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Biochimica Et Biophysica Acta.... May 2019Mitochondrial diseases are a group of rare heterogeneous genetic disorders caused by total or partial mitochondrial dysfunction. They can be caused by mutations in...
Mitochondrial diseases are a group of rare heterogeneous genetic disorders caused by total or partial mitochondrial dysfunction. They can be caused by mutations in nuclear or mitochondrial DNA (mtDNA). MERRF (Myoclonic Epilepsy with Ragged-Red Fibers) syndrome is one of the most common mitochondrial disorders caused by point mutations in mtDNA. It is mainly caused by the m.8344A > G mutation in the tRNA (UUR) gene of mtDNA (MT-TK gene). This mutation affects the translation of mtDNA encoded proteins; therefore, the assembly of the electron transport chain (ETC) complexes is disrupted, leading to a reduced mitochondrial respiratory function. However, the molecular pathogenesis of MERRF syndrome remains poorly understood due to the lack of appropriate cell models, particularly in those cell types most affected in the disease such as neurons. Patient-specific induced neurons (iNs) are originated from dermal fibroblasts derived from different individuals carrying the particular mutation causing the disease. Therefore, patient-specific iNs can be used as an excellent cell model to elucidate the mechanisms underlying MERRF syndrome. Here we present for the first time the generation of iNs from MERRF dermal fibroblasts by direct reprograming, as well as a series of pathophysiological characterizations which can be used for testing the impact of a specific mtDNA mutation on neurons and screening for drugs that can correct the phenotype.
Topics: Adult; Cellular Reprogramming; Cellular Reprogramming Techniques; DNA, Mitochondrial; Dermis; Fibroblasts; Humans; MERRF Syndrome; Male; Middle Aged; Neurons; Point Mutation
PubMed: 30797798
DOI: 10.1016/j.bbamcr.2019.02.010 -
Neurology. Genetics Aug 2019Our goal was to perform a systematic review of the literature to demonstrate the prevalence of cardiac abnormalities identified using cardiac investigations in patients...
OBJECTIVE
Our goal was to perform a systematic review of the literature to demonstrate the prevalence of cardiac abnormalities identified using cardiac investigations in patients with mitochondrial myopathy (MM).
METHODS
This systematic review surveys the available evidence for cardiac investigations in MM from a total of 21 studies including 825 participants. Data were stratified by genetic mutation and clinical syndrome.
RESULTS
We identified echocardiogram and ECG as the principal screening modalities that identify cardiac structural (29%) and conduction abnormalities (39%) in various MM syndromes. ECG abnormalities were more prevalent in patients with m.3243A>G mutations than other gene defects, and patients with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) had a higher prevalence of ECG abnormalities than patients with other clinical syndromes. Echocardiogram abnormalities were significantly more prevalent in patients with m.3243A>G or m.8344A>G mutations compared with other genetic mutations. Similarly, MELAS and MERRF had a higher prevalence compared with other syndromes. We observed a descriptive finding of an increased prevalence of ECG abnormalities in pediatric patients compared with adults.
CONCLUSIONS
This analysis supports the presence of a more severe cardiac phenotype in MELAS and myoclonic epilepsy with ragged red fibres syndromes and with their commonly associated genetic mutations (m.3243A>G and m.8344A>G). This provides the first evidence basis on which to provide more intensive cardiac screening for patients with certain clinical syndromes and genetic mutations. However, the data are based on a small number of studies. We recommend further studies of natural history, therapeutic response, pediatric participants, and cardiac MRI as areas for future investigation.
PubMed: 31403078
DOI: 10.1212/NXG.0000000000000339 -
Journal of Neurology Nov 2020The mitochondrial tRNA (mt-tRNA) mutation is initially associated with myoclonic epilepsy and ragged-red fibers (MERRF). The clinical, laboratory, morphologic and...
The mitochondrial tRNA (mt-tRNA) mutation is initially associated with myoclonic epilepsy and ragged-red fibers (MERRF). The clinical, laboratory, morphologic and molecular findings from 22 mt-tRNA mutation carriers from local database in East China were analyzed retrospectively. We identified 13 symptomatic and 9 asymptomatic individuals with a known pathogenic mitochondrial tRNA mutation. The most common mutations were m.8344 A>G (81.8%), m.8363G>A (9.1%), m.8356 T>C (4.5%) and m.8356 T>G (4.5%). The degree of mutation heteroplasmy in blood was high both in symptomatic (mean 64.5%, range 41-82%) and asymptomatic individuals (mean 53.1%, range 21-78%). Age at onset ranged from 6 year-old to the age of 66 years (mean 35.8 ± 16.4 years old). The most frequent symptoms were muscle weakness (76.9%), exercise intolerance (76.9%), elevated creatine kinase levels (61.5%), peripheral neuropathy (69.2%) and cerebellar ataxia (61.5%), while myoclonus was only present in 23.1% of symptomatic patients. A diagnosis of mitochondrial myopathy (MM) and neuropathy ataxia and retinitis pigmentosa (NARP/NARP-like) syndrome was made in 77% of symptomatic patients, whereas the classic syndrome of myoclonic epilepsy with ragged-red fibers (MERRF) was rare (23%). In this cohort of patients with mt-tRNA mutation, more than one third of our patients did not develop signs and symptoms of central nervous system involvement even in later stages of the disease, indicating the necessity to investigate the mt-tRNA gene in 'pure' mitochondrial 'myo-neuropathy'.
Topics: Child; China; DNA, Mitochondrial; Humans; Lysine; MERRF Syndrome; Mutation; Peripheral Nervous System Diseases; RNA, Transfer; RNA, Transfer, Lys; Retrospective Studies
PubMed: 32577866
DOI: 10.1007/s00415-020-10017-z -
Annals of Neurology Mar 2021
Topics: Aged; Ataxia; DNA, Mitochondrial; Genetic Testing; Humans; Lipomatosis; MERRF Syndrome; Magnetic Resonance Imaging; Male; Myoclonus; Neck
PubMed: 33341990
DOI: 10.1002/ana.25992 -
Life (Basel, Switzerland) Feb 2023Mitochondrial tRNA is considered a hot-spot for non-syndromic and aminoglycoside-induced hearing loss. However, many patients have been described with more extensive... (Review)
Review
Mitochondrial tRNA is considered a hot-spot for non-syndromic and aminoglycoside-induced hearing loss. However, many patients have been described with more extensive neurological diseases, mainly including epilepsy, myoclonus, ataxia, and myopathy. We describe a novel homoplasmic m.7484A>G mutation in the tRNA gene affecting the third base of the anticodon triplet in a girl with profound intellectual disability, spastic tetraplegia, sensorineural hearing loss, a clinical history of epilepsia partialis continua and vomiting, typical of MELAS syndrome, leading to a myoclonic epilepticus status, and myopathy with severe COX deficiency at muscle biopsy. The mutation was also found in the homoplasmic condition in the mother who presented with mild cognitive deficit, cerebellar ataxia, myoclonic epilepsy, sensorineural hearing loss and myopathy with COX deficient ragged-red fibers consistent with MERRF syndrome. This is the first anticodon mutation in the tRNA and the second homoplasmic mutation in the anticodon triplet reported to date.
PubMed: 36836911
DOI: 10.3390/life13020554 -
Scientific Reports Mar 2016Myoclonus epilepsy associated with ragged-red fibers (MERRF) is a mitochondrial disorder characterized by myoclonus epilepsy, generalized seizures, ataxia and myopathy....
Myoclonus epilepsy associated with ragged-red fibers (MERRF) is a mitochondrial disorder characterized by myoclonus epilepsy, generalized seizures, ataxia and myopathy. MERRF syndrome is primarily due to an A to G mutation at mtDNA 8344 that disrupts the mitochondrial gene for tRNA(Lys). However, the detailed mechanism by which this tRNA(Lys) mutation causes mitochondrial dysfunction in cardiomyocytes or neurons remains unclear. In this study, we generated human induced pluripotent stem cells (hiPSCs) that carry the A8344G genetic mutation from patients with MERRF syndrome. Compared with mutation-free isogenic hiPSCs, MERRF-specific hiPSCs (MERRF-hiPSCs) exhibited reduced oxygen consumption, elevated reactive oxygen species (ROS) production, reduced growth, and fragmented mitochondrial morphology. We sought to investigate the induction ability and mitochondrial function of cardiomyocyte-like cells differentiated from MERRF-hiPSCs. Our data demonstrate that that cardiomyocyte-like cells (MERRF-CMs) or neural progenitor cells (MERRF-NPCs) differentiated from MERRF-iPSCs also exhibited increased ROS levels and altered antioxidant gene expression. Furthermore, MERRF-CMs or -NPCs contained fragmented mitochondria, as evidenced by MitoTracker Red staining and transmission electron microscopy. Taken together, these findings showed that MERRF-hiPSCs and MERRF-CM or -NPC harboring the A8344G genetic mutation displayed contained mitochondria with an abnormal ultrastructure, produced increased ROS levels, and expressed upregulated antioxidant genes.
Topics: Adolescent; Cell Dedifferentiation; Cell Differentiation; Cells, Cultured; DNA, Mitochondrial; Female; Humans; Induced Pluripotent Stem Cells; MERRF Syndrome; Mitochondria, Heart; Myocytes, Cardiac; Organelle Shape; Oxygen Consumption; Point Mutation; Reactive Oxygen Species
PubMed: 27025901
DOI: 10.1038/srep23661 -
Journal of Inherited Metabolic Disease May 2020The prevalence of arterial hypertension in mitochondrial diseases remains unknown. Between January 2000 and May 2014, we retrospectively included patients with...
The prevalence of arterial hypertension in mitochondrial diseases remains unknown. Between January 2000 and May 2014, we retrospectively included patients with genetically proven mitochondrial diseases. We recorded clinical, genetic and cardiac exploration data, including the measure of arterial pressure. Among the 260 patients included in the study (mean age = 44 ± 15 years, women = 158), 108 (41.5%) presented with arterial hypertension. The prevalence of hypertension by sex and age was higher than that observed in the general population for all groups. The prevalence of hypertension was significantly higher in patients with MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) mutations (66%) and MERRF (myoclonus, epilepsy, ataxia with ragged ref fibres) mutations (61%). In patients with MELAS mutation, the presence of hypertension was significantly associated with age and mutation rate in the blood (odds ratio = 1.12; P = .02) in multivariate analysis. The prevalence of hypertension was more important in patients having a mitochondrial disease. The increased risk was more important in patient with MELAS or MERRF and depended on the rate of heteroplasmy.
Topics: Adult; DNA, Mitochondrial; Female; France; Humans; Hypertension; Logistic Models; MELAS Syndrome; MERRF Syndrome; Male; Middle Aged; Mutation; Prevalence; Retrospective Studies
PubMed: 31762033
DOI: 10.1002/jimd.12195 -
European Annals of Otorhinolaryngology,... Apr 2019Patients with MERRF syndrome (Myoclonic Epilepsy with Ragged Red Fibres) usually present with encephalomyopathy. However, progressive, recurrent cervicothoracic...
INTRODUCTION
Patients with MERRF syndrome (Myoclonic Epilepsy with Ragged Red Fibres) usually present with encephalomyopathy. However, progressive, recurrent cervicothoracic lipomatosis may be rarely observed.
CASE REPORT
The authors report 4 cases of MERRF syndrome associated with lipomatosis. In 3 patients, the diagnosis of MERRF syndrome was established on the basis of the clinical features of the lipomas and clinical interview revealing a personal or family history of lipomas and myopathy.
DISCUSSION
In the presence of extensive spinal lipomatosis, the presence of other clinical signs of MERRF syndrome in the patient or the patient's family must be investigated. A diagnosis of MERRF syndrome can guide appropriate genetic counselling.
Topics: Adult; Female; Humans; Lipomatosis; MERRF Syndrome; Male; Middle Aged; Neck; Siblings; Spinal Neoplasms; Thorax
PubMed: 30409749
DOI: 10.1016/j.anorl.2018.10.015 -
Cerebellum & Ataxias 2020Despite the broad development of next-generation sequencing approaches recently, such as whole-exome sequencing, diagnostic workup of adult-onset progressive cerebellar...
BACKGROUND
Despite the broad development of next-generation sequencing approaches recently, such as whole-exome sequencing, diagnostic workup of adult-onset progressive cerebellar ataxias without remarkable family history and with negative genetic panel testing for SCAs remains a complex and expensive clinical challenge.
CASE PRESENTATION
In this article, we report a Brazilian man with adult-onset slowly progressive pure cerebellar ataxia, which developed neuropathy and hearing loss after fifteen years of ataxia onset, in which a primary mitochondrial DNA defect (MERRF syndrome - myoclonus epilepsy with ragged-red fibers) was confirmed through muscle biopsy evaluation and whole-exome sequencing.
CONCLUSIONS
Mitochondrial disorders are a clinically and genetically complex and heterogenous group of metabolic diseases, resulting from pathogenic variants in the mitochondrial DNA or nuclear DNA. In our case, a correlation with histopathological changes identified on muscle biopsy helped to clarify the definitive diagnosis. Moreover, in neurodegenerative and neurogenetic disorders, some symptoms may be evinced later during disease course. We suggest that late-onset and adult pure undetermined ataxias should be considered and investigated for mitochondrial disorders, particularly MERRF syndrome and other primary mitochondrial DNA defects, together with other more commonly known nuclear genes.
PubMed: 32922825
DOI: 10.1186/s40673-020-00122-0 -
Molecular Genetics and Metabolism Jul 2022In patients with primary mitochondrial disease (MD), screening with electrocardiogram (ECG) and transthoracic echocardiography (TTE) is warranted according to current...
BACKGROUND
In patients with primary mitochondrial disease (MD), screening with electrocardiogram (ECG) and transthoracic echocardiography (TTE) is warranted according to current guidelines as structural cardiac abnormalities are frequent. This study aims to evaluate the cardiac phenotype of a large Dutch cohort of patients with MD and investigates whether ECG alone is sufficient for predicting structural cardiac abnormalities on TTE.
METHODS
In this retrospective cohort study, genetically confirmed MD patients >18 years old with an available ECG and TTE were included. Newcastle Mitochondrial Disease Scale for Adults (NMDAS) scores were assessed. ECG's were evaluated for rhythm and conduction disorders, voltage criteria for left ventricular hypertrophy (LVH) and repolarization disorders. Echocardiographic evaluation included left and right ventricular volumes and function, and presence of LVH or concentric remodeling.
RESULTS
In total, 200 MD patients were included with a median age of 45 years (IQR; 37-57) of whom 36% were male. Of all MD patients, 35% had abnormalities on ECG and 61% on TTE. Most frequent structural cardiac abnormalities on TTE were: global longitudinal strain > - 18% (54%), concentric remodeling (27%) and left ventricular (LV) ejection fraction <52% (14%). Patients with maternally inherited diabetes and deafness (MIDD) and mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) had the highest prevalence of ECG abnormalities (50% and 47%). TTE abnormalities were most prevalent in patients with MIDD (75%), followed by mitochondrial myopathy (MM) (55%), MELAS (47%) and Mitochondrial Epilepsy and Ragged Red Fibers (MERRF) (47%). MD patients with a high disease severity (NMDAS ≥21) had a higher prevalence of ECG abnormalities (44%, p = 0.039) and structural cardiac abnormalities (72%, p = 0.004) compared to patients with a NMDAS score of 11-20 and ≤ 10 (ECG: 34% and 19%; TTE: 63% and 39%). ECG abnormalities had a positive predictive value of 74% and a negative predictive value of 53% for structural cardiac abnormalities on TTE.
CONCLUSION
MD patients frequently have cardiac involvement especially patients with MIDD, MELAS or high NMDAS score. ECG as sole screening parameter is insufficient to detect structural cardiac abnormalities.
Topics: Deafness; Diabetes Mellitus, Type 2; Echocardiography; Electrocardiography; Female; Heart Defects, Congenital; Humans; Hypertrophy, Left Ventricular; MELAS Syndrome; Male; Mitochondrial Diseases; Prevalence; Retrospective Studies
PubMed: 35659503
DOI: 10.1016/j.ymgme.2022.05.004