Huntington's disease - Wikipedia

Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. ... The earliest symptoms are often subtle ... Huntington'sdisease FromWikipedia,thefreeencyclopedia Jumptonavigation Jumptosearch Inheritedneurodegenerativedisorder MedicalconditionHuntington'sdiseaseOthernamesHuntington'schoreaAneditedmicroscopicimageofamediumspinyneuron(yellow)withaninclusionbody(orange),whichoccursaspartofthediseaseprocess(imagewidth360 µm)SpecialtyNeurologySymptomsProblemswithmotorskills,includingcoordinationandgait,mood,andmentalabilities[1][2]ComplicationsPneumonia,heartdisease,physicalinjuryfromfalls,suicide[3]Usualonset30–50yearsold[4]DurationLongterm[4]CausesGenetic(inheritedornewmutation)[4]DiagnosticmethodGenetictesting[5]DifferentialdiagnosisSydenham'schorea,benignhereditarychorea,lupus,paraneoplasticsyndrome,Wilson'sdisease[6]TreatmentSupportivecare[2]MedicationTetrabenazine[3]Prognosis15–20yearsfromonsetofsymptoms[4]Frequency4–15in100,000(Europeandescent)[1] Huntington'sdisease(HD),alsoknownasHuntington'schorea,isaneurodegenerativediseasethatismostlyinherited.[7]Theearliestsymptomsareoftensubtleproblemswithmoodormentalabilities.[1]Agenerallackofcoordinationandanunsteadygaitoftenfollow.[2]Itisalsoabasalgangliadiseasecausingahyperkineticmovementdisorderknownaschorea.[8][9]Asthediseaseadvances,uncoordinated,involuntarybodymovementsofchoreabecomemoreapparent.[1]Physicalabilitiesgraduallyworsenuntilcoordinatedmovementbecomesdifficultandthepersonisunabletotalk.[1][2]Mentalabilitiesgenerallydeclineintodementia.[3]Thespecificsymptomsvarysomewhatbetweenpeople.[1]Symptomsusuallybeginbetween30and50yearsofagebutcanstartatanyage.[3][4]Thediseasemaydevelopearlierineachsuccessivegeneration.[1]Abouteightpercentofcasesstartbeforetheageof20years,andareknownasjuvenileHD,whichtypicallypresentwiththeslowmovementsymptomsofParkinson'sdiseaseratherthanthoseofchorea.[3] HDistypicallyinheritedfromanaffectedparent,whocarriesamutationinthehuntingtingene(HTT).[4]However,upto10%ofcasesareduetoanewmutation.[1]Thehuntingtingeneprovidesthegeneticinformationforhuntingtinprotein(Htt).[1]ExpansionofCAGrepeatsofcytosine-adenine-guanine(knownasatrinucleotiderepeatexpansion)inthegenecodingforthehuntingtinproteinresultsinanabnormalmutantprotein(mHtt),whichgraduallydamagesbraincellsthroughanumberofpossiblemechanisms.[7][10]Diagnosisisbygenetictesting,whichcanbecarriedoutatanytime,regardlessofwhetherornotsymptomsarepresent.[5]Thisfactraisesseveralethicaldebates:theageatwhichanindividualisconsideredmatureenoughtochoosetesting;whetherparentshavetherighttohavetheirchildrentested;andmanagingconfidentialityanddisclosureoftestresults.[2] NocureforHDisknown,andfull-timecareisrequiredinthelaterstages.[2]Treatmentscanrelievesomesymptoms,andinsome,improvequalityoflife.[3]Thebestevidencefortreatmentofthemovementproblemsiswithtetrabenazine.[3]HDaffectsabout4to15in100,000peopleofEuropeandescent.[1][3]ItisrareamongJapanese,whiletheoccurrencerateinAfricaisunknown.[3]Thediseaseaffectsmenandwomenequally.[3]Complicationssuchaspneumonia,heartdisease,andphysicalinjuryfromfallsreducelifeexpectancy.[3]Suicideisthecauseofdeathinabout9%ofcases.[3]Deathtypicallyoccurs15–20yearsfromwhenthediseasewasfirstdetected.[4] Theearliestknowndescriptionofthediseasewasin1841byAmericanphysicianCharlesOscarWaters.[11]Theconditionwasdescribedinfurtherdetailin1872byAmericanphysicianGeorgeHuntington.[11]Thegeneticbasiswasdiscoveredin1993byaninternationalcollaborativeeffortledbytheHereditaryDiseaseFoundation.[12][13]Researchandsupportorganizationsbeganforminginthelate1960stoincreasepublicawareness,providesupportforindividualsandtheirfamiliesandpromoteresearch.[13][14]Researchdirectionsincludedeterminingtheexactmechanismofthedisease,improvinganimalmodelstoaidwithresearch,testingofmedicationsandtheirdeliverytotreatsymptomsorslowtheprogressionofthedisease,andstudyingproceduressuchasstem-celltherapywiththegoalofreplacingdamagedorlostneurons.[12] Contents 1Signsandsymptoms 2Genetics 2.1Geneticmutation 2.2Inheritance 3Mechanisms 3.1Huntingtinfunction 3.2Cellularchanges 3.3Macroscopicchanges 3.4Transcriptionaldysregulation 4Diagnosis 4.1Clinical 4.2Predictivegenetictesting 4.3Preimplantationgeneticdiagnosis 4.4Prenataltesting 4.5Differentialdiagnosis 5Management 5.1Therapy 5.2Medications 5.3Education 6Prognosis 7Epidemiology 8History 9Societyandculture 9.1Ethics 9.2Supportorganizations 10Researchdirections 10.1Reducinghuntingtinproduction 10.2Increasinghuntingtinclearance 10.3Improvingcellsurvival 10.4Neuronalreplacement 10.5Clinicaltrials 11Seealso 12References 13Externallinks Signsandsymptoms[edit] SignsandsymptomsofHuntington'sdiseasemostcommonlybecomenoticeablebetweentheagesof30and50years,buttheycanbeginatanyage,[4]andpresentasatriadofmotor,cognitive,andpsychiatricsymptoms.[15]In50%ofcases,thepsychiatricsymptomsappearfirst.[15]Theirprogressionisoftendescribedinearlystages,middlestages,andlatestageswithanearlierprodromalphase.[2]Intheearlystages,subtlepersonalitychanges,problemsincognition,andphysicalskills,irritability,andmoodswingsoccur,allofwhichmaygounnoticed,[16][17]andtheseusuallyprecedethemotorsymptoms.[18]AlmosteveryonewithHDeventuallyexhibitssimilarphysicalsymptoms,buttheonset,progression,andextentofcognitiveandbehavioralsymptomsvarysignificantlybetweenindividuals.[19][20] Themostcharacteristicinitialphysicalsymptomsarejerky,random,anduncontrollablemovementscalledchorea.[8]Manypeoplearenotawareoftheirinvoluntarymovements,orimpededbythem.[1]Choreamaybeinitiallyexhibitedasgeneralrestlessness,smallunintentionallyinitiatedoruncompletedmotions,lackofcoordination,orslowedsaccadiceyemovements.[21]Theseminormotorabnormalitiesusuallyprecedemoreobvioussignsofmotordysfunctionbyatleastthreeyears.[19]Theclearappearanceofsymptomssuchasrigidity,writhingmotions,orabnormalposturingappearasthedisorderprogresses.[21]Thesearesignsthatthesysteminthebrainthatisresponsibleformovementhasbeenaffected.[22]Psychomotorfunctionsbecomeincreasinglyimpaired,suchthatanyactionthatrequiresmusclecontrolisaffected.Commonconsequencesarephysicalinstability,abnormalfacialexpression,anddifficultieschewing,swallowing,andspeaking.[21]Sleepdisturbancesandweightlossarealsoassociatedsymptoms.[23]Eatingdifficultiescommonlycauseweightlossandmayleadtomalnutrition.[24][25]JuvenileHDgenerallyprogressesatafasterratewithgreatercognitivedecline,andchoreaisexhibitedbriefly,ifatall;theWestphalvariantofslownessofmovement,rigidity,andtremorsismoretypicalinjuvenileHD,asareseizures.[21][23] Cognitiveabilitiesareprogressivelyimpairedandtendtogenerallydeclineintodementia.[3]Especiallyaffectedareexecutivefunctions,whichincludeplanning,cognitiveflexibility,abstractthinking,ruleacquisition,initiationofappropriateactions,andinhibitionofinappropriateactions.[22]Asthediseaseprogresses,memorydeficitstendtoappear.Reportedimpairmentsrangefromshort-termmemorydeficitstolong-termmemorydifficulties,includingdeficitsinepisodic(memoryofone'slife),procedural(memoryofthebodyofhowtoperformanactivity),andworkingmemory.[22] Reportedneuropsychiatricsignsareanxiety,depression,areduceddisplayofemotions,egocentrism,aggression,andcompulsivebehavior,thelatterofwhichcancauseorworsenaddictions,includingalcoholism,gambling,andhypersexuality.[26]Difficultiesinrecognizingotherpeople'snegativeexpressionshavealsobeenobserved.[22]Theprevalenceofthesesymptomsishighlyvariablebetweenstudies,withestimatedratesforlifetimeprevalenceofpsychiatricdisordersbetween33and76%.[26]Formanysufferersandtheirfamilies,thesesymptomsareamongthemostdistressingaspectsofthedisease,oftenaffectingdailyfunctioningandconstitutingreasonforinstitutionalization.[26]EarlybehavioralchangesinHDresultinanincreasedriskofsuicide.[8]Often,individualshavereducedawarenessofchorea,cognitive,andemotionalimpairments.[27] Mutanthuntingtinisexpressedthroughoutthebodyandassociatedwithabnormalitiesinperipheraltissuesthataredirectlycausedbysuchexpressionoutsidethebrain.Theseabnormalitiesincludemuscleatrophy,cardiacfailure,impairedglucosetolerance,weightloss,osteoporosis,andtesticularatrophy.[28] Genetics[edit] Everyonehastwocopiesofthehuntingtingene(HTT),whichcodesforthehuntingtinprotein(Htt).HTTisalsocalledtheHDgene,andtheIT15gene,(interestingtranscript15).Partofthisgeneisarepeatedsectioncalledatrinucleotiderepeatexpansion–ashortrepeat,whichvariesinlengthbetweenindividuals,andmaychangelengthbetweengenerations.Iftherepeatispresentinahealthygene,adynamicmutationmayincreasetherepeatcountandresultinadefectivegene.Whenthelengthofthisrepeatedsectionreachesacertainthreshold,itproducesanalteredformoftheprotein,calledmutanthuntingtinprotein(mHtt).Thedifferingfunctionsoftheseproteinsarethecauseofpathologicalchanges,whichinturncausethediseasesymptoms.TheHuntington'sdiseasemutationisgeneticallydominantandalmostfullypenetrant;mutationofeitherofaperson'sHTTallelescausesthedisease.Itisnotinheritedaccordingtosex,butbythelengthoftherepeatedsectionofthegene,henceitsseveritycanbeinfluencedbythesexoftheaffectedparent.[21] Geneticmutation[edit] HDisoneofseveraltrinucleotiderepeatdisordersthatarecausedbythelengthofarepeatedsectionofageneexceedinganormalrange.[21]TheHTTgeneislocatedontheshortarmofchromosome4[21]at4p16.3.HTTcontainsasequenceofthreeDNAbases—cytosine-adenine-guanine(CAG)—repeatedmultipletimes(i.e. ...CAGCAGCAG ...),knownasatrinucleotiderepeat.[21]CAGisthethree-lettergeneticcode(codon)fortheaminoacidglutamine,soaseriesofthemresultsintheproductionofachainofglutamineknownasapolyglutaminetract(orpolyQtract),andtherepeatedpartofthegene,thepolyQregion.[29] Graphicshowingattopnormalrangeofrepeats,anddisease-causingrangeofrepeats. Classificationoftrinucleotiderepeats,andresultingdiseasestatus,dependingonthenumberofCAGrepeats[21] Repeatcount Classification Diseasestatus Risktooffspring <27 Normal Willnotbeaffected None 27–35 Intermediate Willnotbeaffected Elevated,but<50% 36–39 ReducedPenetrance Mayormaynotbeaffected 50% 40+ Fullpenetrance Willbeaffected 50% Generally,peoplehavefewerthan36repeatedglutaminesinthepolyQregion,whichresultsintheproductionofthecytoplasmicproteinhuntingtin.[21]However,asequenceof36ormoreglutaminesresultsintheproductionofaproteinwithdifferentcharacteristics.[21]Thisalteredform,calledmutanthuntingtin(mHtt),increasesthedecayrateofcertaintypesofneurons.Regionsofthebrainhavedifferingamountsandrelianceonthesetypesofneuronsandareaffectedaccordingly.[21]Generally,thenumberofCAGrepeatsisrelatedtohowmuchthisprocessisaffected,andaccountsforabout60%ofthevariationoftheageoftheonsetofsymptoms.TheremainingvariationisattributedtotheenvironmentandothergenesthatmodifythemechanismofHD.[21]About36to39repeatsresultinareduced-penetranceformofthedisease,withamuchlateronsetandslowerprogressionofsymptoms.Insomecases,theonsetmaybesolatethatsymptomsarenevernoticed.[21]Withverylargerepeatcounts(morethan60),HDonsetcanoccurbelowtheageof20,knownasjuvenileHD.JuvenileHDistypicallyoftheWestphalvariantthatischaracterisedbyslownessofmovement,rigidity,andtremors.Thisaccountsforabout7%ofHDcarriers.[30][31] Inheritance[edit] Huntington'sdiseaseisinheritedinanautosomaldominantfashion.Theprobabilityofeachoffspringinheritinganaffectedgeneis50%.Inheritanceisindependentofsex,andthephenotypedoesnotskipgenerations. Huntington'sdiseasehasautosomaldominantinheritance,meaningthatanaffectedindividualtypicallyinheritsonecopyofthegenewithanexpandedtrinucleotiderepeat(themutantallele)fromanaffectedparent.[21]Sincethepenetranceofthemutationisveryhigh,thosewhohaveamutatedcopyofthegenewillhavethedisease.Inthistypeofinheritancepattern,eachoffspringofanaffectedindividualhasa50%riskofinheritingthemutantallele,soareaffectedwiththedisorder(seefigure).Thisprobabilityissex-independent.[32] TrinucleotideCAGrepeatsnumberingover28areunstableduringreplication,andthisinstabilityincreaseswiththenumberofrepeatspresent.[21]Thisusuallyleadstonewexpansionsasgenerationspass(dynamicmutations)insteadofreproducinganexactcopyofthetrinucleotiderepeat.[21]Thiscausesthenumberofrepeatstochangeinsuccessivegenerations,suchthatanunaffectedparentwithan"intermediate"numberofrepeats(28–35),or"reducedpenetrance"(36–40),maypassonacopyofthegenewithanincreaseinthenumberofrepeatsthatproducesfullypenetrantHD.[21]Theearlierageofonsetandgreaterseverityofdiseaseinsuccessivegenerationsduetoincreasesinthenumberofrepeatsisknownasgeneticanticipation.[1]Instabilityisgreaterinspermatogenesisthanoogenesis;[21]maternallyinheritedallelesareusuallyofasimilarrepeatlength,whereaspaternallyinheritedoneshaveahigherchanceofincreasinginlength.[21][33]RarelyisHuntington'sdiseasecausedbyanewmutation,whereneitherparenthasover36CAGrepeats.[34] IntheraresituationswherebothparentshaveanexpandedHDgene,theriskincreasesto75%,andwheneitherparenthastwoexpandedcopies,theriskis100%(allchildrenwillbeaffected).Individualswithbothgenesaffectedarerare.Forsometime,HDwasthoughttobetheonlydiseaseforwhichpossessionofasecondmutatedgenedidnotaffectsymptomsandprogression,[35]butithassincebeenfoundthatitcanaffectthephenotypeandtherateofprogression.[21][36] Mechanisms[edit] Huntingtinproteininteractswithover100otherproteins,andappearstohavemultiplefunctions.[37]Thebehaviorofthemutatedprotein(mHtt)isnotcompletelyunderstood,butitistoxictocertaincelltypes,particularlybraincells.Earlydamageismostevidentinthesubcorticalbasalganglia,initiallyinthestriatum,butasthediseaseprogresses,otherareasofthebrainarealsoaffected,includingregionsofthecerebralcortex.Earlysymptomsareattributabletofunctionsofthestriatumanditscorticalconnections—namelycontrolovermovement,mood,andhighercognitivefunction.[21]DNAmethylationalsoappearstobechangedinHD.[38] Huntingtinfunction[edit] Seealso:Huntingtin§ Function Httisexpressedinallcells,withthehighestconcentrationsfoundinthebrainandtestes,andmoderateamountsintheliver,heart,andlungs.Itsfunctionsareunclear,butitdoesinteractwithproteinsinvolvedintranscription,cellsignaling,andintracellulartransporting.[39]InanimalsgeneticallymodifiedtoexhibitHD,severalfunctionsofHtthavebeenidentified.[40]Intheseanimals,Httisimportantforembryonicdevelopment,asitsabsenceisrelatedtoembryonicdeath.Caspase,anenzymewhichplaysaroleincatalyzingapoptosis,isthoughttobeactivatedbythemutatedgenethroughdamagingtheubiquitin-proteasesystem.Italsoactsasanantiapoptoticagentpreventingprogrammedcelldeathandcontrolstheproductionofbrain-derivedneurotrophicfactor,aproteinthatprotectsneuronsandregulatestheircreationduringneurogenesis.Httalsofacilitatessynapticvesiculartransportandsynaptictransmission,andcontrolsneuronalgenetranscription.[40]IftheexpressionofHttisincreased,braincellsurvivalisimprovedandtheeffectsofmHttarereduced,whereaswhentheexpressionofHttisreduced,theresultingcharacteristicsaremoreasseeninthepresenceofmHtt.[40]Accordingly,thediseaseisthoughtnottobecausedbyinadequateproductionofHtt,butbyatoxicgain-of-functionofmHttinthebody.[21] Cellularchanges[edit] Amicroscopeimageofaneuronwithaninclusionbody(stainedorange)causedbyHD,imagewidth250 µm ThetoxicactionofmHttmaymanifestandproducetheHDpathologythroughmultiplecellularchanges.[41][42]Initsmutant(polyglutamineexpanded)form,theproteinismorepronetocleavagethatcreatesshorterfragmentscontainingthepolyglutamineexpansion.[41]Theseproteinfragmentshaveapropensitytoundergomisfoldingandaggregation,yieldingfibrillaraggregatesinwhichnon-nativepolyglutamineβ-strandsfrommultipleproteinsarebondedtogetherbyhydrogenbonds.[10]Theseaggregatessharethesamefundamentalcross-betaamyloidarchitectureseeninotherproteindepositiondiseases.Overtime,theaggregatesaccumulatetoforminclusionbodieswithincells,ultimatelyinterferingwithneuronalfunction.[10][41]Neuronalinclusionsrunindirectinterference.Inclusionbodieshavebeenfoundinboththecellnucleusandcytoplasm.[41]Inclusionbodiesincellsofthebrainareoneoftheearliestpathologicalchanges,andsomeexperimentshavefoundthattheycanbetoxicforthecell,butotherexperimentshaveshownthattheymayformaspartofthebody'sdefensemechanismandhelpprotectcells.[41] SeveralpathwaysbywhichmHttmaycausecelldeathhavebeenidentified.Theseincludeeffectsonchaperoneproteins,whichhelpfoldproteinsandremovemisfoldedones;interactionswithcaspases,whichplayaroleintheprocessofremovingcells;thetoxiceffectsofglutamineonnervecells;impairmentofenergyproductionwithincells;andeffectsontheexpressionofgenes.[10][43] Mutanthuntingtinproteinhasbeenfoundtoplayakeyroleinmitochondrialdysfunction.[39]Theimpairmentofmitochondrialelectrontransportcanresultinhigherlevelsofoxidativestressandreleaseofreactiveoxygenspecies.[44] Glutamineisknowntobeexcitotoxicwhenpresentinlargeamounts,thatcancausedamagetonumerouscellularstructures.ExcessiveglutamineisnotfoundinHD,buttheinteractionsofthealteredhuntingtinproteinwithnumerousproteinsinneuronsleadtoanincreasedvulnerabilitytoglutamine.Theincreasedvulnerabilityisthoughttoresultinexcitotoxiceffectsfromnormalglutaminelevels.[10] Macroscopicchanges[edit] Seealso:Basalgangliadisease TheareaofthebrainmostdamagedinearlyHuntington'sdiseaseisthedorsalstriatummadeupofthecaudatenucleusandtheputamen. Initially,damagetothebrainisregionallyspecificwiththedorsalstriatuminthesubcorticalbasalgangliabeingprimarilyaffected,followedlaterbycorticalinvolvementinallareas.[45][46]Otherareasofthebasalgangliaaffectedincludethesubstantianigra;corticalinvolvementincludescorticallayers3,5,and6;alsoevidentisinvolvementofthehippocampus,Purkinjecellsinthecerebellum,lateraltuberalnucleiofthehypothalamusandpartsofthethalamus.[21]Theseareasareaffectedaccordingtotheirstructureandthetypesofneuronstheycontain,reducinginsizeastheylosecells.[21]Striatalmediumspinyneuronsarethemostvulnerable,particularlyoneswithprojectionstowardstheexternalglobuspallidus,withinterneuronsandspinycellsprojectingtotheinternalglobuspallidusbeinglessaffected.[21][47]HDalsocausesanabnormalincreaseinastrocytesandactivationofthebrain'simmunecells,microglia.[48] Thebasalgangliaplayakeyroleinmovementandbehaviorcontrol.Theirfunctionsarenotfullyunderstood,buttheoriesproposethattheyarepartofthecognitiveexecutivesystem[22]andthemotorcircuit.[49]Thebasalgangliaordinarilyinhibitalargenumberofcircuitsthatgeneratespecificmovements.Toinitiateaparticularmovement,thecerebralcortexsendsasignaltothebasalgangliathatcausestheinhibitiontobereleased.Damagetothebasalgangliacancausethereleaseorreinstatementoftheinhibitionstobeerraticanduncontrolled,whichresultsinanawkwardstarttomotionormotionstobeunintentionallyinitiated,oramotiontobehaltedbefore,orbeyond,itsintendedcompletion.TheaccumulatingdamagetothisareacausesthecharacteristicerraticmovementsassociatedwithHDknownaschorea,adyskinesia.[49]Becauseofthebasalganglia'sinabilitytoinhibitmovements,individualsaffectedbyitinevitablyexperienceareducedabilitytoproducespeechandswallowfoodsandliquids(dysphagia).[50] Transcriptionaldysregulation[edit] CREB-bindingprotein(CBP),atranscriptionalcoregulator,isessentialforcellfunctionbecauseasacoactivatoratasignificantnumberofpromoters,itactivatesthetranscriptionofgenesforsurvivalpathways.[43]Furthermore,theaminoacidsthatformCBPincludeastripof18glutamines.Thus,theglutaminesonCBPinteractdirectlywiththeincreasednumbersofglutamineontheHTTchainandCBPgetspulledawayfromitstypicallocationnexttothenucleus.[51]Specifically,CBPcontainsanacetyltransferasedomaintowhichHTTbindsthroughitspolyglutamine-containingdomain.[52]AutopsiedbrainsofthosewhohadHuntington'sdiseasealsohavebeenfoundtohaveincrediblyreducedamountsofCBP.[51]Inaddition,whenCBPisoverexpressed,polyglutamine-induceddeathisdiminished,furtherdemonstratingthatCBPplaysanimportantroleinHuntington'sdiseaseandneuronsingeneral.[43] Diagnosis[edit] DiagnosisoftheonsetofHDcanbemadefollowingtheappearanceofphysicalsymptomsspecifictothedisease.[21]GenetictestingcanbeusedtoconfirmaphysicaldiagnosisifnofamilyhistoryofHDexists.Evenbeforetheonsetofsymptoms,genetictestingcanconfirmifanindividualorembryocarriesanexpandedcopyofthetrinucleotiderepeat(CAG)intheHTTgenethatcausesthedisease.Geneticcounselingisavailabletoprovideadviceandguidancethroughoutthetestingprocedureandontheimplicationsofaconfirmeddiagnosis.Theseimplicationsincludetheimpactonanindividual'spsychology,career,family-planningdecisions,relatives,andrelationships.Despitetheavailabilityofpresymptomatictesting,only5%ofthoseatriskofinheritingHDchoosetodoso.[21] Clinical[edit] CoronalsectionfromanMRbrainscanofapatientwithHD,showingatrophyoftheheadsofthecaudatenuclei,enlargementofthefrontalhornsofthelateralventricles(hydrocephalusexvacuo),andgeneralizedcorticalatrophy[53] Aphysicalexamination,sometimescombinedwithapsychologicalexamination,candeterminewhethertheonsetofthediseasehasbegun.[21]Excessiveunintentionalmovementsofanypartofthebodyareoftenthereasonforseekingmedicalconsultation.Iftheseareabruptandhaverandomtiminganddistribution,theysuggestadiagnosisofHD.Cognitiveorbehavioralsymptomsarerarelythefirstsymptomsdiagnosed;theyareusuallyonlyrecognizedinhindsightorwhentheydevelopfurther.HowfarthediseasehasprogressedcanbemeasuredusingtheunifiedHuntington'sdiseaseratingscale,whichprovidesanoverallratingsystembasedonmotor,behavioral,cognitive,andfunctionalassessments.[54][55]Medicalimaging,suchasaCTscanorMRIscan,canshowatrophyofthecaudatenucleiearlyinthedisease,asseenintheillustrationtotheright,butthesechangesarenot,bythemselves,diagnosticofHD.Cerebralatrophycanbeseenintheadvancedstagesofthedisease.Functionalneuroimagingtechniques,suchasfunctionalmagneticresonanceimaging(fMRI)andpositronemissiontomography(PET),canshowchangesinbrainactivitybeforetheonsetofphysicalsymptoms,buttheyareexperimentaltoolsandarenotusedclinically.[21] Predictivegenetictesting[edit] BecauseHDfollowsanautosomaldominantpatternofinheritance,astrongmotivationexistsforindividualswhoareatriskofinheritingittoseekadiagnosis.ThegenetictestforHDconsistsofabloodtest,whichcountsthenumbersofCAGrepeatsineachoftheHTTalleles.[56]Cutoffsaregivenasfollows: At40ormoreCAGrepeats,fullpenetranceallele(FPA)exists.[57]A"positivetest"or"positiveresult"generallyreferstothiscase.Apositiveresultisnotconsideredadiagnosis,sinceitmaybeobtaineddecadesbeforethesymptomsbegin.However,anegativetestmeansthattheindividualdoesnotcarrytheexpandedcopyofthegeneandwillnotdevelopHD.[21]Thetestwilltellapersonwhooriginallyhada50%chanceofinheritingthediseaseiftheirriskgoesupto100%oriseliminated.PersonswhotestpositiveforthediseasewilldevelopHDsometimewithintheirlifetimes,providedtheylivelongenoughforthediseasetoappear.[21] At36to39repeats,incompleteorreducedpenetranceallele(RPA)maycausesymptoms,usuallylaterintheadultlife.[57]Themaximumriskis60%thatapersonwithanRPAwillbesymptomaticatage65,and70%at75.[57] At27to35repeats,intermediateallele(IA),orlargenormalallele,isnotassociatedwithsymptomaticdiseaseinthetestedindividual,butmayexpanduponfurtherinheritancetogivesymptomsinoffspring.[57] With26orfewerrepeats,theresultisnotassociatedwithHD.[57] Testingbeforetheonsetofsymptomsisalife-changingeventandaverypersonaldecision.[21]ThemainreasongivenforchoosingtotestforHDistoaidincareerandfamilydecisions.[21]PredictivetestingforHuntington'sdiseasehasbeenavailablevialinkageanalysis(whichrequirestestingmultiplefamilymembers)since1986andviadirectmutationanalysissince1993.[58]Atthattime,surveysindicatedthat50–70%ofat-riskindividualswouldhavebeeninterestedinreceivingtesting,butsincepredictivetestinghasbeenofferedfarfewerchoosetobetested.[59]Over95%ofindividualsatriskofinheritingHDdonotproceedwithtesting,mostlybecauseithasnotreatment.[21]AkeyissueistheanxietyanindividualexperiencesaboutnotknowingwhethertheywilleventuallydevelopHD,comparedtotheimpactofapositiveresult.[21]Irrespectiveoftheresult,stresslevelsarelowertwoyearsafterbeingtested,buttheriskofsuicideisincreasedafterapositivetestresult.[21]Individualsfoundtohavenotinheritedthedisordermayexperiencesurvivorguiltaboutfamilymemberswhoareaffected.[21]Otherfactorstakenintoaccountwhenconsideringtestingincludethepossibilityofdiscriminationandtheimplicationsofapositiveresult,whichusuallymeansaparenthasanaffectedgeneandthattheindividual'ssiblingswillbeatriskofinheritingit.[21]Inonestudy,geneticdiscriminationwasfoundin46%ofindividualsatriskforHuntington'sdisease.Itoccurredathigherrateswithinpersonalrelationshipsthanhealthinsuranceoremploymentrelations.[60]GeneticcounselinginHDcanprovideinformation,adviceandsupportforinitialdecision-making,andthen,ifchosen,throughoutallstagesofthetestingprocess.[61]Becauseoftheimplicationsofthistest,patientswhowishtoundergotestingmustcompletethreecounselingsessionswhichprovideinformationaboutHuntington's.[62] CounselingandguidelinesontheuseofgenetictestingforHDhavebecomemodelsforothergeneticdisorders,suchasautosomaldominantcerebellarataxia.[21][63][64]PresymptomatictestingforHDhasalsoinfluencedtestingforotherillnesseswithgeneticvariantssuchaspolycystickidneydisease,familialAlzheimer'sdiseaseandbreastcancer.[63]TheEuropeanMolecularGeneticsQualityNetworkhavepublishedyearlyexternalqualityassessmentschemeformoleculargenetictestingforthisdiseaseandhavedevelopedbestpracticeguidelinesforgenetictestingforHDtoassistintestingandreportingofresults.[65] Preimplantationgeneticdiagnosis[edit] EmbryosproducedusinginvitrofertilizationmaybegeneticallytestedforHDusingpreimplantationgeneticdiagnosis.Thistechnique,whereoneortwocellsareextractedfromatypically4-to8-cellembryoandthentestedforthegeneticabnormality,canthenbeusedtoensureembryosaffectedwithHDgenesarenotimplanted,soanyoffspringwillnotinheritthedisease.Someformsofpreimplantationgeneticdiagnosis—non-disclosureorexclusiontesting—allowat-riskpeopletohaveHD-freeoffspringwithoutrevealingtheirownparentalgenotype,givingnoinformationaboutwhethertheythemselvesaredestinedtodevelopHD.Inexclusiontesting,theembryo'sDNAiscomparedwiththatoftheparentsandgrandparentstoavoidinheritanceofthechromosomalregioncontainingtheHDgenefromtheaffectedgrandparent.Innondisclosuretesting,onlydisease-freeembryosarereplacedintheuteruswhiletheparentalgenotypeandhenceparentalriskforHDareneverdisclosed.[66][67] Prenataltesting[edit] Obtainingaprenataldiagnosisforanembryoorfetusinthewombisalsopossible,usingfetalgeneticmaterialacquiredthroughchorionicvillussampling.Anamniocentesiscanbeperformedifthepregnancyisfurtheralong,within14–18weeks.ThisprocedurelooksattheamnioticfluidsurroundingthebabyforindicatorsoftheHDmutation.[68]This,too,canbepairedwithexclusiontestingtoavoiddisclosureofparentalgenotype.PrenataltestingcanbedonewhenparentshavebeendiagnosedwithHD,whentheyhavehadgenetictestingshowingtheexpansionoftheHTTgene,orwhentheyhavea50%chanceofinheritingthedisease.Theparentscanbecounseledontheiroptions,whichincludeterminationofpregnancy,andonthedifficultiesofachildwiththeidentifiedgene.[69][70] Inaddition,inat-riskpregnanciesduetoanaffectedmalepartner,noninvasiveprenataldiagnosiscanbeperformedbyanalyzingcell-freefetalDNAinabloodsampletakenfromthemother(viavenipuncture)betweensixand12weeksofpregnancy.[57]Ithasnoprocedure-relatedriskofmiscarriage.[57] Differentialdiagnosis[edit] About99%ofHDdiagnosesbasedonthetypicalsymptomsandafamilyhistoryofthediseaseareconfirmedbygenetictestingtohavetheexpandedtrinucleotiderepeatthatcausesHD.MostoftheremainingarecalledHD-like(HDL)syndromes.[21][71]ThecauseofmostHDLdiseasesisunknown,butthosewithknowncausesareduetomutationsintheprionproteingene(HDL1),thejunctophilin3gene(HDL2),arecessivelyinheritedunknowngene(HDL3—onlyfoundintwofamiliesandpoorlyunderstood),andthegeneencodingtheTATAbox-bindingprotein(SCA17,sometimescalledHDL4).OtherautosomaldominantdiseasesthatcanbemisdiagnosedasHDaredentatorubral-pallidoluysianatrophyandneuroferritinopathy.Also,someautosomalrecessivedisordersresemblesporadiccasesofHD.Theseincludechoreaacanthocytosisandpantothenatekinase-associatedneurodegeneration.OneX-linkeddisorderofthistypeisMcLeodsyndrome.[71] Management[edit] Illustrationfromacasereportin1977ofapersonwithHuntington'sdisease TreatmentsareavailabletoreducetheseverityofsomeofHDsymptoms.[72]Formanyofthesetreatments,evidencetoconfirmtheireffectivenessintreatingsymptomsofHDspecificallyareincomplete.[21][73]Asthediseaseprogresses,theabilitytocareforoneselfdeclines,andcarefullymanagedmultidisciplinarycaregivingbecomesincreasinglynecessary.[21]AlthoughrelativelyfewstudiesofexercisesandtherapieshaveshowntobehelpfultorehabilitatecognitivesymptomsofHD,someevidenceshowstheusefulnessofphysicaltherapy,occupationaltherapy,andspeechtherapy.[21] Therapy[edit] Weightlossandproblemsineatingduetodysphagiaandothermusclediscoordinationarecommon,makingnutritionmanagementincreasinglyimportantasthediseaseadvances.[21]Thickeningagentscanbeaddedtoliquids,asthickerfluidsareeasierandsafertoswallow.[21]Remindingtheaffectedpersontoeatslowlyandtotakesmallerpiecesoffoodintothemouthmayalsobeofusetopreventchoking.[21]Ifeatingbecomestoohazardousoruncomfortable,theoptionofusingapercutaneousendoscopicgastrostomyisavailable.Thisfeedingtube,permanentlyattachedthroughtheabdomenintothestomach,reducestheriskofaspiratingfoodandprovidesbetternutritionalmanagement.[74]Assessmentandmanagementbyspeech-languagepathologistswithexperienceinHuntington'sdiseaseisrecommended.[21] PeoplewithHuntington'sdiseasemayseeaphysicaltherapistfornoninvasiveandnonmedication-basedwaysofmanagingthephysicalsymptoms.Physicaltherapistsmayimplementfallriskassessmentandprevention,aswellasstrengthening,stretching,andcardiovascularexercises.Walkingaidsmaybeprescribedasappropriate.Physicaltherapistsalsoprescribebreathingexercisesandairwayclearancetechniqueswiththedevelopmentofrespiratoryproblems.[75]ConsensusguidelinesonphysiotherapyinHuntington'sdiseasehavebeenproducedbytheEuropeanHDNetwork.[75]Goalsofearlyrehabilitationinterventionsarepreventionoflossoffunction.Participationinrehabilitationprogramsduringtheearlytomiddlestageofthediseasemaybebeneficialasittranslatesintolong-termmaintenanceofmotorandfunctionalperformance.Rehabilitationduringthelatestageaimstocompensateformotorandfunctionallosses.[76]Forlong-termindependentmanagement,thetherapistmaydevelophomeexerciseprogramsforappropriatepeople.[77] Additionally,anincreasingnumberofpeoplewithHDareturningtopalliativecare,whichaimstoimprovequalityoflifethroughthetreatmentofthesymptomsandstressofseriousillness,inadditiontotheirothertreatments.[78] Medications[edit] Chemicalstructureoftetrabenazine,anapprovedcompoundforthemanagementofchoreainHD Tetrabenazinewasapprovedin2000fortreatmentofchoreainHuntington'sdiseaseintheEU,andin2008intheUS.[79]Althoughotherdrugshadbeenused"offlabel,"tetrabenazinewasthefirstapprovedtreatmentforHuntington'sdiseaseintheU.S.Thecompoundhasbeenknownsincethe1950s.Analternativetotetrabenazineisamantadinebutthereislimitedevidenceforitssafetyandefficacy.[80] Otherdrugsthathelptoreducechoreaincludeantipsychoticsandbenzodiazepines.[17]Hypokinesiaandrigidity,especiallyinjuvenilecases,canbetreatedwithantiparkinsoniandrugs,andmyoclonichyperkinesiacanbetreatedwithvalproicacid.[17]Tentativeevidencehasfoundethyleicosapentaenoicacidtoimprovemotorsymptomsatoneyear.[81]In2017DeutetrabenazineaheavierformoftetrabenazinemedicationforthetreatmentofchoreainHDwasapprovedbytheFDA.[82]ThisismarketedasAustedo,andisthefirstsmall-moleculedrugtoreceiveU.S.FDAapproval.[83] Psychiatricsymptomscanbetreatedwithmedicationssimilartothoseusedinthegeneralpopulation.[21][73]Selectiveserotoninreuptakeinhibitorsandmirtazapinehavebeenrecommendedfordepression,whileatypicalantipsychoticsarerecommendedforpsychosisandbehavioralproblems.[73]Specialistneuropsychiatricinputisrecommendedaspeoplemayrequirelong-termtreatmentwithmultiplemedicationsincombination.[21] Education[edit] Thefamiliesofindividuals,andsocietyatlarge,whohaveinheritedorareatriskofinheritingHDhavegenerationsofexperienceofHDbutmaybeunawareofrecentbreakthroughsinunderstandingthedisease,andoftheavailabilityofgenetictesting.Geneticcounselingbenefitstheseindividualsbyupdatingtheirknowledge,seekingtodispelanyunfoundedbeliefsthattheymayhave,andhelpingthemconsidertheirfutureoptionsandplans.ThePatientEducationProgramforHuntington'sDiseasehasbeencreatedtohelpeducatefamilymembers,caretakers,andthosediagnosedwithHuntington'sdisease.[84]Alsocoveredisinformationconcerningfamilyplanningchoices,caremanagement,andotherconsiderations.[21][85] Prognosis[edit] Thelengthofthetrinucleotiderepeataccountsfor60%ofthevariationoftheageofsymptomsonsetandtheirrateofprogress.Alongerrepeatresultsinanearlierageofonsetandafasterprogressionofsymptoms.[21][86]Individualswithmorethansixtyrepeatsoftendevelopthediseasebeforeage20,whilethosewithfewerthan40repeatsmayremainasymptomatic.[87]Theremainingvariationisduetoenvironmentalfactorsandothergenesthatinfluencethemechanismofthedisease.[21] LifeexpectancyinHDisgenerallyaround20 yearsfollowingtheonsetofvisiblesymptoms.[21]Mostlife-threateningcomplicationsresultfrommusclecoordination,andtoalesserextent,behavioralchangesinducedbydecliningcognitivefunction.Thelargestriskispneumonia,whichcausesdeathinonethirdofthosewithHD.Astheabilitytosynchronizemovementsdeteriorates,difficultyclearingthelungs,andanincreasedriskofaspiratingfoodordrinkbothincreasetheriskofcontractingpneumonia.Thesecond-greatestriskisheartdisease,whichcausesalmostaquarteroffatalitiesofthosewithHD.[21]Suicideisthethirdgreatestcauseoffatalities,with7.3%ofthosewithHDtakingtheirownlivesandupto27%attemptingtodoso.Towhatextentsuicidalthoughtsareinfluencedbybehavioralsymptomsisunclear,astheysignifysufferers'desirestoavoidthelaterstagesofthedisease.[88][89][90]Otherassociatedrisksincludechoking,physicalinjuryfromfalls,andmalnutrition.[21] Epidemiology[edit] ThelateonsetofHuntington'sdiseasemeansitdoesnotusuallyaffectreproduction.[21]TheworldwideprevalenceofHDis5–10casesper100,000persons,[91][92]butvariesgreatlygeographicallyasaresultofethnicity,localmigrationandpastimmigrationpatterns.[21]Prevalenceissimilarformenandwomen.TherateofoccurrenceishighestinpeoplesofWesternEuropeandescent,averagingaroundsevenper100,000people,andislowerintherestoftheworld;e.g.,onepermillionpeopleofAsianandAfricandescent.A2013epidemiologicalstudyoftheprevalenceofHuntington'sdiseaseintheUKbetween1990and2010foundthattheaverageprevalencefortheUKwas12.3per100,000.[21][93]Additionally,somelocalizedareashaveamuchhigherprevalencethantheirregionalaverage.[21]OneofthehighestincidencesisintheisolatedpopulationsoftheLakeMaracaiboregionofVenezuela,whereHDaffectsupto700per100,000persons.[21][94]OtherareasofhighlocalizationhavebeenfoundinTasmaniaandspecificregionsofScotland,WalesandSweden.[90]Increasedprevalenceinsomecasesoccursduetoalocalfoundereffect,ahistoricalmigrationofcarriersintoanareaofgeographicisolation.[90][95]Someofthesecarriershavebeentracedbackhundredsofyearsusinggenealogicalstudies.[90]Genetichaplotypescanalsogivecluesforthegeographicvariationsofprevalence.[90][96]Iceland,onthecontrary,hasaratherlowprevalenceof1per100,000,despitethefactthatIcelandersasapeoplearedescendedoftheearlyGermanictribesofScandinaviawhichalsogaverisetotheSwedes;allcaseswiththeexceptionofonegoingbacknearlytwocenturieshavingderivedfromtheoffspringofacouplelivingearlyinthe19thcentury.[97]Finland,aswell,hasalowincidenceofonly2.2per100,000people.[98] Untilthediscoveryofagenetictest,statisticscouldonlyincludeclinicaldiagnosisbasedonphysicalsymptomsandafamilyhistoryofHD,excludingthosewhodiedofothercausesbeforediagnosis.Thesecasescannowbeincludedinstatistics;and,asthetestbecomesmorewidelyavailable,estimatesoftheprevalenceandincidenceofthedisorderarelikelytoincrease.[90][99] History[edit] In1872,GeorgeHuntingtondescribedthedisorderinhisfirstpaper"OnChorea"attheageof22.[100] AlthoughHDhasbeenrecognizedasadisordersinceatleasttheMiddleAges,thecausehasbeenunknownuntilfairlyrecently.Huntington'swasgivendifferentnamesthroughoutthishistoryasunderstandingofthediseasechanged.Originallycalledsimply'chorea'forthejerky,dance-likemovementsassociatedwiththedisease,HDhasalsobeencalled"hereditarychorea"and"chronicprogressivechorea".[101]ThefirstdefinitementionofHDwasinaletterbyCharlesOscarWaters,publishedinthefirsteditionofRobleyDunglison'sPracticeofMedicinein1842.Watersdescribed"aformofchorea,vulgarlycalledmagrums",includingaccuratedescriptionsofthechorea,itsprogression,andthestrongheredityofthedisease.[102]In1846CharlesGormanobservedhowhigherprevalenceseemedtooccurinlocalizedregions.[102]IndependentlyofGormanandWaters,bothstudentsofDunglisonatJeffersonMedicalCollegeinPhiladelphia,[103]JohanChristianLundalsoproducedanearlydescriptionin1860.[102]HespecificallynotedthatinSetesdalen,asecludedmountainvalleyinNorway,thehighprevalenceofdementiawasassociatedwithapatternofjerkingmovementdisordersthatraninfamilies.[104] ThefirstthoroughdescriptionofthediseasewasbyGeorgeHuntingtonin1872.Examiningthecombinedmedicalhistoryofseveralgenerationsofafamilyexhibitingsimilarsymptoms,herealizedtheirconditionsmustbelinked;hepresentedhisdetailedandaccuratedefinitionofthediseaseashisfirstpaper.HuntingtondescribedtheexactpatternofinheritanceofautosomaldominantdiseaseyearsbeforetherediscoverybyscientistsofMendelianinheritance. Ofitshereditarynature.Wheneitherorboththeparentshaveshownmanifestationsofthedisease ...oneormoreoftheoffspringalmostinvariablysufferfromthedisease ...Butifbyanychancethesechildrengothroughlifewithoutit,thethreadisbrokenandthegrandchildrenandgreat-grandchildrenoftheoriginalshakersmayrestassuredthattheyarefreefromthedisease.[100][105] SirWilliamOslerwasinterestedinthedisorderandchoreaingeneral,andwasimpressedwithHuntington'spaper,stating,"Inthehistoryofmedicine,therearefewinstancesinwhichadiseasehasbeenmoreaccurately,moregraphicallyormorebrieflydescribed."[102][106]Osler'scontinuedinterestinHD,combinedwithhisinfluenceinthefieldofmedicine,helpedtorapidlyspreadawarenessandknowledgeofthedisorderthroughoutthemedicalcommunity.[102]GreatinterestwasshownbyscientistsinEurope,includingLouisThéophileJosephLandouzy,Désiré-MagloireBourneville,CamilloGolgi,andJosephJulesDejerine,anduntiltheendofthecentury,muchoftheresearchintoHDwasEuropeaninorigin.[102]Bytheendofthe19thcentury,researchandreportsonHDhadbeenpublishedinmanycountriesandthediseasewasrecognizedasaworldwidecondition.[102] DuringtherediscoveryofMendelianinheritanceattheturnofthe20thcentury,HDwasusedtentativelyasanexampleofautosomaldominantinheritance.[102]EnglishbiologistWilliamBatesonusedthepedigreesofaffectedfamiliestoestablishthatHDhadanautosomaldominantinheritancepattern.[103]Thestronginheritancepatternpromptedseveralresearchers,includingSmithElyJelliffe,toattempttotraceandconnectfamilymembersofpreviousstudies.[102]JelliffecollectedinformationfromacrossNewYorkandpublishedseveralarticlesregardingthegenealogyofHDinNewEngland.[107]Jelliffe'sresearchrousedtheinterestofhiscollegefriend,CharlesDavenport,whocommissionedElizabethMunceytoproducethefirstfieldstudyontheEastCoastoftheUnitedStatesoffamilieswithHDandtoconstructtheirpedigrees.[108]DavenportusedthisinformationtodocumentthevariableageofonsetandrangeofsymptomsofHD;heclaimedthatmostcasesofHDintheUScouldbetracedbacktoahandfulofindividuals.[108]Thisresearchwasfurtherembellishedin1932byP.R.Vessie,whopopularizedtheideathatthreebrotherswholeftEnglandin1630boundforBostonweretheprogenitorsofHDintheUS.[109]TheclaimthattheearliestprogenitorshadbeenestablishedandeugenicbiasofMuncey's,Davenport's,andVessie'sworkcontributedtomisunderstandingsandprejudiceaboutHD.[103]MunceyandDavenportalsopopularizedtheideathatinthepast,someHDsufferersmayhavebeenthoughttobepossessedbyspiritsorvictimsofwitchcraft,andweresometimesshunnedorexiledbysociety.[110][111]Thisideahasnotbeenproven.Researchershavefoundcontraryevidence;forinstance,thecommunityofthefamilystudiedbyGeorgeHuntingtonopenlyaccommodatedthosewhoexhibitedsymptomsofHD.[103][110] Thesearchforthecauseofthisconditionwasenhancedconsiderablyin1968,whentheHereditaryDiseaseFoundation(HDF)wascreatedbyMiltonWexler,apsychoanalystbasedinLosAngeles,California,whosewifeLeonoreSabinhadbeendiagnosedearlierthatyearwithHuntington'sdisease.[112]ThethreebrothersofWexler'swifealsosufferedfromthisdisease. Thefoundationwasinvolvedintherecruitmentofmorethan100scientistsintheUS-VenezuelaHuntington'sDiseaseCollaborativeProject,whichovera10-yearperiodfrom1979,workedtolocatethegeneticcause.[113]Thiswasachievedin1983whenacausalgenewasapproximatelylocated,[95]andin1993,thegenewaspreciselylocatedatchromosome4(4p16.3).[114]ThestudyhadfocusedonthepopulationsoftwoisolatedVenezuelanvillages,BarranquitasandLagunetas,wheretherewasanunusuallyhighprevalenceofHD,andinvolvedover18,000people,mostlyfromasingleextendedfamily,andresultedinmakingHDthefirstautosomaldiseaselocusfoundusinggeneticlinkageanalysis.[114][115]Amongotherinnovations,theprojectdevelopedDNA-markingmethodswhichwereanimportantstepinmakingtheHumanGenomeProjectpossible.[113] Inthesametime,keydiscoveriesconcerningthemechanismsofthedisorderwerebeingmade,includingthefindingsbyAnitaHarding'sresearchgroupontheeffectsofthegene'slength.[116] Modellingthediseaseinvarioustypesofanimals,suchasthetransgenicmousedevelopedin1996,enabledlarger-scaleexperiments.Astheseanimalshavefastermetabolismsandmuchshorterlifespansthanhumansresultsfromexperimentsarereceivedsooner,speedingresearch.The1997discoverythatmHttfragmentsmisfoldledtothediscoveryofthenuclearinclusionstheycause.Theseadvanceshaveledtoincreasinglyextensiveresearchintotheproteinsinvolvedwiththedisease,potentialdrugtreatments,caremethods,andthegeneitself.[102][117] TheconditionwasformerlycalledHuntington'schorea,butthistermhasbeenreplacedbyHuntington'sdiseasebecausenotallpatientsdevelopchoreaandduetotheimportanceofcognitiveandbehavioralproblems.[118] Societyandculture[edit] Seealso:ListofHuntington'sdiseasemediadepictions Ethics[edit] Seealso:Invitrofertilisation§ Ethics,andStemcellcontroversy GenetictestingforHuntington'sdisease,hasraisedseveralethicalissues.Theissuesforgenetictestingincludedefininghowmatureanindividualshouldbebeforebeingconsideredeligiblefortesting,ensuringtheconfidentialityofresults,andwhethercompaniesshouldbeallowedtousetestresultsfordecisionsonemployment,lifeinsuranceorotherfinancialmatters.TherewascontroversywhenCharlesDavenportproposedin1910thatcompulsorysterilizationandimmigrationcontrolbeusedforpeoplewithcertaindiseases,includingHD,aspartoftheeugenicsmovement.[119]Invitrofertilizationhassomeissuesregardingitsuseofembryos.SomeHDresearchhasethicalissuesduetoitsuseofanimaltestingandembryonicstemcells.[120][121] ThedevelopmentofanaccuratediagnostictestforHuntington'sdiseasehascausedsocial,legal,andethicalconcernsoveraccesstoanduseofaperson'sresults.[122][123] Manyguidelinesandtestingprocedureshavestrictproceduresfordisclosureandconfidentialitytoallowindividualstodecidewhenandhowtoreceivetheirresultsandalsotowhomtheresultsaremadeavailable.[21]Insurancecompaniesandbusinessesarefacedwiththequestionofwhethertousegenetictestresultswhenassessinganindividual,suchasforlifeinsuranceoremployment.TheUnitedKingdom'sinsurancecompaniesagreedwiththeDepartmentofHealthandSocialCarethatuntil2017customerswouldnotneedtodisclosepredictivegeneticsteststothem,butthisagreementexplicitlyexcludedthegovernment-approvedtestforHuntington'swhenwritingpolicieswithavalueoverGB£500,000.[124][125]Aswithotheruntreatablegeneticconditionswithalateronset,itisethicallyquestionabletoperformpre-symptomatictestingonachildoradolescent,astherewouldbenomedicalbenefitforthatindividual.Thereisconsensusfortestingonlyindividualswhoareconsideredcognitivelymature,althoughthereisacounter-argumentthatparentshavearighttomakethedecisionontheirchild'sbehalf.Withthelackofaneffectivetreatment,testingapersonunderlegalagewhoisnotjudgedtobecompetentisconsideredunethicalinmostcases.[42][126][127] Thereareethicalconcernsrelatedtoprenatalgenetictestingorpreimplantationgeneticdiagnosistoensureachildisnotbornwithagivendisease.[128]Forexample,prenataltestingraisestheissueofselectiveabortion,achoiceconsideredunacceptablebysome.[128]Asitisadominantdisease,therearedifficultiesinsituationsinwhichaparentdoesnotwanttoknowhisorherowndiagnosis.Thiswouldrequirepartsoftheprocesstobekeptsecretfromtheparent.[128] Supportorganizations[edit] ThedeathofWoodyGuthrieledtothefoundationoftheCommitteetoCombatHuntington'sDisease In1968,afterexperiencingHDinhiswife'sfamily,Dr.MiltonWexlerwasinspiredtostarttheHereditaryDiseaseFoundation(HDF),withtheaimofcuringgeneticillnessesbycoordinatingandsupportingresearch.[13]ThefoundationandWexler'sdaughter,NancyWexler,werekeypartsoftheresearchteaminVenezuelawhichdiscoveredtheHDgene.[13] AtroughlythesametimeastheHDFformed,MarjorieGuthriehelpedtofoundtheCommitteetoCombatHuntington'sDisease(nowtheHuntington'sDiseaseSocietyofAmerica),afterherhusband,folksinger-songwriterWoodyGuthriediedfromcomplicationsofHD.[14] Sincethen,supportandresearchorganizationshaveformedinmanycountriesaroundtheworldandhavehelpedtoincreasepublicawarenessofHD.Anumberofthesecollaborateinumbrellaorganizations,liketheInternationalHuntingtonAssociationandtheEuropeanHDnetwork.[129]ManysupportorganizationsholdanannualHDawarenessevent,someofwhichhavebeenendorsedbytheirrespectivegovernments.Forexample,6Juneisdesignated"NationalHuntington'sDiseaseAwarenessDay"bytheUSSenate.[130]ManyorganizationsexisttosupportandinformthoseaffectedbyHD,includingtheHuntington'sDiseaseAssociationintheUK.ThelargestfunderofresearchisprovidedbytheCureHuntington'sDiseaseInitiativeFoundation(CHDI).[131] Researchdirections[edit] ResearchintothemechanismofHDisfocusedonidentifyingthefunctioningofHtt,howmHttdiffersorinterfereswithit,andthebrainpathologythatthediseaseproduces.[132]Researchisconductedusinginvitromethods,geneticallymodifiedanimals,(alsocalledtransgenicanimalmodels),andhumanvolunteers.Animalmodelsarecriticalforunderstandingthefundamentalmechanismscausingthedisease,andforsupportingtheearlystagesofdrugdevelopment.[117]AnimalswithchemicallyinducedbraininjuryexhibitHD-likesymptomsandwereinitiallyused,buttheydidnotmimictheprogressivefeaturesofthedisease.[133]Theidentificationofthecausativegenehasenabledthedevelopmentofmanygeneticallymodifiedorganismsincludingnematodes(roundworms),Drosophilafruitflies,andgeneticallymodifiedmammalsincludingmice,rats,sheep,pigsandmonkeysthatexpressmutanthuntingtinanddevelopprogressiveneurodegenerationandHD-likesymptoms.[117] ResearchisbeingconductedusingmanyapproachestoeitherpreventHuntington'sdiseaseorslowitsprogression.[132]Disease-modifyingstrategiescanbebroadlygroupedintothreecategories:reducingthelevelofthemutanthuntingtinprotein(includinggenesplicingandgenesilencing);approachesaimedatimprovingneuronalsurvivalbyreducingtheharmcausedbytheproteintospecificcellularpathwaysandmechanisms(includingproteinhomeostasisandhistonedeacetylaseinhibition);andstrategiestoreplacelostneurons.Inaddition,noveltherapiestoimprovebrainfunctioningareunderdevelopment;theseseektoproducesymptomaticratherthandisease-modifyingtherapies,andincludephosphodiesteraseinhibitors.[134][135] Muchresearchhasfocusedonimprovingmethodsofdrugdeliverytothebrainbytheuseofnanotechnology,andisstillongoing.ManydrugshaveshownpotentialfortreatingHuntington'sbuttherehasremainedtheobstacleoftheirpassingthroughtheblood–brainbarriertotheirtargets.Thedevelopmentofdeliveringdrugsusingnanoparticleshasbeenfurtheradvancedbytheuseoflipidnanoparticles,andthisareaisthoughttoplayamajorroleinfuturetreatment.Furtherdevelopmentofpromiseisofdrugdeliverytotargetsinthebrainusingnasaladministration.[136] TheCHDIFoundationfundsagreatmanyresearchinitiativesprovidingmanypublications.[137]TheCHDIfoundationisthelargestfunderofHuntington'sdiseaseresearchgloballyandaimstofindanddevelopdrugsthatwillslowtheprogressionofHD.[131][138]CHDIwasformerlyknownastheHighQFoundation.In2006,itspent$50milliononHuntington'sdiseaseresearch.[131]CHDIcollaborateswithmanyacademicandcommerciallaboratoriesgloballyandengagesinoversightandmanagementofresearchprojectsaswellasfunding.[139] Reducinghuntingtinproduction[edit] Genesilencingaimstoreducetheproductionofthemutantprotein,sinceHDiscausedbyasingledominantgeneencodingatoxicprotein.GenesilencingexperimentsinmousemodelshaveshownthatwhentheexpressionofmHttisreduced,symptomsimprove.[140]ThesafetyofRNAinterference,andallele-specificoligonucleotide(ASO)methodsofgenesilencinghasbeendemonstratedinmiceandthelargerprimatemacaquebrain.[141][142]Allele-specificsilencingattemptstosilencemutanthttwhileleavingwild-typeHttuntouched.Onewayofaccomplishingthisistoidentifypolymorphismspresentononlyonealleleandproducegenesilencingdrugsthattargetpolymorphismsinonlythemutantallele.[143]ThefirstgenesilencingtrialinvolvinghumanswithHDbeganin2015,testingthesafetyofIONIS-HTTRx,producedbyIonisPharmaceuticalsandledbyUCLInstituteofNeurology.[144][145]MutanthuntingtinwasdetectedandquantifiedforthefirsttimeincerebrospinalfluidfromHuntington'sdiseasemutation-carriersin2015usinganovel"single-moleculecounting"immunoassay,[146]providingadirectwaytoassesswhetherhuntingtin-loweringtreatmentsareachievingthedesiredeffect.[147][148]Aphase3trialofthiscompound,renamedtominersenandsponsoredbyRochePharmaceuticals,beganin2019butwashaltedin2021afterthesafetymonitoringboardconcludedthattherisk-benefitbalancewasunfavourable.[149]Ahuntingtin-loweringgenetherapytrialrunbyUniqurebeganin2019,andseveraltrialsoforallyadministeredhuntingtin-loweringsplicingmodulatorcompoundshavebeenannounced.[150]GenesplicingtechniquesarebeinglookedattotrytorepairagenomewiththeerroneousgenethatcausesHD,usingtoolssuchasCRISPR/Cas9.[135] Increasinghuntingtinclearance[edit] Anotherstrategytoreducethelevelofmutanthuntingtinistoincreasetherateatwhichcellsareabletoclearit.[151]AsmHtt(andmanyotherproteinaggregates)aredegradedbyautophagy,increasingtherateofautophagyhasthepotentialtoreducelevelsofmHttandtherebyamelioratedisease.[152]PharmacologicalandgeneticinducersofautophagyhavebeentestedinavarietyofHuntington'sdiseasemodels;manyhavebeenshowntoreducemHttlevelsanddecreasetoxicity.[151] Improvingcellsurvival[edit] Amongtheapproachesaimedatimprovingcellsurvivalinthepresenceofmutanthuntingtinarecorrectionoftranscriptionalregulationusinghistonedeacetylaseinhibitors,modulatingaggregationofhuntingtin,improvingmetabolismandmitochondrialfunctionandrestoringfunctionofsynapses.[140] Neuronalreplacement[edit] Stem-celltherapyisusedtoreplacedamagedneuronsbytransplantationofstemcellsintoaffectedregionsofthebrain.Experimentshaveyieldedmixedresultsusingthistechniqueinanimalmodelsandpreliminaryhumanclinicaltrials.[153]Whatevertheirfuturetherapeuticpotential,stemcellsarealreadyavaluabletoolforstudyingHuntington'sdiseaseinthelaboratory.[154] Clinicaltrials[edit] In2020therewere197clinicaltrialsrelatedtovariedtherapiesandbiomarkersforHuntington'sdiseaselistedaseitherunderway,recruitingornewlycompleted.[155]Compoundstrialled,thathavefailedtopreventorslowtheprogressionofHuntington'sdiseaseincluderemacemide,coenzymeQ10,riluzole,creatine,minocycline,ethyl-EPA,phenylbutyrateanddimebon.[156] Seealso[edit]  Medicineportal References[edit] ^abcdefghijklDayaluP,AlbinRL(February2015)."Huntingtondisease:pathogenesisandtreatment".NeurologicClinics.33(1):101–14.doi:10.1016/j.ncl.2014.09.003.PMID 25432725. 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Externallinks[edit] Huntington'sdiseaseatWikipedia'ssisterprojectsDefinitionsfromWiktionaryMediafromCommonsNewsfromWikinewsTextsfromWikisourceTextbooksfromWikibooksResourcesfromWikiversity Huntington'sdiseaseatCurlie HOPESproject–StanfordUniversity'sHDinformationproject HDBuzz–HDresearchnewswrittenbyscientistsinplainlanguage HDDrugWorks–newsaboutcurrenttreatmentsandplannedtrials ClassificationDICD-10:G10,F02.2ICD-9-CM:333.4,294.1OMIM:143100MeSH:D006816DiseasesDB:6060ExternalresourcesMedlinePlus:000770eMedicine:article/1150165article/792600article/289706PatientUK:Huntington'sdiseaseGeneReviews:HuntingtonDiseaseOrphanet:399 vteMentaldisorders (Classification)AdultpersonalityandbehaviorSexual Ego-dystonicsexualorientation Paraphilia Fetishism Voyeurism Sexualmaturationdisorder Sexualrelationshipdisorder Other Factitiousdisorder Munchausensyndrome Genderdysphoria Intermittentexplosivedisorder Dermatillomania Kleptomania Pyromania Trichotillomania Personalitydisorder ChildhoodandlearningEmotionalandbehavioral ADHD Conductdisorder ODD Emotionalandbehavioraldisorders Separationanxietydisorder Movementdisorders Stereotypic Socialfunctioning DAD RAD Selectivemutism Speech Cluttering Stuttering Ticdisorder Tourettesyndrome Intellectualdisability X-linkedintellectualdisability Lujan–Frynssyndrome Psychologicaldevelopment(developmentaldisabilities) Pervasive Specific Mood(affective) Bipolar BipolarI BipolarII BipolarNOS Cyclothymia Depression Atypicaldepression Dysthymia Majordepressivedisorder Melancholicdepression Seasonalaffectivedisorder Mania NeurologicalandsymptomaticAutismspectrum Autism Aspergersyndrome High-functioningautism PDD-NOS Savantsyndrome Dementia AIDSdementiacomplex Alzheimer'sdisease Creutzfeldt–Jakobdisease Frontotemporaldementia Huntington'sdisease Mildcognitiveimpairment Parkinson'sdisease Pick'sdisease Sundowning Vasculardementia Wandering Other Delirium Organicbrainsyndrome Post-concussionsyndrome Neurotic,stress-relatedandsomatoformAdjustment Adjustmentdisorderwithdepressedmood AnxietyPhobia Agoraphobia Socialanxiety Socialphobia Anthropophobia Specificsocialphobia Specificphobia Claustrophobia Other Generalizedanxietydisorder OCD Panicattack Panicdisorder Stress Acutestressdisorder PTSD Dissociative Depersonalization-derealizationdisorder Dissociativeidentitydisorder Fuguestate Psychogenicamnesia Somaticsymptom Bodydysmorphicdisorder Conversiondisorder Gansersyndrome Globuspharyngis Psychogenicnon-epilepticseizures Falsepregnancy Hypochondriasis Masspsychogenicillness Nosophobia Psychogenicpain Somatizationdisorder PhysiologicalandphysicalbehaviorEating Anorexianervosa Bulimianervosa Ruminationsyndrome Otherspecifiedfeedingoreatingdisorder Nonorganicsleep Hypersomnia Insomnia Parasomnia Nightterror Nightmare REMsleepbehaviordisorder Postnatal Postpartumdepression Postpartumpsychosis SexualdysfunctionArousal Erectiledysfunction Femalesexualarousaldisorder Desire Hypersexuality Hypoactivesexualdesiredisorder Orgasm Anorgasmia Delayedejaculation Prematureejaculation Sexualanhedonia Pain Nonorganicdyspareunia Nonorganicvaginismus Psychoactivesubstances,substanceabuseandsubstance-related Drugoverdose Intoxication Physicaldependence Reboundeffect Stimulantpsychosis Substancedependence Withdrawal Schizophrenia,schizotypalanddelusionalDelusional Delusionaldisorder Folieàdeux Psychosisandschizophrenia-like Briefreactivepsychosis Schizoaffectivedisorder Schizophreniformdisorder Schizophrenia Childhoodschizophrenia Disorganized(hebephrenic)schizophrenia Paranoidschizophrenia Pseudoneuroticschizophrenia Simple-typeschizophrenia Other Catatonia Symptomsanduncategorized Impulse-controldisorder Klüver–Bucysyndrome Psychomotoragitation Stereotypy vteDiseasesofthenervoussystem,primarilyCNSInflammationBrain Encephalitis Viralencephalitis Herpesviralencephalitis Limbicencephalitis Encephalitislethargica Cavernoussinusthrombosis Brainabscess Amoebic Brainandspinalcord Encephalomyelitis Acutedisseminated Meningitis Meningoencephalitis Brain/encephalopathyDegenerativeExtrapyramidalandmovementdisorders Basalgangliadisease Parkinsonism PD Postencephalitic NMS PKAN Tauopathy PSP Striatonigraldegeneration Hemiballismus HD OA Dyskinesia Dystonia Statusdystonicus Spasmodictorticollis Meige's Blepharospasm Athetosis Chorea Choreoathetosis Myoclonus Myoclonicepilepsy Akathisia Tremor Essentialtremor Intentiontremor Restlesslegs Stiff-person Dementia Tauopathy Alzheimer's Early-onset Primaryprogressiveaphasia Frontotemporaldementia/Frontotemporallobardegeneration Pick's Lewybodiesdementia Posteriorcorticalatrophy Vasculardementia Mitochondrialdisease Leighsyndrome Demyelinating Autoimmune Inflammatory Multiplesclerosis Formoredetailedcoverage,seeTemplate:DemyelinatingdiseasesofCNS Episodic/paroxysmalSeizuresandepilepsy Focal Generalised Statusepilepticus Formoredetailedcoverage,seeTemplate:Epilepsy Headache Migraine Cluster Tension Formoredetailedcoverage,seeTemplate:Headache Cerebrovascular TIA Stroke Formoredetailedcoverage,seeTemplate:Cerebrovasculardiseases Other Sleepdisorders Formoredetailedcoverage,seeTemplate:Sleep CSF Intracranialhypertension Hydrocephalus Normalpressurehydrocephalus Choroidplexuspapilloma Idiopathicintracranialhypertension Cerebraledema Intracranialhypotension Other Brainherniation Reyesyndrome Hepaticencephalopathy Toxicencephalopathy Hashimoto'sencephalopathy StaticEncephalopathy Both/eitherDegenerativeSA Friedreich'sataxia Ataxia–telangiectasia MND UMNonly: Primarylateralsclerosis Pseudobulbarpalsy Hereditaryspasticparaplegia LMNonly: Distalhereditarymotorneuronopathies Spinalmuscularatrophies SMA SMAX1 SMAX2 DSMA1 CongenitalDSMA Spinalmuscularatrophywithlowerextremitypredominance(SMALED) SMALED1 SMALED2A SMALED2B SMA-PCH SMA-PME Progressivemuscularatrophy Progressivebulbarpalsy Fazio–Londe Infantileprogressivebulbarpalsy both: Amyotrophiclateralsclerosis vteNon-Mendelianinheritance:anticipationTrinucleotidePolyglutamine(PolyQ),CAG Dentatorubral-pallidoluysianatrophy Huntington'sdisease Kennedydisease Spinocerebellarataxia1,2,3,6,7,17(Machado-Josephdisease) Non-polyglutamine CGG(FragileXsyndrome) GAA(Friedreich'sataxia) CTG(Myotonicdystrophytype1) CTG(Spinocerebellarataxia8) CAG(Spinocerebellarataxia12) Tetranucleotide CCTG(Myotonicdystrophytype2) Pentanucleotide ATTCT(Spinocerebellarataxia10) Authoritycontrol:Nationallibraries Spain France(data) Germany Israel UnitedStates CzechRepublic Retrievedfrom"https://en.wikipedia.org/w/index.php?title=Huntington%27s_disease&oldid=1074515936" Categories:Huntington'sdiseaseAutosomaldominantdisordersDisorderscausingseizuresExtrapyramidalandmovementdisordersGeneticdiseasesanddisordersSystemicatrophiesprimarilyaffectingthecentralnervoussystemTrinucleotiderepeatdisordersMedicalconditionswithnoknowncureHiddencategories:CS1Danish-languagesources(da)CS1:longvolumevalueArticleswithshortdescriptionShortdescriptionisdifferentfromWikidataUsedmydatesfromDecember2017UseAmericanEnglishfromDecember2017AllWikipediaarticleswritteninAmericanEnglishPagesusingSisterprojectlinkswithdefaultsearchArticleswithCurlielinksArticleswithBNEidentifiersArticleswithBNFidentifiersArticleswithGNDidentifiersArticleswithJ9UidentifiersArticleswithLCCNidentifiersArticleswithNKCidentifiersWikipediamedicinearticlesreadytotranslateWikipedianeurologyarticlesreadytotranslate Navigationmenu Personaltools NotloggedinTalkContributionsCreateaccountLogin Namespaces ArticleTalk English expanded collapsed Views ReadEditViewhistory More expanded collapsed Search Navigation 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