Germ line activating AKT3 mutation associated with megalencephaly, polymicrogyria, epilepsy and hypoglycemia
Germ line activating AKT3 mutation associated with megalencephaly, polymicrogyria, epilepsy and hypoglycemia
复制标题
DOI：
10.1016/j.ymgme.2014.11.018
复制
发表时间：
2015-03-01
影响因子：
3.8
通讯作者：
Mancini, Grazia M. S.
中科院分区：
文献类型：
--
作者：
Nellist, Mark;Schot, Rachel;Mancini, Grazia M. S.
AKT 3（OMIM 611223）中的激活性种系和体细胞突变与巨脑-多小脑回-多指-脑积水综合征（MPPH; OMIM # 615937）和巨脑-毛细血管畸形（MCAP; OMIM # 602501）相关。在这里，我们报告一个人与巨脑畸形，多小脑回，难治性癫痫，低血糖症和生殖系AKT 3突变。出生时，头围为43 cm（高于平均值5个标准差）。没有器官肿大，但有全身性张力减退，关节和皮肤松弛，发育迟缓和未能茁壮成长。在6个月大时，患者出现婴儿痉挛，对抗癫痫综合治疗耐药。在促肾上腺皮质激素治疗期间观察到复发性低血糖，但在引入连续的强化喂养后稳定。婴儿痉挛症对生酮饮食有反应，但低血糖复发，直到饮食调整增加静息能量消耗。一种新的从头AKT 3错义变体（外显子5; c.548T>A，p.（V183 D）），并通过体外功能测试显示激活AKT 3。我们假设该患者的持续低血糖是由AKT 3信号传导激活导致的葡萄糖利用增加引起的。这可以解释生酮饮食在这个个体中的功效。(C)2014年爱思唯尔公司All rights reserved.
Activating germ-line and somatic mutations in AKT3 (OMIM 611223) are associated with megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH; OMIM # 615937) and megalencephaly-capillary malformation (MCAP; OMIM # 602501). Here we report an individual with megalencephaly, polymicrogyria, refractory epilepsy, hypoglycemia and a germline AKT3 mutation. At birth, head circumference was 43 cm (5 standard deviations above the mean). No organomegaly was present, but there was generalized hypotonia, joint and skin laxity, developmental delay and failure to thrive. At 6 months of age the patient developed infantile spasms that were resistant to antiepileptic polytherapy. Recurrent hypoglycemia was noted during treatment with adrenocorticotropic hormone but stabilized upon introduction of continuous, enriched feeding. The infantile spasms responded to the introduction of a ketogenic diet, but the hypoglycemia recurred until the diet was adjusted for increased resting energy expenditure. A novel, de novo AKT3 missense variant (exon 5; c.548T>A, p.(V183D)) was identified and shown to activate AKT3 by in vitro functional testing. We hypothesize that the sustained hypoglycemia in this patient is caused by increased glucose utilization due to activation of AKT3 signaling. This might explain the efficacy of the ketogenic diet in this individual. (C) 2014 Elsevier Inc. All rights reserved.