Severe infantile epileptic encephalopathy due to mutations in PLCB1: expansion of the genotypic and phenotypic disease spectrum.
Severe infantile epileptic encephalopathy due to mutations in PLCB1: expansion of the genotypic and phenotypic disease spectrum.
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DOI：
10.1111/dmcn.12450
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发表时间：
2014-11
影响因子：
3.8
通讯作者：
Kurian MA
中科院分区：
文献类型：
--
作者：
Ngoh A;McTague A;Wentzensen IM;Meyer E;Applegate C;Kossoff EH;Batista DA;Wang T;Kurian MA
染色体20p12.3的纯合缺失，破坏了磷脂酶C β1基因（PLCB1）的启动子区域和前三个编码外显子，之前在两份早期婴儿癫痫性脑病（eee）的报告中被描述过。两个孩子都是近亲父母所生，一个表现为婴儿痉挛，另一个表现为婴儿期的迁移性部分癫痫。我们描述了一名患有严重顽固性癫痫的婴儿（没有特定的eieee电临床综合征诊断）和与PLCB1复合杂合突变相关的神经发育迟缓。对一名大约10个月大的儿童进行了病例记录审查和分子遗传学调查，该儿童因发育迟缓和新发癫痫而入住约翰霍普金斯大学医院。患者在6个月大时出现发育迟缓，随后出现顽固性、局灶性和全身性癫痫发作，并从10个月大开始出现发育倒退。目前，在2岁时，孩子有严重的运动和认知迟缓。诊断芯片显示，在母亲中也检测到20p12.3（包括PLCB1）的杂合476kb缺失。确定了杂合缺失的基因组断点。为了研究第二个PLCB1突变的存在，对编码区和侧翼内含子区进行了直接Sanger测序，在索引个体和父亲中发现了一个新的杂合内含子1剪接位点变异（c.99+1G> a）。分子基因检测的进步大大提高了eieee的诊断率，本报告进一步证实了微阵列研究在这类疾病中的重要作用。PLCB1-EIEE现在被报道为许多不同的EIEE表型，我们的报告为早期婴儿癫痫综合征中遇到的表型多效性提供了进一步的证据。
Homozygous deletions of chromosome 20p12.3, disrupting the promoter region and first three coding exons of the phospholipase C β1 gene (PLCB1), have previously been described in two reports of early infantile epileptic encephalopathy (EIEE). Both children were born to consanguineous parents, one presented with infantile spasms, the other with migrating partial seizures of infancy. We describe an infant presenting with severe intractable epilepsy (without a specific EIEE electroclinical syndrome diagnosis) and neurodevelopmental delay associated with compound heterozygous mutations in PLCB1. A case note review and molecular genetic investigations were performed for a child, approximately 10 months of age, admitted to Johns Hopkins University Hospital for developmental delay and new-onset seizures. The patient presented at 6 months of age with developmental delay, followed by the onset of intractable, focal, and generalized seizures associated with developmental regression from 10 months of age. Presently, at 2 years of age, the child has severe motor and cognitive delays. Diagnostic microarray revealed a heterozygous 476kb deletion of 20p12.3 (encompassing PLCB1), which was also detected in the mother. The genomic breakpoints for the heterozygous deletion were determined. In order to investigate the presence of a second PLCB1 mutation, direct Sanger sequencing of the coding region and flanking intronic regions was undertaken, revealing a novel heterozygous intron 1 splice site variant (c.99+1G>A) in both the index individual and the father. Advances in molecular genetic testing have greatly improved diagnostic rates in EIEE, and this report further confirms the important role of microarray investigation in this group of disorders. PLCB1-EIEE is now reported in a number of different EIEE phenotypes and our report provides further evidence for phenotypic pleiotropy encountered in early infantile epilepsy syndromes.
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