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 241Mottled mutant mice are proposed animal models of MD andOHS, and mutations in the Atp7a gene have been identified in thesemutant mice. These brindled and macular mice show phenotypicfeatures similar to classical MD, whereas blotchy mice have prominentconnective tissue abnormalities and resemble OHS. Thesemice have been used in many biochemical and treatment studies[43].4.2. PathologyATP7A is localized in the trans-Golgi membrane and transportscopper from the cytosol into the Golgi apparatus in almost all celltypes, excluding hepatocytes. In MD, copper accumulates in thecytosol of affected cells and cannot be excreted (Fig. 2b). Electronmicroscopy reveals that copper accumulates in cytoplasmic apicesof absorptive epithelial and vascular endothelial cells, and in secretorygranules of Paneth cells located in the intestine of macularmice [44]. Intestinal accumulation of copper results in absorptionfailure, which leads to copper deficiency in the body and reducedcuproenzyme activity. Copper also accumulates in cells comprisingthe blood-brain barrier and choroid plexus, indicating that copper isnot transported from blood vessels to neurons [31,32,45,46]. Thecharacteristic features of MD can be explained by a decrease incuproenzyme activity (Table 2). These enzymes include cytochromeC oxidase (localized in the mitochondria), tyrosinase, andCu/Zn superoxide dismutase (localized in the cytosol). Decreasedenzyme activity of these enzymes that are localized in the mitochondriaand the cytosol in the affected cells, excluding the brain,can be improved by parenteral copper administration.At present, the accepted therapy involves subcutaneous copperhistidineinjections. Unfortunately, cuproenzyme activity in neuronscannot be improved by treatment since copper accumulates in themature blood-brain barrier and fails to be transported into neurons[45-47]. Neuropathological abnormalities are observed in MD,especially in the cerebral cortex and cerebellum. Brain atrophy,diffusely narrowed gyri, and widened sulci are among the abnormalitiesobserved. Other abnormalities include loss of Purkinje cellsand neuronal loss of cerebellar molecular and internal granulecell layers [48]. Neurodegeneration in MD results mainly fromdecreased cytochrome C oxidase activity in neurons. In addition,subdural hemorrhage occurs secondary to abnormalities in brainarteries due to decreased activities of lysyl oxidase, which causesneurological damage.Connective tissue abnormalities are caused by decreased lysyloxidase activity. Lysyl oxidase combines with copper in the GolgiTable 2.Cuproenzymes and Symptoms Due to Decreased Activity (Symptoms of Menkes Disease)Enzyme (Localization in Cells or Characteristics)Cytochrome C oxidase(mitochondria)Lysyl oxidase(secretory enzyme)FunctionElectron transport in mitochondrial respiratorychain, energy productionCrosslinking of collagen and elastinSymptomsBrain damage, hypothermia, muscle hypotoniaArterial abnormalities, subdural hemorrhage, bladderdiverticula, skin and joint laxity, osteoporosis, bonefracture, herniasDopamine s-hydroxylase (secretory enzyme) Norepinephrin production from dopamine Hypotension, hypothermia, diarrhea [121] *Tyrosinase(cytosol)Sulfhydryl oxidase(cytosol)Cu/Zn superoxide dismutase(cytosol)Peptidyl ?-amidating monooxygenase(secretory enzyme [122])Ceruloplasmin(secretory enzyme)Hephaestin**(membrane bound enzyme [123])Angiogenin**(secretory enzyme [122])Amine oxidases**Melanin formationKeratin cross-linkingOxidant defense: superoxide radical detoxicationNeuropeptide bioactivationFerroxidase, Cu transportFerroxidase in enterocytes, involved in ironabsorptionInduction of blood vessel formation, antimicrobialhost defense [125]Oxidation of primary amines, cancer growthinhibition and progression [127]HypopigmentationAbnormal hairCNS degeneration [121]Brain damageAnemiaAnemia??Arterial abnormalities, enteric infections [126] **Carcinogenesis [127] **Blood clotting factors V, VIII** Blood coagulation system [128] Blood clotting [128] *** Diarrhea is often observed in patients with MD, but the relation with dopamine s-hydroxylase is unclear.* * The relation with copper metabolism and MD is unclear.30