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Transcript
MaleswithMECP2Mutations (CanmaleshaveRettsyndrome?) OverviewofRettSyndrome TheclinicalfeaturesofRettsyndromewerefirstdescribedin1966byDr.AndreasRett.Patientswith theseclinicalfeaturesweresubsequentlygiventhedesignationofRettsyndromein1983inrecognition ofDr.Rett’soriginalreport.Rettsyndromeisstillconsideredaclinicaldiagnosisbasedonspecific developmentalhistoryandclinicalcriteria.Theseclinicalcriteriawerelastrevisedin2010. Initially,Rettsyndromewasrecognizedonlyinfemales.ItwashypothesizedthatRettsyndromewas lethalinmales.ThissuggestedthatRettsyndromewasasex-linkedgeneticdisorderwiththegene beinglocalizedontheXchromosome. In1999itwasreportedthatmutationsintheMECP2gene,locatedontheXchromosome,were associatedwiththeclinicalpresentationofRettsyndrome.SincetheabilitytotesttheMECP2genehas beenavailable,therehavebeenover60malesreportedwithmutationsintheMECP2gene.Afewof thesemaleshadaclinicalpictureconsistentwiththeclinicalcriteriaforRettsyndrome;however,most ofthesemalespresentedwithadifferentclinicalpresentation.MostmaleswithmutationsinMECP2 genepresentwithanearlieronsetofsymptoms,typicallywithsignificantproblemsbeginningator shortlyafterbirth. ThediagnosisofRettsyndromeisstillmadebasedonclinicalcriteriaandtheclinicalpresentation.Over 95%offemaleswithclassicRettsyndromewillhaveamutationintheMECP2gene.Mutationsinthe MECP2genebythemselvesarenotsufficienttomakeadiagnosisofRettsyndrome.Patientswith mutationsintheMECP2genethatdonotmeettheclinicalcriteriaforRettsyndromearegiventhe designationofMECP2-relateddisorders. UnderstandingtheMECP2gene ThereisstillmuchtobelearnedaboutthefunctionoftheMECP2gene.Itisaveryimportantgeneand actsasaregulatorygeneforthousandsofothergenes.MECP2cancausebothincreasedexpressionand decreasedexpressionofothergenesatcriticaltimesindevelopment.TheMECP2geneplaysacritical roleinbraindevelopmentandbrainfunction. TheMECP2geneislocatedontheXchromosome,oneofthesexchromosomes.Femalestypicallyhave twoXchromosomesandmalestypicallyhaveoneXchromosomeandoneYchromosome.Thus,all femalestypicallyhavetwocopiesoftheMECP2gene,oneoneachoftheirXchromosomes.Females withRettsyndromehaveamutationorachangeinonecopyoftheMECP2geneononeoftheirtwoX chromosomes.BecauseofaprocessknownasXinactivation,onlyonecopyoftheMECP2geneisactive inanyonecellinfemales.ThisXinactivationprocessesisrandom,sothatinsomecellstheMECP2gene withthemutationisactiveandinothercellstheMECP2genewithoutthemutationisactive.Infemales withRettsyndromethismeansthatroughlyhalfoftheircellshaveanormallyfunctioningMECP2gene andhalftheircellshaveaMECP2genewithamutationpresentthatisnotfunctioningnormally.Thisis thetypicalpatternseeninRettsyndrome. MalesonlyhaveoneXchromosomeand,thus,onlyoneMECP2gene.Thus,amalewithamutationin theMECP2genehasthatmutationpresentintheironlycopyoftheMECP2gene.ThusTherefore,the functionofMECP2isaffectedadverselyinallcellsinthemale.ThisiswhymaleswithMECP2mutations presentdifferentlythanfemaleswithMECP2mutations.Malesthathaveamutationthatissimilarto thetypicalmutationseeninfemaleswithRettsyndromepresentwithearlyonsetandmoresevere clinicalproblemsthanfemaleswithclassicRettsyndrome. EarlyonitwasfeltthatmaleswithMECP2mutationswerenonviable,thus,explainingtheabsenceof thediagnosisofRettsyndromeinmales.However,itwassubsequentlydeterminedthatmostofthe mutationsinMECP2areduetonewspontaneousmutationsintheMECP2genethatoccurduringthe divisionandformationofsperm,themalegermcell.SincefatherstypicallygivetheirXchromosometo theirdaughtersandtheirYchromosometotheirsons,thisexplainsthelowoccurrenceofmaleswith MECP2mutations. ExplanationsformaleswithMECP2-relateddisorders 1. MaleswithRettsyndromeandKlinefeltersyndrome:Therehavebeenraremalesreported withthetypicalhistoryofclassicRettsyndrome.Thesemaleshavealsohadanunrelated geneticdisorderknownasKlinefeltersyndrome.InKlinefeltersyndrome,maleshavetwo copiesoftheXchromosomeandonecopyoftheYchromosome;thus,theyhaveanextra chromosomegivingthemachromosomaldesignationof47,XXY.Klinefeltersyndromeis relativelycommon,appearinginroughly1in500males.Thus,itisnotunexpectedthat occasionallyanindividualwillhavebothKlinefeltersyndromeandamutationintheMECP2 geneastwounrelatedevents.BecausethesemaleshavetwocopiesoftheXchromosomeand undergothesameprocessofXinactivationthatisseeninfemales,thesemalespresentwitha clinicalpresentationthatisveryconsistentwiththeclassicRettsyndromepresentation.These males,willinadditiontohavingtheclinicalfeaturesofRettsyndrome,alsohavefeaturesof Klinefeltersyndrome,includingunderdevelopmentofthegenitaliaandunderproductionofsex hormones. 2. MosaicismasacauseofRettsyndromeinmales:Mosaicismbasicallyisatermdefininga mixtureoftwodifferentpopulationsofcells.Therehavebeenveryrarereportsofmaleswith Rettsyndromeonthebasisofmosaicism.Thesemaleshaveamixtureoftwocelltypes.They havesomecellswithoneXchromosomewithoneMECP2genethatisfunctioningnormally.In othercellsofthebodytheyhaveoneXchromosomewithaMECP2genethathasamutation thatisaffectingthefunctionoftheMECP2gene.Dependingonthepercentageofthemixture ofthesetwocelltypes,thesemaleswillhaveclinicalfeaturessimilartofemaleswithclassicRett syndrome.Thismosaicismoccursbyamutationthatoccursafterconceptionbutearlyin embryologicdevelopment.Thetimingoftheoccurrenceofthismutationwilldeterminethe percentageofcellsaffectedbythemutation. Itshouldbenotedthatbasically,atthecellularlevel,allfemalesaremosaicforthefunctionof theMECP2gene. 3. MECP2-relatedsevereneonatalencephalopathy:Malesthathaveoneofthemutationsthatare typicallyseeninRettsyndromeusuallypresentwithearlieronsetandmoreseveresymptoms thanfemales.Again,thisisbecausethismutationintheMECP2geneisaffectingallthecellsin themale.Mostofthesemalespresentwithearlyonsetbreathingproblems,earlyonsetfeeding problems,andearlyonsetseizures.Withoutaggressivemedicalcaremostofthesemaleswith typicalMECP2genemutationspassawayinthefirstyearoflife.However,withaggressive medicalintervention,thesemalescansurviveintolatechildhood.Theyfrequentlyrequire significantmedicalsupport,includingnutritionalandbreathingsupport. 4. MaleswithMECP2mutationsandmilderpresentations(MECP2-relateddisorders):With increasedsequencingoftheMECP2gene,malesarebeingidentifiedwithmutationsinthe MECP2geneoutsideoftheregionsofthegenethatareusuallyassociatedwithclassicRett syndromeinfemales.ThesemutationsintheMECP2genemaypresentwithamalewith intellectualdisabilityormilderlearningproblemsandbehavioralproblems,butnotclassicor atypicalRettsyndrome.Someofthesemutations,whenseeninfemales,maypresentwithno clinicalfeaturesorverymildclinicalfeatures.Itisthoughtthatthesemutationsincertain regionsoftheMECP2genedonotcausesignificantdisruptionofthefunctionoftheMECP2 gene,and,thus,resultinmildersymptoms. LifeexpectancyofmaleswithMECP2mutations ThelifeexpectancyandthemedicalcomplicationsinmaleswithMECP2mutationsdependsa lotontheunderlyingmutationand/orotherassociatedgeneticproblems.Thus,maleswithRett syndromeandKlinefeltersyndrometogether,willhavealifeexpectancymoreinlinewiththat seeninRettsyndrome.ThustThesemalesmaylivealonglifewithmedicalcomplications. MalesthataremosaicforatypicalMECP2mutationwillhavealifeexpectancysimilarto femaleswithclassicRettsyndrome;thus,thesemalesalsomaylivealonglifewithassociated Rettrelatedmedicalcomplications.MaleswithonlyoneXchromosomewithatypicalMECP2 mutationtypicallyhaveshortenedlifeexpectancy.Withaggressivemedicalinterventionand dedicatedfamilies,thesemalesmaysurviveintolatechildhood;however,theymayrequire significantmedicalsupport.MaleswithatypicalmutationsoftheMECP2gene,mayhavea normallifeexpectancywithproblemsinlearningand/orbehavior. UnderstandingclinicaltrialsinmaleswithMECP2mutations CurrentlythereareactiveclinicaltrialsforRettsyndromeandplansfornewtrialsinthefuture. Atthistime,alltheclinicaltrialshavebeendesignedwitheligibilitycriteriathatareinclusivefor femalesandhaveexcludedmaleswithMECP2mutationsfromparticipating.Thishasgenerally occurredaspartofthestudydesigninattempttohaveauniformgeneticbackgroundthatwill allowinvestigatorstodeterminethesafetyandeffectivenessofthemedicationforRett syndrome.Thereareseveralfactorsinvolvedinthedesignofclinicaltrials.Thefundingagency, typicallyapharmaceuticalcompanyorafoundation,willfrequentlybeinvolvedinthedesignof theclinicaltrialwiththegoalofmaximizingtheinformationthatislearnedfromtheclinicaltrial. Theinvestigatorsinvolvedinconductingtheclinicaltrialmayhavesomeinputintothedesignof theclinicaltrial,butaretypicallyinvolvedwithconductingthetrialasdesignedbythefunding agency.Therearealsoregulatoryagencies,suchastheFDA,whichhavestringentcriteriafor clinicaltrialdesigntoensuresafetyandproperconductoftrials.Lastly,theknowledgeofthe clinicalconditionbeingtreatedwillimpactthedesignofthetrialandtheselectionofthe compoundsusedinthetrial. Challengesinincludingmalesinclinicaltrials 1. MaleswithRettsyndromeorMECP2-relateddisordersareveryrare.Recruitingsufficient numbersofmalesforclinicaltrialsisachallenge.Thereareslightlyover60malepatients withMECP2genechangesreportedinliterature,thoughthereareprobablymore unreportedmaleswithMECP2mutations. 2. MaleswithtypicalMECP2mutationspresentearlierwithmoreseveresymptomsanda differentclinicalcoursethanfemaleswithRettsyndrome.Includingmalesinclinicaltrials forRettsyndromecreateschallengesforinterpretationofdata,safetyandefficacy. 3. TrialdesignandeligibilitycriteriatypicallyexcludemaleswithMECP2mutationsfromthe earlyclinicaltrialsinRettsyndrome.Thisispartlyduetothechallengesofhavingessentially twodifferentpatientpopulationswithinthesameclinicaltrial.Thetrialdesignmaybe differentinamalepopulationthanafemalepopulation,includingsuchfactorsasageof inclusion,outcomemeasures,dosageandsafetyparameters. FutureformaleswithMECP2mutations CurrentresearchandcurrenttechnologyallowsthebetteridentificationofmaleswithMECP2 changes.MaleswithMECP2areeligibleforthecurrentnaturalhistorystudies.Anysuccessof thetreatmenttrialsforgirlswithRettsyndromemaybeapplicabletomaleswithMECP2 mutations.AnyapprovedtherapyforRettsyndromecouldbeconsideredforcompassionateuse inmaleswithMECP2mutations.Rettsyndrome.orgiscommittedtocontinuetofundresearch thatwillimpactqualityoflifeforbothboysandgirlslivingwithMECP2mutations. Rettsyndrome.orgcontinuestosupporteffortstoidentifytreatmentforthesymptomsofRett syndrome,toidentifybestpracticesandtherapiesthatwillmaintainorimproveexistingskills, andtoidentifyacurethroughproteinreplacementorgenetherapy.Alloftheseeffortsare criticaltoastrategythatwillaccelerateresearchtowardacureforRettsyndromeandMECP2relateddisorders.
