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Home Past Issue About IP About IAP Feedback Links Author Info. Subscription Case Reports Indian Pediatrics 2002; 39:183185 Treatment of Menkes Disease with Parenteral Copper Histidine B.G. Kirodian N.J. Gogtay V.P. Udani* N.A. Kshirsagar From the Department of Clinical Pharmacology, Seth G.S. Medical College and KEM Hospital, Parel, Mumbai 400 012, India and *P.D Hinduja Hospital and Research Center, Veer Savarkar Marg, Mahim, Mumbai 400 016, India. Correspondence to: Dr. N.A. Kshirsagar, Dean, Professor and Head of Clinical Pharmacology, Department of Clinical Pharmacology, M.S. Building, 1st Floor, Seth G.S. Medical College and K.E.M. Hospital, Parel, Mumbai 400 012, India. Email: [email protected] Manuscript received: March 14, 2001; Initial review completed: May 3, 2001; Revision accepted: July 16, 2001. Menkes disease, also called as Menkes steely hair disease, or Kinky hair syndrome or Menkes syndrome is a rare Xlinked neurodegenerative disorder of copper metabolism with an estimated prevalence rate of 1 in 100,000250,000 births. This syndrome of copper deficiency results due to accumulation of copper in the intestine, due to defect in intestinal copper absorption. The clinical features of Menkes disease include skeletal abnormalities, severe mental retardation, thrombosis, hypothermia, arterial abnormalities and characteristic facial features. All of these result from decreased activity of cuproenzymes such as dopamine B hydroxylase, cytochrome c oxidase, lysyl oxidase, tyrosinase, ceruloplasmin, sulfhydryl oxidase, and copperzinc superoxide dismutase(1). Parenteral copper in the form of copperhistidine, copperacetate or copperEDTA injected intravenously or subcutaneously has been gaining acceptance as a treatment modality for the last decade. We present in this paper, two cases of Menkes disease treated by us with parenteral copperhistidine manufactured at our department and the results of the treatment. Case Reports Case 1: A 13months child from Goa, born of a consanguineous marriage was referred to us for treatment of mild Menkes disease. The patient had light colored hair, wrinkled skin, pili torti and had repeated episodes of focal seizures. A diagnosis of Menkes disease was confirmed by a reduced basal serum copper and ceruloplasmin levels of 63 µg/dl and 17.9 mg/dl respectively. MR angiography confirmed tortuous, ecstatic intracranial vessels. After informed consent from his guardians, the patient was started on copperhistidine injections as follows 50 µg/d on Day 1, 100 µg/d on Day 2 and 150 µg/d from Day 3 onwards. The drug was administered subcutaneously in the anterolateral thigh region. Biochemical parameters were repeated at 2 weeks and 1 month. Within 2 weeks of initiation of therapy, serum Cu++ and ceruloplasmin values had normalized (Table I ). The texture and color of the hair began to change and there was a reduction in the number of seizures. The patient’s mother was then trained to administer the drug and the patient was discharged. The patient was lost to follow up three months later when the mother cited financial constraints in procuring copper histidine every two months and making repeated trips to Mumbai. Telephonic follow up confirmed
description
Menkes disease
Transcript of Indian Pediatrics - Editorial
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CaseReports
IndianPediatrics200239:183185
TreatmentofMenkesDiseasewithParenteralCopperHistidineB.G.KirodianN.J.GogtayV.P.Udani*N.A.Kshirsagar
FromtheDepartmentofClinicalPharmacology,SethG.S.MedicalCollegeandKEM Hospital, Parel, Mumbai 400 012, India and *P.D Hinduja Hospital andResearchCenter,VeerSavarkarMarg,Mahim,Mumbai400016,India.
Correspondence to:Dr.N.A.Kshirsagar,Dean,ProfessorandHeadofClinicalPharmacology,DepartmentofClinicalPharmacology,M.S.Building,1stFloor,SethG.S.MedicalCollegeandK.E.M.Hospital,Parel,Mumbai400012,India.
Email:[email protected]
Manuscriptreceived:March14,2001Initialreviewcompleted:May3,2001Revisionaccepted:July16,2001.
Menkesdisease,alsocalledasMenkessteelyhairdisease,orKinkyhairsyndromeorMenkessyndromeisarareXlinkedneurodegenerativedisorderofcoppermetabolismwithanestimatedprevalencerateof1in100,000250,000births.Thissyndromeofcopperdeficiencyresultsduetoaccumulationofcopperintheintestine, due to defect in intestinal copper absorption. The clinical features of Menkes disease includeskeletal abnormalities, severe mental retardation, thrombosis, hypothermia, arterial abnormalities andcharacteristic facial features. All of these result from decreased activity of cuproenzymes such asdopamine B hydroxylase, cytochrome c oxidase, lysyl oxidase, tyrosinase, ceruloplasmin, sulfhydryloxidase,andcopperzincsuperoxidedismutase(1).
Parenteralcopperintheformofcopperhistidine,copperacetateorcopperEDTA injected intravenouslyorsubcutaneouslyhasbeengainingacceptanceasa treatmentmodality for the lastdecade.Wepresent inthispaper,twocasesofMenkesdiseasetreatedbyuswithparenteralcopperhistidinemanufacturedatourdepartmentandtheresultsofthetreatment.
CaseReports
Case1:A13monthschildfromGoa,bornofaconsanguineousmarriagewasreferredtousfortreatmentofmildMenkesdisease.Thepatienthadlightcoloredhair,wrinkledskin,pilitortiandhadrepeatedepisodesof focal seizures. A diagnosis ofMenkes diseasewas confirmed by a reduced basal serum copper andceruloplasminlevelsof63g/dland17.9mg/dlrespectively.MRangiographyconfirmed tortuous,ecstaticintracranialvessels.Afterinformedconsentfromhisguardians,thepatientwasstartedoncopperhistidineinjectionsas follows 50g/donDay1,100g/donDay2and150g/d fromDay3onwards.Thedrugwasadministeredsubcutaneously in theanterolateral thigh region.Biochemicalparameterswere repeatedat2weeksand1month.Within2weeksofinitiationoftherapy,serumCu++andceruloplasminvalueshadnormalized(Table I).The textureand color of the hair began to changeand therewas a reduction in thenumber of seizures. The patients mother was then trained to administer the drug and the patient wasdischarged.
Thepatientwaslosttofollowupthreemonthslaterwhenthemothercitedfinancialconstraintsinprocuringcopperhistidineevery twomonthsandmaking repeated trips toMumbai.Telephonic follow up confirmed
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thatthepatientwasalivewithoutfurtherdeteriorationinhiscondition.
Case2:An18montholdchildbornofanonconsanguineousmarriagefromLucknowwasreferredtousforcopperhistidine therapy.Thispatienthadsimilarclinical featuresandMRangiographybut greatermentalretardation.Copperhistidineinhimwasstartedinasimilarmanner,butthepatientdiedonday10,beforehisfirstfollowup.Therelativesdidnotpermitanautopsy.
TableI__BiochemicalChangesAfterAdministrationofCopperHistidine
Parameter Case1BaselineCase12weeks
Case14weeks
Case2Baseline
Case2Followup
Normalranges(34moage)
Normalranges(childrenandadults)
Serumcopper(g/dl) 63 102 118 51 Diedonday10 8814 9820
Serumceruloplasmin(mg/dl) 17.9 37.9 42.3 6.59 1835 2445
Livercopper Notdone 38.450120(g/gdryweight)
Discussion
Amongthedifferentparenteral formsofcopper therapy,copperhistidinehasbeenreportedtobetakenupby thebrainmostefficiently(2).Thedosageofcopperhistidineusedbyvariousauthors ranges from2001000gonceadayor23 times/week(3).Response to therapy is basedonmonitoringof serumcopper,ceruloplasmin,urinarycopperexcretionandlivercoppercontent.
InMenkesdisease,withearlyinitiationoftherapy(within2monthsofbirth),neurologicaldeteriorationcanbe prevented. Copperhistidine after 2 months cannot halt either the neurological deterioration nor can itimproveconnective tissue laxityorbonedeformities, although thehair andbiochemical abnormalitiesdonormalize.Theformulationusedbyusisidenticaltotheoneusedearlierin7casesofMenkesdisease.Of2 patientswhere the therapywas begunwithin 1month of birth didwell neurologically,while the other 5patients did poorly despite intiation of treatment at 27 months of age(4). We saw this in Case 1 withnormalizationofbiochemicalparametersandbeginningofhairnormalization.Case2hadfartooadvanceddiseaseforthetreatmenttohaveanyeffects.
Thecopperhistidineformulationused in twocasesmentionedwassterile,pyrogen freeandmanufacturedusing locally available chemicals.Copperhistidine solutionwas prepared under aseptic condition using alaminarairflowhood.Anhydrouscopperchloride(0.106g)andL(+)Histidine(0.244g)aredissolvedin90mlofsaline.ThepHofthesolutionwasadjustedto7.387.4with0.2NSodiumhydroxidesolutionusingapHmeter.Thefinalvolumewasmadeto100mlwith0.9%sodiumchlorideinjectionUSP.Itwasaquablueincolor,hadtobeprotectedfromlight,wasrefrigeratedandhadashelflifeof56days.Giventherarityofthedisease,therewaswastageoftheformulation.
To date, parenteral copper replacement remains the mainstay of therapy for Menkes disease. To ourknowledge, these are the first two cases in India to have received copperhistidine which may form themainstayoftreatmenttillsuchtimethatothermodalitiessuchaslipidchelatorsandgenetherapyaretriedforthisdisease.Tanakaetal(5)havereportedthatintraperitonealadministrationofdiethyldithiocarbamateanddimethyldithiocarbamateresulted innormalsurvivalwithoutanycopper treatment inmacularmutantmice. These findings suggest that lipid soluble chelators can enhance copper transport across cellularmembranes.Bothpatientstreatedbyusbelongedtothelowersocioeconomicstrata.Thecostper150gdose worked out to be Rs. 40/ and included cost of chemicals, consumables, quality control andpersonnel. Inadevelopingcountry likeours, theeconomicsofgiving life longcopperhistidinewill remainanimportantissueindeterminingpatientcomplianceandfollowup.
Acknowledgement
WearegratefultoDr.B.Sarkar,HeadStructuralBiologyandBiochemistry,TheHospitalforSickChildren,University of Toronto and Karen Walsh, Manufacturing Pharmacist, University of Toronto for help andassistanceinpreparationofsterilecopperhistidinesolution.
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Contributors:BGKwas responsible formanufacture of copperhistidine solution and data collection. NJGcoordinated thestudy,superviseddrugadministration,patient followupanddrafted thepaper.VPUwasresponsible for patient care and followup and drafting of paper.NAKwas responsible for supervision ofdrug manufacture, drug administration, study design and manuscript preparation, and will act as theguarantorforthepaper.
Funding:None.
Competinginterests:Nonestated.
KeyMessagesTreatmentwithparenteralcopperhistidineappearstobeeffectiveinpreventingthe severe neurodegeneration problems in patients with Menkes disease,particularlywhenthetreatmentisinitiatedveryearlyinlife.
Sterile,pyrogenfreecopperhistidinesolutionforsubcutaneousadministrationcanbemanufacturedusinglocallyavailablechemicals.
References
1. Kodama H, Murata Y, Kobayashi M. Clinical manifestations and treatment of Menkesdiseaseanditsvariants.PediatrInt199941:423429.
2.BarneaA,KatzBM.Uptakeof67Coppercomplexedto3Hhistidinebybrainhypothalamicslices:Evidencethatdissociationofthecomplexisnottheonlyfactordetermining67Copperuptake.JInorgBiochem199040:8193.
3.KalerSG.Menkesdisease.AdvPediatr199441:263304.
4.SarkarB,WalshK,ClarkTR.CopperhistidinetherapyforMenkesdisease.JPediatr1993123:828830.
5.TanakaK,KobayashiK,FujitaY,FukuharaC,OnosakaS,MinK.Effectsofchelatorsoncopper therapyofmacularmouse:AmodelanimalofMenkeskinkydisease.ResCommunChemPatholPharmacol199069:217227.
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