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

Current Drug Metabolism, 2012, 13, 237-250 237Inherited Copper Transport Disorders: Biochemical Mechanisms, Diagnosis, andTreatmentHiroko Kodama 1,2, *, Chie Fujisawa 1 and Wattanaporn Bhadhprasit 11Department of Pediatrics, Teikyo University School of Medicine,2Department of health Dietetics, Faculty of Health and MedicalSciences, Teikyo Heisei University, 2-51-4 Higashi Ikebukuro, Toshima-ku, Tokyo, 170-8445, JapanAbstract: Copper is an essential trace element required by all living organisms. Excess amounts of copper, however, results in cellulardamage. Disruptions to normal copper homeostasis are hallmarks of three genetic disorders: Menkes disease, occipital horn syndrome,and Wilson’s disease.Menkes disease and occipital horn syndrome are characterized by copper deficiency. Typical features of Menkes disease result from lowcopper-dependent enzyme activity. Standard treatment involves parenteral administration of copper-histidine. If treatment is initiated before2 months of age, neurodegeneration can be prevented, while delayed treatment is utterly ineffective. Thus, neonatal mass screeningshould be implemented. Meanwhile, connective tissue disorders cannot be improved by copper-histidine treatment. Combination therapywith copper-histidine injections and oral administration of disulfiram is being investigated. Occipital horn syndrome characterized byconnective tissue abnormalities is the mildest form of Menkes disease. Treatment has not been conducted for this syndrome.Wilson’s disease is characterized by copper toxicity that typically affects the hepatic and nervous systems severely. Various other symptomsare observed as well, yet its early diagnosis is sometimes difficult. Chelating agents and zinc are effective treatments, but are inefficientin most patients with fulminant hepatic failure. In addition, some patients with neurological Wilson’s disease worsen or show poorresponse to chelating agents. Since early treatment is critical, a screening system for Wilson’s disease should be implemented in infants.Patients with Wilson’s disease may be at risk of developing hepatocellular carcinoma. Understanding the link between Wilson’s diseaseand hepatocellular carcinoma will be beneficial for disease treatment and prevention.Keywords: Menkes disease, Wilson’s disease, occipital horn syndrome, ATP7A, ATP7B, disulfiram, zinc, trientine.I. INTRODUCTIONCopper is an essential element required by cuproenzymes, includingcytochrome C oxidase, lysyl oxidase, dopamine s-hydroxylase, superoxide dismutase, tyrosinase, ascorbic acid oxidase,and ceruloplasmin. When in excess, copper’s oxidative potentialcan induce free radical production and result in cellular damage.In particular, adequate copper nutrition is critical during pregnancyand lactation for normal infant development [1]. Thus, tight regulationof copper homeostasis, maintained by mechanisms involvinguptake, transport, storage, and excretion of copper, is required [2].Disruptions to normal copper homeostasis are fundamental featuresof Menkes (kinky hair) disease (MD) [3, 4], occipital horn syndrome(OHS) [5], and Wilson’s disease (WD) [6]. Each disease iscaused by the absence of or defect in two copper-transporting AT-Pases encoded by the ATP7A gene (responsible for MD and OHS)[7-11] and ATP7B gene (responsible for WD) [12-15].ATP7A and ATP7B proteins have similar functions in cells;however, the pathology and clinical manifestations associated withMD and OHS are completely different compared to WD. MD andOHS, for example, are characterized by copper deficiency, and WDby toxicity due to excess copper. This difference relates to the particularcell type expressing ATP7A and ATP7B. ATP7A is expressedin almost all cell types except hepatocytes, whereas ATP7Bis mainly expressed in hepatocytes. Diagnostic approaches aremostly established for these diseases, and treatments for MD andWD have been proposed. However, unsolved problems relating todisease diagnosis and management still exist [16-18]. Here we reviewgenetic disorders of copper transport, and highlight clinicalproblems relating to their diagnosis and treatment.II. COPPER HOMEOSTASISFigure 1 highlights the general mechanism of copper metabolismin humans [17,19]. The average daily copper intake is 2-5 mg*Address correspondence to this author at the Department of health Dietetics,Faculty of Health and Medical Sciences, Teikyo Heisei University, 2-51-4 Higashi Ikebukuro, Toshima-ku, Tokyo, 170-8445, Japan; Tel: 81-3-5843-3111; Fax: 81-3-3843-3278; E-mail: kodamah2018@gmail.comin healthy adults. Copper is predominantly absorbed in the duodenumand small intestine where it is transported into the liver via theportal vein. Most of the absorbed copper is excreted in bile, but asmall fraction is excreted in urine. Several parameters affect theabsorption rate of dietary copper, including age, sex, food type,amount of dietary copper, and oral contraceptives. These parameterscould cause the adsorption rate to vary between 12 to 71% [20].A study using 65 Cu isotope showed that a daily copper intake of 0.8mg is sufficient to maintain homeostasis in adults [21]. Figs 2a and3a show copper metabolism in normal cells. The high-affinity coppertransporter (CTR1) is localized to the plasma membrane andmediates copper uptake. Copper uptake occurs in the intestinalbrush border; however, the specific mechanism by which dietaryCu(II) is reduced to a Cu(I) ion remains unknown [20,22]. Additionalcopper transporters, CTR2 and divalent metal transporter 1(DMT1), may contribute to copper uptake in the intestine, althoughto a lesser extent compared to CTR1 [20,22].Cytosolic copper is delivered to Cu/Zn superoxide dismutase inthe cytosol, Golgi apparatus, and mitochondria via the copperchaperones, CCS2, ATOX1 (HAH1), and COX 17, respectively[17,22]. In addition, cytosolic metallothionein maintains copperhomeostasis in cells [23].The liver is the central organ that maintains copper homeostasis.In hepatocytes, copper is excreted via two major pathways: bileand blood. In the excretion pathway leading to the blood, copper isdelivered to the trans-Golgi network by ATOX1, and transportedacross by ATP7B located on the trans-Golgi membrane. Copper istransferred as a Cu(I) ion from ATOX1 to the fourth metal bindingdomain of ATP7B [24]. Once in the trans-Golgi network, copper isincorporated into apo-ceruloplasmin, reduced to holo-ceruloplasmin,and then excreted as ceruloplasmin into the blood. Approximately90% of serum copper is bound to ceruloplasmin, while theremaining 10% is bound to albumin or carried as amino acid-boundcopper (non-ceruloplasmin-bound copper), which is likely the formtransported into various tissues. Similarly, the pathway mediatingcopper excretion from the liver to bile also requires ATP7B.COMM domain-containing protein 1 (COMMD1), formerly1389-2002/12 $58.00+.00 c 2012 Bentham Science Publishers26