Leigh syndrome (LS), the most common childhood mitochondrial disorder, has characteristic clinical and neuroradiologic features. Mutations in more than 75 genes have been identified in both the mitochondrial and nuclear genome, implicating a high degree of genetic heterogeneity in LS. To profile these genetic signatures and understand the pathophysiology of LS, we recruited 64 patients from 62 families who were clinically diagnosed with LS at Seoul National University Children's Hospital. Mitochondrial genetic analysis followed by whole-exome sequencing was performed on 61 patients. Pathogenic variants in mitochondrial DNA were identified in 18 families and nuclear DNA mutations in 22. The following 17 genes analyzed in 40 families were found to have genetic complexity: MTATP6, MTND1, MTND3, MTND5, MTND6, MTTK, NDUFS1, NDUFV1, NDUFAF6, SURF1, SLC19A3, ECHS1, PNPT1, IARS2, NARS2, VPS13D, and NAXE. Two treatable cases had biotin-thiamine responsive basal ganglia disease, and another three were identified as having defects in the newly recognized genes (VPS13D or NAXE). Variants in the nuclear genes that encoded mitochondrial aminoacyl tRNA synthetases were present in 27.3% of cases. Our findings expand the genetic and clinical spectrum of LS, showing genetic heterogeneity and highlighting treatable cases and those with novel genetic causes.

中文翻译：

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Leigh综合征的遗传异质性：突出可治疗和新颖的遗传原因。

Leigh综合征（LS）是儿童中最常见的线粒体疾病，具有特征性的临床和神经放射学特征。在线粒体和核基因组中均已鉴定出超过75个基因的突变，这暗示了LS中高度的遗传异质性。为了剖析这些遗传特征并了解LS的病理生理，我们招募了来自62个家庭的64例患者，这些患者在首尔国立大学儿童医院被临床诊断为LS。对61例患者进行了线粒体遗传分析，然后进行全外显子测序。在18个家族中鉴定出线粒体DNA的致病变异，在22个家族中鉴定了核DNA突变。在40个家族中分析的以下17个基因具有遗传复杂性：MTATP6，MTND1，MTND3，MTND5，MTND6，MTTK，NDUFS1，NDUFV1，NDUFAF6， SURF1，SLC19A3，ECHS1，PNPT1，IARS2，NARS2，VPS13D和NAXE。2例可治愈的生物素对硫胺素反应的基底神经节疾病，另外3例被鉴定为新识别的基因（VPS13D或NAXE）存在缺陷。27.3％的病例中存在编码线粒体氨酰基tRNA合成酶的核基因变异。我们的发现扩大了LS的遗传和临床范围，显示了遗传异质性并突出了可治疗的病例和具有新的遗传原因的病例。