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年度 総括・分担研究報告書（page 16/118）[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年度 総括・分担研究報告書]

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almost normal, although renal copper concentration was higher in treated macular mice than incontrols. These results suggest that disulfiram facilitates the passage of copper across theblood-brain bar....

almost normal, although renal copper concentration was higher in treated macular mice than incontrols. These results suggest that disulfiram facilitates the passage of copper across theblood-brain barrier and that copper-disulfiram combination therapy may be an effective treatmentfor MD patients.Key words: Menkes disease, copper, disulfiram, cytochrome c oxidase, blood-brain barrierIntroductionMenkes disease (MD) is an X-linked recessive disorder caused by a defect incopper-transporting ATPase (ATP7A). In humans, ATP7A is expressed in almost all cell typesexcept hepatocytes. In normal cells, ATP7A is localized in the trans-Golgi network and transportscopper from the cytosol into the Golgi apparatus, where copper is incorporated into secretorycopper enzymes [1]. In MD-affected cells, however, copper accumulates in the cytosol and cannotbe excreted. Copper accumulation in the intestines results in copper absorption failure, leading tooverall copper deficiency in the body, except in the kidney. Copper also accumulates in the cells ofthe blood-brain barrier. Thus, copper cannot be delivered from the bloodstream to neurons afterbarrier maturation [2?4]. Copper concentrations in the serum, liver, and brain of MD patients aresignificantly lower, resulting in reduced activities of copper-dependent enzymes, such ascytochrome c oxidase, dopamineβ-hydroxylase, and lysyl oxidase. Currently, parenteraladministration of copper-histidine is the standard treatment for MD [1,5]. However, the treatment isineffective if initiated after two months of age, because the administered copper accumulates in theblood-brain barrier and is not transported to neurons. Therefore, copper delivery to neurons is themost important objective in the treatment of MD-associated neurological degeneration [6].We previously reported that a combination therapy comprising copper anddiethyldithiocarbonate (DEDTC) improved copper concentrations, cytochrome c oxidase activity,and catecholamine metabolism in the brain of macular mice [7]. A dimer of DEDTC, disulfiram, has