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)