Clinical Characteristics of Diabetes in People with Mitochondrial DNA 3243A>G Mutation in Korea (Diabetes Metab J 2024;48:482-6)

Eun Hoo Rho; Soo Heon Kwak

doi:10.4093/dmj.2024.0154

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Response Clinical Characteristics of Diabetes in People with Mitochondrial DNA 3243A>G Mutation in Korea (Diabetes Metab J 2024;48:482-6): Eun Hoo Rho, Soo Heon Kwak; Diabetes & Metabolism Journal 2024;48(4):818-819.
DOI: https://doi.org/10.4093/dmj.2024.0154
Published online: July 26, 2024

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Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea

Corresponding author: Soo Heon Kwak

Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea E-mail: shkwak@snu.ac.kr

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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See the letter "Clinical Characteristics of Diabetes in People with Mitochondrial DNA 3243A>G Mutation in Korea" on page 482.

We appreciated the insightful comments provided by Finsterer and Mehri on our research [1] and its related implications. First of all, it is important to acknowledge that maternally inherited diabetes and deafness (MIDD) and mitochondrial encephalopathy, lactic acidosis, and stroke-like episode (MELAS) have extensive phenotypes variability [2] and substantial overlap, as they can arise from the same genetic variation. The absence of consistent and uniform diagnostic criteria [3] further complicate matters, making it very difficult to distinguish between the two conditions [4] as they are regarded as a spectrum. Our focus was on describing the clinical characteristic of diabetes resulting from m.3243A>G mutation and their relationship with heteroplasmy. Therefore, we included all individuals with diabetes defined as a glycosylated hemoglobin level greater than 6.5% and carrying the m.3243A>G mutation, who were categorized as having MIDD. This approach could prove beneficial in managing hyperglycemia caused by the mutation and mitigating diabetes-related complications. Unfortunately, lactate was only measured in the serum. As we were not able to perform magnetic resonance spectroscopy, we could not identify patients who showed lactate peaks. Furthermore, the mean % of heteroplasmy in patients with a stroke-like episode (SLE) was similar to those without SLE.

Second, we agree with you that some MIDD patients may exhibit a prediabetic level of hyperglycemia and acknowledge that none of these individuals were included in our study. As previously stated, we were interested in the clinical characteristics, comorbidities, and treatment of hyperglycemia in people with diabetes caused by m.3243A>G mutation. Therefore, the investigation of prediabetes related to this mutation was beyond our scope, but we hope to address this issue in future studies.

Third, we admit the importance of assessing heteroplasmy level in clinically affected tissues or organs [5]. In our study, we focused on blood lymphocytes for heteroplasmy determination due to feasibility. While we understand the limitations of not examining phenotypically affected tissues directly, blood lymphocytes are commonly used in mitochondrial DNA studies due to the ease of sampling. In addition, prior studies have indicated an association between blood leukocyte level of heteroplasmy and the clinical variability of MIDD [6]. We did not specifically investigate immune deficiency due to leukocyte dysfunction in our cohort of patients.

Fourth, C-peptide and lactate levels were measured in only a subset of the participants. Among the individuals for whom these measurements were available, 40% had reduced C-peptide and 70% had increased lactate. There were 25 participants who were receiving basal-bolus insulin injection, indicating insulin dependence. A total of 40% of males and 35% of females were of short stature.

Lastly, our findings revealed a negative correlation between heteroplasmy level and age at diabetes diagnosis. A higher heteroplasmy level was linked to earlier onset of diabetes, with a 10% increase in heteroplasmy level corresponding to 4.6-year earlier development of diabetes. As suggested, we think this association reflects increased severity attributable to higher heteroplasmy levels.

In conclusion, we appreciate the comments and critiques provided by Finsterer and Mehri. Our study, which was published as a brief report, condensed a significant portion of the methods and results. While we recognize the limitations of our study design, including data scope and certain analyses, such as tissue-specific heteroplasmy rates, we believe our findings offer valuable insights. Moving forward, we are committed to addressing these limitations and conducting more comprehensive investigations to enhance our understanding of mitochondrial diabetes.

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CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

REFERENCES

1. Rho EH, Baek SI, Lee H, Seong MW, Chae JH, Park KS, et al. Clinical characteristics of diabetes in people with mitochondrial DNA 3243A>G mutation in Korea. Diabetes Metab J 2024;48:482-6.Article PubMed PMC PDF
2. Finsterer J. Rare phenotypic manifestations of MELAS. Yonsei Med J 2020;61:904-6.Article PubMed PMC PDF
3. Wu G, Shen Y, Zhu F, Tao W, Zhou Y, Ke S, et al. Comprehensive diagnostic criteria for MELAS syndrome: a case study involving an elderly patient with MT-TWm.5541C>T mutation. Neurologist 2023;28:190-4.Article PubMed PMC
4. Goel H, Szczepanczyk K, Mirza FS. Late-onset MELAS with MIDD: an uncommon age of presentation. AACE Clin Case Rep 2018;4:228-31.Article
5. de Laat P, Koene S, van den Heuvel LP, Rodenburg RJ, Janssen MC, Smeitink JA. Clinical features and heteroplasmy in blood, urine and saliva in 34 Dutch families carrying the m.3243A > G mutation. J Inherit Metab Dis 2012;35:1059-69.Article PubMed PMC
6. Laloi-Michelin M, Meas T, Ambonville C, Bellanne-Chantelot C, Beaufils S, Massin P, et al. The clinical variability of maternally inherited diabetes and deafness is associated with the degree of heteroplasmy in blood leukocytes. J Clin Endocrinol Metab 2009;94:3025-30.Article PubMed PDF

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Clinical Characteristics of Diabetes in People with Mitochondrial DNA 3243A>G Mutation in Korea (Diabetes Metab J 2024;48:482-6)

Diabetes Metab J. 2024;48(4):818-819. Published online July 26, 2024

DOI: https://doi.org/10.4093/dmj.2024.0154

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Clinical Characteristics of Diabetes in People with Mitochondrial DNA 3243A>G Mutation in Korea

Clinical Characteristics of Diabetes in People with Mitochondrial DNA 3243A>G Mutation in Korea (Diabetes Metab J 2024;48:482-6)

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Rho EH, Kwak SH. Clinical Characteristics of Diabetes in People with Mitochondrial DNA 3243A>G Mutation in Korea (Diabetes Metab J 2024;48:482-6). Diabetes Metab J. 2024;48(4):818-819.

DOI: https://doi.org/10.4093/dmj.2024.0154.

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