Macular dystrophy, diabetes, and deafness associated with a large mitochondrial dma deletion

doi:10.1016/S0002-9394(99)80243-8

American Journal of Ophthalmology

Volume 125, Issue 1, January 1998, Pages 100-103

https://doi.org/10.1016/S0002-9394(99)80243-8 Get rights and content

Purpose:

To report the mitochondrial DNA in a 17-year-old patient with diabetes, deafness, cataract, and maculopathy.

Method:

Ophthalmologic examination, fluorescein angiography, and electroretinogram were performed. Detection of deletion was analyzed by polymerase chain reaction and Southern blot, and screening for the A3243G mitochondrial DNA mutation was performed.

Results:

A short fragment of approximately 8.5 kb corresponding to deleted mitochondrial DNA was detected. The A3243G mitochondrial DNA mutation was not found.

Conclusion:

A 7-kb heteroplasmic deletion of the mitochondrial genome was found in this patient. No mitochondrial DNA deletion has been reported previously in association with macular dystrophy.

References (5)

RummeltV et al.
Ocular pathology of MELAS syndrome with mitochondrial DNA nucleotide 3243 point mutation
Ophthalmology
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MassinP et al.
Macular pattern dystrophy associated with a mutation of mitochondrial DNA
Am J Ophthalmol
(1995)

There are more references available in the full text version of this article.

Cited by (25)

Clinical phenotype of mitochondrial diabetes due to rare mitochondrial DNA mutations
2020, Annales d'Endocrinologie
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.
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.
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.
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.
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.
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.
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.
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.
Whole mitochondrial genome screening of a family with maternally inherited diabetes and deafness (MIDD) associated with retinopathy: A putative haplotype associated to MIDD and a novel MT-CO2 m.8241 T > G mutation
2017, Journal of Diabetes and its Complications
Citation Excerpt :
In addition, long-range PCR amplification for the patient with severe MIDD (associated to retinopathy) didn't show any deletions in the mitochondrial DNA extracted from blood leukocytes. In previous studies, mitochondrial DNA deletions were reported in maternally inherited diabetes (Rigoli, Salpietro, Caruso, Chiarenza, & Barberi, 1999), MIDD (Ballinger et al., 1992) and wolfram syndrome (Rotig et al., 1993; Souied et al., 1998). Probably, it is necessary to investigate DNA extracted from skeletal muscle.
Mitochondrial diseases are a clinically heterogeneous group of disorders that arise as a result of dysfunction of the mitochondrial respiratory chain. They can be caused by mutations in both nuclear and mitochondrial DNA. In fact, mitochondrial DNA (mtDNA) defects are known to be associated with a large spectrum of human diseases and patients might present wide range of clinical features with various combinations.
Our study reported a Tunisian family with clinical features of maternally inherited diabetes and deafness (MIDD). Accordingly, we performed a whole mitochondrial genome mutational analysis, results revealed a haplotype composed by “A750G, A1438G, G8860A, T12705, T14766C and T16519C”, in homoplasmic state, in the mother and transmitted to her daughter and her son. The patient with MIDD2 and retinopathy presented, in addition to this haplotype associated to the MIDD, two de novo variations including a novel one m.8241 T > G (p. F219C) in MT-CO2 gene and a known one m.13276G > A (p. M314 V) in MT-ND5 gene. The coexistence of these two mutations could explain the retinopathy observed in this patient.
Genetics of mitochondrial respiratory chain deficiencies
2014, Revue Neurologique
Citation Excerpt :
In most cases, the deletion is maternally inherited and always heteroplasmic. Diabetes is frequently associated with deafness, but may also be part of a multiorgan disorder [17–20]. It is worthwhile noting that the most common deletion (4977 bp) found in 30% of patients harbouring a unique deletion, flanked by 13-bp direct repeats, has been described in both Pearson syndrome and KSS, and subsequently also reported in PEO.
Oxidative phosphorylation, i.e. ATP synthesis by the oxygen-consuming respiratory chain (RC), supplies most organs and tissues with a readily usable energy source, and is already fully functioning before birth. This means that, in theory, RC deficiency can give rise to any symptom in any organ or tissue at any age and with any mode of inheritance, due to the twofold genetic origin of RC components (nuclear DNA and mitochondrial DNA). It has long been erroneously believed that RC disorders originate from mutations of mtDNA as, for some time, only mutations or deletions of mtDNA could be identified. However, the number of disease-causing mutations in nuclear genes is now steadily growing. These genes not only encode the various subunits of each complex, but also the ancillary proteins involved in the different stages of holoenzyme biogenesis, including transcription, translation, chaperoning, addition of prosthetic groups and assembly of proteins, as well as the various enzymes involved in mtDNA metabolism.
La phosphorylation oxydative, qui associe la production d’ATP à la consommation d’oxygène par la chaîne respiratoire (CR), fournit les tissus en énergie et est fonctionnelle bien avant la naissance. Ainsi, les déficits de la chaîne respiratoire peuvent théoriquement se traduire par n’importe quel symptôme, dans n’importe quel organe ou tissu, à tout âge et avec tout mode de transmission du fait de la double origine génétique des composants de la CR (ADN nucléaire et ADN mitochondrial). Il a longtemps été considéré, à tort, que les déficits de la CR étaient essentiellement dus à des mutations de l’ADN mitochondrial car, durant un certain temps, seules des mutations ou délétions de ce génome avaient été identifiées chez les patients. Cependant, le nombre de mutations dans des gènes nucléaires codant pour des protéines mitochondriales est continuellement croissant. Ces gènes codent non seulement pour les différentes sous-unités de la CR, mais également pour toute une série de protéines impliquées dans la biogenèse et l’assemblage de la CR, la maturation et la mise en place de ses cofacteurs, le maintien de l’ADN mitochondrial, sa transcription ou la synthèse des protéines qu’il code.
A maternally inherited diabetes and deafness patient with the 12S rRNA m.1555A>G and the ND1 m.3308T>C mutations associated with multiple mitochondrial deletions
2013, Biochemical and Biophysical Research Communications
Citation Excerpt :
In previous studies, mitochondrial DNA deletions were reported in maternally inherited diabetes [12], MIDD [13] and wolfram syndrome [14,42]. It was also reported that a large mitochondrial DNA deletion was detected in the absence of the m.3243A>G mitochondrial DNA mutation in a 17-year-old patient with diabetes, deafness, cataract, and maculopathy [42]. In conclusion, our study reported, the first description of the m.1555A>G mutation in the mitochondrial 12S rRNA mutation in a patient with MIDD in association with ND1 m.3308T>C mutation and multiple mitochondrial deletions in DNA extracted from skeletal muscle.
Maternally inherited diabetes and deafness (MIDD) is a mitochondrial syndrome characterized by the onset of sensorineural hearing loss and diabetes in adults. Some patients may have other additional clinical features common in mitochondrial disorders such as pigmentary retinopathy, ptosis, cardiomyopathy, myopathy and renal affections. We report a 40-year-old Tunisian patient presenting maternally inherited type 2 diabetes and deafness (MIDD). A molecular genetic analysis was conducted in the patient and his twin sister, but no reported mutations in the tRNA^Leu(UUR) and tRNA^Glu genes were found, especially the two mitochondrial m.3243A>G and the m.14709T>C mutations in muscle and blood leukocytes. The results showed the presence of the mitochondrial NADH deshydrogenase 1 (ND1) homoplasmic m.3308T>C mutation the 2 tested tissues (blood leukocytes and skeletal muscle) of the proband and in the patient’s sister blood leukocytes. In addition, we identified the mitochondrial 12S rRNA m.1555A>G mutation in muscle and blood leukocytes. The Long-range PCR amplification revealed the presence of multiple deletions of the mitochondrial DNA extracted from the patient’s skeletal muscle removing several tRNA and protein-coding genes. Our study reported a Tunisian patient with clinical features of MIDD in whom we detected the 12S rRNA m.1555A>G and the ND1 m.3308T>C mutations with mitochondrial multiple deletions.
Animal models of age related macular degeneration
2012, Molecular Aspects of Medicine
Citation Excerpt :
Systemic administration of antibodies to Aβ40 and Aβ42 provide visual protection in these animals suggesting a role for Aβ in the pathogenesis of AMD (Ding et al., 2011). In humans, the APOEe4 allele is correlated with relative protection from the development of AMD compared with the APOEe2, while in the mice the opposite appears to be true (Baird et al., 2004; Klaver et al., 1998; Schmidt et al., 2002; Souied et al., 1998). It is unclear why this discrepancy exists between species.
Age related macular degeneration (AMD) is the leading cause of vision loss of those over the age of 65 in the industrialized world. The prevalence and need to develop effective treatments for AMD has lead to the development of multiple animal models. AMD is a complex and heterogeneous disease that involves the interaction of both genetic and environmental factors with the unique anatomy of the human macula. Models in mice, rats, rabbits, pigs and non-human primates have recreated many of the histological features of AMD and provided much insight into the underlying pathological mechanisms of this disease. In spite of the large number of models developed, no one model yet recapitulates all of the features of human AMD. However, these models have helped reveal the roles of chronic oxidative damage, inflammation and immune dysregulation, and lipid metabolism in the development of AMD. Models for induced choroidal neovascularization have served as the backbone for testing new therapies. This article will review the diversity of animal models that exist for AMD as well as their strengths and limitations.
Genetic bases of mitochondrial respiratory chain disorders
2010, Diabetes and Metabolism
Oxidative phosphorylation – ATP synthesis by the oxygen-consuming respiratory chain (RC) – supplies most organs and tissues with a readily usable energy source, and is already fully functioning at birth. This means that, in theory, RC deficiency can give rise to any symptom in any organ or tissue at any age and with any mode of inheritance, due to the two-fold genetic origin of RC components (nuclear DNA and mitochondrial DNA). It has long been erroneously believed that RC disorders originate from mutations of mtDNA as, for some time, only mutations or deletions of mtDNA could be identified. However, the number of disease-causing mutations in nuclear genes is now steadily growing. These genes not only encode the various subunits of each complex, but also the ancillary proteins involved in the different stages of holoenzyme biogenesis, including transcription, translation, chaperoning, addition of prosthetic groups and assembly of proteins, as well as the various enzymes involved in mtDNA metabolism.
La chaîne respiratoire a pour rôle essentiel la synthèse d’ATP nécessaire à toutes les cellules de l’organisme et elle assure une source d’énergie indispensable à tous les organes. Ainsi, un déficit de la chaîne respiratoire peut se manifester théoriquement par n’importe quel symptôme, toucher n’importe quel tissu ou organe, à n’importe quel âge et avec tous les modes de transmission du fait de la double origine génétique des sous-unités de la chaîne respiratoire (génomes nucléaires et mitochondriaux). On a longtemps considéré que les maladies mitochondriales étaient uniquement dues à des mutations ou des délétions de l’ADN mitochondrial mais les exemples de mutations de gènes nucléaires dans ces maladies sont de plus en plus fréquents. Ces gènes codent des sous-unités de la chaîne respiratoire elle-même mais aussi des protéines impliquées dans la biogenèse des holoenzymes, des protéines de la transcription ou de la traduction des gènes de l’ADN mitochondrial, des protéines qui permettent l’assemblage des complexes de la chaîne respiratoire ou enfin de différentes enzymes du métabolisme de l’ADN mitochondrial.

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^*: Inquiries to Eric Souied, MD, Clinique Ophtalmologique Universitaire de Créteil, 40 Avenue de verdun, 94010 Créteil, France; fax: (33) 1.45.1.17.52.27.

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Brief ReportMacular dystrophy, diabetes, and deafness associated with a large mitochondrial dma deletion

Purpose:

Method:

Results:

Conclusion:

Ophthalmology

Am J Ophthalmol

Brief Report
Macular dystrophy, diabetes, and deafness associated with a large mitochondrial dma deletion