Mitta Nandini, Menon Ramshekhar N, McTague Amy, Radhakrishnan Ashalatha, Sundaram Soumya, Cherian Ajith, Madhavilatha G K, Mannan Ashraf U, Nampoothiri Sheela, Thomas Sanjeev V
R. Madhavan Nayar Center for Comprehensive Epilepsy Care, Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India.
R. Madhavan Nayar Center for Comprehensive Epilepsy Care, Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India; Paediatric Neurology, Great Ormond Street Hospital for Children & Institute of Child Health-University College London, Great Ormond Street, London, United Kingdom.
Epilepsy Res. 2020 Oct;166:106398. doi: 10.1016/j.eplepsyres.2020.106398. Epub 2020 Jun 18.
A paucity of literature exists on genotype- phenotype correlates of 'unknown-etiology' infantile-onset developmental-epileptic encephalopathies (DEE) from India. The primary objective was to explore the yield of genetic testing in identifying potential disease causing variants in electro-clinical phenotypes of DEE METHODS: An observational hospital-based study was undertaken on children with unexplained refractory seizure-onset ≤12 months age and developmental delay, whose families consented and underwent genetic testing during a three year time period (2016-2018) by next-generation sequencing (NGS) or multiplex ligand protein amplification. Yield was considered based on demonstration of pathogenic/likely pathogenic variants only and variants of unknown significance (VUS) were documented.
Pathogenic/likely pathogenic variants were identified in 26 (31.7 %) out of 82 children with DEE. These included those variants responsible for primarily DEE- 21(76.7 %); neuro-metabolic disorders- 3(18.6 %) and chromosomal deletions- 2(4.7 %). Of these patients, early-infantile epilepsy onset ≤ 6 months age was noted in 22(84.6 %). The DEE studied included Ohtahara syndrome associated with STXBP1 and SCN8A variants with yield of 50 % (2/4 tested); early myoclonic encephalopathy (no yield in 2); West syndrome with CDKL5, yield of 13.3 % (2/15 tested); epilepsy of infancy with migrating partial seizures due to CACNA1A and KCNT1 variants, yield of 67 % (2/3 tested); DEE-unclassified with KCNQ2, AP3B2, ZEB2, metabolic variants (SUOX, ALDH7A1, GLDC) and chromosome deletions (chr 1p36, chr2q24.3); yield of 32 % (8/25 tested). Patients with Dravet syndrome/Dravet-like phenotypes (N = 33) had variants in SCN1A (N = 10), SCN1B, CHD2; yield of 36.4 % (12/33 tested; 57.1 % from NGS). Eighteen patients with potential variants (SCN1A, SCN2A, SCN8A, KCNQ2, ALDH7A1 which also included VUS) could be offered targeted therapy.
Our study confirms a good yield of genetic testing in neonatal and infantile-onset DEE provided robust phenotyping of infants is attempted with prognostic and therapeutic implications, particularly relevant to centres with resource constraints.
关于印度“病因不明”的婴儿期起病的发育性癫痫性脑病（DEE）的基因型-表型相关性的文献较少。主要目的是探讨基因检测在识别DEE电临床表型中潜在致病变异方面的成效。方法：对年龄≤12个月、有不明原因难治性癫痫发作和发育迟缓的儿童进行了一项基于医院的观察性研究，其家人同意并在三年时间（2016 - 2018年）内通过下一代测序（NGS）或多重配体蛋白扩增进行基因检测。仅基于致病性/可能致病性变异的证实来考虑成效，并记录意义未明的变异（VUS）。
在82例DEE患儿中，26例（31.7%）鉴定出致病性/可能致病性变异。这些包括主要导致DEE的变异——21例（76.7%）；神经代谢障碍——3例（18.6%）和染色体缺失——2例（4.7%）。在这些患者中，22例（84.6%）在6个月龄前出现早发性婴儿癫痫发作。所研究的DEE包括与STXBP1和SCN8A变异相关的大田原综合征，检出率为50%（4例中检测出2例）；早期肌阵挛性脑病（2例中未检出）；伴有CDKL5的West综合征，检出率为13.3%（15例中检测出2例）；由于CACNA1A和KCNT1变异导致的婴儿期迁移性部分性癫痫发作的癫痫，检出率为67%（3例中检测出2例）；未分类的DEE伴有KCNQ2、AP3B2、ZEB2、代谢变异（SUOX、ALDH7A1、GLDC）和染色体缺失（1p36染色体、2q24.3染色体）；检出率为32%（25例中检测出8例）。患有Dravet综合征/Dravet样表型的患者（N = 33）在SCN1A（N = 10）、SCN1B、CHD2中有变异；检出率为36.4%（33例中检测出12例；NGS检测的检出率为57.1%）。18例有潜在变异（SCN1A、SCN2A、SCN8A、KCNQ2、ALDH7A1，其中也包括VUS）的患者可以接受靶向治疗。
我们的研究证实，在新生儿和婴儿期起病的DEE中，基因检测成效良好，前提是对婴儿进行了有力的表型分析，这具有预后和治疗意义，尤其与资源有限的中心相关。
