Table_1_Two novel SUCLA2 variants cause mitochondrial DNA depletion syndrome, type 5 in two siblings.docx

Mitochondrial DNA depletion syndrome (MDS), characterized by succinate-CoA ligase deficiency and loss of mitochondrial DNA (mtDNA), is caused by specific variants in nuclear genes responsible for mtDNA maintenance. SUCLA2-related mitochondrial DNA depletion syndrome, type 5 (MTDPS-5), presents as a rare, severe early progressive encephalomyopathy. This report investigates a new family exhibiting clinical manifestations of MTDPS-5 and elucidates the genetic basis of this disorder. In two affected siblings, a novel maternally inherited nonsense variant [c.1234C>T (p.Arg412*)] in the SUCLA2 gene and a unique paternally inherited indel variant (g.48569263–48571020del1758insATGA) were identified. Additionally, the siblings exhibited blood mtDNA content lower than 33% compared to age-matched controls. These findings underscore the importance of assessing SUCLA2 variants in patients with severe early progressive encephalomyopathy, even in the absence of methylmalonic aciduria or mtDNA loss, thereby broaden the mutational spectrum of this gene.

线粒体DNA耗竭综合征（Mitochondrial DNA depletion syndrome, MDS）以琥珀酰辅酶A连接酶缺乏及线粒体DNA（mtDNA）丢失为特征，由负责mtDNA维持的核基因的特定变异所引发。SUCLA2相关线粒体DNA耗竭综合征5型（SUCLA2-related mitochondrial DNA depletion syndrome, type 5, MTDPS-5）表现为一种罕见且严重的早发性进展性脑肌病。本研究针对1个表现为MTDPS-5临床表型的新家族展开调查，阐明该疾病的遗传基础。研究在2名受累同胞中分别检出1种新的母系遗传SUCLA2基因无义变异[c.1234C>T (p.Arg412*)]以及1种独特的父系遗传插入缺失变异(g.48569263–48571020del1758insATGA)。此外，与年龄匹配的健康对照相比，该同胞的血液mtDNA含量低于33%。本研究结果强调，对于早发性进展性脑肌病患者，即便未出现甲基丙二酸尿症或mtDNA丢失，也应评估SUCLA2基因变异，该发现拓展了该基因的突变谱。