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

H. Kodama et al. / Brain & Development 33 (2011) 243?251 247Fig. 2. Brain CT of a patient with MD. The image was taken at theage of 2 months. This was prior to the diagnosis of MD because noneurologic symptoms were observed at that time. CT scan wasperformed following a head trauma accident. The patient wasdiagnosed with MD at the age of 8 months. The brain atrophyprogressed despite continual treatment with copper?histidine injections.A subdural hemorrhage was observed at the age of 11 months.neurologic degeneration is progressive when copper?histidinetherapy is initiated at an age after the onset ofsymptoms. A potential reason could be that the administeredcopper accumulates at the blood?brain barrierand is not transported to neurons. When treatment isinitiated in the neonatal period and the blood?brain barrieris immature, neurologic degeneration can be preventedin some patients [14,15]. In some patients withMD, however, early treatment does not normalize neurologicfunction; however, their overall clinical outcomeis better than for untreated patients [16]. Symptomsreflecting connective tissue disorders are not improvedby treatment with copper?histidine injections. No treatmenttrials have been reported in patients with OHS.As described above, a true effective treatment for neurologicand connective tissue disorders has not yet beenestablished. If copper could be delivered to the trans-Golgi apparatus in the affected cells, the treatmentwould probably normalize the activity of lysyl oxidaseand improve connective tissue disorders associated withMD and OHS. In addition, if copper could be deliveredto the Golgi apparatus in the component cells of theblood?brain barrier, copper could reach neurons andbe available for incorporation into copper-dependentenzymes, including cytochrome C oxidase. We reportedthat combination therapy with injections of copper anddiethyldithiocarbamate (DEDTC), a lypophilic chelator,improved copper concentration, cytochrome C oxidaseactivity, and catecholamine metabolism in the brainsof macular mice (Fig. 5) [17]. The combination therapyalso increased the ratios of dopamine to noradrenalineand dopamine to adrenaline. Since dopamine b-hydroxylaseacts to convert dopamine to noradrenaline, whichsubsequently metabolizes to adrenaline, the ratios mayreflect the activity of dopamine b-hydroxylase. Theseresults suggest that DEDTC facilitates the passage ofcopper across the Golgi apparatus and blood?brain barrierand that combination therapy may be an effectivetreatment for the neurologic degeneration and connectivetissue disorders associated with MD and OHS.4. Wilson’s disease (WD)4.1. GeneticsThe global prevalence of WD, an autosomal recessivecondition, is approximately one in 30,000, although thisFig. 3. Depigmented, lusterless and kinky hair of 3-month-old patient with MD.21