Leigh syndrome is a genetically heterogeneous disorder resulting from deficient oxidative energy biogenesis. The syndrome is characterized by subacute episodic decompensations, transiently elevated lactate, and necrotizing brain lesions most often in the striatum and brainstem. Acute decompensation is often triggered by viral infections. Sequalae from repeated episodes leads to progressive neurological deterioration and death. The severity of Leigh syndrome varies widely, from a rapid demise in childhood to rare adult presentations. Although the causes of Leigh syndrome include genes affecting a variety of different pathways, more than 75 of them are nuclear or mitochondrial encoded genes involved in the assembly and catalytic activity of mitochondrial respiratory complex I.

Here we report the detailed clinical and molecular phenotype of two adults with mild presentations of NDUFS3 and NDUFAF6-related Leigh Syndrome. Mitochondrial assays revealed slightly reduced complex I activity in one proband and normal complex I activity in the other. The proband with NDUFS3-related Leigh syndrome was mildly affected and lived into adulthood with novel biallelic variants causing aberrant mRNA splicing (NM_004551.2:c.419G > A; p.Arg140Gln; NM_004551.2:c.381 + 6 T > C). The proband with NDUFAF6-related Leigh syndrome had biallelic variants that cause defects in mRNA splicing (NM_152416.3:c.371 T > C; p.Ile124Thr; NM_152416.3:c.420 + 2_420 + 3insTA). The mild phenotypes of these two individuals may be attributed to some residual production of normal NDUFS3 and NDUFAF6 proteins by NDUFS3 and NDUFAF6 mRNA isoforms alongside mutant transcripts. Taken together, these cases reported herein suggest that splice-regulatory variants to complex I proteins could result in milder phenotypes.

Leigh 综合征是一种由氧化能生物合成不足导致的遗传异质性疾病。该综合征的特征是亚急性发作性失代偿、暂时性乳酸升高和坏死性脑损伤，最常见于纹状体和脑干。急性代偿失调通常由病毒感染引发。反复发作的后遗症导致进行性神经功能恶化和死亡。Leigh 综合征的严重程度差异很大，从儿童时期的快速死亡到罕见的成人表现。尽管 Leigh 综合征的病因包括影响多种不同途径的基因，但其中超过 75 种是核或线粒体编码基因，参与线粒体呼吸复合体 I 的组装和催化活性。

在这里，我们报告了两名患有NDUFS3和NDUFAF6相关 Leigh 综合征轻度表现的成人的详细临床和分子表型。线粒体分析显示，一个先证者的复合物 I 活性略有降低，而另一名先证者的复合物 I 活性正常。患有NDUFS3相关 Leigh 综合征的先证者受到轻度影响并活到成年，具有导致异常 mRNA 剪接的新型双等位基因变异 (NM_004551.2:c.419G > A; p.Arg140Gln; NM_004551.2:c.381 + 6 T > C ）。NDUFAF6-的先证者相关的 Leigh 综合征具有导致 mRNA 剪接缺陷的双等位基因变异（NM_152416.3:c.371 T > C；p.Ile124Thr；NM_152416.3:c.420 + 2_420 + 3insTA）。这两个个体的温和表型可能归因于NDUFS3和NDUFAF6 mRNA 同种型以及突变转录本产生的正常NDUFS3和NDUFAF6蛋白的一些残留。总之，本文报道的这些病例表明复合物 I 蛋白的剪接调节变体可能导致更温和的表型。