PI3K/AKT pathway mutations cause a spectrum of brain malformations from megalencephaly to focal cortical dysplasia
PI3K/AKT pathway mutations cause a spectrum of brain malformations from megalencephaly to focal cortical dysplasia
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DOI：
10.1093/brain/awv045
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发表时间：
2015-06-01
期刊：
影响因子：
14.5
通讯作者：
Dobyns, William B.
中科院分区：
文献类型：
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作者：
Jansen, Laura A.;Mirzaa, Ghayda M.;Dobyns, William B.
含有发育不良的神经元和神经胶质成分的皮质发育畸形，包括半巨脑畸形和局灶性皮质发育不良，是难治性小儿癫痫的常见原因。在这项研究中，我们对33名接受手术切除发育不良皮质治疗难治性癫痫的儿童脑组织中PI3K/AKT通路的10个基因进行了多重靶向测序。测序结果与临床、影像学、病理和免疫组织学表型相关。我们在该队列中发现了PIK3CA和AKT3的马赛克激活突变，包括与癌症相关的PIK3CA突变在发育不良的巨脑畸形、半巨脑畸形和局灶性皮质发育不良IIa型中。此外，在一名患有半大脑畸形但没有PTEN错构瘤综合征外周表现的男性中发现了种系PTEN突变。在这个队列中发现了一系列临床、影像学和病理异常。而更严重的脑成像异常和全身性表现的患者更有可能检测到突变，常规组织病理学研究并不能预测突变状态。此外，无论是否检测到PI3K/AKT通路突变，在所有半巨脑畸形和局灶性皮质发育不良II型标本的神经元和星形胶质细胞中均发现磷酸化S6核糖体蛋白水平升高。相比之下，T308和S473磷酸化形式的AKT的表达模式和体外AKT激酶活性在突变阳性的异常增生皮质、突变阴性的异常增生皮质和非异常增生癫痫皮质中区分开来。我们的研究结果确定PI3K/AKT通路突变是癫痫性脑畸形的重要原因，并确定巨脑畸形、半巨脑畸形和局灶性皮质发育不良是单一致病谱的一部分。
Malformations of cortical development containing dysplastic neuronal and glial elements, including hemimegalencephaly and focal cortical dysplasia, are common causes of intractable paediatric epilepsy. In this study we performed multiplex targeted sequencing of 10 genes in the PI3K/AKT pathway on brain tissue from 33 children who underwent surgical resection of dysplastic cortex for the treatment of intractable epilepsy. Sequencing results were correlated with clinical, imaging, pathological and immunohistological phenotypes. We identified mosaic activating mutations in PIK3CA and AKT3 in this cohort, including cancer-associated hotspot PIK3CA mutations in dysplastic megalencephaly, hemimegalencephaly, and focal cortical dysplasia type IIa. In addition, a germline PTEN mutation was identified in a male with hemimegalencephaly but no peripheral manifestations of the PTEN hamartoma tumour syndrome. A spectrum of clinical, imaging and pathological abnormalities was found in this cohort. While patients with more severe brain imaging abnormalities and systemic manifestations were more likely to have detected mutations, routine histopathological studies did not predict mutation status. In addition, elevated levels of phosphorylated S6 ribosomal protein were identified in both neurons and astrocytes of all hemimegalencephaly and focal cortical dysplasia type II specimens, regardless of the presence or absence of detected PI3K/AKT pathway mutations. In contrast, expression patterns of the T308 and S473 phosphorylated forms of AKT and in vitro AKT kinase activities discriminated between mutation-positive dysplasia cortex, mutation-negative dysplasia cortex, and non-dysplasia epilepsy cortex. Our findings identify PI3K/AKT pathway mutations as an important cause of epileptogenic brain malformations and establish megalencephaly, hemimegalencephaly, and focal cortical dysplasia as part of a single pathogenic spectrum.