Mitochondrial DNA A3243G variant-associated retinopathy: a meta-analysis of the clinical course of visual acuity and correlation with systemic manifestations

Coussa, Razek Georges; Sohn, Elliott H.; Han, Ian C.; Parikh, Sumit; Traboulsi, Elias I.

doi:10.1080/13816810.2021.1907598

Cited by 4 publications

(4 citation statements)

References 87 publications

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“… 49 Interestingly, a recent meta-analysis revealed that patients with the m.A3243G mutation and pigmentary retinopathy maintained highly-functional visual acuity until around the fifth decade of life, after which significant visual decline ensued. 50 Importantly, cybrid cell lines containing the m.A3243G mutation above a certain heteroplasmy threshold led to a reduction in oxygen consumption and OXPHOS. 51 This mutation also affected the processing of longer mitochondrial RNA precursors and the post-transcriptional modification of tRNA Leu(UUR) .…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Diabetes is Associated with tRNALeu(UUR) A3243G and ND6 T14502C Mutations

Ding¹,

Shunrong²,

Guo³

et al. 2022

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Background Mutations in mitochondrial DNA (mtDNA) are associated with type 2 diabetes mellitus (T2DM). In particular, m.A3243G is the most common T2DM-related mtDNA mutation in many families worldwide. However, the clinical features and pathophysiology of m.A3243G-induced T2DM are largely undefined. Methods Two pedigrees with maternally inherited T2DM were underwent clinical, molecular and biochemical assessments. The mtDNA genes were PCR amplified and sequenced. Mitochondrial adenosine triphosphate (ATP) and reactive oxygen species (ROS) were measured in polymononuclear leukocytes derived from three patients with both the m.A3243G and m.T14502C mutations, three patients with only the m.A3243G mutation and three controls without these mutations. Moreover, GJB2, GJB3 and GJB6 mutations were screened by PCR-Sanger sequencing. Results Members of the two pedigrees manifestated variable clinical phenotypes including diabetes and hearing and vision impairments. The age at onset of T2DM varied from 31 to 66 years, with an average of 41 years. Mutational analysis of mitochondrial genomes indicated the presence of the m.A3243G mutation in both pedigrees. Matrilineal relatives in one of the pedigrees harbored the coexisting of m.A3243G and m.T14502C mutations. Remarkably, the m.T14502C mutation, which causes the substitution of a conserved isoleucine for valine at position 58 in ND6 mRNA, may affect the mitochondrial respiratory chain functions. Biochemical analysis revealed that cell lines bearing both the m.A3243G and m.T14502C mutations exhibited greater reductions in ATP levels and increased ROS production compared with those carrying only the m.A3243G mutation. However, we did not find any mutations in the GJB2, GJB3 and GJB6 genes. Conclusion Our study indicated that mitochondrial diabetes is associated with the tRNA Leu(UUR) A3243G and ND6 T14502C mutations.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial Diabetes is Associated with tRNALeu(UUR) A3243G and ND6 T14502C Mutations

Ding¹,

Shunrong²,

Guo³

et al. 2022

DMSO

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“…A recent meta-analysis found a high prevalence of retinopathy (74.4%) and a linear correlation with visual acuity and age for those with m.3243A>G mutation-related mitochondriopathy. The fifth decade of life was identified as the inflection point for vision loss ( Coussa et al, 2021 ). The fundus presentation of retinopathy has been described to range from mild RPE mottling to advanced and diffuse atrophy.…”

Section: Phenotypementioning

confidence: 99%

“…Macular dystrophy is thought to be more frequent in MIDD patients, which might reduce metabolism and decrease oxygen consumption in the retina to protect against the development of diabetic retinopathy ( Yang et al, 2021 ). Although many patients with retinopathy are asymptomatic at an early age, some more sensitive methods (e.g., multimodal imaging with fundus autofluorescence and optical coherence tomography) can aid in earlier diagnosis ( Coussa et al, 2021 ).…”

Section: Phenotypementioning

confidence: 99%

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

Liang

Zhang

et al. 2022

Front. Genet.

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The mitochondrial DNA (mtDNA) m.3243A>G mutation is one of the most common pathogenic mtDNA variants, showing complex genetics, pathogenic molecular mechanisms, and phenotypes. In recent years, the prevention of mtDNA-related diseases has trended toward precision medicine strategies, such as preimplantation genetic diagnosis (PGD) and mitochondrial replacement therapy (MRT). These techniques are set to allow the birth of healthy children, but clinical implementation relies on thorough insights into mtDNA genetics. The genotype and phenotype of m.3243A>G vary greatly from mother to offspring, which compromises genetic counseling for the disease. This review is the first to systematically elaborate on the characteristics of the m.3243A>G mutation, from genetics to phenotype and the relationship between them, as well as the related influencing factors and potential strategies for preventing disease. These perceptions will provide clarity for clinicians providing genetic counseling to m.3243A>G patients.

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“…Mitochondrial disorders can present with a wide phenotypic spectrum of ocular findings ranging from dominant optic atrophy, Leber hereditary optic neuropathy, Kearns-Sayre syndrome, and Wolfram syndrome [1,48]. Specifically, the A3243G mutation in MTTL1 (OMIM #520000) can cause a retinal phenotype similar to SD known as Maternally Inherited Diabetes and Deafness (MIDD) [49]. As the name suggests, distinguishing clinical features from SD include personal or family history of diabetes and early-onset hearing loss, though these need not be present for the diagnosis, and ocular findings may precede the systemic manifestations.…”

Section: Other Masqueradesmentioning

confidence: 99%

Stargardt disease masquerades

Ricca

Han

Sohn

2021

Current Opinion in Ophthalmology

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Purpose of reviewStargardt disease is the most common inherited macular dystrophy but has a wide clinical spectrum, and several inherited macular dystrophies have phenotypic similarities that can make clinical diagnosis challenging. This review seeks to highlight key clinical and multimodal imaging features to aid clinicians in accurate diagnosis. Recent findingsMultimodal imaging has provided additional information to aid in the diagnosis of Stargardt disease and its masquerades. These data from multimodal imaging are important to correlate with findings from clinical examination to help support the clinical diagnosis or guide molecular investigations.

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Mitochondrial DNA A3243G variant-associated retinopathy: a meta-analysis of the clinical course of visual acuity and correlation with systemic manifestations

Cited by 4 publications

References 87 publications

Mitochondrial Diabetes is Associated with tRNALeu(UUR) A3243G and ND6 T14502C Mutations

Mitochondrial Diabetes is Associated with tRNALeu(UUR) A3243G and ND6 T14502C Mutations

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

Stargardt disease masquerades

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