with variable clinical course Poster
Transcript of with variable clinical course Poster
References
Cu(e)thebalancingact:Copperhomeostasisexploredin5siblingswithvariableclinicalcourse
CasePresentation
ConclusionsvRecognizingtheuniqueclinicalcourseinourpatientsisimportantinguidingmanagementandprovidingappropriategeneticcounseling.
vImportanceofcuproenzymesshouldnotbeoverlookedwhentreatingMenkes
vFutureresearchisindicatedtoclarifytheaffectedcommonpathwaysandresultingphenotypicsimilarities.
vSufficientcopperdeliverytothebrainisessentialforproperneurodevelopment.Therefore,earlycoppersupplementationshouldbeconsideredifconcernedforMenkes
SoniaAVargheseMDMPHMBAandYaelShiloh-Malawsky MD
Poster595
Discussion
1.StephenG.Kaler.NatRevNeurol.2011January;7(1):15–29.ATP7A-relatedcoppertransportdiseases—emergingconceptsandfuturetrends2.Kaler SG.MetabolicandMolecularBasesofMenkesDiseaseandOccipitalHornSyndrome. PediatricandDevelopmentalPathology.1998;1(1):85-98.3.Borm B,Møller LB,Hausser I,Emeis M,Baerlocher K,HornN,RossiR.VariableclinicalexpressionofanidenticalmutationintheATP7AgeneforMenkesdisease/occipitalhornsyndromeinthreeaffectedmalesinasinglefamily.JPediatr.2004Jul;145(1):119-21..
v ATP7Amutationsproduceaclinicalspectrumv Siblings1,2,and5followamoreclassicMenke’scourse,whilesiblings3and4exhibitaphenotypicvariation
v ThisvariationissuggestiveofamilderformofMenkessuchasoccipitalhornsyndromewithresidualcoppertransportfunction
v Siblings3and4hadimprovementwithcoppersupplementation,howeverdeclinedwhenoffsupplementation-suggestingresidualATP7Acoppertransportfunction
v Incomparison,sibling5receivedCu(His)twicedailysincebirthandhadlimitedbenefit-suggestingthathehadminimaltonofunctioningtransporters
Sibling:birthorder
Presentation Exam Diagnostictesting TreatmentCopperHistidine Outcomes
1O/AD:
Infancy/12mosFTT,Seizures,DD
N/A N/A NoD:16mosBrain
hemorrhage
2O/AD:Infancy/NA
FTTN/A N/A No
D:13mosFTT,
Meningitis
3
O/AD:6yo/BirthFTT,DD, Ataxiaandmotorregression,
Urogenitalcomplications,Syncopalevents,Foodaversion2/2chokingfear,Pyloric
stenosis
- Macrocephaly- Frontalbossing- Milddysmorphic
features- Pectuscarinatum
- Ataxia(Speech,gait,hands)
- Lowmuscletone- Normalreflexes
Ceruloplasmin7.1mg/dL(L)Copper0.20mcg/mL(L)VitC<0.1mg/dL(L)
CThead(2015):UnusuallyprominentCSFspace
ventraltobrainstemandcerebellarhemispheres
Yes- infancyto3y- 1repeatcourse(notresponsive)
L:motorregression- Unabletoambulateunassisted
4
O/AD:4yo/nottested
FTT, Ataxiaandmotorregression,
Urogenitalcomplications,Syncopalevents,Chronicb/l radialdislocations,
Behavioralconcerns
- Dysmorphicfeatures:angularface,wideseteyes- Musclewasting- Ataxia(Speech,gait,hands)
- Lowmuscletone- Normalreflexes
MRIbrain(2017):Non-enhancinglesionwithinthe
leftneck,possiblyalymphaticmalformationCThead(2017):Torturous
intracranialvesselsNormalEKG,ECHO,EEG
Yes: infancy-3yo,1repeat
course(responsive)
L:motorregression- Unabletoambulateunassisted
5
O/AD:Infancy/BirthFTT, Seizures
(Infantilespasms),Developmentalregression
- Occipitalflattening- Hypotonia
- Nocontractures- Malnourished
MRIbrain: FociofT2hyperintensityinb/l frontal,parietal,temporallobesEEG:infantilespasms
Microarrary:Hemizygousdeletionoftheentireexon1
withinATP7Agene
Yes:Neonatalperiodonward- NIHMenkes
study
D:19mosSevere
malnutrition.
Methodsv PresentauniquevariationofphenotypeandcourseinsiblingswithMenkesDisease(MD)
Objective
Background
v Reviewliteraturedescribingcoppertransportdisorders
v Applyfindingstoourcaseoffiveaffectedsiblings
v MutationsinATP7A:copperdeficiency(Menkesdisease)
v MutationsinATP7B:copperoverload(Wilsondisease)
v Theamountofresidualfunctioningcoppertransportinfluencesdiseaseseverityaswellastreatmentresponse
v Phenotypesareinfluencedbytheresultingdeficientactivityofcuproenzymes
O=SymptomOnset,AD=AgeofDiagnosis,FTT:FailuretothriveDD=Developmentaldelay,D=Deceased,L=livingUrogenitalcomplications:Bladderdiverticula, recurrentUTIs,VUR
v EarlyCu(His)supplementationappears tolowerriskofsevereneuro-degenerationinsomepatients
v Treatmentefficacyvarieshowever,anddependsonamountoffunctioning Cutransporters1
v Thegraphbelowdepictsthephenotypicspectrumseeninthe5brothersv Mom is a known carrier of ATP7A mutationv Thereis limitedinformation on thesiblingswho werenotseenatUNCv The 6th sibling is the youngest and isahealthyfemaleinfant(notincludedhere)