Huntington's disease
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225810995
2008-07-15T14:48:41Z
SilkTork
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{{Infobox Disease |
Name = {{PAGENAME}} |
Image = georgehuntington.jpg |
Caption = [[George Huntington]]'s 1872 paper described the disorder. |
DiseasesDB = 6060 |
ICD10 = {{ICD10|G|10||g|10}}, {{ICD10|F|02|2|f|00}} |
ICD9 = {{ICD9|333.4}}, {{ICD9|294.1}} |
ICDO = |
OMIM = 143100 |
MedlinePlus = |
eMedicineSubj = |
eMedicineTopic = |
MeshID = D006816 |
}}
'''Huntington's disease''', also called '''Huntington's chorea''', '''chorea major''', or '''HD''', is a [[Genetics|genetic]] [[Neurodegenerative disease|neurological disorder]] characterized by abnormal body movements called [[Chorea (disease)|chorea]] and a lack of coordination; it also affects a number of mental abilities and some aspects of behavior.
The name is derived from the physician [[George Huntington]] who described the disorder in 1872. In 1993 the gene causing HD was found, making it one of the first inherited [[genetic disorder]]s for which an accurate test could be performed. Because of this, and the disorder having aspects applicable to other neurological disorders such as [[Alzheimer's disease]], it has been extensively researched since then.
The gene causing the disorder is [[dominance relationship|dominant]] and may, therefore, be inherited from a single parent. Global incidence varies, from 3 to 7 per 100,000 people of Western European descent, down to 1 per 1,000,000 of Asian and African descent. The onset of physical symptoms in Huntington's disease occur in a large range around a [[arithmetic mean|mean]] of a person's late forties to early fifties. If symptoms become noticeable before a person is twenty, then their condition is known as '''Juvenile HD'''.
<!-- Note: Huntingtin protein and gene are correctly spelled with an 'i' in place of the 'o'. -->
Huntington's disease is one of several [[trinucleotide repeat disorders|polyglutamine]] diseases caused by a [[Trinucleotide repeat disorders#Trinucleotide repeat expansion|trinucleotide repeat expansion]]. This expansion is in the [[Huntingtin]] [[gene]], which normally codes for [[Huntingtin protein]] (Htt), producing mutant Huntingtin (mHtt). The presence of this protein increases the rate of [[neuron]] [[cell death]] in select areas of the [[brain]], affecting certain neurological functions. The loss of neurons isn't fatal, but complications caused by symptoms reduce life expectancy. There is currently no proven cure, so symptoms are managed with a range of medications and supportive services.
== Symptoms ==
Symptoms increase in severity progressively, but aren't often recognised until they reach certain stages. Physical symptoms are usually the first to cause problems and be noticed, but these are accompanied by [[cognition|cognitive]] and [[psychiatry|psychiatric]] ones which aren't often recognized. Almost everyone with Huntington's Disease eventually exhibits all physical symptoms, but cognitive symptoms vary, and so any [[psychopathology|psychopathological]] problems caused by these, also vary per individual. The symptoms of juvenile HD differ in that they generally progress faster and are more likely to exhibit rigidity and [[bradykinesia]] instead of chorea and often include [[seizure]]s.<ref name="Huntington1">Kremer B. Clinical neurology of Huntington's disease. In: Huntington's Disease (Third ed.), edited by Bates GP, Harper PS and Jones L. Oxford: Oxford University Press, 2002, p. 28-61.</ref>
=== Physical ===
The most characteristic symptoms are jerky, random, and uncontrollable movements called [[Chorea (disease)|chorea]], although sometimes very slow movement and stiffness ([[bradykinesia]], [[dystonia]]) can occur instead or in later stages. These abnormal movements are initially exhibited as general lack of coordination, an unsteady [[gait (human)|gait]] and slurring of speech. As the disease progresses, any function that requires muscle control is affected, this causes reduced physical stability, abnormal facial expression, impaired speech comprehensibility, and difficulties chewing and [[Dysphagia|swallowing]]. Eating difficulties commonly cause weight loss.<ref>{{cite journal |author=Gaba AM, Zhang K, Marder K, Moskowitz CB, Werner P, Boozer CN |title=Energy balance in early-stage Huntington disease |journal=Am. J. Clin. Nutr. |volume=81 |issue=6 |pages=1335–41 |year=2005 |pmid=15941884 |doi=}}</ref><ref>[http://www.hdac.org/caregiving/pdf/Caregiver_Handbook.pdf Caregiver's Handbook for Advanced-Stage Huntington Disease.] Booklet by the Huntington Society of Canada, retrieved 2007-04-11.</ref> HD has been associated with [[Circadian rhythm|sleep cycle]] disturbances, including [[insomnia]] and [[Rapid_eye_movement_sleep | rapid eye movement sleep]] alterations.<ref>{{cite journal |author=Arnulf I, Nielsen J, Lohmann E, Schieffer J, Wild E, Jennum P, Konofal E, Walker M, Oudiette D, Tabrizi S, Durr A |title=Rapid eye movement sleep disturbances in Huntington disease. |journal=Arch Neurol |volume=65 |issue=4 |pages=482–488 |year=2008 | month=April |pmid=18413470 |doi=}}</ref>
Counter intuitively, there may be some health benefits as carriers of the gene are hypothesized to have higher levels of the tumor suppressor [[p53 (protein)|protein p53]] and a better than average immune system than non-carriers. As of April 2008, neither of these hypotheses have been supported by rigorous study.<ref>{{cite journal |author=Eskenazi BR, Wilson-Rich NS, Starks PT |title=A Darwinian approach to Huntington's disease: Subtle health benefits of a neurological disorder |journal=Med. Hypotheses |volume=69 |issue=6 |pages=1183–9 |year=2007 |pmid=17689877 |doi=10.1016/j.mehy.2007.02.046 |url=}}</ref>
=== Cognitive ===
Selective cognitive abilities are progressively impaired, including [[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), [[perceptual]] and [[spatial]] skills of self and surrounding environment, selection of correct methods of remembering information (but not actual [[memory]] itself), short-term memory, and ability to learn new skills, depending on the [[pathology]] of the individual.<ref>[http://www.topalbertadoctors.org/NR/rdonlyres/81361178-AF09-4C92-8B21-6D3CD3841037/0/cognitive_impairment_symptoms_to_diagnosis_guideline.pdf]Cognitive Impairment: Symptoms to Diagnosis Toward Optimized Practice. 2007</ref>
=== Psychopathological ===
Psychopathological symptoms vary more than cognitive and physical ones, and may include [[anxiety]], [[Clinical depression|depression]], a reduced display of emotions ([[blunted affect]]) and decreased ability to recognize negative expressions like anger, disgust, fear or sadness in others,<ref name="pmid17584778">{{cite journal |author=Johnson SA, Stout JC, Solomon AC, ''et al'' |title=Beyond disgust: Impaired recognition of negative emotions prior to diagnosis in Huntington's disease |journal=Brain |volume=130 |issue=Pt 7 |pages=1732–44 |year=2007 |pmid=17584778 |doi=10.1093/brain/awm107}}</ref> [[egocentrism]], [[aggression]], and [[compulsive behavior]]. The latter can cause, or worsen, [[hypersexuality]] and [[addictions]] such as [[alcoholism]] and [[gambling]].{{Fact|date=May 2008}}
==Genetics==
{{see also|Trinucleotide repeat disorders}}
The gene involved in Huntington's disease, called [[Huntingtin]] (Htt), or Interesting Transcript 15 (IT15) gene, known historically as the HD gene, is located on the short arm of [[chromosome 4 (human)|chromosome 4]] (4p16.3). In the first part, called the [[Directionality (molecular biology)|5' end]] of the gene, is a sequence of three [[DNA]] [[nucleobase|bases]]—[[cytosine]]-[[adenine]]-[[guanine]] (CAG)— repeated multiple times (i.e. ...CAGCAGCAG...) and known as a [[Trinucleotide repeat disorders|trinucleotide repeat]]. CAG is the [[genetic code]] for the [[amino acid]] [[glutamine]]; thus a series of CAG forms a chain of glutamine known as polyglutamine (polyQ).<ref>{{cite journal |author=Katsuno M, Banno H, Suzuki K, ''et al'' |title=Molecular genetics and biomarkers of polyglutamine diseases |journal=Curr. Mol. Med. |volume=8 |issue=3 |pages=221–34 |year=2008 |month=May |pmid=18473821 |doi= |url=http://www.bentham-direct.org/pages/content.php?CMM/2008/00000008/00000003/0005M.SGM}}</ref>
{| class="wikitable" style="float:right"
|-
! Effect
! classification
! repeat count
|-
| unaffected
| normal
| < 27
|-
|
| intermediate
| 27 - 35
|-
| affected
| Reduced Penetrance
| 36 - 39
|-
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| Full Penetrance
| > 39
|}
A polyQ length of less than 36 glutamines produces a [[cytoplasmic]] [[protein]] called [[huntingtin protein]] ('''Htt'''), whereas a sequence of 36 or more produces an erroneous form of Htt, '''mHtt''' (standing for mutant Htt), this causes certain neurons, in select areas of the brain, to have an increased mortality. As the number of neurons reduces in these areas their functionality is impaired. Generally, the number of CAG repeats is related to the rate that these neurons die, affecting the age at onset and progression of symptoms.<ref>{{cite journal |author=Kieburtz K, MacDonald M, Shih C, ''et al'' |title=Trinucleotide repeat length and progression of illness in Huntington's disease |journal=J. Med. Genet. |volume=31 |issue=11 |pages=872–4 |year=1994 |pmid=7853373 |doi=}}</ref> Counts of 36-39 repeats result in later onset and slower progression of symptoms termed "reduced [[penetrance]]". No case of HD has been diagnosed with a count of less than 36.<ref>Chong, S.S., Almqvist, E., Telenius, ''et al'': (1997). Contribution of DNA sequence and CAG size to mutation frquences of intermediate alleles for Huntington Disease: Evidence from single sperm analyses. Human Molecular Genetics 6:302-309</ref>
===Inheritance===
[[Image:Autosomal Dominant Pedigree Chart2.svg|thumb|270px|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 is more complex due to potential [[dynamic mutation]]s, where [[DNA replication]] doesn't produce an exact copy of itself. This can cause the number of repeats to change in successive generations. This can mean that a parent with a count close to the threshold, may pass on a gene with a count either side of the threshold. Repeat counts maternally inherited are usually similar, whereas paternally inherited ones tend to increase.<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| pmid=2972838}}</ref> This potential increase in repeats in successive generations is known as [[anticipation (genetics)|anticipation]].
In families where neither parent has HD, [[De novo mutation|new mutations]] account for truly sporadic cases of the disease. The frequency of these ''de novo'' mutations is extremely low.<ref>{{cite journal| author=Myers ''et al.''| title=De novo expansion of a (CAG)n repeat in sporadic Huntington's disease| journal=Nature Genetics| year=1993| volume=5| pages=168-173| url=http://www.nature.com/ng/journal/v5/n2/abs/ng1093-168.html| doi=doi:10.1038/ng1093-168}}</ref>,<ref>{{cite journal| author=Sánchez A, Milà M, Castellví-Bel S, Rosich M, Jiménez D, Badenas C, Estivill X.| title=Maternal transmission in sporadic Huntington's disease| journal=J Neurol Neurosurg Psychiatry| year=1997| volume=62| issue=5| pages=535-537| url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=9153618| pmid=9153618}}</ref>
[[Homozygous]] individuals, who carry two mutated genes because both parents passed on one, are rare. While HD seemed to be the first disease for which homozygotes did not differ in clinical expression or course from typical heterozygotes<ref name="pmid2881213">{{cite journal |author=Wexler NS, Young AB, Tanzi RE, ''et al'' |title=Homozygotes for Huntington's disease |journal=Nature |volume=326 |issue=6109 |pages=194–197 |year=1987 |pmid=2881213 |doi=10.1038/326194a0}}</ref>, more recent analysis suggest that homozygosity affects the phenotype and the rate of disease progression though it does not alter the age of onset<ref>{{cite journal |author=Squitieri F, Gellera C, Cannella M, Mariotti C, Cislaghi G, Rubinsztein DC, Almqvist EW, Turner D, Bachoud-Lévi AC, Simpson SA, Delatycki M, Maglione V, Hayden MR, Donato SD |title=Homozygosity for CAG mutation in Huntington disease is associated with a more severe clinical course |journal=Brain |volume=126 |issue=4 |pages=946-955 |year=2003 |pmid=12615650| url=http://brain.oxfordjournals.org/cgi/content/full/126/4/946}}</ref> suggesting that the mechanisms underlying the onset and the progression are different.
==Mechanism==
{{see also|Huntingtin protein}}
Like all proteins, Htt and mHtt are [[Translation (biology)|translated]], perform or affect [[biology|biological]] functioning, and are finally dissolved in a process called [[biodegradation]]. The exact role mHtt has in DNA replication and its influence in [[apoptosis|programmed cell death]] is unknown. Research focuses on identifying the functioning of Htt, how mHtt differs or interferes with it, and the detrimental effects of remnants of mHtt left after biodegradation ([[Proteopathy]]).
===Function===
The Htt protein is involved in [[vesicle (biology)|vesicle]] trafficking as it interacts with HIT1, a [[clathrin]] binding protein, to mediate [[endocytosis]], the absorption of materials into a cell.<ref>{{cite journal |author=Velier J, Kim M, Schwarz C, ''et al'' |title=Wild-type and mutant huntingtins function in vesicle trafficking in the secretory and endocytic pathways |journal=Exp. Neurol. |volume=152 |issue=1 |pages=34–40 |year=1998 |pmid=9682010 |doi=10.1006/exnr.1998.6832}}</ref><ref>{{cite journal |author=Waelter S, Scherzinger E, Hasenbank R, ''et al'' |title=The huntingtin interacting protein HIP1 is a clathrin and alpha-adaptin-binding protein involved in receptor-mediated endocytosis |journal=Hum. Mol. Genet. |volume=10 |issue=17 |pages=1807–17 |year=2001 |pmid=11532990| doi = 10.1093/hmg/10.17.1807 <!--Retrieved from CrossRef by DOI bot-->}}</ref>
The mHtt protein reduces the production of [[brain-derived neurotrophic factor]] (BDNF). BDNF protects neurons and regulates the [[neurogenesis]] of new ones. The precise way it does this is unknown but a reduction in its level increases neuron cell death and creation, leading to atrophy of areas of the brain.<ref>{{cite journal |author=Canals JM, Pineda JR, Torres-Peraza JF, ''et al'' |title=Brain-derived neurotrophic factor regulates the onset and severity of motor dysfunction associated with enkephalinergic neuronal degeneration in Huntington's disease |journal=J. Neurosci. |volume=24 |issue=35 |pages=7727–39 |year=2004 |pmid=15342740 |doi=10.1523/JNEUROSCI.1197-04.2004}}</ref><ref>{{cite journal |author=Sawa A, Nagata E, Sutcliffe S, ''et al'' |title=Huntingtin is cleaved by caspases in the cytoplasm and translocated to the nucleus via perinuclear sites in Huntington's disease patient lymphoblasts |journal=Neurobiol. Dis. |volume=20 |issue=2 |pages=267–74 |year=2005 |pmid=15890517 |doi=10.1016/j.nbd.2005.02.013}}</ref><ref name="pmid17959817">{{cite journal |author=Strand AD, Baquet ZC, Aragaki AK, ''et al'' |title=Expression profiling of Huntington's disease models suggests that brain-derived neurotrophic factor depletion plays a major role in striatal degeneration |journal=[[J. Neurosci.]] |volume=27 |issue=43 |pages=11758–68 |year=2007 |month=October |pmid=17959817 |doi=10.1523/JNEUROSCI.2461-07.2007 |url=http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=17959817}}</ref>
===Degradation===
Both Htt and mHtt are cleaved (the first step in degradation) by [[caspase|caspase-3]], which removes the protein's amino end (the [[N-terminus|N-terminal]]).<ref>{{cite journal |author=Kim YJ, Yi Y, Sapp E, ''et al'' |title=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 |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=98 |issue=22 |pages=12784–9 |year=2001 |pmid=11675509 |doi=10.1073/pnas.221451398}}</ref> Caspase-2 then further breaks down the amino terminal fragment (the part with the CAG repeat) of Htt, but cannot process all of the mHtt protein.<ref>{{cite journal |author=Hermel E, Gafni J, Propp SS, ''et al'' |title=Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington's disease |journal=Cell Death Differ. |volume=11 |issue=4 |pages=424–38 |year=2004 |pmid=14713958 |doi=10.1038/sj.cdd.4401358}}</ref> The unprocessed pieces left in the cell are called aggregates, or N-fragments, and are able to affect genetic [[Transcription (genetics)|transcription]].<ref>{{cite journal |author=Freiman RN, Tjian R |title=Neurodegeneration. A glutamine-rich trail leads to transcription factors |journal=Science |volume=296 |issue=5576 |pages=2149–50 |year=2002 |pmid=12077389 |doi=10.1126/science.1073845}}</ref> Specifically, mHtt binds with [[TAF4|TAF<sub>II</sub>130]], a coactivator to [[CREB]] dependent transcription.<ref>{{cite journal |author=Bae BI, Xu H, Igarashi S, ''et al'' |title=p53 mediates cellular dysfunction and behavioral abnormalities in Huntington's disease |journal=Neuron |volume=47 |issue=1 |pages=29–41 |year=2005 |pmid=15996546 |doi=10.1016/j.neuron.2005.06.005}}</ref> The aggregates also interact with the [[transcription factor]] protein [[Sp1|SP<sub>1</sub>]], preventing it from binding to [[DNA]].<ref>{{cite journal |author=Dunah AW, Jeong H, Griffin A, ''et al'' |title=Sp1 and TAFII130 transcriptional activity disrupted in early Huntington's disease |journal=Science |volume=296 |issue=5576 |pages=2238–43 |year=2002 |pmid=11988536 |doi=10.1126/science.1072613}}</ref>
In transgenic mice neurodegeneration caused by mHtt is related to the [[Caspase|caspase-6]] enzyme cleaving the Htt protein, as they did not show effects of HD in experiments.<ref name="pmid16777606">{{cite journal |author=Graham RK, Deng Y, Slow EJ, ''et al'' |title=Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin |journal=Cell |volume=125 |issue=6 |pages=1179–91 |year=2006 |pmid=16777606 |doi=10.1016/j.cell.2006.04.026}}</ref>
In genetically altered "knockin" mice, the extended CAG repeat portion of the gene is all that is needed to cause disease.<ref>{{cite journal |author=Murphy KP, Carter RJ, Lione LA, ''et al'' |title=Abnormal synaptic plasticity and impaired spatial cognition in mice transgenic for exon 1 of the human Huntington's disease mutation |journal=J. Neurosci. |volume=20 |issue=13 |pages=5115–23 |year=2000 |pmid=10864968 |doi=}}</ref> Aggregates of mHtt are present in the brains of people and mice with HD,<ref name="pmid9302293">{{cite journal |author=DiFiglia M, Sapp E, Chase KO, ''et al'' |title=Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain |journal=Science |volume=277 |issue=5334 |pages=1990–3 |year=1997 |pmid=9302293 |doi=10.1126/science.277.5334.1990}}</ref><ref>{{cite journal |author=Davies SW, Turmaine M, Cozens BA, ''et al'' |title=Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation |journal=Cell |volume=90 |issue=3 |pages=537–48 |year=1997 |pmid=9267033| doi = 10.1016/S0092-8674(00)80513-9 <!--Retrieved from CrossRef by DOI bot-->}}</ref> and are most prevalent in [[Pyramidal cell|cortical pyramidal neurons]], less so in [[Medium spiny neuron|striatal medium-sized spiny neurons]] and almost absent in most other brain regions including the [[hippocampus]] and [[cerebellum]].<ref name="pmid9302293"/><ref>{{cite journal |author=Gutekunst CA, Li SH, Yi H, ''et al'' |title=Nuclear and neuropil aggregates in Huntington's disease: Relationship to neuropathology |journal=J. Neurosci. |volume=19 |issue=7 |pages=2522–34 |year=1999 |pmid=10087066 |doi=}}</ref><ref>{{cite journal |author=Sieradzan KA, Mechan AO, Jones L, ''et al'' |title=Huntington's disease intranuclear inclusions contain truncated, ubiquitinated huntingtin protein |journal=Exp. Neurol. |volume=156 |issue=1 |pages=92–9 |year=1999 |pmid=10192780 |doi=10.1006/exnr.1998.7005}}</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>{{cite journal |author=Cooper JK, Schilling G, Peters MF, ''et al'' |title=Truncated N-terminal fragments of huntingtin with expanded glutamine repeats form nuclear and cytoplasmic aggregates in cell culture |journal=Hum. Mol. Genet. |volume=7 |issue=5 |pages=783–90 |year=1998 |pmid=9536081| doi = 10.1093/hmg/7.5.783 <!--Retrieved from CrossRef by DOI bot-->}}</ref> The presence of these aggregates however does not correlate with cell death.<ref>{{cite journal |author=Fusco FR, Chen Q, Lamoreaux WJ, ''et al'' |title=Cellular localization of huntingtin in striatal and cortical neurons in rats: Lack of correlation with neuronal vulnerability in Huntington's disease |journal=J. Neurosci. |volume=19 |issue=4 |pages=1189–202 |year=1999 |pmid=9952397 |doi=}}</ref> Thus mHtt acts in the nucleus but does not cause apoptosis through aggregation.<ref>{{cite journal |author=Saudou F, Finkbeiner S, Devys D, Greenberg ME |title=Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions |journal=Cell |volume=95 |issue=1 |pages=55–66 |year=1998 |pmid=9778247| doi = 10.1016/S0092-8674(00)81782-1 <!--Retrieved from CrossRef by DOI bot-->}}</ref>
===Pathophysiology===
====Brain====
Studies on physiopathology are mainly focused on the brain because most notable symptoms are related to it.
Profound [[neuron]]al degeneration in the [[striatum]] with some additional atrophy of the [[Frontal lobe|frontal]] and [[Temporal lobe|temporal]] cortices.<ref>{{cite book
| last = Purves
| first = Dale
| authorlink = Dale Purves
| coauthors = Augustine GA, Fitzpatrick D, Hall W, LaMantia A-S, McNamara JO, Williams SM
| editor = Dale Purves
| title = Neuroscience
| origdate=
| origyear = 2001
| url = http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=neurosci.TOC&depth=2
| accessdate = 2008-06-10
| edition = 2nd edition
| publisher = Sinauer Associates
| location = Sunderland, MA
| isbn = 0-87893-742-0
| chapter = Modulation of Movement by the Basal Ganglia - Box A. Huntington's Disease
| chapterurl = http://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=Huntington's%20disease&rid=neurosci.box.1240}}
</ref> There is also [[astrogliosis]]{{Fact|date=May 2008}} and loss of medium spiny neurons.<ref>{{cite book
| last = Purves
| first = Dale
| authorlink = Dale Purves
| coauthors = Augustine GA, Fitzpatrick D, Hall W, LaMantia A-S, McNamara JO, Williams SM
| editor = Dale Purves
| title = Neuroscience
| origdate=
| origyear = 2001
| url = http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=neurosci.TOC&depth=2
| accessdate = 2008-06-10
| edition = 2nd edition
| publisher = Sinauer Associates
| location = Sunderland, MA
| isbn = 0-87893-742-0
| chapter = Modulation of Movement by the Basal Ganglia - Circuits within the Basal Ganglia System
| chapterurl = http://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=Huntington's%20disease&rid=neurosci.section.1251}}
</ref>
The brain initiates motion by sending a signal down the spinal cord from the external [[globus pallidus]]. At the same time that the stimulus is being sent down the spinal cord, the [[Subthalamic nucleus|subthalamic nuclei]] of the [[striatum]] excite the internal globus pallidus, which inhibits the [[thalamus]] and modulates motion.{{Fact|date=May 2008}}
In Huntington's disease the external globus pallidus over-inhibits the flow of excitation from the subthalamic nuclei, which interferes with the initiation of motion. The
subthalamic nuclei also generate reduced excitation to the internal globus pallidus, resulting in a weak inhibitory signal to the thalamus. The thalamus in turn then sends a strong excitatory signal to the [[putamen]] resulting in unmodulated motion.{{Fact|date=May 2008}}
====Other systems====
Huntington's disease appears to affect non nervous physiological functions. One study in humans highlighted a systemic, early hypermetabolic state and a lower level of [[branched chain amino acids]] in the plasma as the disease progresses;<ref>{{cite journal |author=Mochel F, Charles P, Seguin F, Barritault J, Coussieu C, Perin L, Le Bouc Y, Gervais C, Carcelain G, Vassault A, Feingold J, Rabier D, Durr A |title=Early energy deficit in Huntington disease: identification of a plasma biomarker traceable during disease progression |journal=PLoS ONE |volume=2 |issue=7 |pages= |year=2007 |pmid=17653274 |doi= |url=http://www.plosone.org/article/info:doi/10.1371/journal.pone.0000647}}</ref> this seems to originate from the brain's own need for energetic substrates.
In a murine model, heart restricted expression of amyloid-forming polyglutamine fragments resulted in heart failure.<ref>{{cite journal |author=Pattison JS, Sanbe A, Maloyan A, Osinska H, Klevitsky R, Robbins J |title=Cardiomyocyte Expression of a Polyglutamine Preamyloid Oligomer Causes Heart Failure |journal=Circulation |volume= |issue= |pages= |year=2008 |month=May |pmid=18490523 |doi= |url=}}</ref>
== Diagnosis ==
{{see|Genetic testing}}
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. [[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. {{Fact|date=May 2008}}
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 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. Embryonic screening is also possible, giving HD carriers or at-risk individuals the option of ensuring their children will not inherit the disease if abortion is acceptable to them. It is possible to test an embryo either in the womb ([[prenatal diagnosis]]) or to ensure a child will not have HD by utilising [[in vitro fertilisation]] and testing before implantation. {{Fact|date=May 2008}}
A full pathological diagnosis can only be established by a neurological examination's findings and/or demonstration of cell loss in the areas affected by HD, supported by a cranial [[Computed axial tomography|CT]] or [[MRI]] scan findings.{{Fact|date=May 2008}}
== Management ==
There is no treatment to fully arrest the progression of the disease, but symptoms can be reduced or alleviated through the use of medication and care methods. Huntington mice models exposed to better [[animal husbandry|husbandry]] techniques, especially better access to food and water, lived much longer than mice that were not well cared for.{{Fact|date=December 2007}}
=== Medication ===
Other standard treatments to alleviate emotional symptoms include the use of [[antidepressant]]s and sedatives, with [[antipsychotic]]s (in low doses) for psychotic symptoms.{{Fact|date=May 2008}}
=== Therapies ===
[[Speech therapy]] helps by improving speech and swallowing methods; this therapy is more effective if started early on, as the ability to learn is reduced as the disease progresses.
A two-year pilot study, of intensive speech, pyschiatric and physical therapy, applied to inpatient rehabilitation, showed motor decline was greatly reduced.<ref>{{cite web
|url=http://www.ncbi.nlm.nih.gov/pubmed/17702702
|title=Effects of an intensive rehabilitation programme on patients with Huntington's disease: A pilot study.
|publisher= Clin Rehabil. 2007 Jul;21(7):603-13.
|author=Zinzi P, Salmaso D, De Grandis R, ''et al''.
|date=2007-Jul-21
|language=English }}</ref>
=== Nutrition ===
Nutrition is an important part of treatment; most third and fourth stage HD sufferers need two to three times the [[calories]] of the average person to maintain body weight.<ref>{{cite web
|url=http://www.hdsa.org/site/PageServer?pagename=family_guide_nutrition
|title=Family Guide Series - Nutrition and Huntington's Disease
|publisher=Huntington's Disease Society of America Publications
|author=Gaba, Anna
|date=
|language=English
|accessdate=2008-04-02
}}</ref> Healthier foods in pre-symptomatic and earlier stages may slow down the onset and progression of the disease. High calorie intake in pre-symptomatic and earlier stages has been shown to speed up the onset and reduce IQ level.{{Fact|date=May 2008}}
[[Thickening agent]] can be added to drinks as swallowing becomes more difficult, as thicker fluids are easier and safer to swallow. The option of using a [[Percutaneous endoscopic gastrostomy|stomach PEG]] is available when eating becomes too hazardous or uncomfortable; this greatly reduces the chances of [[Aspiration pneumonia|aspiration]] of food, and the subsequent increased risk of pneumonia, and increases the amount of nutrients and calories that can be ingested.{{Fact|date=May 2008}}
[[Eicosapentaenoic acid|EPA]], an Omega-3 fatty acid, may slow and possibly reverse the progression of the disease.<ref>[http://hdlighthouse.org/see/treat/epa.htm Huntington's Disease Reversed<!-- Bot generated title -->]</ref> As of April 2008, it is in FDA clinical trial as ethyl-EPA, (brand name Miraxion), for prescription use. Clinical trials utilise 2 grams per day of EPA. In the United States, it is available over the counter in lower concentrations in Omega-3 and fish oil supplements. Results of the first Phase III trial showed an improvement in motor function scores over the control group, but the small sample size render the result inconclusive. A larger trial is near completion and will be more statistically robust when results are posted.{{Fact|date=May 2008}}
== Prognosis ==
Development of Huntington’s disease is highly dependent on how many times [[Codon|CAG]] is repeated. Usually, CAG is repeated between 7 and 35 times; more than this, however, will cause the disease.<ref>{{cite journal |author=Andrew SE, Goldberg YP, Kremer B, ''et al'' |title=The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease |journal=Nat. Genet. |volume=4 |issue=4 |pages=398–403 |year=1993 |pmid=8401589 |doi=10.1038/ng0893-398}}</ref> The age of onset (and to a degree the severity of the disease), and hence the age at death, are inversely correlated with the length of the expanded CAG repeat, such that those with longer repeats develop the disease earlier. Individuals with greater than approximately 60 CAG repeats often develop juvenile Huntington's disease.<ref>{{cite journal |author=Harper PS |title=Huntington's disease: A clinical, genetic and molecular model for polyglutamine repeat disorders |journal=Philos. Trans. R. Soc. Lond., B, Biol. Sci. |volume=354 |issue=1386 |pages=957–61 |year=1999 |pmid=10434293 |doi=10.1098/rstb.1999.0446}}</ref> There is a large variation in age of onset for any given CAG repeat length within the intermediate range (40-50 CAGs). For example, a repeat length of 40 CAGs leads to an onset ranging from 40 to 70 years of age in the North American and Canadian population. This variation means that, although [[logarithm]]ic [[algorithm]]s have been proposed for predicting the age of onset,<ref>{{cite journal |author=Rubinsztein DC, Leggo J, Chiano M, ''et al'' |title=Genotypes at the GluR6 kainate receptor locus are associated with variation in the age of onset of Huntington disease |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=94 |issue=8 |pages=3872–6 |year=1997 |pmid=9108071| doi = 10.1073/pnas.94.8.3872 <!--Retrieved from CrossRef by DOI bot-->}}</ref><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> in reality predicting the precise age of onset can be generalised, but not precisely predicted with confidence.
Following the onset of obvious physical diagnosis of the disorder, life expectancy is generally a further 15 to 20 years.<ref>{{cite journal |author=Roos RA, Hermans J, Vegter-van der Vlis M, ''et al'' |title=Duration of illness in Huntington's disease is not related to age at onset |journal=J. Neurol. Neurosurg. Psychiatr. |volume=56 |issue=1 |pages=98–100 |year=1993 |pmid=8429330 |doi=}}</ref> Mortality is not caused by Huntington’s disease directly, but by associated complications, these include [[pneumonia]] (which causes one third of fatalities), [[heart failure]] (although [[heart disease]], cerebrovascular disease and [[atherosclerosis]] show no increase), choking and nutritional deficiencies.<ref>{{cite journal |author=Lanska DJ, Lanska MJ, Lavine L, Schoenberg BS |title=Conditions associated with Huntington's disease at death. A case-control study |journal=Arch. Neurol. |volume=45 |issue=8 |pages=878–80 |year=1988 |pmid=2969233 |doi=}}</ref> [[Suicide]] is an associated risk, with suicide rates of up to 7.3 percent; four times that of the general population.<ref>{{cite journal |author=Di Maio L, Squitieri F, Napolitano G, ''et al'' |title=Suicide risk in Huntington's disease |journal=J. Med. Genet. |volume=30 |issue=4 |pages=293–5 |year=1993 |pmid=8487273 |doi=}}</ref><ref>{{cite journal |author=Schoenfeld M, Myers RH, Cupples LA, ''et al'' |title=Increased rate of [[suicide]] among patients with Huntington's disease |journal=J. Neurol. Neurosurg. Psychiatr. |volume=47 |issue=12 |pages=1283–7 |year=1984 |pmid=6239910 |doi=}}</ref> Suicide, in general, is likely to be underestimated; reports, which have accounted for this, estimate up to 27 percent of possibly affected individuals attempt suicide. <ref name="Huntington1"/>
=== Social impact ===
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, [[health insurance|insurability]]). Testing of a descendant of a person, who is 'at-risk', has serious ethical implications as a positive result automatically diagnoses one of the parents.
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.
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 [[embryo]]nic [[genetic screening]] now make it possible (with 99 percent certainty) to have an HD-free child; however, the cost of this process can easily reach tens of thousands of dollars.{{Fact|date=May 2008}}
Huntington's disease was one of the targets of the [[eugenics]] movement, for example the [[United States|American]] scientist [[Charles Davenport]] proposed in 1910 that compulsory [[sterilization]] and [[immigration]] control be used for people with certain disease, including HD.<ref>[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]</ref>
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.{{Fact|date=May 2008}}
== Epidemiology ==
As HD is autosomal dominant, and does not usually affect reproduction, areas of increased prevalence occur according to historical migration of carriers, some of which can be traced back thousands of years using the genes [[haplotypes]].<ref>{{cite journal |author=Squitieri F, Andrew SE, Goldberg YP, ''et al'' |title=DNA haplotype analysis of Huntington disease reveals clues to the origins and mechanisms of CAG expansion and reasons for geographic variations of prevalence |journal=Hum. Mol. Genet. |volume=3 |issue=12 |pages=2103–14 |year=1994 |month=December |pmid=7881406 | doi = 10.1093/hmg/3.12.2103 <!--Retrieved from CrossRef by DOI bot-->|url=http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=7881406}}</ref>
New mutations are less than 10 percent of HD carriers, but account for the less localised occurrences, and origins, of the disorder.<ref>{{cite journal |author=García-Planells J, Burguera JA, Solís P, ''et al'' |title=Ancient origin of the CAG expansion causing Huntington disease in a Spanish population |journal=Hum. Mutat. |volume=25 |issue=5 |pages=453–9 |year=2005 |month=May |pmid=15832309 |doi=10.1002/humu.20167}}</ref>
Since the discovery of a genetic test that can also be used pre-symptomatically, estimates of the incidence of the disorder are likely to increase. This is because, without the genetic test, only individuals displaying physical symptoms and a few neurologically examined cases were diagnosed, which excluded anyone who died of other causes before diagnosis. These cases can now be included in statistics as the test becomes more widely available.{{Fact|date=May 2008}}
The prevalence is, on average, between 3 to 7 per 100,000 people of Western European descent, down to 1 per 1,000,000 of Asian and African descent, but this varies greatly according to geographical location, both by ethnicity and local migration.<ref>{{cite web|title=Huntington's Disease|author=NCBI OMIM|url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=OMIM&dopt=Detailed&tmpl=dispomimTemplate&list_uids=143100#143100_POPULATION_GENETICS' |accessdate=2008-05-22}}</ref> The highest occurrence is in peoples of Western Europe descent, and relatively lower in the rest of the world. For example the isolated populations of the Lake Maracaibo region of Venezuela ( where the marker for the gene was discovered ), have an extremely high prevalence of up to 700 per 100,000<ref>R. Avila-Giron Medical and Social Aspects of Huntington's Chorea in the State of Zulia, Venezuela in: Advances in Neurology, Vol 1 (eds A. Barbeau, T.N. Chase and G.W. Paulson) New York: Raven Press, 1973, pp. 261-266</ref>, leading to the conclusion that one of their initial founders must have been a carrier of the gene.This is known as the local [[founder effect]].<ref>{{cite journal |author=Gusella JF, Wexler NS, Conneally PM, ''et al'' |title=A polymorphic DNA marker genetically linked to Huntington's disease |journal=Nature |volume=306 |issue=5940 |pages=234–8 |year=1983 |pmid=6316146| doi = 10.1038/306234a0 <!--Retrieved from CrossRef by DOI bot-->|url= }}</ref>
About 7 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.
<ref>{{cite journal |author=Nance MA, Myers RH |title=Juvenile onset Huntington's disease--clinical and research perspectives |journal=Ment Retard Dev Disabil Res Rev |volume=7 |issue=3 |pages=153–7 |year=2001 |pmid=11553930 |doi=10.1002/mrdd.1022}}</ref>
== History ==
In the first part of the twentieth century and earlier, many people with HD were misdiagnosed as suffering from alcoholism or manic depression. Previously mortality due to starvation or dehydration was a major risk.
*c. 300: Along with other conditions with abnormal movements, it may have been referred to as St Vitus' dance. [[St Vitus]] is the [[patron saint]] of [[epilepsy|epileptics]] who was [[martyr]]ed in 303.
*[[Middle Ages]]: People with the condition were probably persecuted as being [[Witch-hunt|witches]] or as being possessed by spirits, and were [[shunning|shunned]], [[exile]]d 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>
*1860: One of the early medical descriptions of HD was made in 1860 by a [[Norway|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]].
*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|Middleport]], [[Ohio]].
*c. 1923: [[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.
*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<ref name="pmid1303283">{{cite journal |author=La Spada AR, Roling DB, Harding AE, ''et al'' |title=Meiotic stability and genotype-phenotype correlation of the trinucleotide repeat in X-linked spinal and bulbar muscular atrophy |journal=Nat. Genet. |volume=2 |issue=4 |pages=301–4 |year=1992 |pmid=1303283 |doi=10.1038/ng1292-301}}</ref>
*1993: The Huntington's Disease Collaborative Research Group isolates the precise gene at 4p16.3.
*1996: A [[transgenic]] mouse ([[the R6 line]]) was created that could be made to exhibit HD, greatly advancing how much experimentation can be achieved.
*1997: DiFiglia M, Sapp E, Chase KO, et al., discover that mHtt aggregates ([[Protein folding|misfolds]]) to form [[Inclusion bodies|nuclear inclusions]].<ref name="pmid9302293"/>
*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>
==Society and culture==
{{seealso|List of Huntington's disease media depictions}}
As public awareness has increased, HD has been depicted increasingly in numerous books, films and TV series. Early works were [[Arlo Guthrie]]'s 1969 film ''[[Alice's Restaurant (film)|Alice's Restaurant]]'' and [[Jacqueline Susann]]'s 1966 American novel ''[[Valley of the Dolls]]'' , with more recent references in [[ER (TV series)|ER]], [[Private Practice]], [[Everwood]], [[All Saints (TV series)|All Saints]], and [[House (TV series)|House]].
As of 2008, June 6th is designated "National Huntington's Disease Awareness Day" by the USA senate, and the UK HDA holds an awareness week the third week of June.<ref>[http://www.hdsa.org/static/resolutionhdprint.pdf]</ref>
=== Organizations ===
*1967: [[Woody Guthrie]]'s wife, [[Marjorie Guthrie|Marjorie]], helped found the Committee to Combat Huntington's Disease, after his death from HD complications. This eventually became the [[Huntington's Disease Society of America]].<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.
*1968: After experiencing HD in his wife's family Dr. Milton Wexler was inspired to start the [[Hereditary Disease Foundation]] (HDF). Professor Nancy S. Wexler, Dr. Wexler's daughter, was in the research team in [[Venezuela]] and is now president of the HDF.
*1974: The first international meeting took place when the founders of the Canadian HD Society (Ralph Walker) and of the British HD Society (Mauveen Jones) attended the annual meeting of the American HD Society.
*1977: second meeting organized by the [[Netherlands|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|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]].<ref>[http://www.worldcongress-hd.net/ World Congress on Huntington's Disease]</ref> 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>
==Research directions==
Appropriate animal models are critical for understanding the fundamental mechanisms causing the disease and for supporting the early steps of drug development before moving on to human clinical trials. Neurochemically induced mice or monkeys were first available<ref>{{cite journal |author=Beal MF, Kowall NW, Ellison DW, Mazurek MF, Swartz KJ, Martin JB |title=Replication of the neurochemical characteristics of Huntington's disease by quinolinic acid. |journal=Nature |volume= 321|issue=321 | year=1986 |month= |pages=168–171|doi=10.1038/321168a0}}</ref> <ref>{{cite journal |author=Brouillet E, Hantraye P, Ferrante RJ, Dolan R, Leroy-Willig A, Kowall NW, Beal MF |title=Chronic mitochondrial energy impairment produces selective striatal degeneration and abnormal choreiform movements in primates. |journal=Proc Natl Acad Sci USA |volume=92 |issue= | year=1995 |month= |pages=7105–7109 |pmid= 7624378|doi=10.1073/pnas.92.15.7105}}</ref>, but they could not mimick the progressive features of the disease. After the HD gene was discovered, transgenic animals exhibiting HD were generated by inserting a CAG repeat expansion into the genome of mice (strain R6/2<ref>{{cite journal |author=Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, Hetherington C, Lawton M, Trottier Y, Lehrach H, Davies SW, Bates GP |title=Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. |journal=Cell |volume=87 |issue=3 | year=1996 |month=November |pages=493–506 |pmid=8898202 |doi=10.1016/S0092-8674(00)81369-0}}</ref> <ref>{{cite journal |author=Carter RJ, Lione LA, Humby T, Mangiarini L, Mahal A, Bates GP, Dunnett SB, and Morton AJ |title=Characterization of Progressive Motor Deficits in Mice Transgenic for the Human Huntington's Disease Mutation. |journal=The Journal of Neuroscience |volume=19 |issue=8 | year=1999 |month=April |pages=3248–3257 |pmid= 10191337| url=http://www.jneurosci.org/cgi/content/full/19/8/3248}}</ref>), ''[[Drosophila melanogaster|Drosophila]]'' fruit flies<ref>{{cite journal |author=Marsh JL, Pallos J and Thompson LM |title=Fly models of Huntington's disease. |journal=Human Molecular Genetics |volume=12 |issue=2 | year=2003 |month= |pages=187–193 |pmid= 12925571|doi=10.1093/hmg/ddg271| url=http://hmg.oxfordjournals.org/cgi/content/full/12/suppl_2/R187}}</ref>, or more recently in monkeys<ref>[http://www.sciencedaily.com/releases/2008/05/080518152643.htm First Transgenic Monkey Model Of Huntington's Disease Developed] Science Daily article on HD monkey model, May 19, 2008.</ref>. Expression without insertion of a CAG repeat in [[nematode]] worms<ref>{{cite journal |author=Voisine C, Varma H, Walker N, Bates EA, Stockwell BR, and Hart AC |title=Identification of Potential Therapeutic Drugs for Huntington's Disease using Caenorhabditis elegans. |journal=PLoS ONE |volume=2 |issue=6 | year=2007 |month=June |pages= e504|pmid=1876812 |doi=10.1371/journal.pone.0000504| url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1876812}}</ref> also produced a valuable model.
As for humans, there are trials of various compounds that are in development, recruiting volunteers<ref>[http://clinicaltrials.gov/ct2/results?cond=%22Huntington+Disease%22 Trials for Huntington's disease at clinicaltrials.gov]</ref>, in progress or completed. Some of these trials are at the point of testing on larger numbers of people, known as [[Clinical trial#Phases|phase III]] of the clinical trials.
=== Intrabody therapy ===
Genetically engineered [[antibody]] fragments called [[intrabody|intrabodies]] have shown therapeutic results against mHtt aggregates in drosophila models. This was achieved using an intrabody called '''C4 sFv''', a [[single chain variable fragment]] which binds to the end of mHtt [[Intracellular|within a cell]]. C4 sFv has been shown to reduce mHtt aggregate formation and accumulation in cultures of tissue taken from the model.<ref>{{cite journal |author=Lecerf JM, Shirley TL, Zhu Q, ''et al'' |title=Human single-chain Fv intrabodies counteract in situ huntingtin aggregation in cellular models of Huntington's disease |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=98 |issue=8 |pages=4764–9 |year=2001 |pmid=11296304 |doi=10.1073/pnas.071058398}}</ref><ref>{{cite journal |author=Miller TW, Zhou C, Gines S, ''et al'' |title=A human single-chain Fv intrabody preferentially targets amino-terminal Huntingtin's fragments in striatal models of Huntington's disease |journal=Neurobiol. Dis. |volume=19 |issue=1-2 |pages=47–56 |year=2005 |pmid=15837560 |doi=10.1016/j.nbd.2004.11.003}}</ref> The intrabody increased [[larva]]l and [[pupa]]l survival from 23% to 100% and delayed neurodegeneration in the adult, significantly increasing their lifespan.<ref>{{cite journal |author=Wolfgang WJ, Miller TW, Webster JM, ''et al'' |title=Suppression of Huntington's disease pathology in ''Drosophila'' by human single-chain Fv antibodies |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=102 |issue=32 |pages=11563–8 |year=2005 |pmid=16061794 |doi=10.1073/pnas.0505321102}}</ref> [[Intrabody therapy]] shows promise as a tool for drug discovery, and as a potential therapy for neurodegenerative disorders caused by protein mis-folding or abnormal protein interactions.<ref>{{cite journal |author=Miller TW, Messer A |title=Intrabody applications in neurological disorders: Progress and future prospects |journal=Mol. Ther. |volume=12 |issue=3 |pages=394–401 |year=2005 |pmid=15964243 |doi=10.1016/j.ymthe.2005.04.003}}</ref>
=== Gene silencing ===
Since HD has been conclusively linked to a single gene, [[gene silencing]] could be simpler than with multiple-gene disorders. Researchers have investigated using [[gene knockdown]] of mHtt as a potential treatment. Using a mouse model, [[siRNA]] therapy achieved a 60 percent reduction in expression of the mHtt and progression of the disease was stalled.<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> However, this study used the human form of the Htt gene in the mouse, and were therefore able to directly target the mHtt gene, leaving endogenous, wild-type Htt gene expression unaffected. Since no [[single nucleotide polymorphisms]] have yet been discovered in mHtt it would be impossible, using siRNA, to distinguish between wild-type and mutant forms of the gene. The precise function of Htt is unknown, but the htt knockout mutation is lethal and kills mice during emryogenesis<ref>{{cite journal| author=Jamal Nasira ''et al'' |title=Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes |journal=Cell |volume=81 |issue=5 |pages=811-23 |year=1995 |doi=10.1016/0092-8674(95)90542-1}}</ref>. Thus, using RNA interference to knockout both wild-type and mutant ''htt'' could have unforseen, unfavourable consequences. (This is distinct from the other problems associated with using siRNA as a therapy, e.g. delivering the gene; off-target effects of siRNA; toxicity from shRNA over-expression <ref>{{cite journal| author=Jodi L. McBride ''et al'' |title=Artificial miRNAs mitigate shRNA-mediated toxicity in the brain: Implications for the therapeutic development of RNAi |journal=PNAS |volume=105 |issue=15 |pages=5868-5873 |doi=10.1073/pnas.0801775105}}</ref>.)
In another study, mouse models in late stages of the disease recovered motor function after expression of mHtt was shut down.<ref>{{cite journal| author=Miguel Díaz-Hernández, Jesús Torres-Peraza, Alejandro Salvatori-Abarca, ''et al''| 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| doi=10.1523/JNEUROSCI.3183-05.2005| pmid=16237181}}</ref>
=== Stem cell implants ===
{{main|Stem cell treatments}}
Treatment using stem cell implants is based on the replacement of damaged neurons by injecting [[stem cell]]s, which can form themselves into specialized cells, into the damaged area. The stem cell then transforms itself into a replacement neuron. If enough damaged neurons are replaced, symptoms should be alleviated. This treatment would not prevent further neuronal damage, so would be an ongoing treatment. The treatment has yielded some positive results in animal models.<ref>{{cite web |url=http://www.worldhealth.net/p/pig-cell-implants-in-huntingtons-trial-2005-08-19.html |title=Pig cell implants in Huntington's trial |publisher=WorldHealth.net |accessdate=2008-05-15}}</ref>
=== Others ===
Other agents and measures that have shown promise in initial experiments include [[dopamine]] receptor blockers, select [[dopamine antagonists]], such as [[tetrabenazine]], [[creatine]], [[CoQ10]], the antibiotic [[Minocycline]], exercise, antioxidant-containing foods and nutrients, and antidepressants (notably, but not exclusively, selective serotonin reuptake inhibitors [[SSRI]]s, such as sertraline, fluoxetine, and paroxetine).
{{Fact|date=May 2008}}
==References==
{{reflist|2}}
==Sources ==
*{{cite web| last= Conomy|first=John P., M.D., J.D | url=http://www.lkwdpl.org/hdsa/conomy.htm| title=Dr. George Sumner Huntington and the Disease Bearing His Name}}
* {{cite journal| last=Huntington |first= G.| title=On Chorea| journal=Medical and Surgical Reporter of Philadelphia| volume=26| issue=15| date=1872-04-13| pages=317–321}}
* [[Mendelian Inheritance in Man|Online Mendelian Inheritance in Man]], [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=143100 Article 143100 - Huntington Disease], [[Johns Hopkins University]]
* [[Mendelian Inheritance in Man|Online Mendelian Inheritance in Man]], [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=606438 Article 606438 - Huntingtons Disease-Like 2], [[Johns Hopkins University]]
* {{cite journal |last= Stevenson |first= Charles S. |year= 1934 |month= April |title=A Biography of George Huntington, M.D. |journal=Bulletin of the Institute of the History of Medicine |volume= II |issue= 2 | publisher =[[Johns Hopkins University]] |url= http://www.shv.ch/download/BiographyGeorgeHuntington.doc | format = Microsoft Word |accessdate= 2007-12-05}}
* {{cite journal| last=Vessie| first= P. R. | 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}}
==Bibliography==
* {{cite book| author= Gillian Bates, Peter Harper, and Lesley Jones| title=Huntington's Disease - Third Edition| publisher=Oxford University Press| location=Oxford| year=2002| id=ISBN 0-19-851060-8}}
==External links==
{{wikisource|On Chorea}}
[http://www.dmoz.org/Health/Conditions_and_Diseases/Neurological_Disorders/Huntington's_Disease DMOZ HD links directory] at the [[Open Directory Project]].
===Professional and research===
* [http://www.huntingtonproject.org/ Huntington Project] - worldwide umbrella organization for the clinical research efforts for HD.
* [http://www.huntington-study-group.org/ Huntington Study Group]
* [http://huntingtonsdisease.researchtoday.net/ Huntington's Disease Research] - Research abstracts on HD.
* [http://hopes.stanford.edu/ Huntington's Outreach Project for Education, at Stanford (HOPES)] - A layperson's guide to HD
* [http://www.wemove.org/hd/ Worldwide Education and Awareness for Movement Disorders] - HD section
* [http://hdresearch.ucl.ac.uk/ University College London Huntington's Disease Research]
* [http://www.track-hd.net/ TRACK-HD], an international observational study of HD
* University California and San Francisco Memory and Aging Center - [http://memory.ucsf.edu/Education/Disease/hd.html HD Info]
{{Mental and behavioural disorders}}
{{Diseases of the nervous system}}
[[Category:Genetic disorders]]
[[Category:Neurological disorders]]
[[ca:Malaltia de Huntington]]
[[da:Huntingtons chorea]]
[[de:Chorea Huntington]]
[[es:Enfermedad de Huntington]]
[[fa:بیماری هانتینگتون]]
[[fr:Chorée de Huntington]]
[[ko:헌팅턴 무도병]]
[[id:Penyakit Huntington]]
[[it:Morbo di Huntington]]
[[he:מחלת הנטינגטון]]
[[nl:Ziekte van Huntington]]
[[ja:ハンチントン病]]
[[no:Huntingtons sykdom]]
[[pl:Pląsawica Huntingtona]]
[[pt:Doença de Huntington]]
[[ru:Болезнь Хантингтона]]
[[simple:Huntington's disease]]
[[sr:Хантингтонова хореа]]
[[fi:Huntingtonin tauti]]
[[sv:Huntingtons sjukdom]]
[[tr:Huntington hastalığı]]
[[zh:亨丁頓舞蹈症]]