Huntington's disease

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Huntington's disease
Classification & external resources

George Huntington wrote a paper describing the disease in 1872.
ICD-10	G10.
ICD-9	333.4
OMIM	143100

Dementia in Huntington's disease
Classification & external resources

ICD-10	F02.2
ICD-9	294.1

Huntington's disease (HD), also known as Huntington disease and previously as Huntington's chorea and chorea maior, is a rare inherited neurological disorder affecting up to 8 people per 100,000. It affects 1 out of 20,000 people of Western European descent and 1 out of one million in people of Asian and African descent. It takes its name from the Ohio physician George Huntington who described it precisely in 1872 in his first medical paper. HD has been heavily researched in the last few decades and it was one of the first inherited genetic disorders for which an accurate test could be performed.

HD is caused by a trinucleotide repeat expansion in the Huntingtin (Htt) gene and is one of several polyglutamine (or PolyQ) diseases. This expansion produces an altered form of the Htt protein, mutant Huntingtin (mHtt), which results in neuronal cell death in select areas of the brain and is a terminal illness.

HD's most obvious symptoms are abnormal body movements called chorea and a lack of coordination, but it also affects a number of mental abilities and some aspects of personality. These physical symptoms commonly become noticeable in a person's forties, but can occur at any age. If the age of onset is below 20 years then it is known as Juvenile HD. Being a genetic disorder, there is currently no cure, but the symptoms are managed with medication and appropriate care.

Contents 1 Symptomatology and Pathology 1.1 Physical 1.2 Cognitive 1.3 Psychopathological 2 Inheritance 3 Causes 4 Mechanism 5 Diagnosis 6 Management 6.1 Medication 6.2 Nutrition 6.3 Potential Treatments 6.3.1 Gene silencing 6.3.2 Others 7 Prognosis 8 Epidemiology 8.1 Ethical aspects 9 Cultural references 10 History 10.1 Research and Discovery 10.2 Relevant organizations 11 References 12 Bibliography 13 External links 13.1 Professional and research 13.2 Support and advocacy

[edit] Symptomatology and Pathology

Although there is no sudden loss of abilities or exhibition of symptoms, there is a progressive decline. Physical signs are usually the first noticed, but it is unknown how long before this the cognitive and psychiatric deficits manifest. Physical symptoms are almost always visible, cognitive symptoms are exhibited differently from person to person, and psychiatric problems may not be evident. Degeneration of neuronal cells, especially in the frontal lobes, the basal ganglia, and caudate nucleus (the striatum) occurs. There is also astrogliosis and loss of medium spiny neurons. This results in the selective degeneration of the indirect (inhibitory) pathway of the basal ganglia, via the lateral pallidum and the subthalamic nucleus coupled pacemaker system.

[edit] Physical

Most people with HD eventually exhibit chorea, which is jerky, random, uncontrollable, rapid movements, although some exhibit very slow movement and stiffness (bradykinesia, dystonia). These abnormal movements gradually increase as the disease progresses, initially exhibited as general lack of coordination and an unsteady gait. This causes problems with loss of facial expression (called "masks in movement") or exaggerated facial gestures, ability to sit or stand stably, speech, chewing and swallowing (which can lead to weight loss if diet or eating methods are not adjusted accordingly^{[citation needed]}), and loss of determination. In the later stages of the disease, speaking is impaired with slurred words and uncontrollable movements of the mouth, eating and mobility are extremely difficult if not impossible, and full-time care is required.

[edit] Cognitive

Selective cognitive abilities are progressively impaired, whereas others remain intact. Abilities affected are executive function (planning; cognitive flexibility, abstract thinking, rule acquisition, initiating appropriate actions, and inhibiting inappropriate actions), psychomotor function (slowing of thought processes to control muscles), speech like slurring of the words and a bit of uncontrollable movement of the lips, perceptual and spatial skills of self and surrounding environment, selection of correct methods of remembering information (but not actual memory itself), and ability to learn new skills, depending on the affected parts of the brain.

[edit] Psychopathological

Psychopathological symptoms vary more than cognitive and physical symptoms, and may include anxiety, depression, a reduced display of emotions called blunting, egocentrism, aggressive behaviour, compulsivity which can cause addictions such as alcoholism and gambling, or hypersexuality.

Many patients are unable to recognize expressions of disgust in others and also don't show reactions of disgust to foul odors or tastes.^[1] The inability to recognize disgust in others appears in carriers of the Huntington gene before symptoms are manifest.^[2] A number of related studies have been published.^[3]

[edit] Inheritance

HD is autosomal dominant, needing only one affected allele from either parent to inherit the disease. Although this generally means there is a one in two chance of inheriting the disorder from an affected parent, the inheritance of HD and other trinucleotide repeat disorders is more complex.

When the gene has more than 36 copies of the repeated trinucleotide sequence, the DNA replication process becomes unstable and the number of repeats can change in successive generations. If the gene is inherited from the mother, the count is usually similar. Paternal inheritance tends to increase the number of repeats.^[4] Because of the progressive increase in length of the repeats, the disease tends to increase in severity and have an earlier onset in successive generations. This is known as anticipation.

[edit] Causes

See also: HD (gene)

The gene involved in HD, called the HD gene, is located on the short arm of chromosome 4 (4p16.3). The end of the HD gene has a sequence of three DNA bases, cytosine-adenine-guanine (CAG), that is repeated multiple times (i.e. ...CAGCAGCAG...), this is called a trinucleotide repeat. CAG is the codon for the amino acid glutamine, thus a CAG repeat may be termed a polyglutamine (polyQ) expansion. A sequence of fewer than 36 glutamine amino acid residues is the normal form, producing a 348 kDa cytoplasmic protein called huntingtin (Htt). A sequence of 40 or more CAG repeats produces a mutated form of Htt, mHtt. The greater the number of CAG repeats, the earlier the onset of symptoms.^[5] In genetically altered "knockin" mice, the mutant CAG repeat portion of the gene (which codes for the N-terminal end of mHtt) is all that is needed to cause disease.^[6] Aggregates of mHtt are present in the brains of both HD patients^[7] and HD mice ^[8], specifically in striatal neurons.^[9] These aggregates consist mainly of the amino terminal end of mHtt (CAG repeat), and are found in both the cytoplasm and nucleus of neurons.^[10] The presence of these aggregates however does not correlate with cell death.^[11] Thus mHtt acts in the nucleus but does not cause apoptosis through aggregation.^[12]

[edit] Mechanism

See also: Huntingtin

The exact mechanism by which mHtt causes or contributes towards neuronal cell death and HD symptoms remains unclear. Research exploring the actions of Htt and mHtt have shed light on the subject. Like all proteins Htt is first transcribed, then performs an action, and then is degraded. Both Htt and mHtt are cleaved (the first step in degradation) by Caspase-3, which removes the (amino end) N-terminal.^[13] Caspase-2 then further breaks down the amino terminal fragment of Htt, but cannot act upon mHtt.^[14] The mHtt amino fragments are thus able to affect gene expression in polyQ dependent transcription.^[15] Specifically, mHtt binds with TAF_II130, a coactivator to CREB dependent transcription.^[16] The mHtt N-fragments also interact with SP₁, thereby preventing it from binding to DNA.^[17] Thus mHtt alters the normal functioning of these proteins. Mutant Huntingtin also downregulates brain-derived neurotropic factor (BDNF) which protects striatal neurons.^[18] This loss of BDNF may contribute to striatal cell death, which does not follow apoptotic pathways as the neurons appear to die of starvation.^[19] Huntingtin appears to be involved in vesicle trafficking as it interacts with HIT1, a clathrin binding protein, to mediate endocytosis.^[20][21]

In the June 16, 2006 issue of Cell, scientists at the University of British Columbia (UBC) and Merck Labs presented findings that the neurodegeneration caused by mHtt is related to the caspase-6 enzyme cleaving the Htt protein. Transgenic mice that have caspase-6 resistant Htt did not show effects of HD.^[22] The researchers found "substantial support for the hypothesis that cleavage at the caspase-6 site in mHtt represents a crucial rate-limiting event in the pathogenesis of HD.... Our study highlights the importance of preventing cleavage of Htt at this site and also reinforces the importance of modulating excitotoxicity as a potential therapeutic approach for HD." In essence, scientists have managed to prevent the appearance of HD in genetically modified mice. Dr. Marian DiFiglia, a world-renowned HD researcher and neurobiologist at Harvard University, called this find "very important" and "extremely intriguing".^[23]

[edit] Diagnosis

To determine whether initial symptoms are evident, a physical and/or psychological examination is required. The uncontrollable movements are often the symptoms which cause initial alarm and lead to diagnosis; however, the disease may begin with cognitive or emotional symptoms, which are not always recognized. Every child of a person with HD has a fifty percent chance of inheriting the faulty copy of the gene and therefore the disease. Pre-symptomatic testing is possible by means of a blood test which counts the number of repetitions in the gene. A negative blood test means that the individual does not carry the expanded copy of the gene, will never develop symptoms, and cannot pass it on to children. A positive blood test means that the individual does carry the expanded copy of the gene, will develop the disease, and has a 50% chance of passing it on to children. A pre-symptomatic positive blood test is not considered a diagnosis, because it may be decades before onset. Because of the ramifications on the life of an at-risk individual, with no cure for the disease and no proven way of slowing it, several counseling sessions are usually required before the blood test. Unless a child shows significant symptoms of the juvenile form or is sexually active or considered to be Gillick competent, children under eighteen will not be tested. The members of the Huntington's Disease Society of America strongly encourage these restrictions in their testing protocol. A pre-symptomatic test is a life-changing event and a very personal decision. For those living in America, there is a list of testing centers available on the HDSA homepage^[24] and embryonic genetic screening is also possible, giving mutation-positive or at-risk individuals the option of making sure their children will not inherit the disease. Expense and the ethical considerations of abortion are potential drawbacks to these procedures. The full pathological diagnosis is established by a neurological examination's findings and/or demonstration of cell loss, especially in the caudate nucleus, supported by a cranial CT or MRI scan findings.

[edit] Management

There is no treatment to fully stop the progression of the disease, but symptoms can be reduced or alleviated through the use of medication and care methods. Huntington mice models exposed to better husbandry techniques, better access to water especially, lived much longer than mice who were not well cared for.

[edit] Medication

There are treatments available to help control the chorea, although these may have the side effect of aggravating bradykinesia or dystonia.

Other standard treatments to alleviate emotional symptoms include the use of antidepressants and sedatives, with antipsychotics (in low doses) for psychotic symptoms. Care needs to be taken with antipsychotic usage as people suffering psychotic symptoms of organic origin are often more sensitive to the side effects of these drugs.

[edit] Nutrition

Nutrition is an important part of treatment; most HD sufferers need two to three times the calories than the average person to maintain body weight, so a nutritionist's advice is needed (the normal population's average daily intake is approximately 2000 calories for women and 2500 for children and men).

Speech therapy can help by improving speech and swallowing methods. This advice should be sought early on, as the ability to learn is reduced as the disease progresses.

To aid swallowing, thickener can be added to drinks. The option of using a stomach PEG is available when eating becomes too hazardous or uncomfortable, this will reduce the chances of pneumonia due to aspiration of food and increase the amount of nutrients and calories that can be ingested.

EPA, an Omega-III fatty acid, slows and possibly reverses the progression of the disease. It is currently in FDA clinical trial, as Miraxion© (LAX-101), for prescription use. Clinical trials utilize 2 grams per day of EPA. In the United States, it is available over the counter in lower concentrations in Omega-III and fish oil supplements.

A calorie restrictive diet delays the onset of symptoms in HD mice.^[25]

[edit] Potential Treatments

Trials and research are conducted on Drosophila fruit flies and mice that have been genetically modified to exhibit HD, before moving on to human trials.

Research is reviewed on various websites for HD sufferers and their families, including the Huntington's Disease Lighthouse, Hereditary Disease Foundation, and Stanford HOPES websites. Primary research can be found by searching the National Library of Medicine's PubMed. Clinical trials of various treatments are ongoing, or yet to be initiated. For example, the US registrar of trials has nine that are currently recruiting volunteers.^[26]

[edit] Gene silencing

The most hopeful prospective treatment currently studied is based on gene silencing. Since HD is caused by expression of a single gene, silencing of the gene could theoretically halt the progression of the disease. One study with a mouse model of HD treated with siRNA therapy achieved 60% knockdown in expression of the defective gene. Progression of the disease halted.^[27] Full recovery of motor function is observed in late stage Tet/HD94 mice after addition of doxycycline.^[28]

[edit] Others

Other agents and measures that have shown promise in initial experiments include dopamine receptor blockers, creatine, CoQ10, the antibiotic Minocycline, exercise, antioxidant-containing foods and nutrients, antidepressants (notably, but not exclusively, selective serotonin reuptake inhibitors SSRIs, such as sertraline, fluoxetine, and paroxetine) and select Dopamine antagonists, such as Tetrabenazine.

Pig cell implants in HD trial: Living Cell Technologies in New Zealand has attempted trials with positive results in primates, but is yet to conduct a human trial.^[29]

[edit] Prognosis

Onset of HD seems to be correlated to the number of CAG repeats a person has in their HD gene. Generally, the higher the number of repeats the sooner is the onset.^[30] The number of repeats may change slightly with each successive generation, so that the age of onset may vary as well. Symptoms of Huntington’s disease usually become noticeable in the mid 30s to mid 40s.

Juvenile HD has an age of onset anywhere between infancy and 20 years of age. The symptoms of juvenile HD are different from those of adult-onset HD in that they generally progress faster and are more likely to exhibit rigidity and bradykinesia (very slow movement) instead of chorea.

Mortality is due to infection (mostly pneumonia), fall-related injuries, other complications resulting from HD, or suicide (The suicide rate for HD sufferers is much greater than the national average.^[31]), rather than the disease itself. Life expectancy is generally between 10 and 25 years after the onset of obvious symptoms.

[edit] Epidemiology

The prevalence is 5 to 8 per 100,000, varying geographically.

About 10 percent of HD cases occur in people under the age of 20 years. This is referred to as Juvenile HD, "akinetic-rigid", or "Westphal variant" HD.

[edit] Ethical aspects

Whether or not to have the test for HD Genetic counseling may provide perspective for those at risk of the disease. Some choose not to undergo HD testing due to numerous concerns (for example, insurability). Testing of grandchildren of a sufferer has serious ethical implications if their parent declines testing, as a positive result in a grandchild's test automatically diagnoses the parent. Parents and grandparents have to decide when and how to tell their children and grandchildren. The issue of disclosure also comes up when siblings are diagnosed with the disease, and especially in the case of identical twins. It is not unusual for entire segments of a family to become alienated as a result of such information or the withholding of it.

For those at risk, or known to have the disease, consideration is necessary prior to having children due to the genetically dominant nature of the disease. In vitro and embryonic genetic screening now make it possible (with 99% certainty) to have an HD-free child; however, the cost of this process can easily reach tens of thousands of dollars. Financial institutions are also faced with the question of whether to use genetic testing results when assessing an individual, e.g. for life insurance. Some countries organisations have already agreed not to use this information.

[edit] Cultural references

HD has been depicted in books, in films and in television programmes, including an episode of the BBC drama Waterloo Road, Arlo Guthrie's film Alice's Restaurant, Pål Johan Karlsen's 2002 Norwegian novel Daimler (main character Daniel Grimsgaard is afflicted), Nancy Werlin's "Double Helix" (Ava Samuels, Kayla Matheson and others), Kurt Vonnegut's novel Galapagos, "Valley of the Dolls" by Jacqueline Susann (night club singer Tony Polar has HD), and the book "Saving Jasey" by Diane Tulson (Trist, Jasey and their Grandfather). Ian McEwan, in his 2005 novel Saturday, has the character of Baxter suffering from HD, which the protagonist Dr Henry Perowne diagnoses correctly. However, in a comment published by the Lancet,^[32] Nancy Wexler and Michael Rowlins deplore that "Mc Ewan sadly reinforces the stigma and stereotypes from which families with Huntington's disease suffer, and which make them hide both their inheritance and their destiny". Woody Guthrie suffered with this disease and finally died from it. In the TV series "Everwood", Hannah's father has HD, and she undergoes testing to see if she has the inherent gene. At first she is afraid to learn the results, but is relieved when the test is negative.

[edit] History

[edit] Research and Discovery

• c300 There is evidence that doctors as far back as the Middle Ages knew of this disease. It was known, amongst other conditions with abnormal movements, as St Vitus dance. St Vitus is the Christian patron saint of epileptics who was martyred in 303.
• Middle ages. People with the condition were often 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.^[33]
• 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 one of three generations of medical practitioners 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.
• c1923 Smith Ely Jelliffe (1866-1945) and Frederick Tilney (1875-1938) began analyzing the history of HD sufferers in New England.
• 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 Essex for Suffolk bound for Boston in 1630.

• 1979 The U.S-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 and isolated Venezuelan fishing villages of Barranquitas and Lagunetas. Families there have a high presence of the disease, which has proved invaluable in the research 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^[34]
• 1993 The Huntington's Disease Collaborative Research Group isolates the precise gene at 4p16.3.
• 1996 A transgenic mouse was created that could be made to exhibit HD greatly advancing how much experimentation can be achieved.
• 1997 Researchers discovered that mHtt bunches up (misfolds) to form nuclear inclusions.
• The full record of research is extensive.^[35][36]

[edit] Relevant organizations

• 1967 Woody Guthrie's wife, Marjorie Guthrie, helped found the Committee to Combat Huntington's Disease, after his death whilst suffering from HD. This eventually became the Huntington's Disease Society of America.^[37] 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 Venezeula 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^[38] was started as part of the Huntington Project,^[39] funded by the High-Q Foundation.^[40]

[edit] References

[edit] Bibliography

• John P. Conomy, M.D., J.D.. Dr. George Sumner Huntington and the Disease Bearing His Name.
• P. R. Vessie (1932). "On the transmission of Huntington's chorea for 300 years – the Bures family group". Journal of Nervous and Mental Disease, Baltimore 76: 553-573. 
• G. Huntington (1872-04-13). "On Chorea". Medical and Surgical Reporter of Philadelphia 26 (15): 317-321. 
• Gillian Bates, Peter Harper, Lesley Jones (2002). Huntington's Disease - Third Edition. Oxford: Oxford University Press. ISBN 0-19-851060-8. 
• Article 143100 - Huntington Disease , Online Mendelian Inheritance in Man, Johns Hopkins University
• Article 606438 - Huntingtons Disease-Like 2 Online Mendelian Inheritance in Man, Johns Hopkins University
• History of Medicine Bulletin,The Johns Hopkins University, a biography of George Huntington and other relevant information.

[edit] External links

[edit] Professional and research

• Huntington Project - worldwide umbrella organization for the clinical research efforts for HD.
• Huntington Study Group
• Huntington's Disease Research - Research abstracts on HD.
• Huntington's Outreach Project for Education, at Stanford (HOPES) - A layperson's guide to HD
• Worldwide Education and Awareness for Movement Disorders - HD section
• University College London Huntington's Disease Research

[edit] Support and advocacy

• The International Huntington Association - Coordinates support organizations in 39 countries, and individual contacts in others.
• Hereditary Disease Foundation - Spearheaded Venezuela Collaborative Huntington's Disease Project.
• Huntington's Disease Lighthouse - Reports on the latest research and studies.
• Huntington's Disease Advocacy Center - Provides community support through shared stories and forums.
• Huntington's Disease Support Club
• Huntington's Disease Society of America
• Huntington Society of Canada - Resource materials, latest in Canadian and International HD research and description of comprehensive services portfolio to help families struggling with HD
• European HD Network
• Australian Huntington's Disease Association (NSW) Inc.
• Huntington's Disease Association UK
• [1] RTE Radio 1 programme on Huntington's Disease, featuring a family affected from Ireland. Podcast feed: www.rte.ie/radio1/podcast/podcast_mindmatters.xml