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 33 (2011) 243?251Review articlePathology, clinical features and treatments of congenitalcopper metabolic disorders ? Focus on neurologic aspectsHiroko Kodama ? , Chie Fujisawa, Wattanaporn BhadhprasitDepartment of Pediatrics, Teikyo University School of Medicine, Tokyo 173-8605, Japanwww.elsevier.com/locate/braindevAbstractGenetic disorders of copper metabolism, including Menkes kinky hair disease (MD), occipital horn syndrome (OHS) andWilson’s disease (WD) are reviewed with a focus on the neurological aspects. MD and OHS are X-linked recessive disorders characterizedby a copper deficiency. Typical features of MD, such as neurologic disturbances, connective tissue disorders and hairabnormalities, can be explained by the abnormally low activity of copper-dependent enzymes. The current standard-of-care fortreatment of MD is parenteral administration of copper?histidine. When the treatment is initiated in newborn babies, neurologicdegeneration can be prevented, but delayed treatment is considerably less effective. Moreover, copper?histidine treatment doesnot improve connective tissue disorders. Novel treatments targeting neurologic and connective tissue disorders need to be developed.OHS is the mildest form of MD and is characterized by connective tissue abnormalities. Although formal trials have not been conductedfor OHS, OHS patients are typically treated in a similar manner to MD. WD is an autosomal recessive disorder characterizedby the toxic effects of chronic exposure to high levels of copper. Although the hepatic and nervous systems are typically mostseverely affected, initial symptoms are variable, making an early diagnosis difficult. Because early treatments are often critical, especiallyin patients with neurologic disorders, medical education efforts for an early diagnosis should target primary care physicians.Chelating agents and zinc are effective for the treatment of WD, but neurologic symptoms become temporarily worse just after treatmentwith chelating agents. Neurologic worsening in patients treated with tetrathiomolybdate has been reported to be lower thanrates of neurologic worsening when treating with other chelating agents.O 2010 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.Keywords: Copper; Menkes disease; Wilson’s disease; Occipital horn syndrome; ATP7A; ATP7B; Neurologic diseases1. Introduction? Corresponding author. Tel.: +81 3 3964 1211x1494; fax: +81 33579 8212.E-mail address: hkodama@med.teikyo-u.ac.jp (H. Kodama).Copper is an essential trace element for all livingorganisms and functions as an integral component ofcuproenzymes, which include cytochrome C oxidase,lysyl oxidase, dopamine-b-hydroxylase, superoxide dismutase,tyrosinase, ascorbic acid oxidase and ceruloplasmin.When present in excess amounts, however, itsoxidative potential induces reactive free radical productionthat results in cellular damage. Thus, the tight regulationof copper homeostasis, which is maintained bymechanisms including uptake, transport, storage andexcretion of copper, is required. Disruptions to normalcopper homeostasis are evident in three human geneticdisorders: Menkes disease (MD), occipital horn syndrome(OHS) and Wilson’s disease (WD) [1]. Each diseaseis caused by the absence or dysfunction ofhomologous copper-transporting ATPases. The responsiblegene for MD and OHS is the ATP7A gene, and theATP7B gene is responsible for WD [1]. These three diseasesexhibit neurologic disorders. However, the pathologyof MD and OHS is completely different from that ofWD; that is, MD and OHS are characterized by a copperdeficiency while WD is characterized by toxicity due0387-7604/$ - see front matter O 2010 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.doi:10.1016/j.braindev.2010.10.02117