Successful early copper therapy in Menkes disease associated with a mutant transcript containing a small in-frame deletion
Successful early copper therapy in Menkes disease associated with a mutant transcript containing a small in-frame deletion
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DOI：
10.1006/bmme.1996.0007
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发表时间：
1996-02-01
期刊：
影响因子：
--
通讯作者：
Gahl, WA
中科院分区：
文献类型：
--
作者：
Kaler, SG;Das, S;Gahl, WA
经典门克斯病是一种致命的X连锁神经退行性疾病，由编码铜转运ATPase的基因(MNK)缺陷引起。肠外铜治疗已被建议用于在症状发展之前被发现的患者，我们最近描述了尽管在两名经典的Menkes患者中早期进行铜替代，但结果并不理想，这两名患者的突变几乎不能预测任何功能性的铜转运蛋白，在这里，我们描述了一例具有剪接受体突变(IVS8，AS，dup5)的Menkes病患者的成功的铜替代治疗，该突变导致外显子跳过，并在非关键区域产生具有少量框内缺失的突变转录本。患者是通过分析脐带血中的神经化学水平诊断出来的，在出生8天时开始肠外铜替代，整个婴儿期，他表现出正常的头部发育、脑髓鞘形成和与年龄相适应的神经发育，包括14个月大的独立行走。相比之下，他的同父异母兄弟和具有相同突变的表亲，但从小就没有得到诊断和治疗，表现出头部生长停滞、大脑萎缩、髓鞘形成延迟和神经发育异常。我们认为，这位患者成功的神经学结果与早期循环铜水平的恢复有关，并与含有少量缺失的部分功能的MNK-ATPase对铜的残存转运有关。我们假设，用一些残留的功能基因产物提高Menkes病患者的血浆铜浓度可以增加配体：转运体的比率，从而有利于改变铜进入和脑内运输的动力学。(C)1996年学术出版社。
Classical Menkes disease is a fatal X-linked neurodegenerative disorder caused by defects in a gene (MNK) that encodes a copper-transporting ATPase. Treatment with parenteral copper has been proposed for patients identified before symptoms develop, We recently described suboptimal outcomes despite early copper replacement in two classical Menkes patients whose mutation predicts little if any functional copper transporter, Here, we describe successful copper replacement therapy in a patient with Menkes disease with a splice acceptor site mutation (IVS8,AS,dup5) that causes exon-skipping and generates a mutant transcript with a small in-frame deletion in a noncritical region. The patient was diagnosed by analysis of neurochemical levels in cord blood, and parenteral copper replacement was begun at 8 days of life, Throughout infancy, he showed normal head growth, brain myelination, and age-appropriate neurodevelopment, including independent walking at 14 months of age. In contrast, his affected half-brother and first cousin with the same mutation, but who were not diagnosed and treated from an early age, showed arrested head growth, cerebral atrophy, delayed myelination, and abnormal neurodevelopment. We propose that the successful neurological outcome in this patient was related to early repletion of circulating copper levels, in combination with residual copper transport by a partially functional MNK ATPase containing the small deletion. We hypothesize that raising plasma copper concentrations in patients with Menkes disease with some residual functional gene product can increase the ligand: transporter ratio and thus alter favorably the kinetics of copper transport into and within the brain. (C) 1996 Academic Press, Inc.