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Chinese Medical Journal Oct 2018Treatment of myoclonic seizures in myoclonic epilepsy with ragged-red fibers (MERRFs) has been empirical and ineffective. Guideline on this disease is not available....
BACKGROUND
Treatment of myoclonic seizures in myoclonic epilepsy with ragged-red fibers (MERRFs) has been empirical and ineffective. Guideline on this disease is not available. Additional trials must be conducted to find more suitable treatments for it. In this study, the antimyoclonic effects of monotherapies, including levetiracetam (LEV), clonazepam (CZP), valproic acid (VPA), and topiramate (TPM) compared to combination therapy group with LEV and CZP on MERRF, were evaluated to find a more advantageous approach on the treatment of myoclonic seizures.
METHODS
Treatments of myoclonic seizures with VPA, LEV, CZP, and TPM were reported as monotherapies in 17 MERRF patients from Qilu Hospital between 2003 and 2016, who were diagnosed through clinical data and genetic testing. After 1-4 months of follow-up (mean: 82.9 ± 28.1 days), 12 patients that exhibited poor responses to monotherapy were given a combined treatment consisting of LEV and CZP subsequently. The follow-up period was 4-144 months (mean: 66.3 ± 45.3 months), the effective rates of monotherapy group (17 patients) and combination therapy group (12 patients) were analyzed by Chi-square test.
RESULTS
The m.8344 A>G mutation was detected in all patients. There were four patients with partial response (4/17, two in the CZP group and two in the LEV group), ten patients with stable disease (10/17, six in the CZP group, three in the LEV group, and one in the TPM group), and three patients with progressive disease (3/18, two in the VPA group and one in the TPM group). Twelve of the patients with LEV combined with CZP showed a positive effect and good tolerance (12/12), eight of them demonstrated improved cognition and coordination. There was a significant difference between the monotherapy group and combination therapy group in the efficacy of antimyoclonic seizures (χ = 13.7, P < 0.001).
CONCLUSIONS
LEV in combination with CZP is an efficient and safe treatment for myoclonic seizures in patients with this disease exhibiting the m.8344A>G mutation.
Topics: Adolescent; Adult; Chi-Square Distribution; Clonazepam; Epilepsies, Myoclonic; Female; Humans; Levetiracetam; MERRF Syndrome; Magnetic Resonance Imaging; Male; Mutation; Young Adult
PubMed: 30334528
DOI: 10.4103/0366-6999.243568 -
Revista de Neurologia Oct 2018
Topics: DNA, Mitochondrial; Humans; MERRF Syndrome; Mitochondria; Muscular Diseases; Mutation
PubMed: 30289158
DOI: No ID Found -
Frontiers in Neurology 2018We present the case of a 16-year-old boy with a family history of epilepsy who presented with acute respiratory failure, limb weakness, diabetes mellitus, sinus...
We present the case of a 16-year-old boy with a family history of epilepsy who presented with acute respiratory failure, limb weakness, diabetes mellitus, sinus tachycardia, lactic acidosis, and pneumonia. He went on to develop cranial nerve palsy, myoclonus, generalized seizures, ataxia, recurrent pneumonia, and hypotension. Biochemical investigation revealed elevated lactate, pyruvate, and glucose levels. Cerebral magnetic resonance imaging (MRI) revealed bilateral, symmetric, high-intensity T2-weighted signals in the thalamus, brainstem, and gray matter of the spinal cord. Histochemical analyses revealed ragged red fibers (RRF) and decreased cytochrome oxidase activity. Blood and muscle-derived DNA demonstrated a high level (95% and 96%, respectively) of the m.8344A>G mutation, while almost all of his maternal relatives ( = 17, including his mother) carried the same point mutation. The point mutation level of his mother (who had short stature, high blood lactate levels, and epilepsy) was 77% (blood-derived DNA). Although this mutation has been identified in approximately 30 individuals with these disorders, to our knowledge, this is the first reported case of overlapping Leigh syndrome/myoclonic epilepsy with RRF in an adolescent patient, and the largest reported pedigree of mitochondrial DNA A8344G mutation.
PubMed: 30271374
DOI: 10.3389/fneur.2018.00724 -
Nature Communications Sep 2018Post-transcriptional RNA modifications play a critical role in the pathogenesis of human mitochondrial disorders, but the mechanisms by which specific modifications...
Post-transcriptional RNA modifications play a critical role in the pathogenesis of human mitochondrial disorders, but the mechanisms by which specific modifications affect mitochondrial protein synthesis remain poorly understood. Here we used a quantitative RNA sequencing approach to investigate, at nucleotide resolution, the stoichiometry and methyl modifications of the entire mitochondrial tRNA pool, and establish the relevance to human disease. We discovered that a N-methyladenosine (mA) modification is missing at position 58 in the mitochondrial tRNA of patients with the mitochondrial DNA mutation m.8344 A > G associated with MERRF (myoclonus epilepsy, ragged-red fibers). By restoring the modification on the mitochondrial tRNA, we demonstrated the importance of the mA58 to translation elongation and the stability of selected nascent chains. Our data indicates regulation of post-transcriptional modifications on mitochondrial tRNAs is finely tuned for the control of mitochondrial gene expression. Collectively, our findings provide novel insight into the regulation of mitochondrial tRNAs and reveal greater complexity to the molecular pathogenesis of MERRF.
Topics: Base Sequence; HEK293 Cells; Humans; MERRF Syndrome; Mitochondria; Muscle, Skeletal; Myoblasts; Nucleic Acid Conformation; Protein Biosynthesis; RNA, Transfer, Lys
PubMed: 30262910
DOI: 10.1038/s41467-018-06471-z -
JAAD Case Reports Sep 2018
PubMed: 30238046
DOI: 10.1016/j.jdcr.2018.05.004 -
Molecules (Basel, Switzerland) Sep 2018Mitochondria are the energy-producing organelles of cells. Mitochondrial dysfunctions link to various syndromes and diseases including myoclonic epilepsy and ragged-red... (Review)
Review
Mitochondria are the energy-producing organelles of cells. Mitochondrial dysfunctions link to various syndromes and diseases including myoclonic epilepsy and ragged-red fiber disease (MERRF), Leigh syndrome (LS), and Leber hereditary optic neuropathy (LHON). Primary mitochondrial diseases often result from mutations of mitochondrial genomes and nuclear genes that encode the mitochondrial components. However, complete intracellular correction of the mutated genetic parts relevant to mitochondrial structures and functions is technically challenging. Instead, there have been diverse attempts to provide corrected genetic materials with cells. In this review, we discuss recent novel physical, chemical and biological strategies, and methods to introduce genetic cargos into mitochondria of eukaryotic cells. Effective mitochondria-targeting gene delivery systems can reverse multiple mitochondrial disorders by enabling cells to produce functional mitochondrial components.
Topics: Animals; Gene Transfer Techniques; Genetic Therapy; Humans; Mitochondrial Diseases; Molecular Targeted Therapy; Mutation
PubMed: 30208599
DOI: 10.3390/molecules23092316 -
EMBO Molecular Medicine Sep 2018Pathogenic mitochondrial DNA (mtDNA) mutations often co-exist with wild-type molecules (mtDNA heteroplasmy). Phenotypes manifest when the percentage of mutant mtDNA is...
Pathogenic mitochondrial DNA (mtDNA) mutations often co-exist with wild-type molecules (mtDNA heteroplasmy). Phenotypes manifest when the percentage of mutant mtDNA is high (70-90%). Previously, our laboratory showed that mitochondria-targeted transcription activator-like effector nucleases (mitoTALENs) can eliminate mutant mtDNA from heteroplasmic cells. However, mitoTALENs are dimeric and relatively large, making it difficult to package their coding genes into viral vectors, limiting their clinical application. The smaller monomeric GIY-YIG homing nuclease from T4 phage (I-TevI) provides a potential alternative. We tested whether molecular hybrids (mitoTev-TALEs) could specifically bind and cleave mtDNA of patient-derived cybrids harboring different levels of the m.8344A>G mtDNA point mutation, associated with myoclonic epilepsy with ragged-red fibers (MERRF). We tested two mitoTev-TALE designs, one of which robustly shifted the mtDNA ratio toward the wild type. When this mitoTev-TALE was tested in a clone with high levels of the MERRF mutation (91% mutant), the shift in heteroplasmy resulted in an improvement of oxidative phosphorylation function. mitoTev-TALE provides an effective architecture for mtDNA editing that could facilitate therapeutic delivery of mtDNA editing enzymes to affected tissues.
Topics: Cells, Cultured; DNA Repair; DNA, Mitochondrial; Endonucleases; Humans; Hydrolysis; MERRF Syndrome; Molecular Targeted Therapy; Protein Binding; Recombinant Proteins; Transcription Activator-Like Effector Nucleases; Viral Proteins
PubMed: 30012581
DOI: 10.15252/emmm.201708084 -
Internal Medicine (Tokyo, Japan) Dec 2018Myoclonus epilepsy associated with ragged-red fibers (MERRF) is traditionally characterized by myoclonus, generalized epilepsy and ragged-red fibers. We herein report a...
Myoclonus epilepsy associated with ragged-red fibers (MERRF) is traditionally characterized by myoclonus, generalized epilepsy and ragged-red fibers. We herein report a 42-year-old man who complained of falling after starting running, symptoms resembling those of paroxysmal kinesigenic dyskinesia. He showed only slight muscle weakness of the right quadriceps femoris. Muscle pathology and a genetic analysis identified him as having MERRF with a 8344A>G mtDNA mutation. We diagnosed his symptoms as having been caused by slight quadriceps femoris muscle weakness and exercise intolerance. This case suggests that mitochondrial myopathy should be considered in cases with strong muscle symptoms for muscle weakness.
Topics: Accidental Falls; Adult; DNA, Mitochondrial; Diagnosis, Differential; Dystonia; Exercise Tolerance; Genetic Testing; Humans; MERRF Syndrome; Male; Muscle Weakness; Muscle, Skeletal; Point Mutation; Running
PubMed: 29984755
DOI: 10.2169/internalmedicine.1210-18 -
Stem Cell Research Jul 2018MERRF syndrome is predominantly caused by A8344G mutation in the mitochondrial DNA (mtDNA), affecting MT-TK gene, which impairs the mitochondrial electron transport...
MERRF syndrome is predominantly caused by A8344G mutation in the mitochondrial DNA (mtDNA), affecting MT-TK gene, which impairs the mitochondrial electron transport chain function. Here, we report the generation of two isogenic induced pluripotent stem cell (iPSC) lines, TVGH-iPSC-MRF-M and TVGH-iPSC-MRF-M, from the skin fibroblasts of a female MERRF patient harboring mtDNA A8344G mutation by using retrovirus transduction system. Both cell lines share the same genetic background except containing different proportions of mtDNA with the A8344G mutation. Both cell lines exhibited the pluripotency and capacity to differentiate into three germ layers.
Topics: Adolescent; Animals; DNA, Mitochondrial; Female; Humans; Induced Pluripotent Stem Cells; MERRF Syndrome; Mice; Mutation
PubMed: 29960149
DOI: 10.1016/j.scr.2018.05.011 -
Chinese Medical Journal Jul 2018Myoclonic epilepsy with ragged red fibers (MERRF) syndrome is characterized by myoclonus, generalized epilepsy, cerebellar ataxia, and ragged red fibers (RRFs) in the...
BACKGROUND
Myoclonic epilepsy with ragged red fibers (MERRF) syndrome is characterized by myoclonus, generalized epilepsy, cerebellar ataxia, and ragged red fibers (RRFs) in the muscle. T-to-C transition at nucleotide position 14709 in the mitochondrial tRNA glutamic acid (tRNA) gene has previously been associated with maternally inherited diabetes and deafness. However, the association between MERRF and mitochondrial T14709C mutation (m.T14709C) has never been reported before.
METHODS
Clinical information of a 17-year-old patient was collected; muscle biopsy and next-generation sequencing (NGS) of whole mitochondrial and neuromuscular disease panel were then conducted. Finally, sanger sequencing was carried out to confirm the mutations.
RESULTS
The patient presented a typical MERRF phenotype with muscle weakness, epileptic seizure, clonic episodes, cerebellar ataxia, and spinal scoliosis. Muscle biopsy showed RRFs which indicated abnormal mitochondrial functions. NGS of whole mitochondrial gene revealed m.T14709C mutation, confirmed by Sanger sequencing.
CONCLUSION
We present a sporadic patient with typical MERRF presentation carrying the mutation of m.T14709C, which expanded the spectrum of m.T14709C.
Topics: Adolescent; DNA, Mitochondrial; Deafness; Humans; MERRF Syndrome; Male; Mutation
PubMed: 29941710
DOI: 10.4103/0366-6999.235120