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Molecular Medicine (Cambridge, Mass.) Aug 2022Myoclonus, Epilepsy and Ragged-Red-Fibers (MERRF) is a mitochondrial encephalomyopathy due to heteroplasmic mutations in mitochondrial DNA (mtDNA) most frequently...
BACKGROUND
Myoclonus, Epilepsy and Ragged-Red-Fibers (MERRF) is a mitochondrial encephalomyopathy due to heteroplasmic mutations in mitochondrial DNA (mtDNA) most frequently affecting the tRNA gene at position m.8344A > G. Defective tRNA severely impairs mitochondrial protein synthesis and respiratory chain when a high percentage of mutant heteroplasmy crosses the threshold for full-blown clinical phenotype. Therapy is currently limited to symptomatic management of myoclonic epilepsy, and supportive measures to counteract muscle weakness with co-factors/supplements.
METHODS
We tested two therapeutic strategies to rescue mitochondrial function in cybrids and fibroblasts carrying different loads of the m.8344A > G mutation. The first strategy was aimed at inducing mitochondrial biogenesis directly, over-expressing the master regulator PGC-1α, or indirectly, through the treatment with nicotinic acid, a NAD precursor. The second was aimed at stimulating the removal of damaged mitochondria through prolonged rapamycin treatment.
RESULTS
The first approach slightly increased mitochondrial protein expression and respiration in the wild type and intermediate-mutation load cells, but was ineffective in high-mutation load cell lines. This suggests that induction of mitochondrial biogenesis may not be sufficient to rescue mitochondrial dysfunction in MERRF cells with high-mutation load. The second approach, when administered chronically (4 weeks), induced a slight increase of mitochondrial respiration in fibroblasts with high-mutation load, and a significant improvement in fibroblasts with intermediate-mutation load, rescuing completely the bioenergetics defect. This effect was mediated by increased mitochondrial biogenesis, possibly related to the rapamycin-induced inhibition of the Mechanistic Target of Rapamycin Complex 1 (mTORC1) and the consequent activation of the Transcription Factor EB (TFEB).
CONCLUSIONS
Overall, our results point to rapamycin-based therapy as a promising therapeutic option for MERRF.
Topics: DNA, Mitochondrial; Humans; MERRF Syndrome; Mitochondria; Mitochondrial Proteins; Mutation; RNA, Transfer, Lys; Sirolimus
PubMed: 35922766
DOI: 10.1186/s10020-022-00519-z -
Child Neurology Open 2021In the field of mitochondrial medicine, correlation of clinical phenotype with mutation heteroplasmy remains an outstanding question with few, if any, clear thresholds...
In the field of mitochondrial medicine, correlation of clinical phenotype with mutation heteroplasmy remains an outstanding question with few, if any, clear thresholds corresponding to a given phenotype. The m.8344A>G mutation is most commonly associated with myoclonus epilepsy and ragged red fiber syndrome (MERRF) at varying levels of heteroplasmy. However, a handful of cases been previously reported in which individuals homoplasmic or nearly homoplasmic for this mutation in the blood have presented with multiple bulbar palsies, respiratory failure, and progressive neurologic decline almost uniformly following a respiratory illness. MRI brain in all affected individuals revealed symmetric T2 hyperintense lesions of subcortical gray matter structures, consistent with Leigh syndrome. Here, we present 3 cases with clinical, biochemical, and neuro-imaging findings with the additional reporting of spinal lesions. This new phenotype supports a heteroplasmy-dependent phenotype model for this mutation and recognition of this can help clinicians with diagnosis and anticipatory clinical guidance.
PubMed: 33718511
DOI: 10.1177/2329048X21991382 -
Pathology International Nov 2020
Topics: Adult; Aged; Autopsy; Fatal Outcome; Female; Genes, Mitochondrial; Humans; Immunohistochemistry; Islets of Langerhans; MELAS Syndrome; MERRF Syndrome; Male; Middle Aged; Point Mutation
PubMed: 32808720
DOI: 10.1111/pin.13008 -
The FEBS Journal Sep 2020Various pathogenic variants in both mitochondrial tRNA and Phenylalanyl-tRNA synthetase mitochondrial protein coding gene (FARS2) gene encoding for the human...
Various pathogenic variants in both mitochondrial tRNA and Phenylalanyl-tRNA synthetase mitochondrial protein coding gene (FARS2) gene encoding for the human mitochondrial PheRS have been identified and associated with neurological and/or muscle-related pathologies. An important Guanine-34 (G34)A anticodon mutation associated with myoclonic epilepsy with ragged red fibers (MERRF) syndrome has been reported in hmit-tRNA . The majority of G34 contacts in available aaRSs-tRNAs complexes specifically use that base as an important tRNA identity element. The network of intermolecular interactions providing its specific recognition also largely conserved. However, their conservation depends also on the invariance of the residues in the anticodon binding domain (ABD) of human mitochondrial Phenylalanyl-tRNA synthetase (hmit-PheRS). A defect in recognition of the anticodon of tRNA may happen not only because of G34A mutation, but also due to mutations in the ABD. Indeed, a pathogenic mutation in FARS2 has been recently reported in a 9-year-old female patient harboring a p.Asp364Gly mutation. Asp364 is hydrogen bonded (HB) to G34 in WT hmit-PheRS. Thus, there are two pathogenic variants disrupting HB between G34 and Asp364: one is associated with G34A mutation, and the other with Asp364Gly mutation. We have measured the rates of tRNA aminoacylation catalyzed by WT hmit-PheRS and mutant enzymes. These data ranked the residues making a HB with G34 according to their contribution to activity and the signal transduction pathway in the hmit-PheRS-tRNA complex. Furthermore, we carried out extensive MD simulations to reveal the interdomain contact topology on the dynamic trajectories of the complex, and gaining insight into the structural and dynamic integrity effects of hmit-PheRS complexed with tRNA . DATABASE: Structural data are available in PDB database under the accession number(s): 3CMQ, 3TUP, 5MGH, 5MGV.
Topics: Amino Acid Substitution; Anticodon; Aspartic Acid; Child; Consanguinity; DNA, Mitochondrial; Disease Progression; Female; Genetic Pleiotropy; Guanine; Humans; Hydrogen Bonding; MERRF Syndrome; Mitochondrial Proteins; Models, Molecular; Molecular Dynamics Simulation; Motion; Mutation, Missense; Paraparesis, Spastic; Phenotype; Phenylalanine-tRNA Ligase; Point Mutation; Protein Conformation; Protein Domains; RNA, Transfer, Phe
PubMed: 32115907
DOI: 10.1111/febs.15268 -
Neurology India 2020Neurological diseases can be due to direct diseases of the central nervous system (CNS) or peripheral nervous system (PNS) or be a bystander syndrome of systemic...
INTRODUCTION
Neurological diseases can be due to direct diseases of the central nervous system (CNS) or peripheral nervous system (PNS) or be a bystander syndrome of systemic diseases. Treatment options depend on the cause. Toxic, metabolic and nutritional, and immune-mediated consequences of clinically occult neoplasms produce a spectrum of neurological diseases, recognition of which has therapeutic and prognostic importance.
PATIENTS AND METHODS
Children, as well as adults who presented to the authors in the last 5 years with neurological diseases and later their diseases could be diagnosed or attributed to neoplasms which were occult, were included for the study.
OBSERVATION
28 patients were seen by the authors in the last 5 years with neurological manifestation and hidden tumor. Maximum incidence was in the age of above 60 years followed by the age group of 21-40 years. The commonest neurological presentation was muscle and nerve in adults and seizure in children.
DISCUSSION
Short duration, rapid progression, severe weight loss, and poor response to treatment given for nontumor associated neurological syndrome are the red flags which point to the diagnosis.
CONCLUSION
Seizures and psychosis formed the commonest features in children, muscle and nerve in adults. Short duration, rapid progression, and resistance to treatment are the markers for possible underlying neoplasm.
Topics: Adenoma; Adolescent; Adult; Anti-N-Methyl-D-Aspartate Receptor Encephalitis; Ataxia; Carcinoma; Child; Dementia; Diagnosis, Differential; Diagnostic Errors; Female; Ganglioneuroma; Humans; Hypokalemic Periodic Paralysis; Lipoma; Lymphoma, Non-Hodgkin; MERRF Syndrome; Male; Middle Aged; Myoclonic Epilepsy, Juvenile; Neoplasms; Nervous System Diseases; Neuroblastoma; Opsoclonus-Myoclonus Syndrome; Ovarian Neoplasms; POEMS Syndrome; Pancreatic Neoplasms; Paraneoplastic Syndromes, Nervous System; Parathyroid Neoplasms; Parkinsonian Disorders; Plasmacytoma; Polymyositis; Stomach Neoplasms; Subacute Combined Degeneration; Teratoma; Thymus Neoplasms; Young Adult
PubMed: 32415012
DOI: 10.4103/0028-3886.280647 -
Annales D'endocrinologie Jun 2020While the most frequent mutation responsible for mitochondrial diabetes is the point mutation m.3243 A>G of mitochondrial DNA (mtDNA), few data are available about the...
OBJECTIVE
While the most frequent mutation responsible for mitochondrial diabetes is the point mutation m.3243 A>G of mitochondrial DNA (mtDNA), few data are available about the role of rare mtDNA mutations in the pathophysiology of diabetes. The main objective of our study was to describe the phenotypic characteristics of patients suffering from diabetes linked to rare mtDNA mutations.
RESEARCH DESIGN AND METHODS
We performed a post-hoc analysis of a prospective multicenter cohort of 743 patients with mitochondrial disorder (previously published by the French Network of Mitochondrial Diseases), associated to a literature review of the PubMed database from 1992 to May 2016. We extracted all reported patients with diabetes and identified rare mtDNA mutations and described their clinical and metabolic phenotypes.
RESULTS
The 50 identified patients (10 from the princeps study; 40 from the review of the literature) showed a heterogeneous metabolic phenotype in terms of age, symptoms prior to diagnosis, treatments, and associated clinical and biological signs. However, neurological symptoms were more frequent in case of rare mtDNA mutations compared to the classical m.3243 A>G mutation (P=0.024). In contrast, deafness (65% vs. 95%, P=3.7E-5), macular pattern dystrophy (20% vs. 86%, P=1.6E-10) and nephropathy (8% vs. 28%, P=0.018) were significantly less frequent than in case of the classical m.3243 A>G mutation.
CONCLUSION
Although no specific metabolic phenotype could be identified suggesting or eliminating implication of rare mtDNA mutations in diabetes, clinical phenotypes featured more frequent neurological signs.
Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Cohort Studies; DNA Mutational Analysis; DNA, Mitochondrial; Deafness; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; France; Gene Frequency; Genetic Association Studies; Humans; Infant; Infant, Newborn; MERRF Syndrome; Male; Middle Aged; Mitochondrial Diseases; Mutation; Phenotype; Prospective Studies
PubMed: 32409007
DOI: 10.1016/j.ando.2020.04.007 -
Cureus Aug 2022A myoclonic epilepsy with ragged-red fibers (MERRF) patient who carried the m.8344A>G variant in the homoplasmic form manifested a milder phenotype than his sister who...
A myoclonic epilepsy with ragged-red fibers (MERRF) patient who carried the m.8344A>G variant in the homoplasmic form manifested a milder phenotype than his sister who carried the same variant in the heteroplasmic form, which has not yet been reported. The 27-year-old male, with an uneventful history, presented at age 19 with fatigue and persistent tremor in both hands. When he talked for a long time, his speech would slow down, and he would stutter. Although electroencephalography showed spike-wave complexes in both occipital projections with generalization, no anti-seizure drugs were given. At age 20, the patient suffered a fall due to muscle weakness. From age 21, generalized myocloni occurred. Because the sister had been diagnosed with MERRF-plus syndrome, the patient underwent genetic testing, which revealed the m.8344A>G variant in homoplasmy. L-carnitine was started. At age 27, the patient experienced a first "syncope" after a long walk, which subsequently recurred up to 2-3 times per day. EEG showed low-amplitude spikes, slow-spike waves at the posterior vertex, and generalized slow-spike waves. Clonazepam was recommended but declined by the patient. In conclusion, the m.8344A>G variant may manifest milder and with a later onset in the homoplasmic as compared to the heteroplasmic form. Further, the homoplasmy of the m.8344A>G variant appears to be more beneficial than harmful.
PubMed: 36176839
DOI: 10.7759/cureus.28490 -
Beijing Da Xue Xue Bao. Yi Xue Ban =... Oct 2020Mitochondrial deoxyribonucleic acid (mtDNA) 8344 A>G (m.8344A>G) mutation is the common mutation associated with mitochondrial myoclonus epilepsy with ragged-red fibers...
[Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes / myoclonus epilepsy with ragged-red fibers /Leigh overlap syndrome caused by mitochondrial DNA 8344A>G mutation].
OBJECTIVE
Mitochondrial deoxyribonucleic acid (mtDNA) 8344 A>G (m.8344A>G) mutation is the common mutation associated with mitochondrial myoclonus epilepsy with ragged-red fibers (MERRF) syndrome. Herein we report a rare case with mitochondrial encephalopathy, lactic acidosis and stroke-like episodes/MERRF/Leigh (MELAS/MERRF/Leigh) overlap syndrome caused by m.8344A>G mutation.
METHODS
The clinical and imaging data of the patient were collected and an open muscle biopsy was carried out. We further employed molecular genetic analyses to detect mtDNA mutation in the proband and his mother. And then a clinical and neuroimaging follow-up was performed.
RESULTS
This patient was a 25-year-old male, who developed exercise intolerance since the age of 6. At age 10, he suffered from acute episodes of hemianopia, and cranial magnetic resonance imaging (MRI) showed occipital stroke-like lesions and cranial magnetic resonance spectroscopy (MRS) revealed a lactate peak corresponding to the lesion. After that the patient presented slowly progressive psychomotor decline. He had myoclonic seizures and cerebellar ataxia since the age of 12. At age 21, he was admitted to our hospital because of confusion and cranial MRI revealed symmetrical lesions in bilateral posterior putamen, thalami and midbrain. Then repeated MRI showed progression of original lesions and new frontal multiple stroke-like lesions. Symptomatic and rehabilitation treatment relieved his condition. Follow-up cranial MRI at age 24 showed the lesions in basal ganglia and thalami diminished, and the midbrain lesions even completely vanished. Muscle pathology indicated the presence of numerous scattered ragged-red fibers (RRF), suggestive of a mitochondrial disorder. Polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP) detected the m.8344A>G mutation of the gene encoding mitochondrial transfer RNA for lysine in the patient's blood. Next generation sequencing (NGS) of the whole mitochondrial genome identified that the proportion of m.8344A>G was 90%, and no other mtDNA mutation was detected. Sanger sequencing further identified this mutation both in the proband and his mother's blood, although the mutation load was much lower in his mother's blood with approximately 10% heteroplasmy.
CONCLUSION
The present study is the first to describe a patient with m.8344A>G mutation in association with the MELAS/MERRF/Leigh overlap syndrome, which expands the phenotypic spectrum of the m.8344A>G mutation.
Topics: Acidosis, Lactic; Adult; Child; DNA, Mitochondrial; Humans; Male; Mitochondrial Encephalomyopathies; Mutation; Stroke; Young Adult
PubMed: 33047718
DOI: 10.19723/j.issn.1671-167X.2020.05.009 -
A&A Practice Feb 2021Myoclonic epilepsy with ragged red fibers (MERRF) syndrome is a rare mitochondrial disease potentially associated with increased sensitivity to anesthesia and metabolic...
Myoclonic epilepsy with ragged red fibers (MERRF) syndrome is a rare mitochondrial disease potentially associated with increased sensitivity to anesthesia and metabolic decompensation. We present the perioperative management in a 59-year-old man with MERRF scheduled for lipomatosis cure under general anesthesia (GA). Following a reduced fasting period, the patient had an uneventful balanced GA with propofol, sevoflurane, and rocuronium. The patient did not present metabolic decompensation nor malignant hyperthermia but prolonged neuromuscular blockade. Propofol and sevoflurane may be used in asymptomatic MERRF adult patients. Such patients present high risk of residual neuromuscular blockade that should be monitored and reversed.
Topics: Adult; Anesthesia, General; Humans; MERRF Syndrome; Male; Malignant Hyperthermia; Middle Aged; Mitochondrial Diseases; Sevoflurane
PubMed: 33577170
DOI: 10.1213/XAA.0000000000001401 -
A&A Practice Sep 2021
Topics: Documentation; Epilepsies, Myoclonic; Humans; MERRF Syndrome; Mutation
PubMed: 34529593
DOI: 10.1213/XAA.0000000000001525