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IndianPediatricsEditorial

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CaseReports
IndianPediatrics200239:183185

TreatmentofMenkesDiseasewithParenteralCopperHistidine

B.G.Kirodian
N.J.Gogtay
V.P.Udani*
N.A.Kshirsagar
FromtheDepartmentofClinicalPharmacology,SethG.S.MedicalCollegeand
KEM Hospital, Parel, Mumbai 400 012, India and *P.D Hinduja Hospital and
ResearchCenter,VeerSavarkarMarg,Mahim,Mumbai400016,India.
Correspondence to: Dr. N.A. Kshirsagar, Dean, Professor and Head of Clinical
Pharmacology, Department of Clinical Pharmacology, M.S. Building, 1st Floor,
SethG.S.MedicalCollegeandK.E.M.Hospital,Parel,Mumbai400012,India.
Email:dcpkem@vsnl.com
Manuscriptreceived:March14,2001
Initialreviewcompleted:May3,2001
Revisionaccepted:July16,2001.
Menkesdisease,alsocalledasMenkessteelyhairdisease,orKinkyhairsyndromeorMenkessyndrome
isarareXlinkedneurodegenerativedisorderofcoppermetabolismwithanestimatedprevalencerateof1
in100,000250,000births.Thissyndromeofcopperdeficiencyresultsduetoaccumulationofcopperinthe
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,andcopperzincsuperoxidedismutase(1).
Parenteralcopperintheformofcopperhistidine,copperacetate or copperEDTA injected intravenously or
subcutaneously has been gaining acceptance as a treatment modality for the last decade. We present in
thispaper,twocasesofMenkesdiseasetreatedbyuswithparenteralcopperhistidinemanufacturedatour
departmentandtheresultsofthetreatment.
CaseReports
Case1:A13monthschildfromGoa,bornofaconsanguineousmarriagewasreferredtousfortreatmentof
mildMenkesdisease.Thepatienthadlightcoloredhair,wrinkledskin,pilitortiand had repeated episodes
of focal seizures. A diagnosis of Menkes disease was confirmed by a reduced basal serum copper and
ceruloplasminlevelsof63g/dland17.9mg/dlrespectively.MRangiographyconfirmed tortuous, ecstatic
intracranialvessels.Afterinformedconsentfromhisguardians,thepatientwasstartedoncopperhistidine
injections as follows 50 g/d on Day 1, 100 g/d on Day 2 and 150 g/d from Day 3 onwards. The drug
was administered subcutaneously in the anterolateral thigh region. Biochemical parameters were repeated
at2weeksand1month.Within2weeksofinitiationoftherapy,serumCu++andceruloplasminvalueshad
normalized (Table I). The texture and color of the hair began to change and there was a reduction in the
number of seizures. The patients mother was then trained to administer the drug and the patient was
discharged.
Thepatientwaslosttofollowupthreemonthslaterwhenthemothercitedfinancialconstraintsinprocuring
copper histidine every two months and making repeated trips to Mumbai. Telephonic follow up confirmed
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thatthepatientwasalivewithoutfurtherdeteriorationinhiscondition.
Case2:An18montholdchildbornofanonconsanguineousmarriagefromLucknowwasreferredtousfor
copperhistidine therapy. This patient had similar clinical features and MR angiography but greater mental
retardation.Copperhistidineinhimwasstartedinasimilarmanner,butthepatientdiedonday10,before
hisfirstfollowup.Therelativesdidnotpermitanautopsy.
TableI__BiochemicalChangesAfterAdministrationofCopperHistidine
Case1
Case2 Normal
Normalranges
Case1
Case1 Case2
Parameter
2
Follow ranges(34 (childrenand
Baseline
4weeks Baseline
weeks
up
moage)
adults)
Diedon
Serumcopper(g/dl)
63
102
118
51
8814
9820
day10
Serumceruloplasmin
17.9
37.9
42.3
6.59
1835
2445
(mg/dl)
Livercopper

Not
done

38.4

50120(g/g
dryweight)

Discussion
Amongthedifferentparenteralformsofcoppertherapy,copperhistidinehasbeenreportedtobetakenup
by the brain most efficiently(2). The dosage of copperhistidine used by various authors ranges from 200
1000 g once a day or 23 times/week(3). Response to therapy is based on monitoring of serum copper,
ceruloplasmin,urinarycopperexcretionandlivercoppercontent.
InMenkesdisease,withearlyinitiationoftherapy(within2monthsofbirth),neurologicaldeteriorationcan
be prevented. Copperhistidine after 2 months cannot halt either the neurological deterioration nor can it
improve connective tissue laxity or bone deformities, although the hair and biochemical abnormalities do
normalize.Theformulationusedbyusisidenticaltotheoneusedearlierin7casesofMenkesdisease.Of
2 patients where the therapy was begun within 1 month of birth did well neurologically, while the other 5
patients did poorly despite intiation of treatment at 27 months of age(4). We saw this in Case 1 with
normalizationofbiochemicalparametersandbeginningofhairnormalization.Case2hadfartooadvanced
diseaseforthetreatmenttohaveanyeffects.
Thecopperhistidineformulationusedintwocasesmentioned was sterile, pyrogen free and manufactured
using locally available chemicals. Copperhistidine solution was prepared under aseptic condition using a
laminarairflowhood.Anhydrouscopperchloride(0.106g)andL(+)Histidine(0.244g)aredissolvedin90ml
ofsaline.ThepHofthesolutionwasadjustedto7.387.4with0.2NSodiumhydroxidesolutionusingapH
meter.Thefinalvolumewasmadeto100mlwith0.9%sodiumchlorideinjectionUSP.Itwasaquabluein
color,hadtobeprotectedfromlight,wasrefrigeratedandhadashelflifeof56days.Giventherarityofthe
disease,therewaswastageoftheformulation.
To date, parenteral copper replacement remains the mainstay of therapy for Menkes disease. To our
knowledge, these are the first two cases in India to have received copperhistidine which may form the
mainstayoftreatmenttillsuchtimethatothermodalitiessuchaslipidchelatorsandgenetherapyaretried
forthisdisease.Tanakaetal(5)havereportedthatintraperitonealadministrationofdiethyldithiocarbamate
and dimethyl dithio carbamate resulted in normal survival without any copper treatment in macular mutant
mice. These findings suggest that lipid soluble chelators can enhance copper transport across cellular
membranes.Bothpatientstreatedbyusbelongedtothelowersocioeconomicstrata.Thecostper150g
dose worked out to be Rs. 40/ and included cost of chemicals, consumables, quality control and
personnel. In a developing country like ours, the economics of giving life long copper histidine will remain
animportantissueindeterminingpatientcomplianceandfollowup.
Acknowledgement
WearegratefultoDr.B.Sarkar,HeadStructuralBiologyandBiochemistry,TheHospitalforSickChildren,
University of Toronto and Karen Walsh, Manufacturing Pharmacist, University of Toronto for help and
assistanceinpreparationofsterilecopperhistidinesolution.
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Contributors: BGK was responsible for manufacture of copperhistidine solution and data collection. NJG
coordinated the study, supervised drug administration, patient follow up and drafted the paper. VPU was
responsible for patient care and follow up and drafting of paper. NAK was responsible for supervision of
drug manufacture, drug administration, study design and manuscript preparation, and will act as the
guarantorforthepaper.
Funding:None.
Competinginterests:Nonestated.
KeyMessages
Treatmentwithparenteralcopperhistidineappearstobeeffectiveinpreventing
the severe neurodegeneration problems in patients with Menkes disease,
particularlywhenthetreatmentisinitiatedveryearlyinlife.
Sterile,pyrogenfreecopperhistidinesolutionforsubcutaneousadministration
canbemanufacturedusinglocallyavailablechemicals.
References

1. Kodama H, Murata Y, Kobayashi M. Clinical manifestations and treatment of Menkes

diseaseanditsvariants.PediatrInt199941:423429.
2.BarneaA,KatzBM.Uptakeof67Coppercomplexedto3Hhistidinebybrainhypothalamic
slices:Evidencethatdissociationofthecomplexisnottheonlyfactordetermining67Copper
uptake.JInorgBiochem199040:8193.
3.KalerSG.Menkesdisease.AdvPediatr199441:263304.
4.SarkarB,WalshK,ClarkTR.CopperhistidinetherapyforMenkesdisease.JPediatr1993
123:828830.
5.TanakaK,KobayashiK,FujitaY,FukuharaC,OnosakaS,MinK.Effectsofchelatorson
copper therapy of macular mouse: A model animal of Menkes kinky disease. Res Commun
ChemPatholPharmacol199069:217227.

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