• Hyun-Wook Chae, Ji-Hoon Na, Ho-Seong Kim, and Young-Mock Lee.
• Department of Pediatrics, Gangnam Severance Hospital, Severance Children's Hospital, Yonsei University College of Medicine, Seoul, Korea.
• Eur. J. Endocrinol. 2020 Nov 1; 183 (5): 505-512.

ObjectiveMitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a very rare condition; it encompasses a diverse group of disorders including diabetes. Phenotypic variability can be attributed to heteroplasmy along with varying proportions of mutant and WT mitochondrial DNA (mtDNA). To examine the clinical relationship between mitochondrial diabetes and mutational load, we analyzed the mtDNA of children and young adolescents with MELAS syndrome using next generation sequencing (NGS).Design And MethodsOf 57 subjects with suspected MELAS syndrome, 32 children and young adolescents were diagnosed as MELAS syndrome with mtDNA A-to-G transition at nucleotide 3243. Mutation load studies and NGS were performed for 25 subjects.ResultsThe mean mutation load was 60.4 ± 18.4% (range: 22.5‒100). Of the 25 subjects with NGS results, 15 (60%) were diagnosed with DM and 2 (8%) were diagnosed with impaired glucose tolerance (IGT). The mutational load of subjects inversely correlated with first symptom onset, age at diagnosis of MELAS syndrome, and DM (P < 0.001). However, mutational load did not correlate with the clinical severity or progression of DM/IGT. There was no significant difference in insulin resistance or sensitivity indices between the low- and high-mutation load groups. During the 3.7 years of follow-up, insulin resistance indices were not significantly different between baseline and follow-up.ConclusionsWe can infer that the mutation load in the MELAS syndrome is significantly associated with the onset of symptoms and associated diseases, including mitochondrial diabetes. However, it may not influence disease progression.

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