Definitions

hdsa

Huntington's disease

Huntington's disease, also called Huntington's chorea, chorea major, or HD, is a genetic neurological disorder characterized after onset by uncoordinated, jerky body movements called chorea and a decline in some mental abilities, which can lead to affected aspects of behavior. As the disorder progresses, these symptoms can cause complications that significantly reduce life expectancy.

The exact mechanism of HD is unproven and there is currently no proven cure, so individual symptoms are managed with a range of medications and supportive services. Global incidence varies, from 3 to 7 per 100,000 people of Western European descent, down to 1 per 1,000,000 of Asian and African descent. The onset of physical symptoms in Huntington's disease can occur at any age, but commonly occurs in a person's thirties to early fifties. If onset is before a person is twenty, their condition is classified as juvenile HD. Huntington's disease is one of several trinucleotide repeat disorders, caused by the length of a repeated section of a gene exceeding the normal range. The huntingtin gene (HTT) normally provides the information to produce Huntingtin protein, but when affected, produces mutant Huntingtin (mHTT) instead. The presence of mHTT causes an increase in the rate of neuronal cell death in select areas of the brain, affecting neurological functions.

The disorder is named after George Huntington, the American physician who first described it in 1872. In 1983 a marker for the altered DNA causing the disease was found, followed a decade later by discovery of a single, causal, gene. As it was caused by a single gene, an accurate genetic test for HD was developed, this was one of the first inherited genetic disorders for which this was possible. Due to the availability of this test, and similar characteristics with other neurological disorders, the amount of HD research has been increasing over time.

Signs and symptoms

Physical symptoms are usually the first to cause problems and to be noticed, but at this point they are usually accompanied by cognitive and psychiatric ones that are often not recognized. Almost everyone with Huntington's disease eventually exhibits all physical symptoms, but cognitive and psychiatric symptoms vary significantly between individuals.

Physical

The most characteristic symptoms are jerky, random, and uncontrollable movements called chorea, although, in a few cases, very slow movement and stiffness (called bradykinesia and dystonia) can occur instead, these can also become more prominent in later stages of the disorder. Abnormal movements are initially exhibited as general lack of coordination, an unsteady gait and slurring of speech, but, as the disease progresses, any function that requires muscle control is affected, causing physical instability, abnormal facial expression, impaired speech comprehensibility and difficulties chewing and swallowing. Eating difficulties commonly cause weight loss and may lead to malnutrition. Associated symptoms involve sleep cycle disturbances, including insomnia and rapid eye movement sleep alterations. Juvenile HD generally progress faster and symptoms more likely to exhibit rigidity and bradykinesia, instead of chorea, and commonly include seizures.

Cognitive

Select cognitive abilities are impaired progressively. Specially affected are executive functions which include planning, cognitive flexibility, abstract thinking, rule acquisition, initiating appropriate actions and inhibiting inappropriate actions. psychomotor function which is the capacity of thought processes to control muscles, and perceptual and spatial skills are also affected. As the disease progresses, memory deficits tend to appear. Memory impairments reported 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.

Psychiatric

These symptoms vary far more than cognitive and physical ones, and may include anxiety, depression, a reduced display of emotions (blunted affect), egocentrism, aggression, and compulsive behavior, which can cause, or worsen addictions, including alcoholism and gambling, or hypersexuality. Difficulties in recognizing emotions, with particularly severe problems regarding recognition of expressions of disgust have also been repeatedly described.

Genetics

The Huntingtin gene (HTT) is located on the short arm of chromosome 4 (4p16.3). HTT contains a sequence of three DNA basescytosine-adenine-guanine (CAG)—repeated multiple times (i.e. ...CAGCAGCAG...) on its 5' end, known as a trinucleotide repeat. 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 polyglutamine or polyQ.
Repeat count Classification Disease status
<27 Normal Unaffected
27–35 Intermediate Unaffected
36–39 Reduced Penetrance +/- Affected
>39 Full Penetrance Affected

The polyQ region contains fewer than 36 glutamines results in production of the cytoplasmic protein called huntingtin (HTT). In the general population this count rarely exceeds 27 glutamines. A sequence of 36 or more glutamines, however, results in the production of form of HTT which has different characteristics, this form is called mutant HTT or more commonly mHTT. The presence of mHTT increases the rate of neuronal decay in select types of neurons in various regions of the brain. Generally, the number of CAG repeats is related to how much this process is affected, and correlates with age at onset and the rate of progression of symptoms. For example, 36–39 repeats result in much later onset and slower progression of symptoms than the mean, such that some individuals may die of other causes before they even manifest symptoms of Huntington disease, this is termed "reduced penetrance". With very large repeat counts, HD can occur under the age of 20 years, when it is then referred to as juvenile HD, akinetic-rigid, or Westphal variant HD and accounts for about 7 percent of HD carriers. Inital studies show carriers of the gene may have better than average immune systems, with higher levels of Interleukin 6 and tumor suppressor protein p53.

Inheritance

Huntington's disease is inherited autosomal dominantly, meaning that an affected individual typically inherits a copy of the gene with an expanded trinucleotide repeat (the mutant allele) from an affected parent. 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). It is extremely rare for Huntington's disease to be caused by a de novo mutation, however, the inheritance of HD is more complex due to potential dynamic mutations, where DNA replication does not produce an exact copy of the trinucleotide repeat. This can cause the number of repeats to change in successive generations, such that an unaffected parent with an "intermediate" number of repeats (28-35), or "reduced penetrance" (36-39), may pass on a copy of the gene with an increase in the number of repeats that produces fully penetrant HD. These new mutations have occurred in less than 10 percent of people with HD, but explain the origins of the disorder. Maternally inherited alleles are usually of a similar repeat length, whereas paternally inherited ones seem to have a higher chance of increasing in length. Increases in the number of repeats (and hence earlier age of onset and severity of disease) in successive generations is known as genetic anticipation.

Homozygous individuals, who have two affected genes, are very rare except in large consanguineous families. While HD seemed to be the first disease for which homozygotes did not differ in clinical expression or course from typical heterozygotes, more recent analysis suggests that homozygosity affects the phenotype and the rate of disease progression but does not alter the age of onset, suggesting that the mechanisms for these factors differ.

Mechanism

Like all proteins, Htt and mHtt are translated, perform or affect biological functions, and are then marked by Ubiquitin to be degraded by Proteasomes, but their exact roles are unknown. Research has focused on identifying the functioning of Htt, how mHtt differs or interferes with it, including its influence in programmed cell death, and the proteopathy of remnants of mHtt left after degradation.

Function

Although the function of Huntingtin is unclear, some hypotheses have been drawn from numerous observations. In mouse models HTT is essential for development and survival. In "knockin" mice, the extended CAG repeat portion of the gene is all that is needed to cause disease. The protein has no sequence homology with other proteins and is highly expressed in neurons and testes. Experiments have shown HTT acts as a transcription factor in upregulating the expression of Brain Derived Neurotrophic Factor (BDNF), a protein which protects neurons and regulates the neurogenesis of new ones, whereas mHTT suppresses this transcription regulatory function of Huntingtin and hence underexpression of BDNF, which leads to progressive atrophy of select areas of the brain.From immunohistochemistry, electron microscopy, subcellular fractionation studies of the molecule, it has been found that Huntingtin is primarily associated with vesicles and microtubules..These indicate a functional role in cytoskeletal anchoring or transport of mitochondria. The HTT protein is involved in vesicle trafficking as it interacts with HIT1, a clathrin binding protein, to mediate endocytosis, the absorption of materials into a cell.

Degradation

In the first step of degradation, both Htt and mHtt are cleaved by caspase-3, which removes the protein's amino end (the N-terminal). Caspase-2 then further breaks down the amino terminal fragment (which includes the CAG repeat) of Htt, but cannot process all of the mHtt protein. In transgenic mice, the caspase-6 enzyme has been shown to be involved in cleaving the Htt protein, as mice made resistant to this enzyme did not suffer neurodegeneration.The uncleaved pieces of mHTT, left in the cell, called N-fragments, and are able to affect genetic transcription. Specifically, mHtt binds with TAFII130, a coactivator to CREB dependent transcription. The mHTT protein also interacts with the transcription factor protein SP1, preventing it from binding to DNA.

Neuronal intranuclear inclusions, containing the proteins huntingtin and ubiquitin have been found in both humans and mice with HD, and are most prevalent in cortical pyramidal neurons, less so in striatal medium-sized spiny neurons and almost entirely absent in most other regions. These inclusions consist mainly of the amino terminal end of mHtt (CAG repeat), and are found in both the cytoplasm and nucleus of neurons, however their presence does not correlate with cell death. Thus, mHtt acts in the nucleus but does not cause apoptosis through protein aggregation.

Pathophysiology

HD causes astrogliosis and loss of medium spiny neurons Areas of the brain are affected according to their structure and the types of neurons they contain, reducing in size as they cumulatively lose cells. The areas affected are mainly in the striatum, but also the frontal and temporal cortices. The striatum's subthalamic nuclei send control signals to the globus pallidus, which initiates and modulates motion. The weaker signals from subthalamic nuclei thus cause reduced initiation and modulation of movement, resulting in the characteristic movements of the disorder.

Although studies are mainly focused on physiopathology of the brain, a few look at how Huntington's disease appears to affect other physiological functions. One study in humans highlighted a systemic, early hypermetabolic state and a lower level of branched chain amino acids in the plasma as the disease progresses, which is hypothesised to be caused by the brain's use of these.

Diagnosis

To determine whether initial symptoms are evident, a physical and/or psychological examination is required. Abnormal movements are often the symptoms that cause initial impetus to seek medical consultation and lead to diagnosis; however, the disease may begin with cognitive or pyschiatric symptoms, which are not always recognized until they develop further. pre-symptomatic testing is possible using a blood test which counts the numbers of CAG repeats in each of the HTT alleles, although a positive result is not considered a diagnosis, since it may be obtained decades before onset of symptoms. A negative blood test means that the individual does not carry the expanded copy of the gene. A full pathological diagnosis can only be established by a neurological examination's findings and/or demonstration of cell loss in the areas affected by HD, supported by a cranial CT or MRI scan findings.

A pre-symptomatic test is a life-changing event and a very personal decision. The personal ramifications to an at-risk individual and lack of cure for the disease necessitate several counseling sessions to ensure that they are prepared for either result before it is given. Unless a person under eighteen years of age is considered to be Gillick competent, testing is not offered by many institutions unless they show significant symptoms or are sexually active. Many organisations and lay groups strongly endorse these restrictions in their testing protocol. Embryonic screening is also possible, giving affected or at-risk individuals the option of ensuring their children will not inherit the disease. If abortion is acceptable to the individual it is possible to test an embryo in the womb (prenatal diagnosis) but it can be ensured to have an unaffected child by utilising in vitro fertilisation and testing before implantation.

Management

There is no treatment to fully arrest the progression of the disease, but symptoms can be reduced or alleviated through the use of medication, rehabilitation methods, nutrition management and general care methods.

Pharmacological

Treatments for cognitive and psychological symptoms include antidepressants and sedatives, and low doses of antipsychotics. There is limited evidence for specific treatments aimed at controlling the chorea and other movement abnormalities, although tetrabenazine has been shown to reduce the severity of the chorea; it was approved in 2008 specifically for this indication.

Rehabilitation

Although there are relatively few studies of rehabilitation for HD, its general effectiveness when conducted by a team of specialists has been clearly demonstrated in other pathologies such as stroke, or head trauma. As for any patient with neurologic deficits, a multidisciplinary approach is key to limiting and overcoming disability. There is partial evidence for the usefulness of physiotherapy and speech therapy but most studies on the subject have been of low quality and further evidence is needed for health authorities to endorse them.

Nutrition

Nutrition is an important part of treatment; most people in the later stages of the disease require two to three times more calories than average to maintain body weight. Thickening agent can be added to drinks as swallowing becomes more difficult, as thicker fluids are easier and safer to swallow. The option of using a percutaneous endoscopic gastrostomy (i.e., a feeding tube into the stomach) is available when eating becomes too hazardous or uncomfortable. A "stomach PEG" greatly reduces the chances of aspiration of food, which can lead to aspiration pneumonia, one of the most common causes of death of the condition. A PEG also increases the amount of nutrients and calories that can be ingested, aiding the body's natural defenses.

Prognosis

The age of onset decreases, and the rate of progression of symptoms increase, with the number of CAG repeats. Individuals with greater than approximately 60 CAG repeats often develop juvenile Huntington's disease. There is a variation in age of onset for any given CAG repeat length, particularly within the intermediate range (40–50 CAGs). For example, a repeat length of 40 CAGs leads to an onset ranging from 40 to 70 years of age in one study. This variation means that, although algorithms have been proposed for predicting the age of onset, in practice, it can not be predicted confidently.

The life expectancy is around 15 to 20 years following the onset of characteristic manifestations of the disorder. Mortality is not caused by Huntington’s disease directly, but by associated complications; these include pneumonia (which causes one third of fatalities), heart failure (although heart disease, cerebrovascular disease and atherosclerosis show no increase), choking, malnutrition and physical injury. Suicide is an associated risk, with increased suicide rates of up to 7.3 percent, and attempted suicides of up to 27 percent.

Epidemiology

As HD is autosomal dominant, and does not usually affect reproduction, areas of increased prevalence occur according to historical migration of carriers, some of which can be traced back thousands of years using genetic haplotypes. Since the discovery of a genetic test that can also be used pre-symptomatically, estimates of the incidence of the disorder are likely to increase. Without the genetic test, only individuals displaying physical symptoms or neurologically examined cases were diagnosed, excluding any who died of other causes before symptoms or diagnosis occurred. These cases can now be included in statistics as the test becomes more widely available and estimates have shown the incidence of HD could be two to three times higher when these results are included.

The prevalence varies greatly according to geographical location, both by ethnicity and local migration; The highest occurrence is in peoples of Western Europe descent, averaging between 3 to 7 per 100,000 people, but is relatively lower in the rest of the world, e.g. 1 per 1,000,000 of Asian and African descent. Some localised areas have a much higher prevalence than their geographical average, for example the isolated populations of the Lake Maracaibo region of Venezuela (where the marker for the gene was discovered), have an extremely high prevalence of up to 700 per 100,000, leading to the conclusion that one of their initial founders must have been a carrier of the gene. This is known as the local founder effect.

History

In the first part of the twentieth century and earlier, many people with HD were misdiagnosed as suffering from alcoholism or manic depression. Previously mortality due to starvation or dehydration was a major risk.

  • Middle Ages: People with the condition were probably persecuted as being witches or as being possessed by spirits, and were shunned, exiled or worse. Some speculate that the "witches" in the Salem Witch Trials in 1692 had HD.
  • 1860: One of the early medical descriptions of HD was made in 1860 by a Norwegian district physician, Johan Christian Lund. He noted that in Setesdalen, a remote and rather secluded area, there was a high prevalence of dementia associated with a pattern of jerking movement disorders that tended to run in families. This is the reason for the disease being commonly referred to as Setesdalsrykkja (Setesdalen=the location, rykkja=jerking movements) in Norwegian.
  • 1872: George Huntington was the third generation of a family medical practice in Long Island. With their combined experience of several generations of a family with the same symptoms, he realised their conditions were linked and set about describing it. A year after leaving medical school, in 1872, he presented his accurate definition of the disease to a medical society in Middleport, Ohio.
  • c. 1902: Smith Ely Jelliffe (1866–1945) began studying the history of HD sufferers in New England and published several articles over the next few decades..
  • 1932: P. R. Vessie expanded Jelliffe and Tilney's work, tracing about a thousand people with HD back to two brothers and their families who left Bures in Suffolk, England bound for Boston, MA in 1630.
  • 1979: The US-Venezuela Huntington's Disease Collaborative Research Project began an extensive study which gave the basis for the gene to be discovered. This was conducted in the small, isolated Venezuelan fishing villages of Barranquitas and Lagunetas, where families have a high presence of the disease.
  • 1983: James Gusella, David Housman, P. Michael Conneally, Nancy Wexler, and their colleagues find the general location of the gene, using DNA marking methods for the first time—an important first step toward the Human Genome Project.
  • 1992: Anita Harding, et al. find that trinucleotide repeats affect disease severity
  • 1993: The Huntington's Disease Collaborative Research Group isolates the precise gene at 4p16.3.
  • 1996: A transgenic mouse (the R6 line) was created that could be made to exhibit HD, greatly advancing how much experimentation can be achieved.
  • 1997: DiFiglia M, Sapp E, Chase KO, et al., discover that mHtt fragments misfold, leading to the formation of nuclear inclusions.
  • The full record of research is extensive.

Society and culture

As public awareness has increased, HD has been depicted increasingly in numerous books, films and TV series. Early works were Arlo Guthrie's 1969 film Alice's Restaurant and Jacqueline Susann's 1966 American novel Valley of the Dolls; more recent references were made in ER, Private Practice, Everwood, All Saints, and House. Steven T. Seagle's 2004 graphic novel "It's a Bird" discusses Huntington's disease and the effects on his family. Many support organizations hold an annual HD awareness event, and some have been endorsed by their respective governments, for example, June 6 is designated "National Huntington's Disease Awareness Day" by the USA senate, and the UK HDA holds an awareness campaign in the third week of June.

Social impact

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 There have been guidelines created by the IHA and WFN for the use of genetic testing in HD, but many governments and institutions, although agreeing not to genetically discriminate against an individual, have not reached a consensus. As for the individual, the decision to undergo a presymptomatic test, thereby learning whether they will inherit the disorder, is a complicated one. Genetic counseling is designed to provide information, advice and support for a person to decide, and then throughout all stages of the testing process, if so chosen.

One of the key issues is the level of anxiety that an individual experiences about "not knowing" whether they will some day develop HD, compared to the psychological impact that might occur if the test indicates that one will eventually succumb to the disease. In contrast individuals found to have inherited the normal allele may experience Survivor guilt with regard to their affected family members. Some individuals choose not to undergo testing due to concerns about prejudice in areas such as insurability, employment and financial matters. An important ethical consideration is the testing of asymptomatic minors. As with other genetic conditions with later onset for which no treatment is available, it is ethically questionable to perform presymptomatic testing for a child or individual who has not made a mature, informed decision for themselves. Such information may cause psychological harm, jeopardize that individual's employment or ability to obtain health and life insurance. For this reason, presymptomatic testing in minors is a controversial area, with arguments in favor of permitting testing only when the individual is mature enough to provide assent versus minimizing medical paternalism in favor of parental preferences. The balance of opinion would change drastically if an effective treatment was discovered.

Genetic testing may infer information about relatives who do not want it. Testing a descendant of a undiagnosed parent has implications to other family members, since a positive result automatically reveals the parent as carrying the affected gene, and siblings (and especially identical twins) as being 'at risk' of also inheriting it. This emphasizes the importance of disclosure, as individuals have to decide when and how to reveal the information to their children and other family members. For those at risk, or known to carry a mutant allele, there can be the consideration of prenatal genetic testing and preimplantation genetic diagnosis in order to ensure that the disorder is not passed on.

Huntington's disease has tested society's ethics in various ways. HD was one of the targets of the eugenics movement, in which American scientist Charles Davenport proposed in 1910 that compulsory sterilization and immigration control be used for people with certain diseases, including HD. Since the development of genetic testing for HD, financial institutions and businesses are also faced with the question of whether to use results when assessing an individual, e.g. for life insurance or employment. Some countries' organizations have already agreed not to use this information. Recent passage of the Genetic Information Nondiscrimination Act (GINA) in the United States prevents health insurance companies from denying coverage or charging higher premiums for individuals with predisposition to genetic disease.

Organizations

  • 1967: Woody Guthrie's wife, Marjorie, helped found the Committee to Combat Huntington's Disease, after his death from HD complications. This eventually became the Huntington's Disease Society of America. Since then, lay organizations have been formed in many countries around the world.
  • 1968: After experiencing HD in his wife's family Dr. Milton Wexler was inspired to start the Hereditary Disease Foundation (HDF). Professor Nancy S. Wexler, Dr. Wexler's daughter, was in the research team in Venezuela and is now president of the HDF.
  • 1974: The first international meeting took place when the founders of the Canadian HD Society (Ralph Walker) and of the British HD Society (Mauveen Jones) attended the annual meeting of the American HD Society.
  • 1977: Second meeting organized by the Dutch Huntington Society the "Vereniging van Huntington", representatives of six countries were present.
  • 1979: International Huntington Association (IHA) formed during international meeting in Oxford, England organized by HDA of England.
  • 1981–2001: Biennial meetings held by IHA which became the World Congress on HD.
  • 2003: The first World Congress on Huntington's Disease was held in Toronto. This is a biennial meeting for associations and researchers to share ideas and research, which is held on odd-number years. The Euro-HD Network was started as part of the Huntington Project, funded by the High-Q Foundation.

Research directions

Appropriate animal models are critical for understanding the fundamental mechanisms causing the disease and for supporting the early stages of drug development. Neurochemically induced mice or monkeys were first available, but they did not mimic the progressive features of the disease. After the HD gene was discovered, transgenic animals exhibiting HD were generated by inserting a CAG repeat expansion into their genome, these were of mice (strain R6/2),), Drosophila fruit flies, and more recently monkeys. Expression without insertion of a CAG repeat in nematode worms also produced a valuable model.

Intrabody therapy

Genetically engineered intracellular antibody fragments called intrabodies have shown therapeutic results, by inhibiting mHtt aggregation, in drosophila models. This was achieved using an intrabody called C4 sFv, a single chain variable fragment which binds to the end of mHtt within a cell. This therapy prevented larval and pupal mortality (without therapy 77% died) and delayed neurodegeneration in the adult, significantly increasing their lifespan. Intrabody therapy shows promise as a tool for drug discovery, and as a potential therapy for HD and other neurodegenerative disorders caused by protein mis-folding or abnormal protein interactions.

Gene silencing

As HD has been conclusively linked to a single gene, gene silencing is potentially possible. Researchers have investigated using gene knockdown of mHTT as a potential treatment. Using a mouse model, siRNA therapy achieved a 60 percent reduction in expression of the mHTT and progression of the disease was stalled. However, this study used the human form of the mHTT protein in the mouse, and was therefore only able to directly target the mHTT, leaving endogenous, wild-type mouse Htt gene expression unaffected. From a practical standpoint, it would be difficult in humans to use siRNA to target the mutant form while leaving the normal copy unaffected. The precise function of HTT is unknown, but in mice, complete deletion of the Htt gene is lethal. Thus, using RNA interference to treat HD could have unexpected effects unless knock-down of the normal HTT protein can be avoided. Other issues include problems delivering the siRNA to the appropriate target tissue, off-target effects of siRNA, and toxicity from shRNA over-expression. Another study showed that mouse models already in late stages of the disease recovered motor function after expression of mHTT was stopped.

Stem cell implants

Stem cell therapy is the replacement of damaged neurons by transplantation of stem cells (or possibly neural stem cells - a type of somatic (adult) stem cell ) into affected regions of the brain. Hypothetically, embryonic stem cells can be differentiated into neuronal precursors in vitro, and transplanted into damaged areas of the brain to generate replacement neurons, if enough damaged neurons can be replaced and develop the correct synaptic connectivity, symptoms could be alleviated. This treatment would not prevent further neuronal damage, so it would have to be an ongoing treatment. Experiments have yielded some positive results in animal models, but remains highly speculative and has not been tested in clinical trials.

Pharmacological

As of August 2008, several trials of various compounds are in development or ongoing, a few at the point of testing on larger numbers of people, known as phase III of clinical trials. Substances that have shown promise in initial experiments include dopamine receptor blockers, select dopamine antagonists, such as tetrabenazine, creatine, CoQ10, the antibiotic Minocycline, antioxidant-containing foods and nutrients, and antidepressants, including selective serotonin reuptake inhibitors (SSRIs) such as sertraline, fluoxetine, and paroxetine.

References

Bibliography

External links

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