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

Inherited Cu Disorders Current Drug Metabolism, 2012, Vol. 13, No. 3 247H 2N NH 2H 2NNH+ Cu 2+Cu 2+H 2NNHH 2N NH 2STrientine-SMoSS-Tetrathiomolybdate+ Cu 2+Trientine-copper complexSSCu MoCuSSCuTetrathiomolybdate-copper complexFig. (14). Chemical reaction of chelation by trientine (upper) and tetrathiomolybdate (lower) [126].Patients with Hepatic SymptomsPatients with mild and moderate liver disorders are initiallytreated with chelating agents (trientine preferred over penicillamine)[89,99]. Serum levels of aminotransferases and nonceruloplasmin-boundcopper are normalized a few months afterinitial treatment, reaching adequate urinary copper excretion levelsthat range between 200-500 ?g/day. Once this occurs, maintenancetherapy is initiated with zinc alone or with a lower dose of chelatingagents (i.e., trientine). In patients with fulminant hepatitis or hemolysis,liver transplantation is the most likely solution [114].One major obstacle regarding long-term treatment of patientswith WD is poor drug compliance. A recent report showed that25% of patients were not persistently taking their medication, resultingin deterioration and occasionally fatal outcomes [115]. Accordingly,it is important for physicians to make an effort to promotecompliance during therapy.Hepatocellular carcinoma (HCC) has become an importantissue for patients with WD as current treatments have improved lifeexpectancy. In a previous study, we examined the characteristics of25 WD patients with HCC and compared them to non-WD patientswith HCC in a cohort from the Liver Cancer Study group in Japan,1994-2003 (LCS-J) [17]. The average age at diagnosis of HCC inWD patients was considerably lower compared to non-WD patients.In addition, male to female ratios were high in WD patients. Takentogether, these results show that patients with WD (mainly males)are in danger of developing HCC despite treatment. The mechanismthat leads to carcinogenesis in WD remains unknown and is currentlyunder investigation. LEC rats harboring a deletion in ATP7Bdevelop HCC [76]. Tsubota et al reported that mRNA expression oftumorigenic proteins, Ras GTPase-activating-like protein(IQGAP1) and vimentin, was induced by persistent oxidative stressin the liver of LEC rats, making these proteins important clinicaltargets for HCC [116]. Production of oxygen and nitrogen reactivespecies, and unsaturated aldehydes that arise from copper overloadin patients with WD has been reported to cause mutations in thep53 tumor suppressor gene [117]. These findings suggest that oxidativestress is associated with HCC. Vitamin E may act as an antioxidantadjunct for WD therapy [118]. The copper chelating agent,TTM, inhibits angiogenesis, fibrosis, and inflammation [119,120].However, how these affect HCC development is unclear. Elucidationof these mechanisms will help devise strategies aimed at preventingHCC in patients with long-term WD.ACKNOWLEDGEMENTSThis work was in part by a Grant of Research on IntractableDiseases from Ministry of Health, Labour and Welfare of Japan(22-271) and a memorial fund for Naoki, a former patient withMenkes disease.REFERENCES[1] Uriu-Adams, J.Y.; Scherr, R.E.; Lanoue, L.; Keen, C.L. Influenceof copper on early development: Prenatal and postnatal considerations.BioFactors, 2010, 36(2), 136-152.[2] Lalioti, V.; Muruais, G.; Tsuchiya, Y.; Pulido, D; Sandoval, I.V.Molecular mechanisms of copper homeostasis. Front. Biosci.,2009, 14, 4878-4903.[3] Menkes, J.H; Alte, M.; Steigleder, G.K.; Weakley, D.R.; Sung, J.H.A sex-linked reccesive disorder with retardation of growth, peculiarhair, and focal cerebral and cerebellar degeneration. Pediatrics,1962, 29, 764-769.[4] Danks, D.M.; Campbell, P.E.; Stevens, B.J.; Mayne, V.; Cartwright,E. Menkes's kinky hair syndrome. An inherited defect incopper absorption with widespread effects. Pediatrics, 1972, 50,188-201.[5] Lazoff, S.G.; Rybak, J.J.; Parker, B.R.; Luzzatti, L. Skeletal dysplasia,occipital horns, diarrhea and obstructive uropathy- a newhereditary syndrome. Birth Defects Orig. Artic. Ser., 1975, 11(5),71-74.[6] Wilson, S.A.K. Progressive lenticular degeneration: a familialnervous disease associated with cirrhosis of the liver. Brain, 1912,34, 295?509.[7] Vulpe, C.; Levinson, B.; Whitney, S.; Packman, S.; Gitschier, J.Isolation of a candidate gene for Menkes disease and evidence thatit encodes a copper-transporting ATPase. Nat. Genet., 1993, 3, 7-13.[8] Chelly, J.; Tumer, Z.; Tonnesen, T.; Petterson, A.; Ishikawa-Brush,Y.; Tommerup, N.; Horn, N.; Monaco, A.P. Isolation of a candidategene for Menkes disease that encodes a potential heavy metal bindingprotein. Nat. Genet., 1993, 3(1), 14-19.[9] Mercer, J.F.; Livingston, J.; Hall, B.; Paynter, J.A.; Begy, C.;Chandrasekharappa, S.; Lockhart, P.; Grimes, A.; Bhave, M.;Siemieniak, D.; Glover, T.W. Isolation of a partial candidate genefor Menkes disease by positional cloning. Nat. Genet., 1993, 3(1),20-25.[10] Kaler SG, Gallo LK, Proud VK, Percy AK, Mark Y, Segal NA,Goldstein S, Holmes CS, Gahl WA. Occipital horn syndrome and amild Menkes disease phenotype associated with splice mutations atthe MNK locus. Nat. Genet., 1994, 8(2), 195-202.[11] Das, S.; Levinson, B.; Vulpe, C.; Whitney, S.; Gitschier, J.; Packman,S. Similar splicing mutations of the Menkes/mottled copper-36