Mitochondrial leukodystrophies (MLs) are mainly caused by impairments of the mitochondrial respiratory chains. This study reports the mutation and phenotypic spectrum of a cohort of 41 pediatric patients from 39 distinct families with MLs among 320 patients with a molecular diagnosis of leukodystrophies. This study summarizes the clinical, imaging, and molecular data of these patients for five years. The three most common symptoms were neurologic regression (58.5%), pyramidal signs (58.5%), and extrapyramidal signs (43.9%). Because nuclear DNA mutations are responsible for a high percentage of pediatric MLs, whole exome sequencing was performed on all patients. In total, 39 homozygous variants were detected. Additionally, two previously reported mtDNA variants were identified with different levels of heteroplasmy in two patients. Among 41 mutant alleles, 33 (80.4%) were missense, 4 (9.8%) were frameshift (including 3 deletions and one duplication), and 4 (9.8%) were splicing mutations. Oxidative phosphorylation in 27 cases (65.8%) and mtDNA maintenance pathways in 8 patients (19.5%) were the most commonly affected mitochondrial pathways. In total, 5 novel variants in , and were also detected. In silico analyses showed how each novel variant may contribute to ML pathogenesis. The findings of this study suggest whole-exome sequencing as a strong diagnostic genetic tool to identify the causative variants in pediatric MLs. In comparison between oxidative phosphorylation (OXPHOS) and mtDNA maintenance groups, brain stem and periaqueductal gray matter (PAGM) involvement were more commonly seen in OXPHOS group (P value of 0.002 and 0.009, respectively), and thinning of corpus callosum was observed more frequently in mtDNA maintenance group (P value of 0.042).

中文翻译：

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儿童线粒体脑白质营养不良突变和表型异质性的综合研究

线粒体脑白质营养不良（ML）主要是由线粒体呼吸链损伤引起的。本研究报告了来自 39 个不同家庭的 41 名患有 ML 的儿科患者的队列，其中包括 320 名分子诊断为脑白质营养不良的患者。本研究总结了这些患者五年来的临床、影像和分子数据。三种最常见的症状是神经退行（58.5%）、锥体征（58.5%）和锥体外系征（43.9%）。由于核 DNA 突变是导致儿童 ML 比例较高的原因，因此对所有患者进行了全外显子组测序。总共检测到 39 个纯合变异。此外，之前报道的两种 mtDNA 变异在两名患者中被鉴定出具有不同水平的异质性。41个突变等位基因中，错义突变等位基因33个（80.4%），移码突变4个（9.8%）（其中3个缺失和1个重复），剪接突变4个（9.8%）。27 例 (65.8%) 患者的氧化磷酸化和 8 例 (19.5%) 患者的线粒体 DNA 维持途径是最常受影响的线粒体途径。总共还检测到了 、 和 中的 5 个新变体。计算机分析显示了每种新变异如何促进 ML 发病机制。这项研究的结果表明，全外显子组测序是一种强大的诊断遗传工具，可以识别儿科 ML 的致病变异。氧化磷酸化（OXPHOS）组和线粒体DNA维持组相比，OXPHOS组脑干和导水管周围灰质（PAGM）受累更常见（P值分别为0.002和0.009），胼胝体变薄更常见mtDNA 维持组（P 值为 0.042）。