Abstract：
Variants in the mitochondrial genome can result in dysfunction of Complex I within the electron transport chain, thus causing disruptions in oxidative phosphorylation. Pathogenic variants in the MT-ND1 (NADH:ubiquinone oxidoreductase core subunit 1) gene that result in Complex I dysfunction are a known cause of Leigh syndrome. The patient is a 4-yr-old female who initially presented with generalized tonic-clonic seizures, with other symptoms of Leigh syndrome becoming apparent after the seizures. A three-generation pedigree revealed no family history of mitochondrial disorders. Laboratory studies were remarkable for elevated blood lactate, alanine, and GDF15. T2-weighted magnetic resonance imaging (MRI) revealed bilateral asymmetric signal hyperintensities in the basal ganglia, specifically in the bilateral putamen and right caudate. Magnetic resonance spectroscopy showed regionally elevated glucose and lactate. Mitochondrial respiratory chain enzyme analysis on skin fibroblasts demonstrated slightly reduced Complex I function. A 16-gene dystonia panel and chromosomal microarray analysis did not identify any disease-causing variants. Combined exome and mitochondrial genome sequencing identified the m.3685T > C (MT-ND1 p.Tyr127His) variant with 62.3% heteroplasmy with no alternative cause for the patient\'s condition. Mitochondrial genome sequencing of the mother demonstrated that the m.3685T > C variant occurred de novo. The m.3685T > C variant is absent from population databases. The tyrosine 127 residue is highly conserved, and several nearby pathogenic variants in the MT-ND1 gene have been previously associated with Leigh syndrome. We propose that the m.3685T > C variant is a novel mitochondrial DNA variant that causes Leigh syndrome, and we classify this variant as likely pathogenic based on currently available information.
摘要：
线粒体基因组中的变异可导致电子传递链内复合物I的功能障碍,从而导致氧化磷酸化的破坏。导致复合物I功能障碍的MT-ND1（NADH：泛醌氧化还原酶核心亚基1）基因中的致病变体是Leigh综合征的已知原因。患者是一名4岁的女性，最初表现为全身性强直阵挛性癫痫发作，Leigh综合征的其他症状在癫痫发作后变得明显。三代谱系显示没有线粒体疾病的家族史。实验室研究对血液乳酸升高有显著意义，丙氨酸,gdf15T2加权磁共振成像（MRI）显示基底神经节双侧不对称信号高信号，特别是在双侧壳核和右侧尾状。磁共振波谱显示葡萄糖和乳酸区域升高。对皮肤成纤维细胞的线粒体呼吸链酶分析显示复合物I功能略微降低。16基因肌张力障碍小组和染色体微阵列分析未发现任何致病变异。外显子组和线粒体基因组联合测序鉴定了m.3685T>C（MT-ND1p.Tyr127His）变异体，具有62.3％的异质性，没有其他原因导致患者病情。母亲的线粒体基因组测序表明m.3685T>C变体从头发生。m.3685T>C变体不存在于群体数据库中。酪氨酸127残基高度保守，MT-ND1基因中的几个附近致病变异以前与Leigh综合征相关。我们认为m.3685T>C变异体是导致Leigh综合征的一种新型线粒体DNA变异体,我们根据当前可用的信息将这种变异分类为可能的致病性。
