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

250 H. Kodama et al. / Brain & Development 33 (2011) 243?251the diagnosis of WD have been proposed to account forthe deficiencies of any one test [28]. Although the diagnosisof WD can be made in the vast majority of cases,a small number of patients cannot be diagnosed with theabove tests.4.5. TherapyWhen patients are diagnosed with WD, they should bepromptly treated with chelating agents, including penicillamine,trientine, and/or zinc [29]. However, severe sideeffects, including immunological effects (lupus-like reactions,nephrotic syndrome, and myasthenia gravis) andneutropenia are often observed in patients treated withpenicillamine. Trientine is significantly less toxic.Recently, zinc has been recommended as a treatmentfor presymptomatic patients and for maintenance treatmentof WD. In neurologic patients, however, clinicalworsening is observed during the first few weeks of therapyin approximately 50% and 26% of patients treatedwith penicillamine and trientine, respectively. In addition,25% of patients treated with penicillamine are atrisk of permanent neurologic damage and never recoverto their baseline level of function [30,31]. Neurologicworsening is also observed in a few patients treated withzinc. In the case of patients treated with tetrathiomolybdate,such neurologic worsening is much rarer than withother chelating agents, and a clinical trial of tetrathiomolybdateis ongoing in the United States as the first choiceof an initial treatment for neurologic patients with WD[32]. Since tetrathiomolybdate has not yet been availablecommercially, Brewer and Askari have recommendedthe 2nd and 3rd choices as initial therapy of neurologic/psychiatricpatients is zinc alone and a combinationof trientine and zinc, respectively [32].Another serious problem for patients with neurologicdisease is that symptoms sometimes do not completelyresolve with treatment. Because early treatment is criticalin patients with neurologic disorders, medical educationefforts for early diagnosis should target physiciansinvolved in primary care [33].In the case of patients with fulminant hepatitis orhemolysis, liver transplantation is the most appropriateoption [34]. Liver transplantation is also performed insome patients with neurologic disorders and improvesthe neurologic symptoms [35].Once a patient is diagnosed with WD, all first- andsecond-degree relatives should be screened for WD.Treatment should be offered to presymptomatic patients.AcknowledgementThis study was presented at the 10th Asian & OceanianCongress of Child Neurology in Daegu, Korea,which was held on June 10?13th, 2009.References[1] Kodama H, Fujisawa C. Copper metabolism and inherited coppertransport disorders: molecular mechanisms, screening, and treatment.Metallomics 2009;1:42?52.[2] Lutsenko S, Barnes NL, Bartee MY, Dmitriev OY. Function andregulation of human copper-transporting ATPases. Physiol Rev2007;87:1011?46.[3] de Bie P, Muller P, Wijmenga C, Klomp LW. Molecularpathogenesis of Wilson and Menkes disease: correlation ofmutations with molecular defects and disease phenotypes.J Med Genet 2007;44:673?88.[4] Moller LB, Mogensen M, Horn N. Molecular diagnosis ofMenkes disease: genotype?phenotype correlation. Biochimie2009;91:1273?7.[5] Gu YH, Kodama H, Shiga K, Nakata S, Yanagawa Y, Ozawa H.A survey of Japanese patients with Menkes disease from 1990 to2003: incidence and early signs before typical symptomatic onset,pointing the way to earlier diagnosis. J Inherit Metab Dis2005;28:473?8.[6] Gu YH, Kodama H, Murata Y, Mochizuki D, Yanagawa Y,Ushijima H, et al. ATP7A gene mutations in 16 patients withMenkes disease and a patient with occipital horn syndrome. Am JMed Genet 2001;99:217?22.[7] Kodama H. Gene defects and clinical aspects in Menkesdisease and occipital hornsyndrom. In: Massaro E, editor.Handbook of Copper Pharmacology. Totowa, USA: HumanPress; 2002. p. 319?38.[8] Agertt F, Crippa AC, Lorenzoni PJ, Scola RH, Bruck I, Paola L,et al. Menkes’s disease: case report. Arq Neuropsiquiatr2007;65:157?60.[9] Bahi-Buisson N, Kaminska A, Nabbout R, Barnerias C,Desguerre I, De Lonlay P, et al. Epilepsy in Menkes disease:analysis of clinical stages. Epilepsia 2006;47:380?6.[10] Ozawa H, Otaki U, Gu YH, Kodama H. The symptoms andtreatment of 20 patients with Menkes disease in Japan (inJapanese). Nihon Shonika Gakkai Zasshi (Tokyo) 2009;113:1234?7.[11] Ito H, Mori K, Sakata M, Naito E, Harada M, Minato M, et al.Pathophysiology of the transient temporal lobe lesion in a patientwith Menkes disease. Pediatr Int 2008;50:825?7.[12] Ozawa H, Kodama H, Murata Y, Takashima S, Noma S.Transient temporal lobe changes and a novel mutation in apatient with Menkes disease. Pediatr Int 2001;43:437?40.[13] Gu YH, Kodama H, Sato E, Mochizuki D, Yanagawa Y,Takayanagi M, et al. Prenatal diagnosis of Menkes disease bygenetic analysis and copper measurement. Brain Dev2002;24:715?8.[14] Sarkar B, Lingertat-Walsh K, Clarke JT. Copper?histidinetherapy for Menkes disease. J Pediatr 1993;123:828?30.[15] Christodoulou J, Danks DM, Sarkar B, Baerlocher KE, Casey R,Horn N, et al. Early treatment of Menkes disease with parenteralcopper?histidine: long-term follow-up of four treated patients.Am J Med Genet 1998;76:154?64.[16] Kaler SG, Holmes CS, Goldstein DS, Tang J, Godwin SC,Donsante A, et al. Neonatal diagnosis and treatment of Menkesdisease. N Engl J Med 2008;358:605?14.[17] Kodama H, Sato E, Gu YH, Shiga K, Fujisawa C, Kozuma T.Effect of copper and diethyldithiocarbamate combination therapyon the macular mouse, an animal model of Menkes disease. JInherit Metab Dis 2005;28:971?8.[18] Mak CM, Lam CW. Diagnosis of Wilson’s disease: a comprehensivereview. Crit Rev Clin Lab Sci 2008;45:263?90.[19] Gu YH, Kodama H, Du SL, Gu QJ, Sun HJ, Ushijima H.Mutation spectrum and polymorphisms in ATP7B identified ondirect sequencing of all exons in Chinese Han and Hui ethnicpatients with Wilson’s disease. Clin Genet 2003;64:479?84.24