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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 -
Case Reports in Neurological Medicine 2018Mitochondrial (mt) tRNA (MTT) gene mutations are an important cause of mitochondrial diseases and are associated with a wide range of clinical presentations. Most...
Mitochondrial (mt) tRNA (MTT) gene mutations are an important cause of mitochondrial diseases and are associated with a wide range of clinical presentations. Most mutations fall into three mitochondrial tRNAs (tRNAIle, tRNALeu (UUR), and tRNALys) and are responsible for half of the mitochondrial diseasees associated with tRNA mutation, with MERRF, MELAS, mitochondrial myopathy, and Leigh syndrome being the most frequent phenotypes. More than 100 tRNA pathogenetic mutations are described, showing little correlation between the observed clinical phenotype and a specific mitochondrial tRNA mutation. Furthermore different mutation can manifest with similar clinical phenotypes, making the genotype-phenotype correlation difficult. Here we report the case of an Italian 53-year-old woman presenting with a proximal myopathy and the m.5835G>A mutation in MT-TY gene coding for the mitochondrial tRNA Tyrosine gene.
PubMed: 30643656
DOI: 10.1155/2018/8406712 -
Journal of Cardiovascular Magnetic... May 2015Mitochondrial myopathies (MM) are a heterogeneous group of inherited conditions resulting from a primary defect in the mitochondrial respiratory chain with consecutively... (Comparative Study)
Comparative Study
Characteristic cardiac phenotypes are detected by cardiovascular magnetic resonance in patients with different clinical phenotypes and genotypes of mitochondrial myopathy.
BACKGROUND
Mitochondrial myopathies (MM) are a heterogeneous group of inherited conditions resulting from a primary defect in the mitochondrial respiratory chain with consecutively impaired cellular energy metabolism. Small sized studies using mainly electrocardiography (ECG) and echocardiography have revealed cardiac abnormalities ranging from conduction abnormalities and arrhythmias to hypertrophic or dilated cardiomyopathy in these patients. Recently, characteristic patterns of cardiac involvement were documented by cardiovascular magnetic resonance (CMR) in patients with chronic progressive external ophthalmoplegia (CPEO)/Kearns-Sayre syndrome (KSS) and with mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS). The present study aimed to characterize the prevalence and pattern of cardiac abnormalities and to test the additional diagnostic value of CMR in this patient population. The hypothesis that different neuromuscular MM syndromes present with different cardiac disease phenotypes was evaluated.
METHODS
Sixty-four MM patients (50 ± 15 years, 44% male) and 25 matched controls (52 ± 14 years, 36% male) prospectively underwent cardiac evaluations including CMR (comprising cine- and late-gadolinium-enhancement (LGE) imaging). Based on the neuromuscular phenotype and genotype, the patients were grouped: (a) CPEO/KSS (N = 33); (b) MELAS/-like (N = 11); c) myoclonic epilepsy with ragged-red fibers (MERRF) (N = 3) and d) other non-specific MM forms (N = 17).
RESULTS
Among the 64 MM patients, 34 (53%) had at least one abnormal CMR finding: 18 (28%) demonstrated an impaired left ventricular ejection-fraction (LV-EF <60%), 14 (22%) had unexplained LV hypertrophy and 21 (33%) were LGE-positive. Compared to controls, MM patients showed significantly higher maximal wall thickness (10 ± 3 vs. 8 ± 2 mm, p = 0.005) and concentricity (LV mass to end-diastolic volume: 0.84 ± 0.27 vs. 0.67 ± 0.11, p < 0.0001) with frequent presence of non-ischemic LGE (30% vs. 0%, p = 0.001). CPEO/KSS showed a predominantly intramural pattern of LGE mostly confined to the basal LV inferolateral wall (8/10; 80%) in addition to a tendency toward concentric remodelling. MELAS/-like patients showed the highest frequency of cardiac disease (in 10/11 (91%)), a mostly concentric LV hypertrophy (6/9; 67%) with or without LV systolic dysfunction and a predominantly focal, patchy LGE equally distributed among LV segments (8/11; 73%). Patients with MERRF and non-specific MM had no particular findings. Pathological CMR findings indicating cardiac involvement were detected significantly more often than pathological ECG results or elevated cardiac serum biomarkers (34 (53%) vs. 18 (28%) vs. 21 (33%); p = 0.008).
CONCLUSION
Cardiac involvement is a frequent finding in MM patients - and particularly present in KSS/CPEO as well as MELAS/-like patients. Despite a high variability in clinical presentation, CPEO/KSS patients typically show an intramural pattern of LGE in the basal inferolateral wall whereas MELAS patients are characterized by overt concentric hypertrophy and a rather unique, focally accentuated and diffusely distributed LGE.
Topics: Adult; Aged; Cardiomyopathies; Case-Control Studies; Female; Genetic Predisposition to Disease; Germany; Humans; Hypertrophy, Left Ventricular; Kearns-Sayre Syndrome; MELAS Syndrome; MERRF Syndrome; Magnetic Resonance Imaging; Male; Middle Aged; Mitochondrial Myopathies; Myocardium; Ophthalmoplegia, Chronic Progressive External; Phenotype; Predictive Value of Tests; Prevalence; Prospective Studies; Stroke Volume; Ventricular Function, Left; Ventricular Remodeling
PubMed: 26001801
DOI: 10.1186/s12968-015-0145-x -
Stem Cell Research Nov 2016Human iPSC line iMERRF-C7 was generated from PBMCs of a patient with mitochondrial disorder MERRF. Using Sendai virus, the reprogramming factors Oct3/4, Sox2, Klf4, and...
Human iPSC line iMERRF-C7 was generated from PBMCs of a patient with mitochondrial disorder MERRF. Using Sendai virus, the reprogramming factors Oct3/4, Sox2, Klf4, and cMyc were delivered non-integratively. The resulting iPSCs expressed pluripotency markers, could differentiate into the three germ layers in vivo, had normal genomic structure, and retained the disease-causing m.8344 mutation with similar heteroplasmic level.
Topics: Animals; Base Sequence; Cell Line; Cellular Reprogramming; Female; Genetic Loci; Genetic Vectors; Humans; Induced Pluripotent Stem Cells; Karyotype; Kruppel-Like Factor 4; Leukocytes, Mononuclear; MERRF Syndrome; Mice; Mice, Inbred NOD; Mice, SCID; Microscopy, Fluorescence; Polymorphism, Single Nucleotide; Sendai virus; Sequence Analysis, DNA; Teratoma; Transcription Factors
PubMed: 27934592
DOI: 10.1016/j.scr.2016.11.008 -
Kidney International Mar 2015We studied the extent and nature of renal involvement in a cohort of 117 adult patients with mitochondrial disease, by measuring urinary retinol-binding protein (RBP)...
We studied the extent and nature of renal involvement in a cohort of 117 adult patients with mitochondrial disease, by measuring urinary retinol-binding protein (RBP) and albumin; established markers of tubular and glomerular dysfunction, respectively. Seventy-five patients had the m.3243A>G mutation and the most frequent phenotypes within the entire cohort were 14 with MELAS, 33 with MIDD, and 17 with MERRF. Urinary RBP was increased in 29 of 75 of m.3243A>G patients, whereas albumin was increased in 23 of the 75. The corresponding numbers were 16 and 14, respectively, in the 42 non-m.3243A>G patients. RBP and albumin were higher in diabetic m.3243A>G patients than in nondiabetics, but there were no significant differences across the three major clinical phenotypes. The urine proteome (mass spectrometry) and metabonome (nuclear magnetic resonance) in a subset of the m.3243A>G patients were markedly different from controls, with the most significant alterations occurring in lysosomal proteins, calcium-binding proteins, and antioxidant defenses. Differences were also found between asymptomatic m.3243A>G carriers and controls. No patients had an elevated serum creatinine level, but 14% had hyponatremia, 10% had hypophosphatemia, and 14% had hypomagnesemia. Thus, abnormalities in kidney function are common in adults with mitochondrial disease, exist in the absence of elevated serum creatinine, and are not solely explained by diabetes.
Topics: Adolescent; Adult; Aged; Albuminuria; Antioxidants; Biomarkers; Calcium-Binding Proteins; Case-Control Studies; Creatinine; Cross-Sectional Studies; Deafness; Diabetes Mellitus, Type 2; Heterozygote; Humans; Hyponatremia; Hypophosphatemia; Kidney Diseases; MELAS Syndrome; MERRF Syndrome; Magnesium; Metabolome; Middle Aged; Mitochondrial Diseases; Mutation; Proteins; Proteome; RNA, Transfer; Retinol-Binding Proteins; Young Adult
PubMed: 25207879
DOI: 10.1038/ki.2014.297 -
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 -
Urology Case Reports Jan 2019
PubMed: 30364532
DOI: 10.1016/j.eucr.2018.10.006 -
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 -
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