Original article
Clinical phenotype of mitochondrial diabetes due to rare mitochondrial DNA mutationsPhénotype clinique du diabète mitochondrial induit par des mutations rares de l’ADN mitochondrial

https://doi.org/10.1016/j.ando.2020.04.007Get rights and content

Abstract

Objective

While the most frequent mutation responsible for mitochondrial diabetes is the point mutation m.3243 A>G of mitochondrial DNA (mtDNA), few data are available about the role of rare mtDNA mutations in the pathophysiology of diabetes. The main objective of our study was to describe the phenotypic characteristics of patients suffering from diabetes linked to rare mtDNA mutations.

Research design and methods

We performed a post-hoc analysis of a prospective multicenter cohort of 743 patients with mitochondrial disorder (previously published by the French Network of Mitochondrial Diseases), associated to a literature review of the PubMed database from 1992 to May 2016. We extracted all reported patients with diabetes and identified rare mtDNA mutations and described their clinical and metabolic phenotypes.

Results

The 50 identified patients (10 from the princeps study; 40 from the review of the literature) showed a heterogeneous metabolic phenotype in terms of age, symptoms prior to diagnosis, treatments, and associated clinical and biological signs. However, neurological symptoms were more frequent in case of rare mtDNA mutations compared to the classical m.3243 A > G mutation (P = 0.024). In contrast, deafness (65% vs. 95%, P = 3.7E-5), macular pattern dystrophy (20% vs. 86%, P = 1.6E-10) and nephropathy (8% vs. 28%, P = 0.018) were significantly less frequent than in case of the classical m.3243 A>G mutation.

Conclusion

Although no specific metabolic phenotype could be identified suggesting or eliminating implication of rare mtDNA mutations in diabetes, clinical phenotypes featured more frequent neurological signs.

Résumé

Objectif

Alors que la mutation la plus fréquente responsable du diabète mitochondrial est la mutation ponctuelle m.3243 A>G de l’ADN mitochondrial (ADNmt), peu de données sont disponibles sur le rôle des mutations rares de l’ADNmt dans la physiopathologie du diabète. L’objectif principal de notre étude était de décrire les caractéristiques phénotypiques des patients souffrant de diabète lié à des mutations rares de l’ADNmt.

Méthodes

Nous avons effectué une analyse post-hoc d’une cohorte prospective et multicentrique de 743 patients atteints de maladies mitochondriales (précédemment publiée par le Réseau français des maladies mitochondriales), associée à une revue de la littérature sur la base de données PubMed de 1992 à mai 2016. Nous en avons extrait tous les patients diabétiques porteurs de mutations rares de l’ADNmt et décrit leur phénotype clinique et métabolique.

Résultats

Parmi les 50 patients que nous avons identifiés (10 de l’étude princeps et 40 de la revue de la littérature), nous avons observé un phénotype métabolique hétérogène en termes d’âge, de symptômes observés avant le diagnostic, de traitements et de signes cliniques et biologiques associés. Cependant, les symptômes neurologiques étaient plus fréquents en cas de mutations rares de l’ADNmt par rapport à la mutation classique m.3243 A>G (p = 0,024). En revanche, la surdité (65 vs 95 %, p = 3,7E-5), la dystrophie maculaire (20 vs 86 %, p = 1,6E-10) et la néphropathie (8 vs 28 %, p = 0,018) étaient significativement moins fréquentes que ce qui est observé en cas de mutation m.3243 A>G classique.

Conclusion

Bien que nous n’ayons pas identifié de phénotype métabolique spécifique évoquant ou éliminant l’implication de mutations rares de l’ADNmt dans le diabète, les phénotypes cliniques sont dominés par des signes neurologiques plus fréquents.

Section snippets

Abbreviations

    MIDD

    Maternally Inherited Diabetes and Deafness

    MERFF

    Myoclonic Epilepsy with Ragged Red Fibers

    mtDNA

    mitochondrial DNA

    IU

    International Unit

Study design

In order to determine the phenotype of rare mitochondrial mutations associated with diabetes, two groups were compared:

  • •

    the first one comprised rare mitochondrial mutations identified in 2 subgroups: the French Network of Mitochondrial Diseases, and a literature review on PubMed database;

  • •

    the second one (considered as control group) included patients with classical phenotype associated with the most frequent mtDNA mutation, m.3243 A>G, published by the GEDIAM (Mitochondrial Diabetes French Study

Patients with rare mitochondrial mutations from the French Network of mitochondrial diseases

In the princeps study [10], 45 of the 743 patients (6%) had diabetes. Ten carried a confirmed or putative pathogenic point mutation (22%). The characteristics of these ten patients are detailed in Table 1. The sex ratio was 1:1. Family history suggestive of mitochondrial disease in accordance with maternal transmission was present in 4 patients, absent in 5 and unspecified in 1. Further data about diabetes (natural history and glycemic control) were obtained for 6 of the 10 patients, as follows:

Discussion

Although the m.3243 A>G mtDNA mutation is the most frequent variant associated with mitochondrial diabetes, other point mutations can be responsible for clinical presentations involving diabetes. However, few data are available regarding their role in mitochondrial pathology. Through a review of the literature and a prospective clinical study, we identified 50 patients with diabetes due to rare mtDNA mutations and showed that these patients more frequently exhibited neurological symptoms, while

Conclusion

For clinicians, the main concern is probably to consider a diagnosis of mitochondrial diabetes. Clinical selection of patients is crucial in order to maximize molecular diagnosis of mitochondrial diabetes. Close collaboration with medical geneticists is essential to determine the most appropriate diagnostic strategy, given the major implications not only for the patient but also for the family, who get access to genetic counseling.

A diagnosis of mitochondrial diabetes must be considered in case

Disclosure of interest

The authors declare that they have no competing interest.

Ethics

Blood and tissue samples were taken after parents of affected children and adult patients had given informed consent. Authorizations for individual data protection were obtained through our Institutional Ethics Committee.

Funding

This work was made possible by grants to VP-F from the French Ministry of Health (PSTIC 2008, Programme de Soutien aux Techniques Innovantes et Coûteuses).

Contributions of the authors

Inclusion of patients by A.G.D.P., S.B., V.P., A.S.L., C.J., B.V., V.P.F., writing by A.G.D.P. and N.C., correction by N.C., V.P.F., S.B.

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