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

104 E. Ogawa, H. Kodama / Journal of Trace Elements in Medicine and Biology 26 (2012) 102?104about 70% of the mean. Low BMD is indicative of connective tissueimpairment, however, it is greatly affected by mobility. Therefore,the very low values in the bed-ridden MD patients may be dueto immobilization. BMD slightly increased in patients 1 and 3,whereas slightly decreased in patient 2 after the treatment.Urinary ?-2 microglobulin, an index of renal tubular function,which was quite high in the two MD patients with copper-histidinetreatment, and normal in the OHS patient, did not change afteraddition of disulfiram, and serum urea nitrogen and creatinine levelsremained normal during the period. No other adverse effectsrelated to disulfiram have been recognized.Thus, disulfiram treatment appeared marginally effective withregard to serum Cu and Cp in patient 1, but not in two other patients,and showed no beneficial changes in markers for dopamine?-hydroxylase. Reasons for failure of a favorable outcome by disulfiramtreatment in the patients, in contrast to the previous animalstudies with DEDTC, might be the differences in blood?brain barrierbetween humans and rodents, the observed rather small effectsin the previous studies, and the much smaller disulfiram dosageused in this study than that of the animal studies. As blood?brainbarrier is known to be immature in the mouse, the effect ofDEDTC might have been modified by the immatureness. Increasein the copper concentrations by addition of DEDTC in the mousebrain was rather small, less than 50%, and the concentration wasstill below half of the normal control [4], therefore, such smalleffect may not cause clinical and biochemical improvement inhumans. The dose of DEDTC (or disulfiram) used in the animalstudies was 200 mg/kg body weight, which was more than 20-foldlarger than that used in this study. Future studies will be requiredin younger patients with larger doses to clarify the effects ofdisulfiram.ConclusionsAlthough major improvement was not observed clinically orbiochemically by disulfiram treatment so far, the trial will be continuedto see the possible effects in these disorders with coppertransport defect.AcknowledgementsThis work was supported in part by a Grant of Research onIntractable Diseases from Ministry of Health, Labour and Welfareof Japan (23-326) and a memorial fund for Naoki, a former patientwith Menkes disease.References[1] Kodama H, Fujisawa C, Bhadhprasit W. Inherited copper transport disorders:biochemical mechanisms, diagnosis, and treatment. Curr Drug Metab2012;13:237?50.[2] Kaler SG, Holmes CS, Goldstein DS, Tang J, Godwin SC, Donsante A, et al. Neonataldiagnosis and treatment of Menkes disease. N Engl J Med 2008;358:605?14.[3] Tanaka K, Kobayashi K, Fujita Y, Fukuhara C, Onosaka S, Min K. Effects of chelatorson copper therapy of macular mouse, a model animal of Menkes’kinky disease.Res Commun Chem Pathol Pharmacol 1990;69:217?27.[4] Kodama H, Gu Y-H, Shiga K, Fujisawa C, Kozuma T. Effect of copper anddiethyldithiocarbamate combination therapy on the macular mouse, an animalmodel of Menkes disease. J Inherit Metab Dis 2005;28:971?8.[5] Mogensen M, Skjorringe T, Kodama H, Silver K, Horn N, Moller LB. Exon duplicationsin the ATP7A gene: frequency and transcriptional behaviour. Orphanet JRare Dis 2011;6:73.[6] Gu Y-H, Kodama H, Murata Y, Mochizuki D, Yanagawa Y, Ushijima H, et al. ATP7Agene mutations in 16 patients with Menkes disease and a patient with occipitalhorn syndrome. Am J Med Genet 2001;99:217?22.[7] Moller LB, TuEmer Z, Lund C, Petersen C, Cole T, Hanusch R, et al. Similar splicesitemutations of the ATP7A gene lead to different phenotypes: classical Menkesdisease or occipital horn syndrome. Am J Hum Genet 2000;66:1211?20.16