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Lissencephaly in an epilepsy cohort: Molecular, radiological and clinical aspects
European Journal of Paediatric Neurology ( IF 3.1 ) Pub Date : 2021-01-01 , DOI: 10.1016/j.ejpn.2020.12.011
Sintia Kolbjer 1 , Daniel A Martin 2 , Maria Pettersson 3 , Maria Dahlin 4 , Britt-Marie Anderlid 3
Affiliation  

INTRODUCTION Lissencephaly is a rare malformation of cortical development due to abnormal transmantle migration resulting in absent or reduced gyration. The lissencephaly spectrum consists of agyria, pachygyria and subcortical band heterotopia. In this study we compared genetic aetiology, neuroradiology, clinical phenotype and response to antiepileptic drugs in patients with epilepsy and lissencephaly spectrum malformations. METHODS The study group consisted of 20 patients - 13 males and 7 females, aged 18 months to 21 years at the time of data collection. Genetic testing was performed by oligonucleotide array comparative genomic hybridization (microarray), multiplex ligation-dependent probe amplification (MLPA), targeted gene panels and whole exome/genome sequencing. All neuroradiological investigations were re-evaluated and the malformations were classified by the same neuroradiologist. Clinical features and response to anti-epileptic drugs (AEDs) were evaluated by retrospective review of medical records. RESULTS In eleven patients (55%) mutations in PAFAH1B1 (LIS1) or variable microdeletions of 17p13.3 including the PAFAH1B1 gene were detected. Four patients (20%) had tubulin encoding gene mutations (TUBA1A, TUBG1 and TUBGCP6). Mutations in DCX, DYNC1H1, ADGRG1 and WDR62 were identified in single patients. In one patient, a possibly pathogenic intragenic deletion in TRIO was detected. A clear radiologic distinction could be made between tubulinopathies and PAFAH1B1 related lissencephaly. The majority of the patients had therapy resistant epilepsy and epileptic spasms was the most prominent seizure type. The best therapeutic response to seizure control in our cohort was obtained by the ketogenic diet, vigabatrin, clobazam, phenobarbital and valproate. CONCLUSION The most common genetic aetiologies in our cohort of 20 individuals with epilepsy and lissencephaly spectrum were intragenic deletions or single nucleotide mutations in PAFAH1B1 or larger deletions in 17p13.3, encompassing PAFAH1B1, followed by mutations in tubulin encoding genes. Radiological findings could reliably predict molecular results only in agyria with a posterior to anterior gradient. Radiological and molecular findings did not correlate consistently with severity of clinical outcome or therapeutic response.

中文翻译:

癫痫队列中的无脑畸形:分子、放射学和临床方面

引言 无脑畸形是一种罕见的皮质发育畸形,由于异常的跨膜迁移导致回旋缺失或减少。lissencephaly 谱包括 agyria、pachygyria 和皮层下带异位。在这项研究中,我们比较了癫痫和无脑畸形谱系畸形患者的遗传病因、神经放射学、临床表型和对抗癫痫药物的反应。方法 研究组由 20 名患者组成 - 13 名男性和 7 名女性,在数据收集时年龄为 18 个月至 21 岁。通过寡核苷酸阵列比较基因组杂交(微阵列)、多重连接依赖性探针扩增(MLPA)、靶向基因组和全外显子组/基因组测序进行基因检测。重新评估所有神经放射学检查,并由同一位神经放射科医生对畸形进行分类。临床特征和对抗癫痫药物 (AED) 的反应通过回顾性医疗记录进行评估。结果 在 11 名患者 (55%) 中检测到 PAFAH1B1 (LIS1) 突变或包括 PAFAH1B1 基因在内的 17p13.3 的可变微缺失。四名患者(20%)有微管蛋白编码基因突变(TUBA1A、TUBG1 和 TUBGCP6)。在单个患者中发现了 DCX、DYNC1H1、ADGRG1 和 WDR62 的突变。在一名患者中,检测到 TRIO 中可能存在致病性基因内缺失。微管病变和 PAFAH1B1 相关的无脑畸形之间可以进行明确的放射学区分。大多数患者患有难治性癫痫,癫痫痉挛是最突出的癫痫发作类型。在我们的队列中,对癫痫控制的最佳治疗反应是通过生酮饮食、氨己烯酸、氯巴占、苯巴比妥和丙戊酸盐获得的。结论 在我们的 20 名癫痫和无脑畸形谱系患者队列中,最常见的遗传病因是基因内缺失或 PAFAH1B1 中的单核苷酸突变或 17p13.3 中更大的缺失,包括 PAFAH1B1,其次是微管蛋白编码基因的突变。放射学发现只能可靠地预测具有后前梯度的 agyria 的分子结果。放射学和分子学发现与临床结果或治疗反应的严重程度不一致。结论 在我们的 20 名癫痫和无脑畸形谱系患者队列中,最常见的遗传病因是基因内缺失或 PAFAH1B1 中的单核苷酸突变或 17p13.3 中更大的缺失,包括 PAFAH1B1,其次是微管蛋白编码基因的突变。放射学发现只能可靠地预测具有后前梯度的 agyria 的分子结果。放射学和分子学发现与临床结果或治疗反应的严重程度不一致。结论 在我们的 20 名癫痫和无脑畸形谱系患者队列中,最常见的遗传病因是基因内缺失或 PAFAH1B1 中的单核苷酸突变或 17p13.3 中更大的缺失,包括 PAFAH1B1,其次是微管蛋白编码基因的突变。放射学发现只能可靠地预测具有后前梯度的 agyria 的分子结果。放射学和分子学发现与临床结果或治疗反应的严重程度不一致。放射学发现只能可靠地预测具有后前梯度的 agyria 的分子结果。放射学和分子学发现与临床结果或治疗反应的严重程度不一致。放射学发现只能可靠地预测具有后前梯度的 agyria 的分子结果。放射学和分子学发现与临床结果或治疗反应的严重程度不一致。
更新日期:2021-01-01
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