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

当該ページの概要

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

Journal of Trace Elements in Medicine and Biology 26 (2012) 102?104Contents lists available at SciVerse ScienceDirectJournal of Trace Elements in Medicine and Biologyjo u rn al homepage: www.elsevier.de/jtembEffects of disulfiram treatment in patients with Menkes disease and occipitalhorn syndromeEishin Ogawa a,? , Hiroko Kodama a,ba Department of Pediatrics, Teikyo University School of Medicine, Tokyo, Japanb Department of Health Dietetics, Faculty of Health and Medical Sciences, Teikyo Heisei University, Tokyo, Japana r t i c l e i n f oArticle history:Received 2 March 2012Accepted 2 April 2012Keywords:Menkes diseaseOccipital horn syndromeDisulfirama b s t r a c tThe clinical and biochemical effects of disulfiram were evaluated in three boys with the disorders characterizedby copper deficiency due to the defect of ATP7A. Two suffered from Menkes disease (MD) and onefrom occipital horn syndrome. Disulfiram was orally given, in addition to a parenteral administration ofcopper-histidine in the case of MD patients. Serum levels of copper and ceruloplasmin slightly increasedin one MD patient, and he showed favorable emotional expression and behavior more often than beforeaccording to his caretakers. However, no obvious changes were observed in the other two patients. Serumratios of noradrenaline to dopamine, and adrenaline to dopamine, which are thought to be the indicatorsof dopamine ?-hydroxylase activity, one of the copper requiring enzymes, were unaltered afterdisulfiram treatment. No adverse effects were recognized during the treatment period in all patients.Although the major improvement was not observed clinically or biochemically by disulfiram treatmentso far, the trial will be continued to see the possible effects in these disorders with copper transportdefect.c 2012 Elsevier GmbH. All rights reserved.IntroductionA clinical phenotype of Menkes disease (MD) is characterized bycopper deficiency due to the functional loss of ATP7A, the coppertransporter, and occipital horn syndrome (OHS) is a milder formof this defect. The current standard therapy for copper deficiencyis a parenteral administration of copper-histidine, however, thetreatment is not effective for neurologic symptoms or connectivetissue abnormalities, because administered copper is not transportedacross to the neurons nor to the trans Golgi network [1]. Onlyif the treatment is started at the very early neonatal period whenthe blood?brain barrier is still immature, and also in those withresidual function of ATP7A, it may modify the disease progression[2].Diethyldithiocarbamate (DEDTC), a lipophilic chelator, hasshown beneficial effects in macular mice, an animal model of MD,on copper metabolism in the brain [3,4]. Therefore, DEDTC mayact to transport copper to neurons and to the Golgi apparatusin the brains of the animals. Disulfiram, a dimer of DEDTC, is adrug used for treatment of chronic alcoholism, and is immediatelyconverted to DEDTC in vivo, including in the human body. In the? Corresponding author at: Department of Pediatrics, Teikyo University School ofMedicine, 2-11-1 Kaga, Itabashi, Tokyo 173-8605, Japan.E-mail address: eogawaster@gmail.com (E. Ogawa).macular mouse, disulfiram showed similar effects to DEDTC, such asincrease in copper concentrations in the 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 10and 19 years old, were enrolled in this study as shown in Table 1.Two MD patients were clinically diagnosed during infancy, andcopper-histidine treatment was initiated immediately after thediagnosis, but both are now bed-ridden, fed through nasogastrictube, with seizures despite of several anti-epileptic medications.Their diagnosis was later confirmed by genetic study. In patient 1,deletion of two base pairs in exon 3 of the ATP7A gene caused frameshift, resulting in premature termination of transcription. In patient2, duplication of exon 3 to exon 5 reduced the estimated normalprotein production to 4% of normal [5]. The OHS patient was diagnosedat 4 years of age. His uncle also suffered from OHS, and died36 years old due to respiratory failure. They shared the same splicesite mutation causing skipping of exon 6, which has been found alsoin other OHS patients [6,7]. He is usually on a wheelchair, but canwalk slowly. He can communicate with others, and goes to workat a place for handicapped people. He has had frequent episodesof urinary tract infection due to the diverticulum of the bladder,and needs self-catheterization. Their body weights at study initi-0946-672X/$ ? see front matter c 2012 Elsevier GmbH. All rights reserved.http://dx.doi.org/10.1016/j.jtemb.2012.04.01714