タイトル厚生労働科学研究費補助金（難治性疾患克服研究事業）「Menkes 病・occipital horn 症候群の実態調査、早期診断基準確立、治療法開発に関する研究」平成23-24年度 総合研究報告書

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厚生労働科学研究費補助金（難治性疾患克服研究事業）「Menkes 病・occipital horn 症候群の実態調査、早期診断基準確立、治療法開発に関する研究」平成23-24年度 総合研究報告書

246 H. Kodama et al. / Brain & Development 33 (2011) 243?251Table 1Characteristics of inherited copper transport disorders in humans.Menkes diseaseOccipital horn syndromeWilson’s diseaseInheritanceX-linked recessiveX-linked recessiveAutosomal recessivePrevalence1/140,000 male birthsVery rare1/30,000?35,000Responsible geneATP7AATP7AATP7BGene locationXq13.3Xq13.313q14.3Gene productCu-binding P-type ATPase (ATP7A)Cu-binding P-type ATPase (ATP7A)Cu-binding P-type ATPase(ATP7B)Expression in normal humanAll tissues except liverAll tissues except liverLiver, kidney, placenta, lung,brain, heart, muscle, pancreasand intestineMutationNo common mutationsSplice-site mutations are commonR778L and H1069Q are commonin Asian and European patients,respectivelyPathogenesisClinical findingsLaboratory findingsDefect of intestinal Cu absorption;reduced activities of Cu-dependentenzymesSevere neurological degeneration;abnormal hairs; hypothermia;connective tissue disordersDecreased serum Cu andceruloplasmin; increased Cuconcentration in cultured fibroblastsPartial defect of intestinal Cuabsorption; reduced activities of CudependentenzymesConnective tissue disorders; ataxiaSlightly decreased serum Cu andceruloplasmin; increased Cuconcentration in cultured fibroblastDefects of biliary Cu excretionand Cu incorporation intoceruloplasmin in the liverLiver disease; neurologicaldiseases & psychiatricmanifestations, Kayser?Fleischerrings; hematuria; arthritis,cardiomyopathy, pancreatitisDecreased serum Cu andceruloplasmin; increased urinaryCu excretion; increased liver CuconcentrationTreatmentCu injectionsChelating agents (penicillamine,trientine), zincAnimal modelMacular and brindled miceBlotchy mouseLEC ratTable 2Copper enzymes and their suggestive relationship with symptoms of MD.EnzymeBiological activitySymptomCytochrome C oxidaseCellular respirationBrain damage, hypothermia, muscle hypotonia,TyrosinaseMelanin formationHypopigmentationSulfhydryl oxidaseKeratin cross-linkingAbnormal hairDopamine b-hydroxidaseCatecholamine productionHypotension, diarrheaLysyl oxidaseCollagen and elastin cross-linkingArterial abnormalities, subdural hemorrhage, bladder diverticula, looseskin and joints, osteoporosis, bone fracture, and hernia3.3.2. Other manifestationsHair abnormalities, including kinky and tangled hair,are characteristics of MD and often give clues to a diagnosis(Fig. 3). Bladder diverticula, osteoporosis, looseskin and joints, and arterial abnormalities are connectivetissue changes caused by decreased activity of lysyloxidase. The predominant clinical features of OHS includemild muscle hypotonia and connective tissueabnormalities including exostosis in the occipital bones,bladder diverticula and laxity of the skin and joints(Fig. 4).3.4. DiagnosisDiagnosis is not difficult with the appearance of typicalclinical features including intractable seizures, connectivetissue abnormalities, subdural hemorrhage andhair abnormalities. However, early treatment beforethe appearance of typical features is critical for goodneurologic outcomes. The clues for an early diagnosisare hair abnormalities and an episode of temporaryhypothermia. The serum levels of copper and ceruloplasminare significantly low, while the copper concentrationis significantly high in cultured fibroblasts.Carrier and perinatal diagnosis is made by mutationanalysis when a mutation has been identified in thefamily [13].Male patients with ataxia and loose skin should besuspected of OHS, and exostosis in the occipital bonesshould be examined by brain X-ray. The copper concentrationis also high in cultured fibroblasts of patientswith OHS.3.5. TreatmentsThe treatment for MD is parenteral administration ofcopper?histidine, which improves hair abnormalitiesand serum levels of copper and ceruloplasmin. However,20