MELAS Research Articles

LNC-ing Genetics in Mitochondrial Disease.

Primary mitochondrial disease (MD) is a group of rare genetic diseases reported to have a prevalence of 1:5000 and is currently without a cure. This group of diseases includes mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), maternally inherited diabetes and deafness (MIDD), Leber's hereditary optic neuropathy (LHON), Leigh syndrome (LS), Kearns-Sayre syndrome (KSS), and myoclonic epilepsy and ragged-red fiber disease (MERRF). Additionally, secondary mitochondrial dysfunction has been implicated in the most common current causes of mortality and morbidity, including cardiovascular disease (CVD) and cancer. Identifying key genetic contributors to both MD and secondary mitochondrial dysfunction may guide clinicians to assess the most effective treatment course and prognosis, as well as informing family members of any hereditary risk of disease transmission. Identifying underlying genetic causes of primary and secondary MD involves either genome sequencing (GS) or small targeted panel analysis of known disease-causing nuclear- or mitochondrial genes coding for mitochondria-related proteins. Due to advances in GS, the importance of long non-coding RNA (lncRNA) as functional contributors to the pathophysiology of MD is being unveiled. A limited number of studies have thus far reported the importance of lncRNAs in relation to MD causation and progression, and we are entering a new area of attention for clinical geneticists in specific rare malignancies. This commentary provides an overview of what is known about the role of lncRNAs as genetic and molecular contributors to disease pathophysiology and highlights an unmet need for a deeper understanding of mitochondrial dysfunction in serious human disease burdens.

Advancing cardiac 3D organoid-on-chip: integrating iPSC-derived MELAS syndrome models to study electromechanical synchronicity and cardiac memory using contactless technology

Abstract Background Mitochondrial DNA mutations affect 1:5000 newborns, posing life-threatening risks, especially to high-energy organs such as the brain, heart, and muscles. Mortality rates can reach 71% when cardiomyopathy is present. MELAS syndrome (Mitochondrial Encephalopathy with Lactic Acidosis and Stroke-like Episodes), primarily affecting protein synthesis (MTTL1 gene, tRNALeu(UUR)), disrupts the electron transport chain complex I and is associated with cardiac conduction defects and hypertrophy. Manifesting symptoms typically appear between ages 3 and adulthood, presenting a complex clinical scenario. Human induced pluripotent stem cells (hiPSCs) offer a unique platform for studying cardiac manifestations of this disease when differentiated into cardiomyocytes. Purpose We adopted a highly adaptable in-vitro model, organized in 3D cardioids, to explore potential impairments in electromechanical coupling of cells. Methods We utilized hiPSCs carrying the MELAS mutation and their respective isogenic controls differentiated into cardiomyocytes, cultured in 3D cardioids. Electromechanical coupling was assessed using laser-poration technology combined with video kinematics evaluation under various stimulation patterns. Results Morphological analysis revealed a statistically significant reduction in the diameter of MELAS cardioids compared to the isogenic 3D structures (368±17.15 μm vs. 527±36.76 μm). In a spontaneous regimen, MELAS samples exhibited higher beating frequency (0.88±0.28 Hz vs. 0.17±0.05 Hz) and contractile speed (99.35±39.11 μm/s vs. 33.46±5.57 μm/s). Additionally, the response to different electric field stimulation protocols varied significantly, with the isogenic cell line showing better adaptation to sinusoidal stimuli than the pathological one, characterized by rectangular monophasic stimuli. Laser-poration technology, combined with MEA chips and video kinematic evaluation, revealed modulation of electromechanical coupling, affecting action potential upstroke and duration, reducing contraction velocity, and altering electromechanical delay. Furthermore, MELAS hiPSCs and primary cardiomyocytes exhibited reduced protein levels of various OXPHOS subunits (SDHB, ATPB, and COX IV) compared to isogenic controls. The mutated cell line also showed increased ROS production in non-stimulated samples compared to stimulated ones (1.3-fold vs. 1.2-fold), with this difference magnifying after 24 hours from stimulation (1.8-fold vs. 1.3-fold). Conclusions This study characterizes MELAS hiPSCs differentiated into cardiac organoids, offering insight into the cardiac aspect of this complex syndrome. Our findings deepen understanding of the syndrome's cardiac impact and response to extracellular stimuli, potentially benefiting affected tissues. This research defines critical physiological and kinematic parameters for MELAS, paving the way for future investigations.

MELAS syndrome and risk of infection

Abstract This perspective explores the relationship between mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome and an increased risk of infections. Mitochondrial dysfunction impairs immune cell function, impacting the body’s defense against pathogens. Additional effects on the immune system may manifest through altered B-cell function and disruptions in the gut microbiota balance. The complex connection between infections, MELAS symptoms, and treatment complicates patient management. We propose greater focus on genetic abnormalities and their immunologic impacts, indicating a possible path for targeted pharmaceutical therapies to improve overall illness management.

Neurological manifestations in adult patients with the m.3243A>G variant in mitochondrial DNA

BackgroundThe m.3243A>G variant in mitochondrial DNA (mtDNA) is the most common cause of the MELAS (Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes) syndrome usually commencing in childhood or adolescence. In...

Primary pulmonary mucinous adenocarcinoma in a young adult with MELAS syndrome

Primary pulmonary mucinous adenocarcinoma in a young adult with MELAS syndrome

Clinical, imaging, and pathological characteristics of 35 cases of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome

Objective: To summarize the clinical, imaging, and pathological characteristics of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome (MELAS) to improve the diagnosis of this rare disease. Methods: A retrospective case series was conducted to collect the clinical data and results of genetic testing, muscle biopsy, and imaging studies including computed tomography (CT), magnetic resonance imaging (MRI), and magnetic resonance spectroscopy (MRS) of 35 patients with MELAS admitted to the Nanjing Drum Tower Hospital from 2012 to 2021. Descriptive statistical analysis including mean, standard deviation, and frequency percentage were carried out. Results: The average age of onset of the patients was 30.2±2.3 years; the prevalence of family history was 20%. The two main initial symptoms were limb weakness and convulsions. The clinical manifestations of the neuromuscular system were proximal muscle weakness and exercise intolerance. The endocrine system is the most affected outside the neuromuscular system, with diabetes being the most common condition. Among the five patients who underwent brain CT, four showed hypodense lesions and two had calcified lesions. Brain MRI in 26 patients showed that the lesions more often affected the parietal lobe, basal ganglia, temporal lobe, occipital lobe, and frontal lobe than the infratentorial areas. Twelve of these individuals exhibited different levels of brain atrophy. Among the 10 patients who underwent 1H-MRS, nine showed a decrease in N-acetylaspartate (NAA) levels, eight exhibited abnormal lactate elevation (Lac peaks), whereas six had both reduced NAA levels and the presence of Lac peaks. Thirty-one patients underwent genetic testing; among them, 25 were found to have the mt.3243A>G mutation, while the remaining six exhibited rare gene alterations. Muscle biopsies were performed in 21 patients, and 15 showed abnormal mitochondrial proliferation manifested by ragged red fibers and defective oxidative phosphorylation manifested by cytochrome C oxidase (COX) enzyme-deficient muscle fibers. Conclusion: The clinical manifestations of MELAS syndrome are variable and complex, and early atypical symptoms could be missed or misdiagnosed. A detailed clinical history, imaging MRS analysis, muscle biopsy, and genetic testing are necessary to confirm the accurate diagnosis of MELAS.

Adult-onset mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS): A case report and review of its conventional and diffusion- weighted MRI features

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a rare mitochondrial neurodegenerative disorder characterized by stroke-like episodes, seizure, and lactic acidosis. The diagnosis of MELAS is often challenging due to its variable phenotypic manifestations and rarity of this disease. In this article, we report the case of a 38-year-old woman who presented with repeated seizures and clinical stroke-like symptoms. She had no positive family history, and lactic acidosis was only present in her initial episode. Magnetic resonance imaging (MRI) of the brain was also normal in her first presentation. However, subsequent scans due to new clinical events showed migratory stroke-like lesions that were hyperintense on T2/fluid attenuated inversion recovery (FLAIR) sequence and had restricted diffusion. They did not conform to vascular territories but had a predilection for posterior temporal, occipital and parietal regions. The radiological findings prompted the suspicion of MELAS, which diagnosis was confirmed with genetic testing. Here, we also reviewed the MRI features of MELAS from literature, in particular the diffusion-weighted sequence findings, as debate still exists on whether the apparent diffusion coefficient (ADC) signal should be high or low in these lesions. Our case highlights the importance of recognizing key imaging features of this rare and highly heterogenous disease. In addition to helping with earlier diagnosis, these imaging findings also provide more insight into the underlying pathophysiology of MELAS.

MELAS syndrome: Insights into cardiac mechanics

MELAS syndrome: Insights into cardiac mechanics

Lysosomal dysfunction and overload of nucleosides in thymidine phosphorylase deficiency of MNGIE

Inherited deficiency of thymidine phosphorylase (TP), encoded by TYMP, leads to a rare disease with multiple mitochondrial DNA (mtDNA) abnormalities, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). However, the impact of TP deficiency on lysosomes remains unclear, which are important for mitochondrial quality control and nucleic acid metabolism. Muscle biopsy tissue and skin fibroblasts from MNGIE patients, patients with m.3243 A > G mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) and healthy controls (HC) were collected to perform mitochondrial and lysosomal functional analyses. In addition to mtDNA abnormalities, compared to controls distinctively reduced expression of LAMP1 and increased mitochondrial content were detected in the muscle tissue of MNGIE patients. Skin fibroblasts from MNGIE patients showed decreased expression of LAMP2, lowered lysosomal acidity, reduced enzyme activity and impaired protein degradation ability. TYMP knockout or TP inhibition in cells can also induce the similar lysosomal dysfunction. Using lysosome immunoprecipitation (Lyso- IP), increased mitochondrial proteins, decreased vesicular proteins and V-ATPase enzymes, and accumulation of various nucleosides were detected in lysosomes with TP deficiency. Treatment of cells with high concentrations of dThd and dUrd also triggers lysosomal dysfunction and disruption of mitochondrial homeostasis. Therefore, the results provided evidence that TP deficiency leads to nucleoside accumulation in lysosomes and lysosomal dysfunction, revealing the widespread disruption of organelles underlying MNGIE.Graphical

Arginine Supplementation in MELAS Syndrome: What Do We Know about the Mechanisms?

MELAS syndrome, characterized by mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes, represents a devastating mitochondrial disease, with the stroke-like episodes being its primary manifestation. Arginine supplementation has been used and recommended as a treatment for these acute attacks; however, insufficient evidence exists to support this treatment for MELAS. The mechanisms underlying the effect of arginine on MELAS pathophysiology remain unclear, although it is hypothesized that arginine could increase nitric oxide availability and, consequently, enhance blood supply to the brain. A more comprehensive understanding of these mechanisms is necessary to improve treatment strategies, such as dose and regimen adjustments; identify which patients could benefit the most; and establish potential markers for follow-up. This review aims to analyze the existing evidence concerning the mechanisms through which arginine supplementation impacts MELAS pathophysiology and provide the current scenario and perspectives for future investigations.

Metformin adverse event profile: a pharmacovigilance study based on the FDA Adverse Event Reporting System (FAERS) from 2004 to 2022

ABSTRACT Background Metformin has the potential for treating numerous diseases, but there are still many unrecognized and unreported adverse events (AEs). Methods We selected data from the United States FDA Adverse Event Reporting System (FAERS) database from the first quarter (Q1) of 2004 to the fourth quarter (Q4) of 2022 for disproportionality analysis to assess the association between metformin and related adverse events. Results In this study 10,500,295 case reports were collected from the FAERS database, of which 56,674 adverse events related to metformin were reported. A total of 643 preferred terms (PTs) and 27 system organ classes (SOCs) that were significant disproportionality conforming to the four algorithms simultaneously were included. The SOCs included metabolic and nutritional disorders (p = 0.00E + 00), gastrointestinal disorders (p = 0.00E + 00) and others. PT levels were screened for adverse drug reaction (ADR) signals such as acute pancreatitis (p = 0.00E + 00), melas syndrome, pemphigoid (p = 0.00E + 00), skin eruption (p = 0.00E + 00) and drug exposure during pregnancy (p = 0.00E + 00). Conclusion Most of our results were consistent with the specification, but some new signals of adverse reactions such as acute pancreatitis were not included. Therefore, further studies are needed to validate unlabeled adverse reactions and provide important support for clinical monitoring and risk identification of metformin.

Microbleeds within Mitochondrial Stroke-Like Lesion Rather Result from Their Vulnerability Than from Microangiopathy

MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and stroke-like episode) is one of the most common syndromic mitochondrial disorders (MID) and is due to the variant m.3243A>G in MT-TL1 in approximately 80% of cases. MELAS is a multisystem disorder with stroke-like episodes (SLEs) as a pathognomonic feature. The morphological correlate of SLEs in cerebral imaging are stroke-like lesions (SLLs). SLLs present on cerebral MRI with a T2, FLAIR, DWI, and PWI-hyperintense and OEF-hypointense lesion that is not confined to a vascular territory and extends to a nadir before disappearing or terminating as a structural lesion. Occasionally, these features are accompanied by microbleeds within the SLL, usually along the cortex. These microbleeds are thought to result from laminar cortical necrosis, and end-stage of a SLL or seizures, a common manifestation of SLEs.

A Case Report of MELAS Syndrome in a 7-year-old Girl Presented with Neurological Manifestations at Northwest General Hospital and Research Centre, Peshawar, Pakistan

A Case Report of MELAS Syndrome in a 7-year-old Girl Presented with Neurological Manifestations at Northwest General Hospital and Research Centre, Peshawar, Pakistan

Epilepsy and MELAS syndrome: literature review and clinical observation

MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) belongs to the group of mitochondrial diseases. Most MELAS syndrome cases are associated with the A3243G mutation in the MTTL1 gene. A common clinical manifestation of the syndrome is presented by epileptic seizures (ES) characterized by phenotypic polymorphism and resistance to antiepileptic therapy. Diagnosis and treatment of epilepsy in patients with MELAS syndrome often poses difficulties. We present a clinical case of adult patient with MELAS syndrome with identified A3243G mutation and epilepsy. The disease course developed to severe cognitive impairment. The first focal ES occurred during stroke-like episode. Further seizures were observed spontaneously, with high frequency, often manifested as a series. Focal ES often had blurred polymorphic manifestations. The choice of drug therapy took into account the side effects of antiepileptic drugs (AEDs) including potentially mitochondria-related negative effects. While diagnosing EP in MELAS syndrome, it should be considered that seizures often occur during stroke-like episodes and may have blurred polymorphic clinical manifestations. Cognitive impairment in patients complicates ES detection. First-line drugs should be presented by AEDs with low mitochondrial toxicity.

Renal manifestations in adults with mitochondrial disease from the mtDNA m.3243A>G pathogenic variant

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.

What was the cause of Friedrich Nietzsche's illness?

Background. Friedrich Nietzsche (1844-1900) is one of the most profound modern philosophers. Since childhood, Nietzsche suffered from severe headaches, and at the age of thirty he became blind in his right eye. At the age of 44, Nietzsche experienced a mental collapse, after which he became dependent on others. For a long time, it was thought that neurosyphilis was the diagnosis of Nietzsche's symptoms. However, latest studies suggest other hypotheses.Materials and methods. Nietzsche's letters to his friends, the memories of his family members and friends, and the medical records of his doctors were analysed. On the basis of primary sources, a retrospective medical history of Nietzsche is presented. Furthermore, in accordance with secondary articles on Nietzsche's illnesses, the main hypotheses have been provided along with their advantages and disadvantages.Results. The hypothesis of neurosyphilis becomes obsolete. New diagnoses have been proposed: frontotemporal dementia, intracranial mass, MELAS syndrome, and CADASIL.Conclusions. Despite a detailed analysis of Nietzsche's illnesses, the exact diagnosis remains unclear.

Wide diagnostic and genotypic spectrum in patients with suspected mitochondrial disease

BackgroundMitochondrial 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.ResultsThe 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%).ConclusionThe 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.

A rare cause of mixed hypertrophic and dilated phenotype cardiomyopathy – the MELAS syndrome

Abstract Introduction MELAS is a systemic hereditary condition that can present as hypertrophic or mixed hypertrophic and dilated phenotype cardiomyopathy in young individuals, although a late-onset form is also described in the literature. Genetic testing is essential for correct diagnosis and appropriate management. Case presentation We present the case of a 22-year-old male who was referred to our center after being diagnosed with NYHA class III heart failure with a mixed hypertrophic and dilated cardiomyopathy. His medical history included stroke episodes, seizures, progressive hypoacusis, neurocognitive impairment, and muscle atrophy. Lactic acidosis and elevated CK levels were also noted. The ECG revealed short PR interval and delta wave in lateral leads. TTE showed mildly dilated and hypertrophied LV and RV with severe biventricular systolic impairment. The CMR study was relevant for ring-like subepicardial fibrosis, predominantly in the medium and apical segments. Brain MRI showed multifocal supratentorial subcortical stroke-like lesions in both cerebral hemispheres, involving multiple vascular territories and following a migratory pattern. Genetic testing confirmed a pathogenic MT-TL1 mutation (m.324A>G) and the patient was diagnosed with MELAS. Further management included specific lifestyle recommendations and cascade genetic screening, as well as starting GDMT for HFrEF. Three months after discharge, his clinical status improved. However, the LVEF remained reduced. After careful consideration, an ICD was implanted for primary prevention. Conclusion A red-flag approach in this young patient, which took into consideration the stroke-like episodes, lactic acidosis, seizures, hypoacusis, myopathy, as well as the short PR interval, led to the correct diagnosis, further confirmed by using the appropriate genetic test. Failure to diagnose affects the patient’s prognosis, as their prognosis and clinical status are influenced by enforcing specific recommendations.

Negative correlation between organ heteroplasmy, particularly hepatic heteroplasmy, and age at death revealed by post-mortem studies of m.3243A > G cases

Mitochondrial DNA m.3243A > G mutation causes mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and its associated multi-organ disorders, including diabetes. To clarify associations between m.3243A > G organ heteroplasmy and clinical phenotypes, including the age at death, we combined genetic and pathological examinations from seven unreported and 36 literature cases of autopsied subjects. Clinical characteristics of subjects were as follows: male, 13; female, 28; unknown, 2; the age at death, 36.9 ± 20.2 [4–82] years; BMI, 16.0 ± 2.9 [13.0–22.3]; diabetes, N = 21 (49%), diabetes onset age 38.6 ± 14.2 years; deafness, N = 27 (63%); stroke-like episodes (StLEp), N = 25 (58%); congestive heart failure (CHF), N = 15 (35%); CHF onset age, 51.3 ± 14.5 years. Causes of death (N = 32) were as follows: cardiac, N = 13 (41%); infection, N = 8 (25%); StLEp, N = 4 (13%); gastrointestinal, N = 4 (13%); renal, N = 2 (6%); hepatic, N = 1 (2%). High and low heteroplasmies were confirmed in non-regenerative and regenerative organs, respectively. Heteroplasmy of the liver, spleen, leukocytes, and kidney for all subjects was significantly associated with the age at death. Furthermore, the age at death was related to juvenile-onset (any m.3243A > G-related symptoms appeared before 20) and stroke-like episodes. Multiple linear regression analysis with the age at death as an objective variable showed the significant contribution of liver heteroplasty and juvenile-onset to the age at death. m.3243A > G organ heteroplasmy levels, particularly hepatic heteroplasmy, are significantly associated with the age at death in deceased cases.

Mitochondrial dysfunction characterized in human induced pluripotent stem cell disease models in MELAS syndrome: A brief summary

Human induced pluripotent stem cells (hiPSCs) for MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes) may allow deeper understanding of how tissue-specific mitochondrial dysfunction result in multi-systemic disease. Here, we summarize how the m.3243G mtDNA mutation affects mitochondrial function in different tissues using iPSC and iPSC-differentiated cell type disease models and what significant findings have been replicated in the independent studies. Through this brief review and with a focus on mitochondrial dysfunction in iPSC-differentiated cell types, namely fibroblast, neuron, and retinal pigment epithelium cells, we aim to bring awareness of hiPSC as a robust mitochondrial disease model even if many unanswered questions remain.