Leigh syndrome spectrum (LSS) is a primary mitochondrial disorder defined neuropathologically by a subacute necrotizing encephalomyelopathy and characterised by bilateral basal ganglia and/or brainstem lesions. LSS is associated with variants in several mitochondrial DNA (mtDNA) genes and more than 100 nuclear genes, most often related to mitochondrial complex I (CI) dysfunction. Rarely, LSS has been reported in association with primary Leber hereditary optic neuropathy (LHON) variants of the mtDNA, coding for CI subunits (m.3460G>A in MT-ND1, m.11778G>A in MT-ND4, and m.14484T>C in MT-ND6). The underlying mechanism by which these variants manifest as LSS, a severe neurodegenerative disease, as opposed to the LHON phenotype of isolated optic neuropathy, remains an open question. Here, we analyse the exome sequencing of six probands with LSS carrying primary LHON variants, and report digenic co-occurrence of the m.11778G>A variant with damaging heterozygous variants in nuclear disease genes encoding CI subunits as a plausible explanation. Our findings suggest a digenic mechanism of disease for m.11778G>A-associated LSS, consistent with recent reports of digenic disease in individuals manifesting with LSS due to biallelic variants in the recessive LHON-associated disease gene DNAJC30 in combination with heterozygous variants in CI subunits.

中文翻译：

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m.11778G>A Leber 遗传性视神经病变变异背景下的双基因 Leigh 综合征

Leigh 综合征谱 (LSS) 是一种原发性线粒体疾病，在神经病理学上定义为亚急性坏死性脑脊髓病，其特征为双侧基底节和/或脑干病变。LSS 与多个线粒体 DNA (mtDNA) 基因和 100 多个核基因的变异有关，最常与线粒体复合物 I (CI) 功能障碍有关。很少有报道称 LSS 与原发性莱伯遗传性视神经病变 (LHON) 线粒体 DNA 变异相关，编码 CI 亚基（MT-ND1 中的 m.3460G>A、MT-ND4 中的 m.11778G>A 和 m.11778G>A）。 MT-ND6中14484T＞C)。这些变异表现为 LSS（一种严重的神经退行性疾病，而不是孤立性视神经病变的 LHON 表型）的潜在机制仍然是一个悬而未决的问题。在这里，我们分析了 6 个携带 LHON 初级变体 LSS 的先证者的外显子组测序，并报告了 m.11778G>A 变体与编码 CI 亚基的核病基因中的破坏性杂合变体的双基因共现作为合理的解释。我们的研究结果表明m.11778G>A相关LSS的双基因疾病机制，与最近关于由于隐性LHON相关疾病基因DNAJC30中的双等位基因变异与CI中的杂合变异相结合而表现出LSS的个体双基因疾病的报道一致亚单位。