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| '''For patient information, click [[Huntington's disease (patient information)|here]]''' | | '''For patient information, click [[Huntington's disease (patient information)|here]]''' |
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| {{Infobox_Disease | | | {{Infobox_Disease | |
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| MeshID = D006816 | | | MeshID = D006816 | |
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| {{SI}} | | {{Huntington's disease}} |
| {{CMG}} | | {{CMG}} {{AE}} {{SAH}} {{KD}} |
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| ==Overview==
| | '''''Synonyms and keywords:''''' Huntington disease, HD, Huntington's chorea and chorea maior |
| '''Huntington's disease''' ('''HD'''), also mis-spelt as '''Huntington disease''' and previously as '''Huntington's chorea''' and '''chorea maior''', is a [[Rare disease|rare]] inherited [[neurological disorder]] affecting up to approximately 10 people per 100,000 people of Western European descent and 0.1 out of 100,000 in people of Asian and African descent. It takes its name from the New York physician [[George Huntington]] who described it concisely and 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 disorder]]s for which an accurate test could be performed. | |
| Huntington's disease is caused by a [[Trinucleotide repeat disorders|trinucleotide repeat expansion]] in the [[Huntingtin]] ('''Htt''') gene and is one of several '''[[trinucleotide repeat disorders|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. Huntington's disease is a terminal illness.
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| Huntington's disease's most obvious symptoms are abnormal body movements called [[Chorea (disease)|chorea]] and a lack of coordination, but it also affects a number of mental abilities and some aspects of personality. These physical symptoms occur in a large range of ages,with a mean occurence a person's late forties/early fifties <ref name="pmid2973230">{{cite journal |author=Adams P, Falek A, Arnold J |title=Huntington disease in Georgia: age at onset |journal=Am. J. Hum. Genet. |volume=43 |issue=5 |pages=695–704 |year=1988 |pmid=2973230 |doi=}}</ref>. If the age of onset is below 20 years then it is known as Juvenile HD. As there is currently no proven cure, symptoms are managed with various medications and care methods. | | == [[Huntington's disease overview|Overview]] == |
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| == Symptomatology and pathology == | | == [[Huntington's disease historical perspective|Historical Perspective]] == |
| 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 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.
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| Degeneration of [[neuron]]al cells, especially in the [[frontal lobe]]s, 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 [[globus pallidus|lateral pallidum]] and the subthalamic nucleus coupled pacemaker system.
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| === Physical === | | == [[Huntington's disease classification|Classification]] == |
| Most people with HD eventually exhibit jerky, random, uncontrollable movements called chorea, although some exhibit very slow movement and stiffness ([[bradykinesia]], [[dystonia]]). These abnormal movements are initially exhibited as general lack of coordination and an unsteady [[gait]] and gradually increase as the disease progresses; this eventually 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 and eating methods are not adjusted accordingly<ref>Gaba AM, Zhang K, Marder K, Moskowitz CB, Werner P, and Boozer CN. Energy balance in early-stage Huntington disease. ''Am J Clin Nutr.'' 2005; 81(6):1335-41. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=15941884 PMID 15941884]</ref><ref>[http://www.hsc-ca.org/english/pdf/Caregiver_Handbook.pdf Caregiver's Handbook for Advanced-Stage Huntington Disease.] Booklet by the Huntington Society of Canada, retrieved 2007-04-11.</ref>), 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.
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| === Cognitive === | | == [[Huntington's disease pathophysiology|Pathophysiology]] == |
| Selective cognitive abilities are progressively impaired, whereas others remain intact. Abilities affected are; [[Executive system|executive function]] (planning; cognitive flexibility, [[abstract thinking]], rule acquisition, initiating appropriate actions, and inhibiting inappropriate actions), [[Psychomotor retardation|psychomotor]] function (slowing of thought processes to control muscles), speech like slurring of the words and some 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.
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| === Psychopathological === | | == [[Huntington's disease causes|Causes]] == |
| Psychopathological symptoms vary more than cognitive and physical symptoms, and may include [[anxiety]], [[Clinical depression|depression]], a reduced display of emotions such as [[Blunted affect|blunting]], [[egocentrism]], [[Aggression|aggressive behavior]], [[Compulsion|compulsivity]] which can cause [[addictions]] such as [[alcoholism]] and [[gambling]], or [[hypersexuality]].
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| Many patients are unable to recognize expressions of [[disgust]] in others and also don't show reactions of disgust to foul odors or tastes.<ref>Mitchell IJ, Heims H, Neville EA, Rickards H. [http://www.neuro.psychiatryonline.org/cgi/content/full/17/1/119 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</ref> The inability to recognize disgust in others appears in carriers of the Huntington gene before symptoms are manifest.<ref>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 August 11. PMID 16098998</ref> A number of related studies have been published.<ref>[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&term=%22Huntington+Disease%22%5BMAJR%5D+disgust PubMed search for "Huntington's disease" and "disgust"]</ref>
| | == [[Huntington's disease differential diagnosis|Differentiating Huntington's disease from other Diseases]] == |
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| ==Inheritance== | | == [[Huntington's disease epidemiology and demographics|Epidemiology and Demographics]] == |
| [[Image:Autosomal Dominant Pedigree Chart.svg|thumb|right|HD is inherited in an [[autosomal dominant]] fashion.]] | |
| Huntington's disease 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. | |
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| 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.<ref>{{cite journal| author=RM Ridley, CD Frith, TJ Crow and PM Conneally| title=Anticipation in Huntington's disease is inherited through the male line but may originate in the female| journal=Journal of Medical Genetics| year=1988| volume=25| pages=589-595| url=http://jmg.bmjjournals.com/cgi/content/abstract/25/9/589}}</ref>
| | == [[Huntington's disease risk factors|Risk Factors]] == |
| 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 (genetics)|anticipation]].
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| [[De novo mutation]]s are rare. | | == [[Huntington's disease screening|Screening]] == |
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| Homozygous individuals generally do not show an earlier onset of disease, but may have an increased rate of decline.
| | == [[Huntington's disease natural history, complications and prognosis|Natural History, Complications and Prognosis]] == |
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| == Causes == | | ==[[Major or mild neurocognitive disorder due to Huntington's disease|Major or Mild Neurocognitive Disorder Due to Huntington's Disease]]== |
| {{see also|HD (gene)}}
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| The [[gene]] involved in Huntington's disease, called the [[HD (gene)|HD gene or Interesting Transcript 15 (IT15)]], is located on the short arm of [[chromosome 4 (human)|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 disorders|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.<ref>Kieburtz K, MacDonald M, Shih C, Feigin A, Steinberg K, Bordwell K, Zimmerman C, Srinidhi J, Sotack J, Gusella J, et al. Trinucleotide Repeat Length and Progression of Illness in Huntington's Disease. J ''Med Genet''. 1994; 31:872</ref>
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| 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.<ref>Murphy K, Carter R, Lione L, Mangiarini L, Mahal A, Bates G, Dunnett S, and Morton J. Abnormal Synaptic Plasticity and Impaired Spatiail Cognition in Mice Transgenic for Exon 1 of the Human Huntington’s Disease Mutation. ''Journal of Neuroscience'' 2000; 20:5115</ref> Aggregates of mHtt are present in the brains of both HD patients<ref>Difiglia M, Sapp E, Chase E, Davies K. et al. Aggregation of Huntingtin in Neuronal Intranuclear Inclusions and Dystrophic Neurites in Brain. ''Science'' 1997</ref> and HD mice,<ref>Davies S, Turmaine M, Cozens B, Difiglia M, Sharp A, Ross C, Scherzinger E, Wanker E, Mangiarini L, and Bates G. Formation of Neuronal Intranuclear Inclusions Underlies the Neurological Dysfunction in Mice Transgenic for the HD Mutation. ''Cell'' 1997; 90:537</ref> specifically in [[striatal neurons]].<ref>Li H, Li S, Johnston H, Shelbourne P, and Li X. Amino-terminal Fragments of Mutant Huntingtin Show Selective Accumulation in Striatal Neurons and Synaptic Toxicity. ''Nature Genetics'' 2000; 25:385</ref> These aggregates consist mainly of the amino terminal end of mHtt (CAG repeat), and are found in both the [[cytoplasm]] and [[Cell nucleus|nucleus]] of neurons.<ref>Cooper JK, Schilling G, Peters MF, Herring WJ, Sharp AH, Kaminsky Z, Masone J, Khan FA, Delanoy M, Borchelt DR, Dawson VL, Dawson TM, Ross CA. Truncated N-terminal Fragments of Huntingtin with Expanded Glutamine Repeats Form Nuclear and Cytoplasmic Aggregates in Cell Culture. ''Hum Mol Genet''. 1998; 7:783</ref> The presence of these aggregates however does not correlate with cell death.<ref>F. R. Fusco, Q. Chen, W. J. Lamoreaux, G. Figueredo-Cardenas, Y. Jiao, J. A. Coffman, D. J. Surmeier, M. G. Honig, L. R. Carlock, and A. Reiner. Cellular Localization of Huntingtin in Striatal and Cortical Neurons in Rats: Lack of Correlation with Neuronal Vulnerability in Huntington's Disease. ''J. Neurosci'' 1999; 19: 1189</ref> Thus mHtt acts in the nucleus but does not cause [[apoptosis]] through aggregation.<ref>Saudou F, Finkbeiner S, Devys, and Greenberg M. Huntingtin Acts in the Nucleus to Induce Apoptosis but Death Does Not Correlate with the Formation of Intranuclear Inclusions. ''Cell''. 1998; 95:55</ref>
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| ==Mechanism==
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| 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.
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| Like all proteins, Htt is [[Translation (genetics)|translated]], performs an action, and is finally degraded. Both Htt and mHtt are cleaved (the first step in degradation) by [[Caspase|Caspase-3]], which removes the (amino end) N-terminal.<ref>Kim YJ, Yi Y, Sapp E, Wang Y, Cuiffo B, Kegel KB, Qin ZH, Aronin N, DiFiglia M. Caspase 3-cleaved N-terminal Fragments of Wild-type and Mutant Huntingtin are Present in Normal and Huntington's Disease Brains, Associate with Membranes, and Undergo calpain-dependent proteolysis. ''Proc Natl Acad Sci'' U S A. 2001; 98:12784</ref> Caspase-2 then further breaks down the amino terminal fragment of Htt, but cannot act upon mHtt.<ref>Hermel E, Gafni J, Propp SS, Leavitt BR, Wellington CL, Young JE, Hackam AS, Logvinova AV, Peel AL, Chen SF, Hook V, Singaraja R, Krajewski S, Goldsmith PC, Ellerby HM, Hayden MR, Bredesen DE, Ellerby LM. Specific Caspase Interactions and Amplification are Involved in Selective Neuronal Vulnerability in Huntington's Disease. ''Cell Death Differ'' 2004; 11:424</ref> The mHtt amino fragments are thus able to affect gene expression in polyQ dependent [[Transcription (genetics)|transcription]].<ref>Freiman R, and Tjian R. A Glutamine-Rich Trail Leads to Transcription Factors. ''Science'' 2002; 296:2149</ref> Specifically, mHtt binds with TAF<sub>II</sub>130, a coactivator to [[CREB]] dependent transcription.<ref>Bae B.I, Xu H, Igarashi S, Fujimuro M, Agrawal N, Taya Y, Hayward S.D, Moran T.H, Montell C, Ross C.A, Snyder S.H, and Sawa A. p53 Mediates Cellular Dysfunction and Behavioral Abnormalities in Huntington's Disease. ''Neuron'' 2005; 47:29</ref> The mHtt N-fragments also interact with SP<sub>1</sub>, thereby preventing it from binding to [[DNA]].<ref>Dunah A, Jeong H, Griffin A, Kim Y, Standeart D, Hersch S, Mouradian M, Young A, Tanese N, and Krainc D. Sp1 and TAFII130 Transcriptional Activity Disrupted in Early Huntington’s Disease. ''Science'' 2002; 296: 2238</ref> Thus mHtt alters the normal functioning of these proteins.
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| Mutant Huntingtin also downregulates brain-derived neurotropic factor (BDNF) which protects striatal neurons.<ref>Canals J, Pineda J, Torres-Peraza J, Bosch M, Martin-Ibanez R, Munoz M, Mengod G, Ernfors P, and Alberch J. Brain Derived Neurotrophic Factor Regulates the Onset and Severity of Motor Dysfunction Associated with Enkephalinergic Neuronal Degeneration in Huntington’s Disease. ''Neurobiology of Disease'' 2004; 24:7727</ref> This loss of BDNF may contribute to striatal cell death, which does not follow apoptotic pathways as the neurons appear to die of starvation.<ref>Sawa A, Nagata E, Sutcliffe S, Dulloor P, Cascio MB, Ozeki Y, Roy S, Ross CA, Snyder SH. Huntingtin is Cleaved by Caspases in the Cytoplasm and Translocated to the Nucleus via Perinuclear Sites in Huntington's Disease Patient Lymphoblasts. ''Neurobiol Dis'' 2005</ref>
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| Huntingtin appears to be involved in vesicle trafficking as it interacts with HIT1, a [[clathrin]] binding protein, to mediate [[endocytosis]].<ref>Velier J, Kim M, Schwarz C, Kim T.W, Sapp E, Chase K, Aronin N, DiFiglia M. Wild-Type and Mutant Huntingtins Function in Vesicle Trafficking in the Secretory and Endocytic Pathways. ''Experimental Neurology'' 1998; 152:34</ref><ref>Waelter S, Scherzinger E, Hasenbank R, Nordhoff E, Lurz R, Goehler H, Gauss C, Sathasivam K, Bates G, Lehrach H, and Wanker E. The Huntingtin Interacting Protein HIP1 is a Clathrin and α–adaptin-binding Protein Involved in Receptor Mediated Endocytosis. ''Human Molecular Genetics'' 2001; 10:1807</ref>
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| In the [[June 16]], [[2006]] issue of ''[[Cell (journal)|Cell]]'', scientists at the [[University of British Columbia]] (UBC) and [[Merck & Co.|Merck Labs]] presented findings that the neurodegeneration caused by mHtt is related to the [[Caspase|caspase-6]] enzyme cleaving the Htt protein. Transgenic mice that have caspase-6 resistant Htt did not show effects of HD.<ref>{{cite journal| author=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| title=Cleavage at the Caspase-6 site is required for neuronal dysfunction and degeneration due to mutant Huntingtin| journal=[[Cell (journal)|Cell]] | date=2006-06-16 | volume=125| pages=1179-1191}}</ref> 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".<ref>{{cite web| title=Canadian Researchers cure Huntington's disease in mice| url=http://bodyandhealth.canada.com/channel_health_news_details.asp?news_id=10154&news_channel_id=11&channel_id=11|author=S. Ubelacker| accessdate=2006-07-16}}</ref>
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| == Diagnosis == | | == 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. [[wiktionary:pre-symptomatic|Pre-symptomatic]] testing is possible by means of a [[Genetic testing|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 Huntington's disease|juvenile form]] or is sexually active or considered to be [[Gillick competence|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<ref>[http://www.hdsa.org/site/PageServer?pagename=testing_centers www.hdsa.org]</ref> 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 [[Computed axial tomography|CT]] or [[MRI]] scan findings.
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| == Management ==
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| There is no treatment to fully arrest 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.
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| === Medication ===
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| There are treatments available to help control the [[Chorea (disease)|chorea]], although these may have the side effect of aggravating [[bradykinesia]] or [[dystonia]].
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| Other standard treatments to alleviate emotional symptoms include the use of [[antidepressant]]s and sedatives, with [[antipsychotic]]s (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.
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| === Nutrition ===
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| 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).
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| [[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.
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| To aid swallowing, thickener can be added to drinks. The option of using a [[Percutaneous endoscopic gastrostomy|stomach PEG]] is available when eating becomes too hazardous or uncomfortable, this will reduce the chances of pneumonia due to [[Aspiration pneumonia|aspiration]] of food and increase the amount of nutrients and calories that can be ingested.
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| [[Eicosapentaenoic acid|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. | | [[Huntington's disease history and symptoms|History and Symptoms]] | [[Huntington's disease physical examination|Physical Examination]] | [[Huntington's disease laboratory findings|Laboratory Findings]] | [[Huntington's disease CT|CT]] | [[Huntington's disease MRI|MRI]] | [[Huntington's disease other imaging findings|Other Imaging Findings]] | [[Huntington's disease other diagnostic studies|Other Diagnostic Studies]] |
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| A [[Calorie restriction|calorie restrictive]] diet delays the onset of symptoms in HD mice.<ref>Fasting Forestalls Huntington's Disease in Mice [http://www.friendsoffreedom.org/print.php?sid=1377 on friendsoffreedom.org]</ref>
| | == Treatment == |
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| === Potential treatments ===
| | [[Huntington's disease medical therapy|Medical Therapy]] | [[Huntington's disease primary prevention|Primary Prevention]] | [[Huntington's disease secondary prevention|Secondary Prevention]] | [[Huntington's disease cost-effectiveness of therapy|Cost Effectiveness of Therapy]] | [[Huntington's disease future or investigational therapies|Future or Investigational Therapies]] |
| Trials and research are conducted on [[Drosophila melanogaster|Drosophila fruit flies]] and mice that have been [[Genetically modified organism|genetically modified]] to exhibit HD, before moving on to human trials.
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| 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.<ref>[http://clinicaltrials.gov/ct/gui/action/FindCondition?ui=D006816 clinicaltrials.gov]</ref>
| | == Case Studies == |
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| ==== Intrabody Therapy ====
| | [[Huntington's disease case study one|Case #1]] |
| Engineered intracellular antibody fragments (intrabodies) have shown efficacy in vivo as therapeutic agents against pathogenic mutant huntingtin protein in fly models of HD. An intracellularly expressed single-chain Fv against the amino-terminal end of mutant huntingtin (mHtt) has been shown to reduce mHtt aggregate formation and increase turnover of the mHtt fragments in tissue culture models of HD.<ref>Lecerf, J. M., Shirley, T. L., Zhu, Q., Kazantsev, A., Amersdorfer, P., Housman, D. E., Messer, A. & Huston, J. S. Human single-chain Fv intrabodies counteract in situ huntingtin aggregation in cellular models of Huntington's disease. (2001) ''Proc. Natl. Acad. Sci. USA'' '''98''', 4764-4769.</ref><ref>Miller, T. W., Zhou, C., Gines, S., MacDonald, M. E., Mazarakis, N. D., Bates, G. P., Huston, J. S. & Messer, A. A human single-chain Fv intrabody preferentially targets amino-terminal huntingtin fragments in striatal models of Huntington's disease (2005) ''Neurobiol. Dis.'' '''19''', 47-56.</ref> In a drosophila HD model, the expression of this anti-HD intrabody rescued fly survival through the larval and pupal stages to adult emergence. Additionally, the intrabody delayed neurodegeneration in the fly model, and significantly increased the mean adult lifespan.<ref>Wolfgang WJ, Miller TW, Webster JM, Huston JS, Thompson LM, Marsh JL, Messer A. Suppression of Huntington's disease pathology in Drosophila by human single-chain Fv antibodies. (2005) ''Proc Natl Acad Sci USA'' '''32''':11563-8.</ref> The engineered antibody approach shows promise as a tool for drug discovery and as a potential novel therapeutic for other neurodegenerative disorders resulting from protein misfolding or abnormal protein interactions, including Parkinson’s, Alzheimer’s and prion diseases.<ref>Miller, T. W., Messer, A. Intrabody Applications in Neurological Disorders: Progress and Future Prospects. (2005) ''Molecular Therapy''. '''12''', 394-401.</ref>
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| ==== Gene silencing ====
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| The most hopeful prospective treatment currently studied is based on interrupting the effects of the HD gene within cells ( [[gene silencing]]). Since HD is caused by expression of a single gene, it makes an easier target, and silencing it should halt the progression of the disease. Some success has been achieved with mouse models; in a study with a mouse model of HD treated with [[siRNA]] therapy achieved 60% reduction [[knockdown]] in expression of the gene and progression of the disease was stalled.<ref name="pmid15811941">{{cite journal |author=Harper SQ, Staber PD, He X, ''et al'' |title=RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=102 |issue=16 |pages=5820–5 |year=2005 |pmid=15811941 |doi=10.1073/pnas.0501507102}}</ref> ,in another study, mouse models in late stages of the disease recovered their motor functions using [[doxycycline]].<ref>{{cite journal| author=Miguel Díaz-Hernández, Jesús Torres-Peraza, Alejandro Salvatori-Abarca, María A. Morán, Pilar Gómez-Ramos, Jordi Alberch, and José J. Lucas| title=Full Motor Recovery Despite Striatal Neuron Loss and Formation of Irreversible Amyloid-Like Inclusions in a Conditional Mouse Model of Huntington's Disease| journal=The Journal of Neuroscience|date=October 19, 2005| volume=25| issue=42| pages=9773-9781| url=http://www.jneurosci.org/cgi/content/abstract/25/42/9773| accessdate=2006-07-16}} </ref>
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| ==== Others ====
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| 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 [[SSRI]]s, such as sertraline, fluoxetine, and paroxetine) and select [[dopamine antagonists]], such as [[tetrabenazine]].
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| Living Cell Technologies in New Zealand has attempted pig cell implants in trials with positive results in primates, but has yet to conduct a human trial.<ref>[http://www.worldhealth.net/p/pig-cell-implants-in-huntingtons-trial-2005-08-19.html World health Article]</ref>
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| == Prognosis ==
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| 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.<ref>[http://hdlighthouse.org/abouthd/cag/updates/0029cagvonset.shtml The Huntington Disease lighthouse.org]</ref> 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.
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| 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.
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| 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.<ref>http://www.huntington-assoc.com/Critical%20ab05.pdf]</ref>), rather than the disease itself. Life expectancy is generally between 10 and 25 years after the onset of obvious symptoms.
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| == Epidemiology ==
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| The prevalence is 5 to 8 per 100,000, varying geographically.
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| About 10 percent of HD cases occur in people under the age of 20 years. This is referred to as [[Juvenile Huntington's disease|Juvenile HD]], '''"akinetic-rigid"''', or '''"Westphal variant"''' HD.
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| === Ethical aspects ===
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| 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 a descendant of a person 'at-risk', has serious ethical implications, as a positive result in a child's test automatically diagnoses the parent.
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| 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 twin]]s. It is not unusual for entire segments of a family to become alienated as a result of such information or the withholding of it.
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| 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. Another consideration regarding genetic testing is the fact that this kind of screening is a form of [[eugenics]]. Indeed, historically, Huntington's disease patients were one of the targets groups for the eugenic improvement of the human gene pool. The [[united states|American]] scientist [[Charles Davenport]] propsed in 1910 that compulsory sterilization and immigration control be aimed at those afflicted with HD (amongst other diseases) [http://books.google.com/books?id=4LVNI81VM50C&dq=&pg=PP1&ots=dmPQNIGTMg&sig=K_9OyIcAzGobT_uepwbk3S-GB5o&prev=http://www.google.com/search%3Fq%3Dheredity%2Bin%2Brelation%2Bto%2Beugenics%26rls%3Dcom.microsoft:en-us%26ie%3DUTF-8%26oe%3DUTF-8%26startIndex%3D%26startPage%3D1&sa=X&oi=print&ct=title]
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| 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.
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| == History ==
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| === Research and discovery ===
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| *c300 There is evidence that doctors as far back as the [[Middle Ages]] may have known of this disease. Along with other conditions with abnormal movements, it may have been referred to as St Vitus' dance. [[St Vitus]] is the Christian patron saint of epileptics who was martyred in 303.
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| *Middle Ages. People with the condition were probably persecuted as being [[Witch-hunt|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.<ref>The brief history of HD [http://www.stanford.edu/group/hopes/sttools/print/p_r_timeline.pdf on stanford.edu]</ref>
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| *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 language|Norwegian]].
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| *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.
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| *c1923 [[Smith Ely Jelliffe]] (1866-1945) and Frederick Tilney (1875-1938) began analyzing the history of HD sufferers in New England.
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| *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.
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| *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.
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| *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]].
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| *1992 [[Anita Harding]],et al. find that trinucleotide repeats affect disease severity<ref>PMID 1303283</ref>
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| *1993 The Huntington's Disease Collaborative Research Group isolates the precise gene at 4p16.3.
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| *1996 A [[transgenic]] mouse ([the R6 line]) was created that could be made to exhibit HD greatly advancing how much experimentation can be achieved.
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| *1997 Researchers discovered that mHtt aggregates ([[Protein folding|misfolds]]) to form [[Inclusion bodies|nuclear inclusions]].
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| *{{cite web|url=http://www.mayoclinic.org/news2007-rst/4019.html |title=Mayo Clinic Discovers DNA Repair as Key to Huntington's Disease |accessdate=2007-04-23 |date=April 22, 2007 |work=Mayo Clinic }}
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| *The full record of research is extensive.<ref>Achievements of [http://www.hdfoundation.org/achievements.php Hereditary Disease Foundation]</ref><ref>HDA research news - medical research into treatment & prevention [http://www.hda.org.uk/charity/research.html on hda.org.uk]</ref><ref>Bates G, Harper PS, Jones L (2002) Huntington's disease, 3rd Edition. Oxford: Oxford University Press.</ref>
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| === Organizations ===
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| *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.<ref>[http://www.hdsa.org Huntington's Disease Society of America]</ref> Since then, lay organizations have been formed in many countries around the world.
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| *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.
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| *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
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| *1977 second meeting organized by the Dutch Huntington Society the "Vereniging van Huntington", representatives of six countries were present.
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| *1979 International Huntington Association (IHA) formed during international meeting in Oxford (England) organized by HDA of England.
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| *1981-2001 Biennial meetings held by IHA which became the World Congress on HD.
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| *2003 the first [http://www.worldcongress-hd.net 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<ref>[http://www.euro-hd.net Euro-HD Network]</ref> was started as part of the Huntington Project,<ref>[http://www.huntingtonproject.org Huntington Project]</ref> funded by the High-Q Foundation.<ref>[http://www.highqfoundation.org High-Q Foundation]</ref>
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| ==References==
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| {{reflist|2}}
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| ==Bibliography==
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| *{{cite web| author=John P. Conomy, M.D., J.D.| url=http://www.lkwdpl.org/hdsa/conomy.htm| title=Dr. George Sumner Huntington and the Disease Bearing His Name}}
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| * {{cite journal| author=P. R. Vessie| title=On the transmission of Huntington's chorea for 300 years – the Bures family group| journal=Journal of Nervous and Mental Disease, Baltimore| year=1932| volume=76| pages=553-573}}
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| * {{cite journal| author=G. Huntington| title=On Chorea| journal=Medical and Surgical Reporter of Philadelphia| volume=26| issue=15| date=1872-04-13| pages=317-321}}
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| * {{cite book| author=Gillian Bates, Peter Harper, Lesley Jones| title=Huntington's Disease - Third Edition| publisher=Oxford University Press| location=Oxford| year=2002| id=ISBN 0-19-851060-8}}
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| * [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=143100 Article 143100 - Huntington Disease], ''[[Online Mendelian Inheritance in Man]]'', [[Johns Hopkins University]]
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| * [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=606438 Article 606438 - Huntingtons Disease-Like 2] ''[[Online Mendelian Inheritance in Man]]'', [[Johns Hopkins University]]
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| * [http://www.shv.ch/download/BiographyGeorgeHuntington.doc ''History of Medicine Bulletin''],[[The Johns Hopkins University]], a biography of George Huntington and other relevant information.
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| == See also == | | == See also == |
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| [[Category:Genetic disorders]]
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| [[Category:Neurology]]
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| | [[Category:Overview complete]] |
