Mitochondrial diabetes and mitochondrial DNA mutation load in MELAS syndrome

Abstract

Objective: Mitochondrial 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 methods: Of 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. Results: The 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. Conclusions: We 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.

Pathogenic mitochondrial DNA 3243A>G mutation: From genetics to phenotype

“…de Laat et al (2021) followed 151 m.3243A>G patients for 6 years and found phenotypes were slowly progressive, and heteroplasmy levels in leucocytes were only weakly correlated with the severity of the disease. A similar result was reported in MELAS, where heteroplasmy was negatively correlated with the onset and diagnosed age of diabetes, but not with the clinical severity or progression (Chae et al, 2020).…”

The non-syndromic clinical spectrums of mtDNA 3243A>G mutation

“…While lower heteroplasmy level were more likely to suffer from hearing loss, decreased vision, and gastrointestinal disturbance. 44 , 45 Phenotype is also modulated by nuclear gene and environmental factors. Recent report based 238 patients carrying 3243A>G mutation from New Castle found that nuclear factor may contribute larger than other known factors such as age, gender, and heteroplasmy.…”

Inherited Neuromuscular Disorders: Which Role for Serum Biomarkers?

“…About 50% of patients with Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) can manifest with type 2 diabetes mellitus or impaired oral glucose tolerance [16,57,58]. Plasma amino acid testing can reveal elevated alanine, especially after aerobic exercise.…”