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 26/118）[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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across to the neurons nor to the trans Golgi network [1]. Only if the treatment is started at veryearly neonatal period when blood-brain barrier is still immature, and also in those with residualfunct....

across to the neurons nor to the trans Golgi network [1]. Only if the treatment is started at veryearly neonatal period when blood-brain barrier is still immature, and also in those with residualfunction of ATP7A, it may modify the disease progression [2].Diethyldithiocarbamate (DEDTC), a lipophilic chelator, has shown beneficial effects inmacular mice, an animal model of MD, on copper metabolism in the brain [3, 4]. Therefore,DEDTC may act to transport copper to neurons and to the Golgi apparatus in the brains of theanimals. Disulfiram, a dimer of DEDTC, is a drug used for treatment of chronic alcoholism,and is immediately converted to DEDTC in vivo, including human body. In the macular mouse,disulfiram also showed similar effects to DEDTC, such as increase in copper concentrations inthe brain (unpublished data). The purpose of this study is to evaluate clinical and biochemicaleffects of disulfiram in patients with MD and OHS.Patients and methodsTwo patients with MD and a patient with OHS, aged between 10 and 19 years old, were enrolledin this study as shown in Table 1. Two MD patients were clinically diagnosed during infancy,and copper-histidine treatment was initiated immediately after the diagnosis, but both are nowbed-ridden, fed through nasogastric tube, with seizures despite of several anti-epilepticmedications. Their diagnosis was later confirmed by the genetic study. In patient 1, deletionof two base pairs in exon 3 of the ATP7A gene caused frame shift, resulting in prematuretermination of transcription. In patient 2, duplication of exon 3 to exon 5 lead to the estimatednormal protein production down to 4% of normal [5]. The OHS patient was diagnosed at 4years old. His uncle was also suffered from OHS, and died at 36 years old due to respiratoryfailure. They shared the same splice site mutation causing skipping of exon 6, which was foundin other OHS patients [6, 7]. He is usually on a wheelchair, but can walk slowly. He cancommunicate with others, and goes to work at a place for handicapped people. He has hadfrequent episodes of urinary tract infection due to the diverticulum of bladder, and needsself-catheterization. Their body weights at study initiation ranged 10 to 20kg in the MD patients,and 35kg in the OHS patient.Disulfiram was orally given once daily, starting with lower dosage such as 30 to 60mgper day, and then increased to the maintenance dosage of 100mg per day. The dosage approvedin Japan for adult is between 100 and 500mg per day. In the MD patients, the dosage ofcopper-histidine administration and the amount of copper in the formula diet (1.2~1.6mg daily)were unchanged during the study period.