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

Brain & Development 34 (2012) 746?749Original articleCongenital abnormalities in Japanese patients with Menkes disease qYan-Hong Gu a,? , Hiroko Kodama b , Tadaaki Kato aaDepartment of Health Policy, National Research Institute for Child Health and Development, Tokyo, JapanbDepartment of Pediatrics, Teikyo University School of Medicine, Tokyo, JapanReceived 19 July 2011; received in revised form 26 January 2012; accepted 27 January 2012www.elsevier.com/locate/braindevAbstractMenkes disease (MNK) is an X-linked recessive disorder. Incidence of live-born infants with MNK is 2.8 per million live births inJapan. The aim of this study was to observe congenital malformations (CMs) in MNK patients. Subjects comprised 35 Japanesemale patients with classical MNK who received copper histidine treatment. Patient clinical data were obtained anonymously frommedical records or medical record summaries by pediatrician’s retrospective review through a survey. We observed 21 different CMsin 14 patients. Eight of these had a single CM, while six had multiple CMs. The most frequent CM was higher arched palate withother CMs found in five patients. There was no relationship between CMs and mutations in the ATP7A gene. Using Mann?WhitneyU tests, age at death was also significantly lower in MNK patients with CMs (P < 0.05), compared to those without CMs, eventhough there was no significant difference of age onset, age at diagnosis and age at start of treatment with copper histidine betweenboth groups of patients. Sudden death occurred in three MNK patients with CMs only: two with congenital heart disease, and onewith microphallus.O 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.Keywords: Copper; Inherited metabolic disease; Menkes disease; Congenital malformations; Japanese1. IntroductionMenkes disease (MNK, #OMIM 309400) is an X-linked recessive disorder. The combined frequency oflive-born MNK patients in Denmark, France, theNetherlands, the United Kingdom, and West GermanyAbbreviations: MNK, Menkes disease; CMs, congenital malformationsqThis study was supported by the Japan Foundation for PediatricResearch 2009, the Mother and Child Health Foundation of Japan,and Specified Disease Treatment Research Program of Ministry ofHealth, Labour and Welfare of Japan (H23/nanchi/ippan/091).? Corresponding author. Address: Department of Health Policy,National Research Institute for Child Health and Development, 2-10-1Okura, Setagaya-ku, Tokyo 157-8535, Japan. Tel.: +81 3 34160181x4271; fax: +81 3 3417 2694.E-mail address: gyh@nch.go.jp (Y.-H. Gu).was 1 per 298,000 live-born babies in the period 1976?1987 [1]. Incidence of live-born infants with MNK is2.8 per million live births from 1990 to 2003 in Japan[2]. In Japan, three to four individuals with MNK areborn every year [2]. Onset of MNK occurs within threemonths of birth in 52.2%, and within 4?9 months afterbirth in 47.8% of patients with MNK [2]. While mostclassical MNK patients die by the age of three years,some survive until their teens with continued treatment[3]. The gene responsible for MNK is ATP7A (GenBankL06133.1), which is located at chromosome Xq13.3 andencodes a copper-transporting ATPase (ATP7A) [4?6].Mutations in the ATP7A gene or other abnormalitiesin the genome or chromosomes associated with theATP7A gene were found in most, but not all MNKpatients [7?11]. In affected cells, copper transport byATP7A from the cytosol to the Golgi apparatus is0387-7604/$ - see front matter O 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.doi:10.1016/j.braindev.2012.01.0126