Megalencephaly syndromes associated with mutations of core components of the PI3K-AKT-MTOR pathway: PIK3CA, PIK3R2, AKT3, and MTOR
Megalencephaly syndromes associated with mutations of core components of the PI3K-AKT-MTOR pathway: PIK3CA, PIK3R2, AKT3, and MTOR
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DOI：
10.1002/ajmg.c.31736
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发表时间：
2019-08-23
影响因子：
3.1
通讯作者：
Mirzaa, Ghayda M.
中科院分区：
文献类型：
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作者：
Dobyns, William B.;Mirzaa, Ghayda M.
巨脑畸形（MEG）是一种脑发育异常，其特征是早期发病，往往进行性，脑过度生长。与皮质发育不良相关的局灶性巨脑畸形，如半侧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，包括高深度测序以更准确地检测和定量镶嵌突变，使得我们能够鉴定许多MEG综合征的分子病因，包括最显著的PI 3 K-AKT-MTOR相关MEG病症。对受影响个体进行彻底的分子和临床表征，进一步使我们能够根据基因、突变、镶嵌水平和组织分布得出初步的基因型-表型相关性。我们回顾了迄今为止发表的关于这些疾病的数据，结果表明，轻度激活的变异（通常是体质或生殖系）与弥漫性巨脑畸形伴智力残疾和/或自闭症谱系障碍有关;中度激活变体（典型的高水平镶嵌）与巨脑畸形伴皮肤色素异常有关;而强激活变体（通常是非常低水平的嵌合体）与包括半侧巨脑畸形和局灶性皮质发育不良在内的局灶性脑畸形有关。这些疾病的准确分子诊断无疑对于使用PI 3 K-AKT-MTOR通路抑制剂更佳地治疗患有这些疾病的儿童至关重要。
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.