Ferdinando Squi-eri, Roma, 21/11/2014 Mala$a di Hun+ngton George Hun+ngton, 1872 choreia deriva dal Greco χορεία (un /po di danza), per via dei rapidi movemen/ del tronco e degli ar/ simili ad una danza incontrollabile MALATTIA HUNTINGTON: UNA STORIA DI STIGMA E DISCRIMINAZIONE CHARLES DAVENPORT - 1916 Realizza il primo pedigree su larga scala di una famiglia con l’Hun/ngton andando indietro di 12 generazioni A seguito di questo, pubblica un paper sull’ American Journal of Insanity dal /tolo “Hun/ngton's Chorea in Rela/on to Heredity and Eugenics” Director of the Biological Laboratory at Cold Spring Harbor, New York, USA and founder of the Eugenics Record Office La sua teoria è: “ from just a few progenitors came a vast number of vic+ms” mo/vo per cui è opportuno procedere a “immigra+on restric+ons, surveillance of families, and compulsory sterilisa+on” Quest ar+colo è stato per anni considerato nella le<eratura biomedica un testo fondamentale sulla mala$a di Hun+ngton PERCY R VESSIE, 1932 Vessie traccia l’albero genealogico della famiglia di un suo paziente, andando a ritroso fino agli antena/ immigra/ nel New England nel 17mo secolo Iden/fica in tre coppie sposate provenien/ dal villaggio di Bures, Suffolk, in Inghilterra, i “portatori” della mala[a di Hun/ngton negli USA Psichiatra del Connec/cut Per Vessie, le accuse di stregoneria contro una donna di quella famiglia dimostravano la presenza della mala$a di Hun+ngton in quel nucleo familiare Vascello John Winthrop ADOLF HITLER, 1933 This law, which was to be implemented on January 1, 1934 called for the steriliza/on of "lives unworthy of life". These "unworthy lives" included those persons suffering from congenital mental retarda/on, schizophrenia, manic-‐dpressive insanity, epilepsy, Hun+ngton's chorea, hereditary blindness, hereditary deafness, grave bodily malforma/on, and severe alcoholism. To enforce the steriliza/on laws, Nazi leadership created special "Hereditary Health Courts." All physicians were legally required to report to the courts anyone they encountered who fell into any of the categories for steriliza+on. As a result, by 1937 some 225,000 individuals had been sterilized by German authori/es, a figure that was roughly ten /mes the number in the United States. Commifee to Combat Hun/ngton's Disease : Hun+ngton Disease Society of America Commission for the Control of Hun/ngton’s Disease (US Congress) MALATTIA HUNTINGTON: UNA STORIA DI STIGMA E DISCRIMINAZIONE Dr Milton Wexler (psicoanalista e psicologo clinico, padre di Nancy) fonda la Hereditary Diseases Foundation dopo che alla moglie viene diagnosticata la MH Nancy e i suoi collaboratori vanno in Venezuela, studiano un’unica famiglia di 18.000 componenti e raccolgono oltre 4.000 campioni di sangue grazie allo studio di questi campioni, James Gusella localizza il gene della malattia 72,6: 971-‐983, 26 March A novel gene containing a trinucleo+de repeat that is expanded and unstable on Hun+ngton's disease chromosomes Marcy E. MacDonald, Chris/ne M. Ambrose, Mabel P. Duyao, Richard H. Myers, Carol Lin, Lakshmi Srinidhi, Glenn Barnes, Sherryl A. Taylor, Marianne James, Nicolet Groot, Heather MacFarlane, Barbara Jenkins, Mary Anne Anderson, Nancy S. Wexler and James F. Gusella CAG oltre 36 worldwide described a pathological range starting beyond 35 CAG repeats, with 36–39 repeats representing a ‘low-penetrance’ NEURODEGENERATIVE DISEASE range that tends to be associated with very late age at HD onset, if the disease manifests at all (Figure 1). Until recently, expansions in the 27–35-CAG range—termed Ferdinando Squitieri intermediate alleles—were considered to NEWS & V sibility that people carrying an HTT allele that falls within the intermediate range can Figure 1 | Multiple ‘shades’ of CAG trip show marked behavioural changes, includfollow-u CAG repeat stretch inlongitudinal the HTT1 gene fro ing suicidal ideation and sent apathy. The a type of prodro zones, with subtle, heterogeneous and authors argue that these behavioural manianticipating typical with the intermediatemany and years. low-penetran festations, which were observed amongThese 50 ne individuals with intermediatecurrent allelesthinking (5.1% on ‘normal’ range of CAG of the total study cohort) during a 4-yearnatur The unstable | NATURE REVIEWS NEUROLOGY 2013 longitudinal follow-up period, may repre- ‘Fifty shades of grey’ in the Huntington disease gene NEWS & VIEWS DISEASE Huntington disease is causedNEURODEGENERATIVE by a CAG repeat expansion in the huntingtin repeats in HTT unde sent a type of prodromal HD, potentially ‘Fiftyhas shades of grey’ in the anticipating typical motor symptoms by to undergo intergener length gene.Chromosome A repeat length of 35 CAGs long been accepted asCAG therepeat cut-off 4 many years. These new findings challenge Huntington gene the pathological trip current thinking on what constitutes the point beyond which the expansion becomesdisease pathological, but recent findings ‘normal’ range of CAG repeats. Ferdinando Squitieri of animal a The unstablestudies nature of the trinucleotide indicate that intermediate expansions (27–35 repeats) are associated with Huntington disease is caused by a CAG repeat expansion in the huntingtin repeats in HTT underlies their propensity 36–39 10–26 27–35 patient40+ brains have d to undergo intergenerational expansion into gene. A repeat length of an 35 CAGs has long been accepted as the cut-off either a distinct behavioural phenotype or endophenotype. the pathological triplet range. Moreover, point beyond which the expansion becomes pathological, but recent findings CAG CAG G CAG CAG CAG CAG mosaicism CAG CAG of CAGthe CAG CAG CAG C studies of animal and cell models and indicate that intermediate (27–35 associated CAexpansions G CAG Gdoi:10.1038/nrneurol.2013.128 CAG repeats) CAG are CAG CAG with CAG CAG CAG have Squitieri, F. Nat. Rev. Neurol. advance online publication 25 June 2013; CAG CAGsomatic CAG neur patient brains documented differentiated either a distinct behavioural phenotype or an endophenotype. mosaicism of the CAG length in CAG CAG G CAG CAG CAG CAG CAG CAG CAG CAGrepeat CAG CAG genomic instabili differentiated the neurons, indicating that CAG CAG G CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG the genomic instability also Full operates at an Low Huntington disease (HD) is oneHuntington of nine be mutable, potentially increasing in size 2 AGNormal AGmutable,Intermediate CAG CAGincreasing CAG in CAG CAG CAG intraindividual CAG CAG repeat CAG leve disease (HD) isCone ofCAG nineG Cbe intraindividual level. Therefore, potentially size penetrance penetrance expansions samples, neurological disorders that C known toG Cand extending the pathological in G CAG AGto CAGtopathological CAG CAG rangeCAG CAG CAGblood CAG CAG expansions in periph neurological disorders that are known to andareAextending the range in CAGin peripheral result from a CAG repeat expansion in an offspring, but never themselves associated as were measured in the PHAROS study,1 C A G CAG G C AG CAG CAG CAG CAG CAG CAG CAG CAG CAG may theoretically in length from those affected the huntingtin but with a pathological phenotype. Evidence result from a CAG repeat expansion ingene—in an this case, offspring, never themselves associated asdiffer were measured in CAG CAG CAG CAG CAG in the brain. (HTT) gene. The classic clinical feature ofG CisAG beginning to emerge, however, that CAG CAG CAGThe potential CAGeffects CAGof triplet CAG HD is a progressive, untreatable with intermediate allelesEvidence can mosaicism thatmay extends from the intertheoretically affected gene—in this case, the huntingtin with pathological phenotype. CAand Ga highly CAG G Cindividuals AG CAG CAG CAG CAG CAG CAG CAG CAG CAG diffe mediate range in peripheral blood cells to disabling chorea: an uncontrollable dancemanifest either a phenotype typical of HD Squitieri, F. Nat. Rev. Neurol. advance online publication 25 June 2013; doi:10.1038/nrneurol.2013.128 ininthe pote (HTT)4p16.3 gene. The classic clinical feature ofthat affectsisthebeginning toendophenotype emerge, however, that like movement individual for or an suggestive of potenthe full expansion brain brain. cells withinThe the same individual remain to be clarified. many years, followed by severe rigidity, full Unaffected tially developing the disease.Therefore, the Affected HD is a progressive, untreatable and highly with intermediate alleles can mosaicism that exte dementia, cachexia and,individuals ultimately, death. intermediate HTT alleles are considered to The longer the CAG repeat expansion in the represent something of a genetic ‘grey area’. alleles in per mediateHTTrange disabling chorea: an uncontrollable dancemanifest either a phenotype typical of HD…the intermediate HTT gene, the earlier the appearance of Recently, a longitudinal analysis of indiare considered to represent Figure 1 | Multiple ‘shades’ of CAG triplet length in the HTT gene. The increasing length of the the first disabling manifestation. viduals at risk of HD and controls, enrolled like movement that affects the individual for motoror an endophenotype suggestive of potenthe full ‘grey expansion in something of a genetic Soon after the discovery of the HTT gene, in the Prospective Huntington At Risk CAG repeat stretch in the HTT gene from normal size to expansion goes through a series of analysis of large populations patients Study (PHAROS), has highlighted the possame individual rema many years, followed by severe rigidity, full tiallyof developing the disease.Therefore, the area’ worldwide described a pathological range sibility that people carrying an HTT allele zones,cachexia with subtle, and intermediate ambiguous clinical manifestations potentially associated dementia, and, heterogeneous ultimately, death. HTT alleles are considered tofactors that determine The the phenostarting beyond 35 CAG repeats, with 36–39 that falls within the intermediate range can repeats representing a ‘low-penetrance’ typic variability of patients carrying triplet show marked behavioural changes, includthethe intermediate and low-penetrance alleles. Abbreviation: HTT, huntingtin. Thewith longer CAG repeat expansion represent of a genetic . in the low-penetrance expansions range in the that tends to be associated with verysomething ing suicidal ideation and apathy.‘grey The area’ …therange, interme ‘‘ 1 ’’ ? QQQQQQ Sperimentalzione preclinica nei modelli di MH Pratica clinica MH La malattia di Huntington …una sola mutazione… molti diversi volti… Corea Rigidita’ Distonia Corea Depressione Distonia Aggressivita’ Rigidita’ Irritabilita’ Bradicinesia Psicosi Incoordinazione Apa/a Disturbi del movimento Sintomi psichaitrici Ossessioni Disfagia Compulsioni Disatria Dispercezioni Atassia Alto tasso suicidi Aprassia Insonnia Deficit cogni+vo Demenza Alterazioni ritmo Disturbi di memorIa Sonno/Veglia Difficolta’ di riconoscimento dei colori Disinibizione Difficolta’ di riconoscimento del gusto Atrofia muscolare Difficolta’ di riconoscimento delle emozioni Perdita del peso Incon/nenza HUNTINGTON: modello di studio UNA mutazione dominante TEST DNA ica n i l c ilità b a i r Va Insorgenza 90% Complicazioni della mala[a Durata di 15-‐30 anni 90% 10%
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