion protein gene (HDL1), the junctophilin 3 gene (HDL2), a recessively inherited HTT gene (HDL3 — only found in one family and poorly understood), and the gene encoding the TATA box-binding protein (HDL4/SCA17).^[38]

There is no cure for HD, but there are treatments available that offer some symptomatic benefit and are palliative in nature.^[39] As the disease progresses caregiving becomes increasingly important, and should be carefully managed.^[39]

Tetrabenazine, an orphan drug, is useful in the reduction of chorea,^[39] and was approved in 2008 for this use in the US.^[40] Other drugs that help to reduce chorea include neuroleptics and benzodiazepines.^[2] Compounds such as amantadine or remacemide are still under investigation but have shown preliminary positive results.^[41] Hypokinesia and rigidity can be treated with antiparkinsonian drugs, and myoclonic hyperkinesia with valproic acid.^[2]

Psychiatric symptoms can be treated with medications similar to those used in the general population.^[39] Selective serotonin reuptake inhibitors and mirtazapine for depression, and atypical antipsychotic drugs for psychosis and behavioural problems have been recommended, however more studies on the efficacy of these and other treatments are needed.^[42] People who have inherited, or are at risk of inheriting, HD, and their families often benefit from counselling.^[11]

Although there are relatively few studies of rehabilitation for HD, there is some evidence for the usefulness of physical therapy and speech therapy. However, more rigorous studies are needed for health authorities to endorse them.^[43] A multidisciplinary approach may be important to limit disability.^[44]

Nutrition management is important. Weight loss and eating difficulties due to dysphagia, as well as difficulty getting food into the mouth due to lack of muscle coordination, are common as the disease advances.^[39] Thickening agents can be added to liquids as thicker fluids are easier and safer to swallow.^[39] Reminding the patient to eat slowly and to take smaller pieces of food into the mouth may also be of use to prevent choking.^[39] If eating becomes too hazardous or uncomfortable, the option of using a percutaneous endoscopic gastrostomy is available. This is a feeding tube, permanently attached through the abdomen into the stomach, which reduces the chance of aspirating food and provides better nutritional management.^[45]

The age of onset decreases, and the rate of progression of symptoms increases, with the length of the trinucleotide repeat.^[46] However there is a variation in age of onset for any given CAG repeat length: only 60% of the variation in age of onset is explained by the number of CAG repeats, with genes and environment also being important.^[12] Individuals with greater than approximately 60 CAG repeats often develop juvenile Huntington's disease.^[47]

The life expectancy is around 20 years following diagnosis.^[5] Mortality is not caused by Huntington’s disease directly, but by associated complications. The largest risk is pneumonia, which is the cause of one-third of deaths. The risk of pneumonia increases as the ability to synchronise movements to clear the lungs is compromised and sometimes is caused as a result of aspiration of food or drink. The other leading cause of death is heart disease, which causes almost a quarter of fatalities. Other associated risks include choking, physical injury from falls, and malnutrition.^[5] Suicide is an associated risk, with increased suicide rates of up to 7.3%, and attempted suicides of up to 27%.^[48][49] Survival expectancy is similar in all regions independent of their economic development and the accessibility of treatment.^[50]

Because of the late age of symptom onset, Huntington's disease does not usually affect reproduction.^[11] The prevalence is similar for men and women, but varies greatly geographically as a result of ethnicity, local migration and past immigration patterns. The rate of occurrence is highest in peoples of Western European descent, averaging around seventy per million people, but is lower in the rest of the world, e.g. one per million people of Asian and African descent.^[11] Additionally, some localized areas have a much higher prevalence than their regional average.^[11] An example is in the isolated populations of the Lake Maracaibo region of Venezuela, which have prevalences of up to 700 per 100,000 and were studied to locate the marker for the gene.^[11][51] Other areas of high localization have been found in Tasmania and specific regions of Scotland, Wales and Sweden.^[50] Increased prevalence in some cases occurs according to a local founder effect, a historical migration of carriers into an area of geographic isolation.^[50][52] Some of these carriers have been traced back hundreds of years using genealogical studies.^[50] Genetic haplotypes can also give clues for the geographic variations of prevalence.^[50][53]

Earlier statistics use diagnosis based on physical symptoms and a family history of HD, excluding those who died of other causes before diagnosis. Since the discovery of a genetic test that can be used pre-symptomatically, these cases can now be included in statistics. As the test becomes more widely available, estimates of the prevalence and incidence of the disorder are likely to increase.^[50][54]

Before the 19th century, some HD sufferers may have been thought to be possessed by spirits or persecuted as witches, and were shunned or exiled by society.^[56] A well-documented case is that of Elizabeth Knapp, who probably suffered from HD. In 1671 Knapp was accused of witchcraft in Groton, New Hampshire, and subject to an torturous trial, but was not condemned.^[57][58] However, while this persecution may have happened in some places,^[56] other communities were more accepting. The family that prompted George Huntington's description were able to work while healthy and accepted by their town.^[56][59]

The first definite description of HD was in a letter by Charles Oscar Waters, published in the first edition of Robley Dunglison's Practice of Medicine in 1842. Waters described 'a form of chorea, vulgarly called magrums', including accurate descriptions of the chorea, its progression, and the strong heredity of the disease.^[60] In 1846 Charles Gorman observed how prevalence seemed to occur in localized regions.^[60] Both Gorman and Waters were students of Dungison at Jefferson Medical College.^[59] Independently, Johan Christian Lund also produced an early description in 1860.^[60] He specifically noted that in Setesdalen, a rather secluded area, there was a high prevalence of dementia associated with a pattern of jerking movement disorders that ran in families.^[61] The first widely recognized description was by George Huntington in 1872. Huntington was a third generation physician on Long Island. Examining the combined medical history of several generations of a family exhibiting similar symptoms, he realized their conditions must be linked and presented his detailed and accurate definition of the disease as his first paper.^[55][62] Sir William Osler was interested in the disorder and chorea in general, and was impressed with Huntington's paper, even wishing to reassess the family involved a decade later.^[60] Osler's interest in HD combined with his influence in medicine circles helped to spread knowledge of the disorder rapidly.^[60]

As Mendelian inheritance was being rediscovered at the turn of the century, HD was used tentatively as an example of autosomal dominant inheritance.^[60] In 1911 Charles Davenport made major contributions to understanding of the disease, proving that it was indeed autosomal dominant, and proceeding to document most of the inheritance variabilities like age of onset. He also described the range of psychiatric and physical symptoms, providing much of the framework for following research.^[60] Davenport's interest was roused by his college friend Smith Ely Jelliffe's own interest in HD's strong inheritance pattern.^[59] Jellife collected information from across New York State and published several articles regarding the genealogy of HD in New England.^[63] This work was expanded upon in 1932 by P. R. Vessie, who traced about a thousand people with HD back to two brothers who left England in 1630, bound for Boston.^[64]

Research into the disorder continued progressively, and was given a major boost in 1983 when the US–Venezuela Huntington's Disease Collaborative Research Project discovered the approximate location of a causal gene.^[52] This was the result of an extensive study begun in 1979, focusing on the populations of isolated Venezuelan villages of Barranquitas and Lagunetas, where there was an unusually high prevalence of the disease. Among other innovations, the project developed DNA marking methods which were an important step in making the Human Genome Project possible.^[65] In 1993 the research group isolated the precise gene at 4p16.3,^[66] making this the first autosomal disease locus found using genetic linkage analysis.^[67][68] In the same time frame, 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 genes length.^[69]

A transgenic mouse that could be made to exhibit HD was developed in 1996, this model is called the R6 line. Modelling the disease in animals enables larger scale testing, and as their metabolism is faster and lifespan shorter than humans, results are received sooner.^[70][71] The discovery that mHTT fragments misfold in 1997 led to the discovery of the nuclear inclusions they cause.^[72] These advancements and discoveries have led to increasingly extensive research into the interactions of HTT, mHTT, and mHTT fragments, potential drug treatments, care methods, and the gene itself.^[60][73][74]

Huntington's disease has tested society's ethics in various ways. HD was one of the targets of the eugenics movement, in which Charles Davenport proposed in 1910 that compulsory sterilization and immigration control be used for people with certain diseases, including HD.^[75] The development of an accurate diagnostic test for Huntington's disease has caused social, legal, and ethical concerns over access and use of a person's results.^[76][77] Financial institutions and businesses are faced with the question of whether to use results when assessing an individual, such as for life insurance or employment. Some countries' organizations, such as the United Kingdom's insurance companies, have agreed not to use this information.^[78]

As with other genetic conditions with later onset and no treatment, it is ethically questionable to perform pre-symptomatic testing on a child or adolescent.^[25][79][80] There is consensus opposing testing individuals that are not considered cognitively mature, although there are defendants of a parent's right to make the decision.^[25][79][80] 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.^[25][79][80]

Prenatal genetic testing or preimplantation genetic diagnosis to ensure a child is not born with a given disease has some ethical concerns.^[81] For example, prenatal testing raises the issue of selective abortion, a choice considered unacceptable by some. Another argument against this type of testing is that a person with the mutation may be free of the disease for many years.^[81] Using preimplantation testing for HD requires twice as many embryos to be used for in vitro fertilisation, as 50% of them will be positive for HD. For a dominant disease there are also difficulties in situations in which a parent does not want to know his or her own diagnosis, as this would require parts of the process to be kept secret from the parent.^[81] HD research also raises ethical issues around the use of animal testing and embryonic stem cells.^[82][83]

In 1968, after experiencing HD in his wife's family, Dr. Milton Wexler was inspired to start the Hereditary Disease Foundation (HDF), with the aim of curing genetic illness by coordinating and supporting research.^[84] The foundation and Dr. Wexler's daughter, Nancy S. Wexler, were key parts of the research team in Venezuela which discovered the HD gene.^[84] As of 2009, Nancy Wexler is the foundation's president.^[84] At roughly the same time, Woody Guthrie's wife, Marjorie, had helped to found the Committee to Combat Huntington's Disease (now the Huntington's Disease Society of America), after his death from HD complications.^[85][85] Since then, support and research organizations have formed in many countries around the world and have helped to increase the awareness on HD. A number of these collaborate in umbrella organizations, like the International Huntington Association and the EuroHD network.^[86] Many support organizations hold an annual HD awareness event, some of which have been endorsed by their respective governments. For example, June 6 is designated "National Huntington's Disease Awareness Day" by the US senate.^[87]

Research into the mechanism has focused on identifying the functioning of HTT, how mHTT differs or interferes with it, and the brain pathology that the disease produces.^[24] Most research is conducted in animals. Appropriate animal models are critical for understanding the fundamental mechanisms causing the disease and for supporting the early stages of drug development.^[88] Mice and monkeys, chemically induced to exhibit HD like symptoms were initially used,^[88][89][90] but they did not mimic the progressive features of the disease. Since the Huntingtin gene was identified, transgenic animals (mice,^[88][91][92] Drosophila fruit flies,^[88][93] and more recently monkeys^[94]) exhibiting HD-like syndromes can be generated by inserting a CAG repeat expansion into the gene. Nematode worms also provide a valuable model when the gene is expressed.^[88][95]

Genetically engineered intracellular antibody fragments called intrabodies have shown therapeutic results preventing larval and pupal mortality in Drosophila models. Their mechanism of action was an inhibition of mHTT aggregation.^[88][96][97] As HD has been conclusively linked to a single gene, gene silencing is potentially possible. Researchers have investigated using gene knockdown of mHTT in mice as a potential treatment.^[41][98][99] Stem cell therapy is the replacement of damaged neurons by transplantation of stem cells into affected regions of the brain. Experiments have yielded some positive results in animal models and preliminary human clinical trials.^[100] All of these advances are at their first stages and there are important practical difficulties for the use of such techniques in humans.^[41][100]

Numerous drugs have been reported to produce benefits in animals, including creatine, coenzyme Q10 and the antibiotic minocycline.^[41] Some of these have then been tested by humans in clinical trials, and as of 2009 several are at different stages of these trials.^[41]

• DMOZ HD links directory at the Open Directory Project.
• Huntington's Disease Outreach Project for Education, at Stanford (HOPES) - A layperson's guide to HD
• Worldwide Education and Awareness for Movement Disorders - HD section