Section of Neurology, Department of Pediatrics, 14521St. Christopher's Hospital for Children Drexel University College of Medicine, Philadelphia, PA, USA.
12320University of Puerto Rico Medical Sciences Campus, San Juan, PR, USA.
J Child Neurol. 2021 Feb;36(2):93-98. doi: 10.1177/0883073820953001. Epub 2020 Sep 15.
To describe a founder mutation effect and the clinical phenotype of homozygous c.737_739delGAG (p.Gly246del) variant in 15 children of Puerto Rican (Boricua) ancestry presenting with early infantile epileptic encephalopathy (EIEE-37) with prominent movement disorder.
EIEE-37 is caused by biallelic loss of function variants in the gene, which is critical for AMPA-receptor function, resulting in intractable epilepsy and dyskinesia.
A retrospective, multicenter chart review of patients sharing the same homozygous (p.Gly246del) pathogenic variant identified by clinical genetic testing. Clinical information was collected regarding neurodevelopmental outcomes, neuroimaging, electrographic features and clinical response to antiseizure medications.
Fifteen patients from 12 different families of Puerto Rican ancestry were homozygous for the (p.Gly246del) pathogenic variant, with ages ranging from 1 to 25 years. The onset of seizures was from 6 to 24 months. All had hypotonia, severe global developmental delay, and most had hyperkinetic involuntary movements. Developmental regression during the first year of life was common (86%). Electroencephalogram showed hypsarrhythmia in 66% (10/15), with many older children evolving into Lennox-Gastaut syndrome. Six patients demonstrated progressive volume loss and/or cerebellar atrophy on brain magnetic resonance imaging (MRI).
We describe the largest cohort to date of patients with epileptic encephalopathy. We estimate that 0.76% of unaffected individuals of Puerto Rican ancestry carry this pathogenic variant due to a founder effect. Children homozygous for the (p.Gly246del) Boricua variant exhibit a very homogenous phenotype of early developmental regression and epilepsy, starting with infantile spasms and evolving into Lennox-Gastaut syndrome with hyperkinetic movement disorder.
描述一个纯合突变效应以及携带 15 名波多黎各（Boricua）血统的早发性婴儿癫痫性脑病（EIEE-37）患儿的临床表型，这些患儿携带纯合 c.737_739delGAG（p.Gly246del）变异，表现为明显的运动障碍。
EIEE-37 是由 基因的双等位基因功能丧失变异引起的，该基因对 AMPA 受体功能至关重要，导致难治性癫痫和运动障碍。
对通过临床基因检测确定携带相同纯合 （p.Gly246del）致病性变异的患者进行回顾性、多中心病历回顾。收集了关于神经发育结局、神经影像学、脑电图特征和抗癫痫药物治疗反应的临床信息。
12 个不同的波多黎各血统家庭的 15 名患者为 （p.Gly246del）致病性变异的纯合子，年龄从 1 岁到 25 岁不等。癫痫发作的起始时间为 6 至 24 个月。所有患者均有张力减退、严重的全面发育迟缓，大多数患者有不自主的多动。在生命的第一年中，发育退化很常见（86%）。脑电图显示 66%（10/15）的患者存在高振幅慢波，许多年长的孩子发展为 Lennox-Gastaut 综合征。6 名患者的磁共振成像（MRI）显示进行性容积损失和/或小脑萎缩。
我们描述了迄今为止最大的癫痫性脑病患者队列。我们估计，由于存在一个创始效应，波多黎各血统的未受影响个体中有 0.76%携带这种致病性变异。携带 （p.Gly246del）Boricua 变异的纯合子患儿表现出非常同质的早发性发育退化和癫痫表型，起始为婴儿痉挛，随后发展为 Lennox-Gastaut 综合征，伴有不自主运动障碍。
