Megalencephaly (MEG) is a developmental abnormality of brain growth characterized by early onset, often progressive, brain overgrowth. Focal forms of megalencephaly associated with cortical dysplasia, such as hemimegalencephaly and focal cortical dysplasia, are common causes of focal intractable epilepsy in children. The increasing use of high throughput sequencing methods, including high depth sequencing to more accurately detect and quantify mosaic mutations, has allowed us to identify the molecular etiologies of many MEG syndromes, including most notably the PI3K-AKT-MTOR related MEG disorders. Thorough molecular and clinical characterization of affected individuals further allow us to derive preliminary genotype-phenotype correlations depending on the gene, mutation, level of mosaicism, and tissue distribution. Our review of published data on these disorders so far shows that mildly activating variants (that are typically constitutional or germline) are associated with diffuse megalencephaly with intellectual disability and/or autism spectrum disorder; moderately activating variants (that are typically high-level mosaic) are associated with megalencephaly with pigmentary abnormalities of the skin; and strongly activating variants (that are usually very low-level mosaic) are associated with focal brain malformations including hemimegalencephaly and focal cortical dysplasia. Accurate molecular diagnosis of these disorders is undoubtedly crucial to more optimally treat children with these disorders using PI3K-AKT-MTOR pathway inhibitors.

中文翻译：

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与 PI3K-AKT-MTOR 通路核心成分突变相关的巨脑畸形综合征：PIK3CA、PIK3R2、AKT3 和 MTOR。

巨脑畸形 (MEG) 是大脑发育的发育异常，其特征是早发性、通常是进行性的大脑过度生长。与皮质发育不良相关的局灶性巨脑畸形，例如半巨脑畸形和局灶性皮质发育不良，是儿童局灶性难治性癫痫的常见原因。越来越多地使用高通量测序方法，包括更准确地检测和量化镶嵌突变的高深度测序，使我们能够确定许多 MEG 综合征的分子病因，包括最显着的 PI3K-AKT-MTOR 相关的 MEG 疾病。对受影响个体的全面分子和临床特征进一步使我们能够根据基因、突变、嵌合水平和组织分布得出初步的基因型-表型相关性。我们对迄今为止关于这些疾病的已发表数据的审查表明，轻度激活变异（通常是体质或生殖系）与伴有智力障碍和/或自闭症谱系障碍的弥漫性巨脑畸形有关；中度激活变异（通常是高水平马赛克）与伴有皮肤色素异常的巨脑畸形有关；强激活变异（通常是非常低水平的镶嵌）与局灶性脑畸形有关，包括半巨脑畸形和局灶性皮质发育不良。毫无疑问，这些疾病的准确分子诊断对于使用 PI3K-AKT-MTOR 通路抑制剂更优化地治疗患有这些疾病的儿童至关重要。