Huntington's disease
Huntington's disease | |
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Specialty | Neurology ![]() |
Frequency | 0.0123% (United Kingdom) |
Huntington's disease | |
---|---|
Specialty | Neurology ![]() |
Frequency | 0.0123% (United Kingdom) |
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 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 is one of the first inherited genetic disorders for which an accurate test can 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.
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.
Signs and symptoms
There is no sudden loss of abilities or exhibition of symptoms, but there is a progressive decline. Physical signs are usually the first noticed, but it is unknown how long before this that cognition and psychiatric condition are affected. Physical symptoms are almost always shown, cognitive symptoms are exhibited differently from person to person, and psychiatric problems may not be evident at all.
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, eating and mobility are extremely difficult, if not impossible, and full-time care is required.
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 (but not actual language skills), 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
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 already before the disease has broken out.[2] A number of related studies have been published.[3]
Causes
![](http://upload.wikimedia.org/wikipedia/commons/thumb/6/63/Autosomal_Dominant_Pedigree_Chart.svg/220px-Autosomal_Dominant_Pedigree_Chart.svg.png)
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. A sequence of fewer than 40 glutamine amino acid residues is the normal form, producing a 348 kDa cytoplasmic protein called huntingtin (Htt). If there are more repeats of CAG than this, a mutated form of Htt that causes the disease, mHtt, is produced. The continuous build up of the mHtt molecules in neuronal cells causes them to die off in selected regions of the brain. The speed of cell degeneration is generally proportional to the number of extra CAG repeats, also causing earlier onset of symptoms.
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 35 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, but tends to increase if inherited from the father.[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.
Mechanism
The continuous build up of mHtt molecules in neuronal cells causes cell death, especially in the frontal lobes and the basal ganglia (mainly in the caudate nucleus). Degeneration of the striatum (a part of the brain consisting of the caudate nucleus and the putamen) can be found. There is also neuronal loss and astrogliosis, as well as loss of medium spiny neurons, a GABAergic (the chief inhibitory neurotransmitter in the vertebrate central nervous system) result. 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. Intranuclear inclusions that stain for ubiquitin and Htt can be seen, as well as Htt in cortical neurites.
It is suspected that the cross-linking of Htt results in aggregates which are toxic, causing a mitochondrial dysfunction in the proteasome system, leading to neurons being damaged by excitotoxicity and oxidative stress.
The exact link between CAG repeats that produce mHtt and mitochondrial failure is unknown. There is evidence that aggregates may trap critical enzymes that are involved in energy metabolism.[citation needed] Some think that the cause of cell death is the splitting of the lysosome so that the hydrolytic enzymes within it are released. [citation needed]This will cause the cell membrane to split and the cell to die.
While theories as to how the mutation brings about disease remain diverse and speculative, researchers have identified many specific subcellular abnormalities associated with mHtt, as well as unusual properties of the protein in vitro. Just as one example, in 2002, Max Perutz, et al discovered that the glutamine residues form a nanotube in vitro, and the mutated forms are long enough in principle to pierce cell membranes.[5]
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.[6] 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".[7]
Diagnosis
To determine if 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 gene and 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 gene, will never develop symptoms, and cannot pass it on to children. A positive blood test means that the individual does carry 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, children under eighteen cannot 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 [8] and embryonic genetic screenings are also possible, giving gene-positive or at-risk individuals the option of making sure their children will be clear of 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.
Management
There is no treatment to fully stop the progression of the disease, but symptoms can be reduced or alleviated through the use of correct medication and care methods.
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.
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 pnuemonia 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.[9]
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.[10]
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.[11] Full recovery of motor function is observed in late stage Tet/HD94 mice after addition of doxycycline.[12]
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.[13]
The Folding@home project is the second largest distributed processing project on the internet. It models protein folding and HD is listed amongst the potential benefactors of its results.
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.[14] 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.[15]), rather than the disease itself. Life expectancy is generally between 10 and 25 years after the onset of obvious symptoms.
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.
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 organizations have already agreed not to use this information.
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), 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 [16], 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.
History
tombus is so good
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.[17] 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[18] was started as part of the Huntington Project[19], funded by the High-Q Foundation[20].
References
- ^ Mitchell IJ, Heims H, Neville EA, Rickards H. Huntington's disease patients show impaired perception of disgust in the gustatory and olfactory modalities. Journal of Neuropsychiatry and Clinical Neuroscience, 17:119-121, February 2005. PMID 15746492
- ^ Sprengelmeyer R, Schroeder U, Young AW, Epplen JT. "Disgust in pre-clinical Huntington's disease: a longitudinal study." Neuropsychologia. 2006;44(4):518-33. Epub 2005 Aug 11. PMID 16098998
- ^ PubMed search for "Huntington's disease" and "disgust"
- ^ RM Ridley, CD Frith, TJ Crow and PM Conneally (1988). "Anticipation in Huntington's disease is inherited through the male line but may originate in the female". Journal of Medical Genetics. 25: 589–595.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ Perutz, M.F., J.T. Finch, J. Berriman, and A. Lesk (2002). "Amyloid fibers are water-filled nanotubes". Proceedings of the National Academy of Sciences. 99: 5591–5595.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ Graham, RK, Y Deng, EJ Slow, B Haigh, N Bissada, G Lu, J Pearson, J Shehadeh, L Bertram, Z Murphy, SC Warby, CN Doty, S Roy, CL Wellington, BR Leavitt, LA Raymond, DW Nicholson, MR Hayden (2006-06-16). "Cleavage at the Caspase-6 site is required for neuronal dysfunction and degeneration due to mutant Huntingtin". Cell. 125: 1179–1191.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ S. Ubelacker. "Canadian Researchers cure Huntington's disease in mice". Retrieved 2006-07-16.
- ^ www.hdsa.org
- ^ Fasting Forestalls Huntington's Disease in Mice on friendsoffreedom.org
- ^ clinicaltrials.gov
- ^ Sirna Therapeutics. "Huntington's Disease Overview". Retrieved 2006-07-16.
- ^ Miguel Díaz-Hernández, Jesús Torres-Peraza, Alejandro Salvatori-Abarca, María A. Morán, Pilar Gómez-Ramos, Jordi Alberch, and José J. Lucas (October 19, 2005). "Full Motor Recovery Despite Striatal Neuron Loss and Formation of Irreversible Amyloid-Like Inclusions in a Conditional Mouse Model of Huntington's Disease". The Journal of Neuroscience. 25 (42): 9773–9781. Retrieved 2006-07-16.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ World health Article
- ^ The Huntington Disease lighthouse.org
- ^ http://www.huntington-assoc.com/Critical%20ab05.pdf]
- ^ Prejudice in a portrayal of Huntington’s disease, by Nancy S Wexler and Michael D Rawlins, in The Lancet, Vol 366 September 24,2005
- ^ Huntington's Disease Society of America
- ^ Euro-HD Network
- ^ Huntington Project
- ^ High-Q Foundation
Bibliography
- John P. Conomy, M.D., J.D. "Dr. George Sumner Huntington and the Disease Bearing His Name".
{{cite web}}
: CS1 maint: multiple names: authors list (link) - 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.
{{cite book}}
: CS1 maint: multiple names: authors list (link) - 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.
External links
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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
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