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

248 H. Kodama et al. / Brain & Development 33 (2011) 243?251Fig. 4. Loose skin (left) and occipital horns (right) in a patient with OHS.5Cu250CCO5 MA MCng/mg wet weight4321***μmol/min/mg prot.20015010050**432108 5 6 3CC MA MB MC08 7 6 3CC MA MB MC0Noradrenaline/dopamineAdrenaline/dopamineFig. 5. Copper concentration, cytochrome C oxidase activity, noradrenaline/dopamine and adrenaline/dopamine in the cerebrum of macular mice.MA: macular mice treated with injections of copper and DEDTC; MB: macular mice treated with copper injections only; MC: macular mice withouttreatment ( * P < 0.05, ** P < 0.01).varies across populations [18]. WD is caused by mutationsin the ATP7B gene. To date, 654 mutations inthe ATP7B gene have been reported (http://www/wilsondisease.med.ualberta.ca/database.asp).The R778Lmutation is most common in Asian patients, while theH1069Q mutation is most common in Europeanpatients [1,19,20]. A correlation between genotype andphenotype (hepatic vs. neurologic) has not been foundin patients with WD, although several homozygousmutations have been reported to correlate with phenotypes[21,22].4.2. PathologyCopper cannot be transported from the cytosol to theGolgi apparatus in the hepatocytes of patients with WDbecause of a defect of ATP7B that disturbs the biliaryexcretion of copper and secretion of copper as holoceruloplasmin(ceruloplasmin as the general term) into theblood. As a result, copper accumulates in the liver. Theexcessive copper induces reactive free radical productionand causes cellular damage due to its oxidative potential.The serum levels of ceruloplasmin and ceruloplasmin-boundcopper decrease. At that time, theaccumulated copper in the liver is released into theplasma as non-ceruloplasmin-bound copper (free-copper).This is thought to be the cause of the elevationof urinary copper excretion and results in copper depositsin various tissues such as the brain, kidney, cornea,muscle, bone, and joints [1].4.3. Clinical aspects4.3.1. Neurologic manifestationsThe clinical symptoms present mainly as hepatic andneurologic/psychiatric conditions. The neurologic symptomsappear at any age beyond 12 years and are characterizedby extra-pyramidal signs. Lorincz summarizedinitial manifestations of neurologic WD patients basedon the data which had been published, and showed that22