A novel mutation in the mitochondrial MT-ND5 gene in a family with MELAS. The relevance of genetic analysis on targeted tissues

Oliveira, Luísa Panadés-de; Montoya, Julio; Emperador, Sonia; Ruiz‐Pesini, Eduardo; Jericó, Ivonne; Arenas, Joaquín; Hernández-Laín, Aurelio; Blázquez, Alberto; Martín, Miguel; Domínguez‐González, Cristina

doi:10.1016/j.mito.2019.10.001

Cited by 5 publications

(4 citation statements)

References 15 publications

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“…It should be noted that although GDF-15 will help to avoid unnecessary biopsies in patients with CFS, in many cases, biopsy performance is still necessary for the definitive diagnosis of PMM in adults. Identifying the underlying genetic alteration in PMM sometimes requires the analysis of mtDNA extracted from the skeletal muscle to detect large-scale single deletions, somatic variants, or mtDNA variants with low mutation loads in other tissues, such as blood or uroepithelial cells [ 20 ]. On other occasions, the study of muscle mtDNA allows the detection of multiple deletions that guides the diagnosis towards disorders of mtDNA maintenance, which frequently present with muscle symptoms [ 15 , 21 ].…”

Section: Discussionmentioning

confidence: 99%

Serum GDF-15 Levels Accurately Differentiate Patients with Primary Mitochondrial Myopathy, Manifesting with Exercise Intolerance and Fatigue, from Patients with Chronic Fatigue Syndrome

Bermejo-Guerrero

Hoz

Guerrero-Molina

et al. 2023

JCM

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Primary mitochondrial myopathies (PMM) are a clinically and genetically highly heterogeneous group that, in some cases, may manifest exclusively as fatigue and exercise intolerance, with minimal or no signs on examination. On these occasions, the symptoms can be confused with the much more common chronic fatigue syndrome (CFS). Nonetheless, other possibilities must be excluded for the final diagnosis of CFS, with PMM being one of the primary differential diagnoses. For this reason, many patients with CFS undergo extensive studies, including extensive genetic testing and muscle biopsies, to rule out this possibility. This study evaluated the diagnostic performance of growth differentiation factor-15 (GDF-15) as a potential biomarker to distinguish which patient with chronic fatigue has a mitochondrial disorder. We studied 34 adult patients with symptoms of fatigue and exercise intolerance with a definitive diagnosis of PMM (7), CFS (22), or other non-mitochondrial disorders (5). The results indicate that GDF-15 can accurately discriminate between patients with PMM and CFS (AUC = 0.95) and between PMM and patients with fatigue due to other non-mitochondrial disorders (AUC = 0.94). Therefore, GDF-15 emerges as a promising biomarker to select which patients with fatigue should undergo further studies to exclude mitochondrial disease.

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Section: Discussionmentioning

confidence: 99%

Serum GDF-15 Levels Accurately Differentiate Patients with Primary Mitochondrial Myopathy, Manifesting with Exercise Intolerance and Fatigue, from Patients with Chronic Fatigue Syndrome

Bermejo-Guerrero

Hoz

Guerrero-Molina

et al. 2023

JCM

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“…There were three homoplasmic variants identified as likely pathogenic or pathogenic in MT-ND5 across four samples (DGR324 and DGR337 m.12634A > G, DGR338 m.13468, and DGR037 m.13651A > T). Heteroplasmic variants in MT-ND5 have previously been identified in MELAS patients or Leigh syndrome and there have been some theories that this may be a novel hot spot for MELAS causing variants outside of the classical m.3243A > G variant [ 33 – 36 ]. However, none of the variants described in this literature match one that was seen in the CADASIL-related CSVD cohort.…”

Section: Discussionmentioning

confidence: 99%

Investigation of Mitochondrial Related Variants in a Cerebral Small Vessel Disease Cohort

et al. 2022

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Monogenic forms of cerebral small vessel disease (CSVD) can be caused by both variants in nuclear DNA and mitochondrial DNA (mtDNA). Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is known to have a phenotype similar to Cerebral Autosomal Dominant Arteriopathy with Sub-cortical Infarcts and Leukoencephalopathy (CADASIL), and can be caused by variants in the mitochondrial genome and in several nuclear-encoded mitochondrial protein (NEMP) genes. The aim of this study was to screen for variants in the mitochondrial genome and NEMP genes in a NOTCH3-negative CADASIL cohort, to identify a potential link between mitochondrial dysfunction and CSVD pathology. Whole exome sequencing was performed for 50 patients with CADASIL-like symptomology on the Ion Torrent system. Mitochondrial sequencing was performed using an in-house designed protocol with sequencing run on the Ion GeneStudio S5 Plus (S5 +). NEMP genes and mitochondrial sequencing data were examined for rare (MAF < 0.001), non-synonymous variants that were predicted to have a deleterious effect on the protein. We identified 29 candidate NEMP variants that had links to either MELAS-, encephalopathy-, or Alzheimer’s disease–related phenotypes. Based on these changes, variants affecting POLG, MTO1, LONP1, NDUFAF6, NDUFB3, and TCIRG1 were thought to play a potential role in CSVD pathology in this cohort. Overall, the exploration of the mitochondrial genome identified a potential role for mitochondrial related proteins and mtDNA variants contributing to CSVD pathologies.

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“…Furthermore, previous studies suggested that mutations in the ND5 gene were more likely to be associated with an extended phenotype rather than isolated visual dysfunction ( 30 ). Diseases caused by the mutations in ND5 would exhibit various degrees of clinical heterogeneity, such as Leigh syndrome ( 31 ), Idiopathic Parkinson’s disease ( 32 ), mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) ( 33 ), myoclonic epilepsy with ragged-red fibers (MERRF) ( 34 ), and hypertrophic cardiomyopathy ( 35 ). Strikingly, neurological and muscular disorders are the main problems caused by the mutations in ND5 gene, which were also observed in our patients.…”

Section: Discussionmentioning

confidence: 99%

Varying Clinical Phenotypes of Mitochondrial DNA T12811C Mutation: A Case Series Report

Sun

Feng

et al. 2022

Front. Med.

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The T12811C mitochondrial DNA (mtDNA) mutation has been reported in Leber hereditary optic neuropathy (LHON) previously, with vision loss as the main manifestation. The involvement of other organ systems, including the central and peripheral nervous system, heart, and extraocular muscles, has not been well described. This case series report investigated four patients with T12811C mtDNA mutation, verified through a next generation sequencing. Two male patients presented with bilateral subacute visual decrease combined with involvement of multiple organ systems: leukoencephalopathy, hypertrophic cardiomyopathy, neurosensory deafness, spinal cord lesion and peripheral neuropathies. Two female patients presented with progressive ptosis and ophthalmoplegia, one of whom also manifested optic atrophy. This study found out that patients harboring T12811C mtDNA mutation manifested not only as vision loss, but also as a multi-system disorder affecting the nervous system, heart, and extraocular muscles.

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A novel mutation in the mitochondrial MT-ND5 gene in a family with MELAS. The relevance of genetic analysis on targeted tissues

Cited by 5 publications

References 15 publications

Serum GDF-15 Levels Accurately Differentiate Patients with Primary Mitochondrial Myopathy, Manifesting with Exercise Intolerance and Fatigue, from Patients with Chronic Fatigue Syndrome

Serum GDF-15 Levels Accurately Differentiate Patients with Primary Mitochondrial Myopathy, Manifesting with Exercise Intolerance and Fatigue, from Patients with Chronic Fatigue Syndrome

Investigation of Mitochondrial Related Variants in a Cerebral Small Vessel Disease Cohort

Varying Clinical Phenotypes of Mitochondrial DNA T12811C Mutation: A Case Series Report

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