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

Y.-H. Gu et al. / Brain & Development 34 (2012) 746?749 747disturbed, resulting in a reduction of copper efflux, andconsequent reduction of activities of copper-dependentenzymes. This can lead to neurological symptoms, hairchanges and abnormalities of connective tissue includingarterial tortuosity, bladder diverticula, gastrointestinalpolyps and abnormalities of bone. As orally-administratedcopper cannot be absorbed due to ATP7Adysfunction and accumulates in the intestine, a copperdeficiency in various tissues arises. Subcutaneous injectionsof copper?histidine complex, the currentlyaccepted mode of treatment, may prevent neurologicaldegeneration in some patients when treatment is initiatedsoon after birth and prolong lifespan of patients[3]. However, the current treatment does not help to alleviateconnective tissue disorders caused by low activityof a copper enzyme ? lysyl oxidase.To date, congenital malformations (CMs) in MNKpatients have not been reported details. In OMIM(http://omim.org/entry/309400) head and neck ofMNK patients were described as microcephaly, brachycephaly,Wormian bone and pudgy cheeks. The presentstudy analyzed CMs in MNK patients, which were consideredto be unassociated with complications caused byreduced activity of copper enzymes, such as lysyl oxidaseunder current knowledge, and observed the relationshipbetween CMs and the genetic mutation. We comparedlifespan of treated MNK patients with and withoutCMs.2. Methods2.1. SubjectsA total of 35 Japanese MNK patients were investigatedin the study. These patients were referred to theDepartment of Pediatrics of Teikyo University Schoolof Medicine from 18 prefectures for counseling, copperhistidine treatment, and biochemical and/or molecularpre- and post-natal diagnosis of MNK during 1990?2009 [7?10,12?15]. These patients were treated for classicalMNK, which was diagnosed by clinical examination,measurement of the copper concentrations incultured cells, and/or genetic mutation as previouslyreported [7?10,12?15]. Genetic analysis performed inthe 5 0 -upstream region, each of the 23 exons, and theadjacent intronic sequences of the ATP7A genes, asdescribed previously [7]. In Japan MNK patients weresupported by medical aid programs [16], and receiveddetail examinations including head magnetic resonanceimaging and computed tomography scan.Three pairs of patients were siblings, while theremaining patients were unrelated. Patient mortality statusincluded dead (n = 23), alive (10) and unknown (2).Preparation of copper-histidine complex was accordingto the same protocol [3]. The dose of copper histidineparenterally administrated for one time was that couldkeep serum copper and ceruloplasmin within a normalrange. The period of treatment with copper histidinewas 26?183 (mean±SD: 64.2±39.9 months, n = 17)months.2.2. Clinical data and data analysisClinical data for all patients were anonymouslyobtained from medical records or medical record summariesby retrospective review of pediatrician in chargeof.The study protocol was reviewed and approved bythe Ethics Board of the Teikyo University School ofMedicine. All participants provided a signed writteninformed consent.To compare age differences between patients withCMs and those without CMs, the Mann?Whitney U testwas performed, using the statistical package PASW OStatistics 17.0 (SPSS Inc., an IBM Company, Chicago,IL, USA).3. ResultsAmong the 35 MNK patients, we observed a total of21 different CMs in 14 MNK patients (Table 1). Eight ofthese (8/14, 57.1%) had a single CM, while six (6/14,42.9%) had multiple CMs. Eight CMs (8/21, 38.1%)were minor, and the others (13/21, 61.9%) were majoranomalies. The minor anomalies included higher archedpalate, single transverse palmer crease, flat occiput,micrognathia, congenital microblepharia, undescendedtestis at birth, microphallus and accessory spleen(Table 1). Most frequent CMs were higher arched palate(five patients), single transverse palmer crease (three),micrognathis (two), flat occiput (two), and congenitalmicroblepharia (two) (Table 1).Age at onset, age at diagnosis, age at start of treatmentwith parenteral copper histidine, age at death,and age of alive patients (on August 31, 2009) are presentedin Table 2. A comparison of MNK patients withCMs and those without CMs revealed no significant differencesin age at onset, age at diagnosis, and age at startof treatment with parenteral copper histidine, but age atdeath was significantly different between these twogroups (P < 0.05, Table 2).Two unrelated patients with the same mutation(R986X) were both born at 38 gestational weeks weighingmore than 2500 g. They both received parenteralcopper histidine treatment at 6.5 months of age. Onehad CMs and died at 32.5 months due to a bladder hemorrhage(Patient 3 in Table 1). The other had no CMsand died at 59.0 months due to apnea. Another twopatients were siblings who had a mutation of Del2429-2430delTT. Both were born at 36 gestationalweeks and weighed approximately 2300 g. The youngerbrother, who was diagnosed prenatally with having a7