Editing Huntington's disease (section)

==History==

[[File:On Chorea with photo.jpg|thumb|alt=On the right is a young man, dressed in suit and tie, sporting a moustache and tuft of hair on the chin; on the left is the top half of a medical journal titled 'Medical and Surgical Reporter' |In 1872, [[George Huntington]] described the disorder in his first paper "[[s:On Chorea|On Chorea]]" at the age of 22.<ref name="onchorea">{{cite journal |vauthors=Huntington G |title=On Chorea |url=https://babel.hathitrust.org/cgi/pt?id=mdp.39015010956335&view=1up&seq=343&skin=2021 |journal=Medical and Surgical Reporter of Philadelphia |volume=26 |issue=15 |year=1872 |pages=317–321 |isbn=978-90-6186-011-2 |access-date=21 April 2022 |archive-date=21 April 2022 |archive-url=https://web.archive.org/web/20220421034757/https://babel.hathitrust.org/cgi/pt?id=mdp.39015010956335&view=1up&seq=343&skin=2021 |url-status=live }}</ref>]]

In centuries past, various kinds of chorea were at times called by names such as ''[[Saint Vitus' dance (disambiguation)|Saint Vitus' dance]]'', with little or no understanding of their cause or type in each case.

The first definite mention of HD was in a letter by [[Charles Oscar Waters]] (1816–1892), published in the first edition of [[Robley Dunglison]]'s ''Practice of Medicine'' in 1842.<ref>{{cite book |vauthors=Dunglison R |title=The Practice of Medicine ... |date=1842 |publisher=Lea & Blanchard |location=Philadelphia, Pennsylvania, USA |volume=2 |pages=312–313 |url=https://babel.hathitrust.org/cgi/pt?id=chi.092041301&view=1up&seq=316&skin=2021 |access-date=20 April 2022 |archive-date=20 April 2022 |archive-url=https://web.archive.org/web/20220420233417/https://babel.hathitrust.org/cgi/pt?id=chi.092041301&view=1up&seq=316&skin=2021 |url-status=live }}</ref> Waters described "a form of chorea, vulgarly called magrums", including accurate descriptions of the chorea, its progression, and the strong heredity of the disease.<ref name="OxfordMonographHistory">{{cite book | vauthors = Harper P |chapter=Huntington's disease: a historical background |veditors=Bates G, Harper P, Jones L | title=Huntington's Disease – Third Edition| publisher=Oxford University Press| location=Oxford| year=2002| isbn=978-0-19-851060-4|pages= 3–24}}</ref> In 1846 [[Charles Gorman (physician)|Charles Rollin Gorman]] (1817–1879) observed how higher prevalence seemed to occur in localized regions.<ref>{{cite thesis | vauthors = Gorman CR | date = 1846 | degree = Doctor of Medicine | title = On a Form of Chorea, Vulgarly called Magrums | location = Philadelphia | publisher = Jefferson Medical College }}
*  {{cite web | url = https://jdc.jefferson.edu/cgi/viewcontent.cgi?article=1071&context=jmc_catalogs | title = Catalogue of Jefferson Medical College of Philadelphia: Session of 1846-7 | archive-url = https://web.archive.org/web/20220626050233/https://jdc.jefferson.edu/cgi/viewcontent.cgi?article=1071&context=jmc_catalogs | archive-date=26 June 2022 | page = 14 }}
*  {{cite book |vauthors=Dunglison R |title=The Practice of Medicine ... |date=1848 |publisher=Lea & Blanchard |location=Philadelphia, Pennsylvania, USA |volume=2 |page=218 |edition=3rd |url=https://archive.org/details/practiceofmedici248dung/page/218/mode/2up?ref=ol&view=theater }}
*  {{cite journal |vauthors=Boyd WA |title=Hereditary chorea with report of a case |journal=Boston Medical and Surgical Journal |date=6 November 1913 |volume=169 |issue=19 |pages=680–685 |doi=10.1056/NEJM191311061691904 |url=https://books.google.com/books?id=Q80EAAAAYAAJ&pg=RA1-PP12 |access-date=21 April 2022 |archive-date=2 August 2023 |archive-url=https://web.archive.org/web/20230802171644/https://books.google.com/books?id=Q80EAAAAYAAJ&pg=RA1-PP12 |url-status=live }} See p. 680.</ref><ref name="OxfordMonographHistory"/> Independently of Gorman and Waters, both students of Dunglison at [[Jefferson Medical College]] in Philadelphia,<ref name="Wexler2008">{{cite book |title=The Woman Who Walked Into the Sea. Huntington's and the Making of a Genetic Disease|year=2008 |publisher=Yale University Press|isbn=978-0-300-10502-5 |page=288 |url=https://archive.org/details/womanwhowalkedin0000wexl|url-access=registration|vauthors=Wexler A, Wexler N |access-date=15 November 2015}}</ref> {{interlanguage link|Johan Christian Lund|no}} (1830–1906) also produced an early description in 1860.<ref name="OxfordMonographHistory"/> He specifically noted that in [[Setesdalen]], a secluded mountain valley in [[Norway]], the high prevalence of dementia was associated with a pattern of jerking movement disorders that ran in families.<ref>{{cite journal | vauthors = Lund JC| title= Chorea Sti Viti i Sætersdalen. Uddrag af Distriktslæge J. C. Lunds Medicinalberetning for 1860| journal=Beretning Om Sundhedstilstanden| year=1860 | pages=137–138}}</ref>

The first thorough description of the disease was by [[George Huntington]] in 1872. Examining the combined medical history of several generations of a family exhibiting similar symptoms, he realized their conditions must be linked; he presented his detailed and accurate definition of the disease as his first paper. Huntington described the exact pattern of inheritance of autosomal dominant disease years before the rediscovery by scientists of [[Mendelian inheritance]].

{{blockquote|Of its hereditary nature. When either or both the parents have shown manifestations of the disease&nbsp;... one or more of the offspring almost invariably suffer from the disease&nbsp;... But if by any chance these children go through life without it, the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the disease.<ref name="onchorea"/><ref>{{cite journal | vauthors = Lanska DJ | title = George Huntington (1850–1916) and hereditary chorea | journal = Journal of the History of the Neurosciences | volume = 9 | issue = 1 | pages = 76–89 | date = April 2000 | pmid = 11232352 | doi = 10.1076/0964-704X(200004)9:1;1-2;FT076| s2cid = 22659368 }}</ref>}}

Sir [[William Osler]] was interested in the disorder and chorea in general, and was impressed with Huntington's paper, stating, "In the history of medicine, there are few instances in which a disease has been more accurately, more graphically or more briefly described."<ref>{{cite journal |vauthors=Osler W |title=Historical notes on hereditary chorea |journal=Neurographs |date=1908 |volume=1 |issue=2 |pages=113–116 |url=https://wellcomecollection.org/works/sa3gzpxh/items?canvas=35 |access-date=21 April 2022 |archive-date=21 April 2022 |archive-url=https://web.archive.org/web/20220421021137/https://wellcomecollection.org/works/sa3gzpxh/items?canvas=35 |url-status=live }} See p. 115.
*  See also:  {{cite journal |vauthors=Osler W |title=Remarks on the varieties of chronic chorea, and a report upon two families of the hereditary form, with one autopsy |journal=The Journal of Nervous and Mental Disease |date=February 1893 |volume=20 |issue=2 |pages=97–111 |url=https://babel.hathitrust.org/cgi/pt?id=hvd.32044103072369&view=1up&seq=113&skin=2021 |access-date=21 April 2022 |archive-date=21 April 2022 |archive-url=https://web.archive.org/web/20220421030701/https://babel.hathitrust.org/cgi/pt?id=hvd.32044103072369&view=1up&seq=113&skin=2021 |url-status=live }} See p. 97.</ref><ref name="OxfordMonographHistory"/><ref>{{cite journal | vauthors = Brody IA, Wilkins RH | title = Huntington's chorea | journal = Archives of Neurology | volume = 17 | issue = 3 | pages = 331 | date = September 1967 | pmid = 4228262 | doi = 10.1001/archneur.1967.00470270109013 }}</ref> Osler's continued interest in HD, combined with his influence in the field of medicine, helped to rapidly spread awareness and knowledge of the disorder throughout the medical community.<ref name="OxfordMonographHistory"/> Great interest was shown by scientists in Europe, including [[Louis Théophile Joseph Landouzy]], [[Désiré-Magloire Bourneville]], [[Camillo Golgi]], and [[Joseph Jules Dejerine]], and until the end of the century, much of the research into HD was European in origin.<ref name="OxfordMonographHistory"/> By the end of the 19th century, research and reports on HD had been published in many countries and the disease was recognized as a worldwide condition.<ref name="OxfordMonographHistory"/>

During the rediscovery of Mendelian inheritance at the turn of the 20th century, HD was used tentatively as an example of autosomal dominant inheritance.<ref name="OxfordMonographHistory"/>  English biologist [[William Bateson]] used the pedigrees of affected families to establish that HD had an autosomal dominant inheritance pattern.<ref>{{cite book | vauthors = Bateson W |title=Mendel's Principles of Heredity |date=1909 |publisher=Cambridge University Press |location=Cambridge, England |page=229 |url=https://archive.org/details/mendelsprinciple00bate/page/228/mode/2up}}  Bateson refers to "Huntington's disease" as "Hereditary Chorea".</ref><ref name="Wexler2008"/> The strong inheritance pattern prompted several researchers, including [[Smith Ely Jelliffe]], to attempt to trace and connect family members of previous studies.<ref name="OxfordMonographHistory"/> Jelliffe collected information from across [[New York (state)|New York]] and published several articles regarding the genealogy of HD in [[New England]].<ref>{{cite journal |vauthors=Jelliffe SE, Muncey EB, Davenport CB |title=Huntington's Chorea: A Study in Heredity |journal=The Journal of Nervous and Mental Disease |volume=40 |issue=12 |pages=796–799 |year=1913 |doi=10.1097/00005053-191312000-00010 |url=https://zenodo.org/record/1432003 |access-date=19 September 2020 |archive-date=5 April 2022 |archive-url=https://web.archive.org/web/20220405071433/https://zenodo.org/record/1432003 |url-status=live }}</ref> Jelliffe's research roused the interest of his college friend, [[Charles Davenport]], who commissioned Elizabeth Muncey to produce the first field study on the [[East Coast of the United States]] of families with HD and to construct their pedigrees.<ref name="davenportmuncey">{{cite journal |doi=10.1176/ajp.73.2.195 |pmid=<!--none--> |pmc=<!--none--> |vauthors=Davenport CB, Muncey EB |title=Huntington's chorea in relation to heredity and eugenics |journal=American Journal of Insanity|volume=73 |pages=195–222 |year=1916 |issue=2 |url=https://babel.hathitrust.org/cgi/pt?id=mdp.39015076900110&seq=221 }}</ref> Davenport used this information to document the variable age of onset and range of symptoms of HD; he claimed that most cases of HD in the US could be traced back to a handful of individuals.<ref name="davenportmuncey"/> This research was further embellished in 1932 by [[P. R. Vessie]], who popularized the idea that three brothers who left [[England]] in 1630 bound for [[Boston]] were the progenitors of HD in the US.<ref>{{Cite journal | vauthors=Vessie PR | title=On the transmission of Huntington's chorea for 300 years – the Bures family group | journal=Nervous and Mental Disease | volume=76 | issue=6 | year=1932 | pages=553–573 | url=https://scholar.google.co.uk/scholar?q=info:12mCk4CjFKAJ:scholar.google.com/&output=viewport&pg=1 | access-date=1 April 2009 | doi=10.1097/00005053-193212000-00001 | s2cid=147656032 | archive-date=28 August 2021 | archive-url=https://web.archive.org/web/20210828112759/https://scholar.google.co.uk/scholar_host?q=info%3A12mCk4CjFKAJ%3Ascholar.google.com%2F&hl=en&as_sdt=0%2C5&output=viewport | url-status=live }}</ref> The claim that the earliest progenitors had been established and [[eugenic]] bias of Muncey's, Davenport's, and Vessie's work contributed to misunderstandings and prejudice about HD.<ref name="Wexler2008"/> Muncey and Davenport also popularized the idea that in the past, some with HD may have been thought to be possessed by spirits or victims of [[witchcraft]], and were sometimes [[shunning|shunned]] or [[exile]]d by society.<ref name="pmid12486915">{{cite journal | vauthors = Wexler AR | title = Chorea and community in a nineteenth-century town | journal = Bulletin of the History of Medicine | volume = 76 | issue = 3 | pages = 495–527 | year = 2002 | pmid = 12486915 | doi = 10.1353/bhm.2002.0150 | s2cid = 30791504}}</ref><ref name="pmid6233902">{{cite journal | vauthors = Conneally PM | title = Huntington disease: genetics and epidemiology | journal = American Journal of Human Genetics | volume = 36 | issue = 3 | pages = 506–26 | date = May 1984 | pmid = 6233902 | pmc = 1684448}}</ref> This idea has not been proven.  Researchers have found contrary evidence; for instance, the community of the family studied by George Huntington openly accommodated those who exhibited symptoms of HD.<ref name="Wexler2008"/><ref name="pmid12486915"/>

The search for the cause of this condition was enhanced considerably in 1968, when the [[Hereditary Disease Foundation]] (HDF) was created by [[Milton Wexler]], a [[psychoanalyst]] based in [[Los Angeles]], [[California]], whose wife Leonore Sabin had been diagnosed earlier that year with Huntington's disease.<ref name=Wexler2012>{{cite journal | vauthors = Wexler NS | title = Huntington's disease: advocacy driving science | journal = Annual Review of Medicine | volume = 63 | pages = 1–22 | year = 2012 | doi = 10.1146/annurev-med-050710-134457 | pmid = 22248319 | doi-access =free }}</ref> The three brothers of Wexler's wife also had this disease.

The foundation was involved in the recruitment of more than 100 scientists in the US-Venezuela Huntington's Disease Collaborative Project, which over a 10-year period from 1979, worked to locate the genetic cause.<ref name=HDFP/> This was achieved in 1983 when a causal gene was approximately located,<ref name="dnamark"/> and in 1993, the gene was precisely located at chromosome 4 (4p16.3).<ref name="pmid8458085">{{cite journal | vauthors =  | title = A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group | journal = Cell | volume = 72 | issue = 6 | pages = 971–983 | date = March 1993 | pmid = 8458085 | doi = 10.1016/0092-8674(93)90585-E | hdl-access = free | s2cid = 802885 | hdl = 2027.42/30901 }}</ref> The study had focused on the populations of two isolated [[Venezuela]]n villages, Barranquitas and Lagunetas, where there was an unusually high prevalence of HD, and involved over 18,000 people, mostly from a single extended family, and resulted in making HD the first [[autosomal]] disease [[Locus (genetics)|locus]] found using [[Genetic linkage#Linkage analysis|genetic linkage analysis]].<ref name="pmid8458085"/><ref name="pmid15931380">{{cite journal | vauthors = Bertram L, Tanzi RE | title = The genetic epidemiology of neurodegenerative disease | journal = The Journal of Clinical Investigation | volume = 115 | issue = 6 | pages = 1449–1457 | date = June 2005 | pmid = 15931380 | pmc = 1137006 | doi = 10.1172/JCI24761 }}</ref> Among other innovations, the project developed [[Genetic marker|DNA-marking]] methods which were an important step in making the [[Human Genome Project]] possible.<ref name=HDFP>{{cite web |url=http://hdfoundation.org/the-venezuela-huntingtons-disease-project/ |title=The Venezuela Huntington's disease project |access-date=8 September 2008 |work=Hereditary Disease Foundation website |publisher=Hereditary Disease Foundation |year=2008 |url-status=dead |archive-url=https://web.archive.org/web/20150810153514/http://hdfoundation.org/the-venezuela-huntingtons-disease-project/ |archive-date=10 August 2015}}</ref>

In the same time, key discoveries concerning the mechanisms of the disorder were being made, including the findings by [[Anita Harding]]'s research group on the effects of the gene's length.<ref name="pmid1303283">{{cite journal | vauthors = La Spada AR, Roling DB, Harding AE, Warner CL, Spiegel R, [[Hausmanowa-Petrusewicz I]], Yee WC, Fischbeck KH | title = Meiotic stability and genotype–phenotype correlation of the trinucleotide repeat in X-linked spinal and bulbar muscular atrophy | journal = Nature Genetics | volume = 2 | issue = 4 | pages = 301–4 | date = December 1992 | pmid = 1303283 | doi = 10.1038/ng1292-301 | s2cid = 6603129}}</ref>

Modelling the disease in various types of animals, such as the [[transgenic]] mouse developed in 1996, enabled larger-scale experiments. As these animals have faster [[metabolism]]s and much shorter lifespans than humans results from experiments are received sooner, speeding research. The 1997 discovery that mHtt fragments [[Protein folding|misfold]] led to the discovery of the nuclear inclusions they cause. These advances have led to increasingly extensive research into the proteins involved with the disease, potential drug treatments, care methods, and the gene itself.<ref name="OxfordMonographHistory"/><ref name=ross-tabrizi />

The networks of care and support that had developed in Venezuela and Colombia during the research projects there in the 1970s through 2000s were eventually eroded by various forces, such as the ongoing [[crisis in Venezuela]] and the death of a lead researcher in Colombia (Jorge Daza Barriga).<ref name="Smith-NYT-2023-05-23">{{cite news |vauthors=Smith JE, Cordero C |title=Sought Out by Science, and Then Forgotten |url=https://www.nytimes.com/2023/05/23/science/huntingtons-disease-colombia.html |access-date=2023-05-23 |work=The New York Times |date=2023-05-23 |archive-date=23 May 2023 |archive-url=https://web.archive.org/web/20230523222910/https://www.nytimes.com/2023/05/23/science/huntingtons-disease-colombia.html |url-status=live }}</ref> Doctors are working toward rekindling these networks because the people who have contributed to the science of Huntington's disease by participating in these studies deserve adequate follow-up care; societies elsewhere in the world who benefit from the scientific advances thus achieved owe at least that much to those who participated in the research.<ref name="Smith-NYT-2023-05-23"/>

The condition was formerly called Huntington's chorea, but this term has been replaced by Huntington's disease because not all patients develop chorea and due to the importance of cognitive and behavioral problems.<ref name=huntchorea>{{cite web|title=What is HD?|url=http://www.hda.org.uk/huntingtons/what-is-hd.html|publisher=Huntington's disease association|access-date=18 December 2011|url-status=dead|archive-url=https://web.archive.org/web/20111213133025/http://www.hda.org.uk/huntingtons/what-is-hd.html|archive-date=13 December 2011}}</ref>