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Nefrologia Dec 2023Mitochondrial diseases are a phenotype and genotype heterogeneous group of disorders that typically have a multisystemic involvement. The m.3243A>G pathogenic variant is... (Review)
Review
Mitochondrial diseases are a phenotype and genotype heterogeneous group of disorders that typically have a multisystemic involvement. The m.3243A>G pathogenic variant is the most frequent mitochondrial DNA defect, and it causes several different clinical syndromes, such as mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS), and the maternally inherited diabetes and deafness (MIDD) syndromes. Not frequently reported, renal involvement in these diseases is probably underestimated, yet it increases morbidity. It generally manifests as subnephrotic proteinuria and progressive deterioration of kidney function. Adult presentation of mitochondrial diseases is hard to recognize, especially in oligosymptomatic patients or those with exclusive kidney involvement. However, suspicion should always arise when family history, particularly on the maternal side, and multisystemic symptoms, most often of the central nervous system and skeletal muscles, are present. In this review we discuss the clinical diagnosis and approach of patients with renal manifestations in the context of the mtDNA m.3243A>G pathogenic variant.
Topics: Adult; Humans; DNA, Mitochondrial; MELAS Syndrome; Mitochondrial Diseases; Diabetes Mellitus, Type 2; Kidney; Hearing Loss, Sensorineural; Deafness
PubMed: 38355238
DOI: 10.1016/j.nefroe.2024.01.017 -
Revista Espanola de Enfermedades... Feb 2021MELAS syndrome with chronic intestinal pseudo-obstruction and neurological symptoms in a patient with a fatal evolution despite medical and surgical treatment.
MELAS syndrome with chronic intestinal pseudo-obstruction and neurological symptoms in a patient with a fatal evolution despite medical and surgical treatment.
Topics: Chronic Disease; Humans; Intestinal Pseudo-Obstruction; MELAS Syndrome
PubMed: 33226257
DOI: 10.17235/reed.2020.7099/2020 -
JCI Insight Jul 2023Variants within the high copy number mitochondrial genome (mtDNA) can disrupt organelle function and lead to severe multisystem disease. The wide range of manifestations...
Variants within the high copy number mitochondrial genome (mtDNA) can disrupt organelle function and lead to severe multisystem disease. The wide range of manifestations observed in patients with mitochondrial disease results from varying fractions of abnormal mtDNA molecules in different cells and tissues, a phenomenon termed heteroplasmy. However, the landscape of heteroplasmy across cell types within tissues and its influence on phenotype expression in affected patients remains largely unexplored. Here, we identify nonrandom distribution of a pathogenic mtDNA variant across a complex tissue using single-cell RNA-Seq, mitochondrial single-cell ATAC sequencing, and multimodal single-cell sequencing. We profiled the transcriptome, chromatin accessibility state, and heteroplasmy in cells from the eyes of a patient with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and from healthy control donors. Utilizing the retina as a model for complex multilineage tissues, we found that the proportion of the pathogenic m.3243A>G allele was neither evenly nor randomly distributed across diverse cell types. All neuroectoderm-derived neural cells exhibited a high percentage of the mutant variant. However, a subset of mesoderm-derived lineage, namely the vasculature of the choroid, was near homoplasmic for the WT allele. Gene expression and chromatin accessibility profiles of cell types with high and low proportions of m.3243A>G implicate mTOR signaling in the cellular response to heteroplasmy. We further found by multimodal single-cell sequencing of retinal pigment epithelial cells that a high proportion of the pathogenic mtDNA variant was associated with transcriptionally and morphologically abnormal cells. Together, these findings show the nonrandom nature of mitochondrial variant partitioning in human mitochondrial disease and underscore its implications for mitochondrial disease pathogenesis and treatment.
Topics: Humans; Heteroplasmy; MELAS Syndrome; Mitochondrial Diseases; DNA, Mitochondrial; Retina; Retinal Diseases; Chromatin
PubMed: 37289546
DOI: 10.1172/jci.insight.165937 -
Biomolecules Nov 2021Neuromuscular diseases (NMDs) are dysfunctions that involve skeletal muscle and cause incorrect communication between the nerves and muscles. The specific causes of NMDs... (Review)
Review
Neuromuscular diseases (NMDs) are dysfunctions that involve skeletal muscle and cause incorrect communication between the nerves and muscles. The specific causes of NMDs are not well known, but most of them are caused by genetic mutations. NMDs are generally progressive and entail muscle weakness and fatigue. Muscular impairments can differ in onset, severity, prognosis, and phenotype. A multitude of possible injury sites can make diagnosis of NMDs difficult. Mitochondria are crucial for cellular homeostasis and are involved in various metabolic pathways; for this reason, their dysfunction can lead to the development of different pathologies, including NMDs. Most NMDs due to mitochondrial dysfunction have been associated with mutations of genes involved in mitochondrial biogenesis and metabolism. This review is focused on some mitochondrial routes such as the TCA cycle, OXPHOS, and β-oxidation, recently found to be altered in NMDs. Particular attention is given to the alterations found in some genes encoding mitochondrial carriers, proteins of the inner mitochondrial membrane able to exchange metabolites between mitochondria and the cytosol. Briefly, we discuss possible strategies used to diagnose NMDs and therapies able to promote patient outcome.
Topics: Animals; Electron Transport; Humans; Mitochondrial Proteins; Models, Biological; Mutation; Neuromuscular Diseases; Phenotype
PubMed: 34827632
DOI: 10.3390/biom11111633 -
Seizure Jan 2023
Topics: Humans; MELAS Syndrome; Epilepsy; Brain; Stroke
PubMed: 36642493
DOI: 10.1016/j.seizure.2022.09.012 -
Journal of Molecular Medicine (Berlin,... Oct 2020Mitochondrial diseases are highly heterogeneous metabolic disorders caused by genetic alterations in the mitochondrial DNA (mtDNA) or in the nuclear genome. In this...
Mitochondrial diseases are highly heterogeneous metabolic disorders caused by genetic alterations in the mitochondrial DNA (mtDNA) or in the nuclear genome. In this study, we investigated a panel of blood biomarkers in a cohort of 123 mitochondrial patients, with prominent neurological and muscular manifestations. These biomarkers included creatine, fibroblast growth factor 21 (FGF21) and growth/differentiation factor 15 (GDF-15), and the novel cell free circulating-mtDNA (ccf-mtDNA). All biomarkers were significantly increased in the patient group. After stratification by the specific phenotypes, ccf-mtDNA was significantly increased in the Mitochondrial Encephalomyopathy Lactic Acidosis Stroke-like episodes syndrome (MELAS) group, and FGF21 and GDF-15 were significantly elevated in patients with MELAS and Myoclonic Epilepsy Ragged Red Fibers syndrome. On the contrary, in our cohort, creatine was not associated to a specific clinical phenotype. Longitudinal assessment in four MELAS patients showed increased levels of ccf-mtDNA in relation to acute events (stroke-like episodes/status epilepticus) or progression of neurodegeneration. Our results confirm the association of FGF21 and GDF-15 with mitochondrial translation defects due to tRNA mutations. Most notably, the novel ccf-mtDNA was strongly associated with MELAS and may be used for monitoring the disease course or to evaluate the efficacy of therapies, especially in the acute phase. KEY MESSAGES: • FGF21/GDF15 efficiently identifies mitochondrial diseases due to mutations in tRNA genes. • The novel ccf-mtDNA is associated with MELAS and increases during acute events. • Creatine only discriminates severe mitochondrial patients. • FGF21, GDF-15, and ccf-mtDNA are possibly useful for monitoring therapy efficacy.
Topics: Adult; Animals; Biomarkers; Cell-Free Nucleic Acids; DNA, Mitochondrial; Disease Susceptibility; Female; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Mitochondria; Mitochondrial Diseases; Mutation; Phenotype; ROC Curve; Young Adult
PubMed: 32851462
DOI: 10.1007/s00109-020-01967-y -
Journal of the American College of... Oct 2022The heart is commonly involved in maternally inherited mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome caused by the...
BACKGROUND
The heart is commonly involved in maternally inherited mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome caused by the MT-TL1 m.3243A>G mutation of the mitochondrial DNA. Heart transplantation (HTx) is controversial and has rarely been performed with conflicting results.
OBJECTIVES
We analyzed factors preventing HTx in consecutive adult patients with MELAS cardiomyopathy diagnosed and followed during the last 23 years in our HTx referral center.
METHODS
The series consists of 14 unrelated adult probands who were referred for evaluation of cardiomyopathy from 1998 to 2021. None had a suspected diagnosis of MELAS before referral. All patients underwent clinical and genetic visit and counseling, mitochondrial DNA sequencing, cardiovascular investigation (including right heart catheterization and endomyocardial biopsy in 10), multidisciplinary assessment, and biochemical tests. Family screening identified 2 affected relatives.
RESULTS
The cardiac phenotype was characterized by hypertrophic, concentric, nonobstructive cardiomyopathy that often evolved into a dilated cardiomyopathy-like phenotype. Of the 14 probands, 7 were potential candidates for HTx, 2 for heart and kidney Tx, and 1 was on the active HTx list for 3 years. None of the 10 probands underwent HTx. One is currently being evaluated for HTx. All had diabetes, hearing loss, and myopathy, and 10 had chronic kidney disease and progressive encephalomyopathy. During follow-up, 10 died from heart failure associated with multiorgan failure within 5 years of the genetic diagnosis.
CONCLUSIONS
High risk of stroke-like episodes, chronic kidney disease, and wasting myopathy in MELAS patients prevents activation of plans for HTx. As a result, the management of their cardiomyopathy in this syndromic context remains an unmet clinical need.
Topics: Cardiomyopathies; DNA, Mitochondrial; Heart Transplantation; Humans; MELAS Syndrome; Muscular Diseases; Mutation; Renal Insufficiency, Chronic
PubMed: 36202533
DOI: 10.1016/j.jacc.2022.04.067 -
Frontiers in Neurology 2022Mitochondrial myopathy encephalopathy lactic acidosis and stroke-like episodes (MELAS) is an important cause of stroke-mimicking diseases that predominantly affect... (Review)
Review
Mitochondrial myopathy encephalopathy lactic acidosis and stroke-like episodes (MELAS) is an important cause of stroke-mimicking diseases that predominantly affect patients before 40 years of age. MELAS results from gene mutations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) responsible for the wide spectrum of clinical symptoms and imaging findings. Neurological manifestations can present with stroke-like episodes (the cardinal features of MELAS), epilepsy, cognitive and mental disorders, or recurrent headaches. Magnetic resonance imaging (MRI) is an important tool for detecting stroke-like lesions, accurate recognition of imaging findings is important in guiding clinical decision making in MELAS patients. With the development of neuroimaging technologies, MRI plays an increasingly important role in course monitoring and efficacy assessment of the disease. In this article, we provide an overview of the neuroimaging features and the application of novel MRI techniques in MELAS syndrome.
PubMed: 35222261
DOI: 10.3389/fneur.2022.843386 -
Orphanet Journal of Rare Diseases Oct 2023Mitochondrial Diseases (MDs) are a diverse group of neurometabolic disorders characterized by impaired mitochondrial oxidative phosphorylation and caused by pathogenic...
BACKGROUND
Mitochondrial Diseases (MDs) are a diverse group of neurometabolic disorders characterized by impaired mitochondrial oxidative phosphorylation and caused by pathogenic variants in more than 400 genes. The implementation of next-generation sequencing (NGS) technologies helps to increase the understanding of molecular basis and diagnostic yield of these conditions. The purpose of the study was to investigate diagnostic and genotypic spectrum in patients with suspected MD. The comprehensive analysis of mtDNA variants using Sanger sequencing was performed in the group of 83 unrelated individuals with clinically suspected mitochondrial disease. Additionally, targeted next generation sequencing or whole exome sequencing (WES) was performed for 30 patients of the study group.
RESULTS
The overall diagnostic rate was 21.7% for the patients with suspected MD, increasing to 36.7% in the group of patients where NGS methods were applied. Mitochondrial disease was confirmed in 11 patients (13.3%), including few classical mitochondrial syndromes (MELAS, MERRF, Leigh and Kearns-Sayre syndrome) caused by pathogenic mtDNA variants (8.4%) and MDs caused by pathogenic variants in five nDNA genes. Other neuromuscular diseases caused by pathogenic variants in seven nDNA genes, were confirmed in seven patients (23.3%).
CONCLUSION
The wide spectrum of identified rare mitochondrial or neurodevelopmental diseases proves that MD suspected patients would mostly benefit from an extensive genetic profiling allowing rapid diagnostics and improving the care of these patients.
Topics: Humans; Mutation; Mitochondrial Diseases; DNA, Mitochondrial; Mitochondria; Genotype
PubMed: 37784170
DOI: 10.1186/s13023-023-02921-0 -
Journal of Neurology Jun 2022Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a genetically heterogeneous disorder caused by mitochondrial DNA (mtDNA)... (Observational Study)
Observational Study
BACKGROUND
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a genetically heterogeneous disorder caused by mitochondrial DNA (mtDNA) mutations in the MT-TL1 gene. The pathophysiology of neurological manifestations is still unclear, but neuronal hyperexcitability and neuron-astrocyte uncoupling have been suggested. Glutamatergic neurotransmission is linked to glucose oxidation and mitochondrial metabolism in astrocytes and neurons. Given the relevance of neuron-astrocyte metabolic coupling and astrocyte function regulating energetic metabolism, we aimed to assess glutamate and glutamine CSF levels in MELAS patients.
METHODS
This prospective observational case-control study determined glutamate and glutamine CSF levels in patients with MELAS syndrome and compared them with controls. The plasma and CSF levels of the remaining amino acids and lactate were also determined.
RESULTS
Nine adult patients with MELAS syndrome (66.7% females mean age 35.8 ± 3.2 years) and 19 controls (63.2% females mean age 42.7 ± 3.8 years) were included. The CSF glutamate levels were significantly higher in patients with MELAS than in controls (18.48 ± 1.34 vs. 5.31 ± 1.09 μmol/L, p < 0.001). Significantly lower glutamine concentrations in patients with MELAS than controls were shown in CSF (336.31 ± 12.92 vs. 407.06 ± 15.74 μmol/L, p = 0.017). Moreover, the CSF levels of alanine, the branched-chain amino acids (BCAAs) and lactate were significantly higher in patients with MELAS.
CONCLUSIONS
Our results suggest the glutamate-glutamine cycle is altered probably due to metabolic imbalance, and as a result, the lactate-alanine and BCAA-glutamate cycles are upregulated. These findings might have therapeutic implications in MELAS syndrome.
Topics: Adult; Alanine; Case-Control Studies; DNA, Mitochondrial; Female; Glutamic Acid; Glutamine; Humans; Lactic Acid; MELAS Syndrome; Male; Middle Aged; Stroke
PubMed: 35088140
DOI: 10.1007/s00415-021-10942-7