Nuffield Department of Obstetrics and Gynaecology, The Women's Centre, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
Epilepsia. 2013 Jun;54(6):1002-11. doi: 10.1111/epi.12115. Epub 2013 Feb 28.
To assess the frequency and clinical features of childhood-onset intractable epilepsy caused by the most common mutations in the POLG gene, which encodes the catalytic subunit of mitochondrial DNA polymerase gamma.
Children presenting with nonsyndromic intractable epilepsy of unknown etiology but without documented liver dysfunction at presentation were eligible for this prospective, population-based study. Blood samples were analyzed for the three most common POLG mutations. If any of the three tested mutations were found, all the exons and the exon-intron boundaries of the POLG gene were sequenced. In addition, we retrospectively reviewed the notes of patients presenting with intractable epilepsy in which we had found POLG mutations. All available clinical data were collected by questionnaire and by reviewing the medical records.
We analyzed 213 blood DNA samples from patients fulfilling the inclusion criteria of the prospective study. Among these, five patients (2.3%) were found with one of the three common POLG mutations as homozygous or compound heterozygous states. In addition, three patients were retrospectively identified. Seven of the eight patients had either raised cerebrospinal fluid (CSF) lactate (n = 3) or brain magnetic resonance imaging (MRI) changes (n = 4) at presentation with intractable epilepsy. Three patients later developed liver dysfunction, progressing to fatal liver failure in two without previous treatment with sodium valproate (VPA). Furthermore, it is worth mentioning that one patient presented first with an autism spectrum disorder before seizures emerged.
Mutations in POLG are an important cause of early and juvenile onset nonsyndromic intractable epilepsy with highly variable associated manifestations including autistic features. This study emphasizes that genetic testing for POLG mutations in patients with nonsyndromic intractable epilepsies is very important for clinical diagnostics, genetic counseling, and treatment decisions because of the increased risk for VPA-induced liver failure in patients with POLG mutations. We recommend POLG gene testing for patients with intractable seizures and at least one elevated CSF lactate or suggestive brain MRI changes (predominantly abnormal T2 -weighted thalamic signal) with or without status epilepticus, epilepsia partialis continua, or liver manifestations typical for Alpers disease, especially when the disease course is progressive.
评估最常见的 POLG 基因突变所致儿童起病性难治性癫痫的频率和临床特征，POLG 基因编码线粒体 DNA 聚合酶γ的催化亚单位。
本前瞻性、基于人群的研究纳入了表现为不明病因的非综合征性难治性癫痫且初诊时无肝功能障碍记录的患儿。对这些患儿的血样进行了 3 种最常见的 POLG 突变分析。如果发现 3 种检测突变中的任何一种，均对 POLG 基因的所有外显子和外显子-内含子边界进行测序。此外，我们还回顾性分析了在我们发现 POLG 突变的起病性难治性癫痫患儿的病历。通过问卷调查和病历回顾收集所有可获得的临床数据。
我们分析了符合前瞻性研究纳入标准的 213 例患儿的血液 DNA 样本。其中，5 例（2.3%）患儿为纯合或复合杂合状态的 3 种常见 POLG 突变之一。此外，还回顾性识别了 3 例患儿。8 例患儿中有 7 例在起病时即存在脑脊液（CSF）乳酸升高（n = 3）或脑磁共振成像（MRI）改变（n = 4），表现为难治性癫痫。其中 3 例患儿随后出现肝功能障碍，2 例未经丙戊酸钠（VPA）治疗即进展为致命性肝功能衰竭。此外，值得注意的是，1 例患儿在出现癫痫发作之前首先表现为自闭症谱系障碍。
POLG 基因突变是早发性和青少年起病性非综合征性难治性癫痫的重要病因，具有高度可变的相关表现，包括自闭症特征。这项研究强调，对于非综合征性难治性癫痫患儿，进行 POLG 基因突变的基因检测非常重要，因为 POLG 基因突变患者应用 VPA 治疗时发生肝衰竭的风险增加。我们建议对具有难治性癫痫发作、至少 1 项 CSF 乳酸升高或提示性脑 MRI 改变（主要为异常 T2 加权丘脑信号）、伴或不伴癫痫持续状态、部分性癫痫持续状态或 Alpers 病典型肝脏表现的患儿进行 POLG 基因检测，尤其是在疾病呈进行性进展时。
