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

当該ページの概要

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

E. Ogawa, H. Kodama / Journal of Trace Elements in Medicine and Biology 26 (2012) 102?104 103Table 1Patients’profiles.Patient123SexMaleMaleMaleDiagnosisMDMDOHSBirth date10/Jan./200111/Dec./199618/Jul./1992Age atDiagnosis10 m8 m4 y 2 mCopper histidine start (present dosage)10 m (900 ?g/w)8 m (6750 ?g/w)?Disulfiram start9 y 5 m13 y 8 m18 y 3 mATP7A mutationDel 608AADup Ex3-5del TAAG (IVS6, DS)ation ranged 10?20 kg in the MD patients, and 35 kg in the OHSpatient.Disulfiram was given orally once daily, starting with lowerdosages such as 30?60 mg per day, and then increased to the maintenancedosage of 100 mg per day. The dosage approved in Japan foradults is between 100 and 500 mg per day. In the MD patients, thedosage of copper-histidine administration and the amount of copperin the formula diet (1.2?1.6 mg daily) were unchanged duringthe study period.Serum copper (Cu) and ceruloplasmin (Cp), catecholamines suchas noradrenalin (NAD), adrenaline (AD) and dopamine (DA), andurinary vanillylmandelic acid (VMA) and homovanillic acid (HVA)were measured regularly. If the Cu and Cp levels increase, it isassumed that copper is transported through enterocytes. Catecholamineswere measured to see ratios of NAD to DA, and ADto DA, and also to see a ratio of VMA to HVA. These ratios arethought to be indicators of activity of dopamine ?-hydroxylase,which is one of secreting copper enzymes. If these ratios increase,it is assumed that copper is transported into trans-Golgi networkand corporated into this copper requiring enzyme. Other measurementsincluded bone mineral density (BMD) by dual energyX-ray absorptiometry to see probable connective tissue improvement.In addition, as renal dysfunction is a concern as an adverseeffect by the treatment due to the accumulation of copper, serumurea nitrogen and creatinine, and urinary ?-2 microglobulin weremeasured.Informed consent was taken from their parents, and the studywas approved by the Ethical Committee of Teikyo University Hospital(No. 08-114).Results and discussionSerum levels of Cu and Cp are shown in Fig. 1. In patient 1,both Cu and Cp were below the normal limits at the onset ofdisulfiram, in spite of the copper-histidine treatment. The valuesthen increased after disulfiram treatment into the normal range,and Cu has almost remained over 100 ng/ml without changingthe dose of copper-histidine. In patient 2, serum Cu and Cp werewithin normal ranges with copper-histidine administration, withno apparent change after the addition of disulfiram. In patient 3with OHS, both serum Cu and Cp were below the normal rangebefore treatment, and these values did not change after disulfiramadministration.According to the parents of patient 1, he showed favorable emotionalexpression and behavior, such as smiling, laughing, pullinghis nasogastric tube off, and so on, more often than before, shortlyafter starting disulfiram, however, further clinical improvementwas not observed later on. In the other two patients, any beneficialchange was not recognized clinically.The indices of dopamine ?-hydroxylase activity, such as NADto DA, AD to DA, and VMA to HVA, were low before disulfiramtreatment. Since dopamine ?-hydroxylase catalyzes DA to NADconversion, the NAD to DA ratio is low when the activity of thisFig. 1. Serum copper (A) and ceruloplasmin (B) levels in the three patients. Arrowsindicate the start of disulfiram treatment. The normal values range between 80 and130 mg/dl for copper, and between 20 and 35 mg/dl for ceruloplasmin.enzyme is disturbed as in MD. However, these ratios did not changeafter the treatment (NAD to DA ratio is shown in Fig. 2).Lumbar BMDs before disulfiram in the two MD patients were0.245 and 0.541 g/cm 2 , which were around 50% of the mean valuesfor their age, and 0.704 g/cm 2 in the OHS patient, which wasFig. 2. Serum ratio of noradrenaline to dopamine in the three patients. Arrowsindicate the start of disulfiram treatment.15