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Beijing Da Xue Xue Bao. Yi Xue Ban =... Dec 2015To demonstrate the clinical manifestation, diagnosis and treatment of myoclonus epilepsy with ragged-red-fibers (MERRF), a case of MERRF was presented with review of the... (Review)
Review
To demonstrate the clinical manifestation, diagnosis and treatment of myoclonus epilepsy with ragged-red-fibers (MERRF), a case of MERRF was presented with review of the literature. A 4-year-7-month-old girl was diagnosed with MERRF. She had tremor, fatigue and developmental delay for more than 2 years. Laboratory tests showed that the serum and urine lactic acid and pyruvic acid increased significantly. Electroencephalogram showed diffuse and focal spike slow wave and slow wave in right central and parietal regions. Electromyogram showed neurological damage. Gene mutational analysis showed mtDNA 8344 A>G mutation. The mutational rate was 78%. Mitochondrial disease MERRF syndrome was diagnosed. Cocktails therapy with vitamins B1, B6, B12, L-carnitine, and coenzyme Q10 was administrated to the patient. MERRF is a rare disease. The diagnosis can be made by gene mutational analysis. Cocktail therapy may slow down the deterioration of the disease. Gene therapy is still experimental.
Topics: Child, Preschool; DNA, Mitochondrial; Electroencephalography; Electromyography; Female; Humans; MERRF Syndrome; Mutation
PubMed: 26679672
DOI: No ID Found -
Journal of Neurology Jul 2016
Topics: Adult; Electroencephalography; Electron Transport; Female; Follow-Up Studies; Humans; MERRF Syndrome; Male; Mutation; Retrospective Studies
PubMed: 27126455
DOI: 10.1007/s00415-016-8135-y -
Journal of Neurology May 2016The m.8344A>G mutation in the MTTK gene, which encodes the mitochondrial transfer RNA for lysine, is traditionally associated with myoclonic epilepsy and ragged-red...
The m.8344A>G mutation in the MTTK gene, which encodes the mitochondrial transfer RNA for lysine, is traditionally associated with myoclonic epilepsy and ragged-red fibres (MERRF), a multisystemic mitochondrial disease that is characterised by myoclonus, seizures, cerebellar ataxia, and mitochondrial myopathy with ragged-red fibres. We studied the clinical and paraclinical phenotype of 34 patients with the m.8344A>G mutation, mainly derived from the nationwide mitoREGISTER, the multicentric registry of the German network for mitochondrial disorders (mitoNET). Mean age at symptom onset was 24.5 years ±10.9 (6-48 years) with adult onset in 75 % of the patients. In our cohort, the canonical features seizures, myoclonus, cerebellar ataxia and ragged-red fibres that are traditionally associated with MERRF, occurred in only 61, 59, 70, and 63 % of the patients, respectively. In contrast, other features such as hearing impairment were even more frequently present (72 %). Other common features in our cohort were migraine (52 %), psychiatric disorders (54 %), respiratory dysfunction (45 %), gastrointestinal symptoms (38 %), dysarthria (36 %), and dysphagia (35 %). Brain MRI revealed cerebral and/or cerebellar atrophy in 43 % of our patients. There was no correlation between the heteroplasmy level in blood and age at onset or clinical phenotype. Our findings further broaden the clinical spectrum of the m.8344A>G mutation, document the large clinical variability between carriers of the same mutation, even within families and indicate an overlap of the phenotype with other mitochondrial DNA-associated syndromes.
Topics: Adolescent; Adult; Age of Onset; Aged; Brain; Cohort Studies; Female; Germany; Humans; MERRF Syndrome; Male; Middle Aged; Mutation; Pedigree; Phenotype; RNA; RNA, Mitochondrial; RNA, Transfer, Lys; Registries
PubMed: 26995359
DOI: 10.1007/s00415-016-8086-3 -
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 -
Headache Jan 2018Mitochondrial diseases are a heterogeneous group of diseases with different phenotypes and genotypes. Headache and, particularly migraine, seems to occur often in...
BACKGROUND
Mitochondrial diseases are a heterogeneous group of diseases with different phenotypes and genotypes. Headache and, particularly migraine, seems to occur often in patients with MELAS and in patients with CPEO phenotypes. The International Classification of Headache Disorders (ICHD-3 beta) has classified headache as a secondary entity only in MELAS patients. Other headache phenotypes in mitochondrial diseases are not considered in ICHD-3beta. In this study, we analyzed headache phenomenology in a large group of patients with mitochondrial disorders.
METHODS
A cross-sectional questionnaire-based study on 85 patients with mitochondrial disease with different genotypes and phenotypes was conducted between 2010 and 2011. A structured headache questionnaire according to ICHD-2 was used followed by a telephone interview by a headache expert. Prevalence and characteristics of headache could be analyzed in 42 patients. Headache diagnosis was correlated with genotypes and phenotypes. In addition, the mtDNA haplotype H was analyzed.
RESULTS
Headache was reported in 29/42 (70%; 95% CI, from 55.1 to 83.0%) of the patients. Tension-type headache (TTH) showed the highest prevalence in 16/42 (38%; 95% CI, from 23.4 to 52.8%) patients, followed by migraine and probable migraine in 12/42 (29%; 95% CI, from 14.9 to 42.2%) patients. Nine of the 42 (21%; 95% CI, from 9 to 33.8%) patients reported two different headache types. Patients with the mtDNA mutation m.3243A > G (n = 8) and MELAS (n = 7) showed the highest prevalence of headaches (88% and 85%, respectively). In patients with the CPEO phenotype (n = 32), headache occurred in 14/18 (78%; 95% CI, from 58.6 to 97%) of patients with single deletions, and in 7/13 (54%; 95% CI, from 26.7 to 80.9%) patients with multiple mtDNA deletions. There were no association between the mtDNA haplotype Hand the headache-diagnosis.
CONCLUSIONS
The prevalence of headache was higher in patients with mitochondrial diseases than reported in the general population. In all phenotype and genotype groups, TTH was more frequent than migraine. The data also show that the current ICHD-3 beta exclusively focused on MELAS syndrome as vasculopathy does not consider the broader spectrum of headache phenotypes in mitochondrial disorders.
Topics: Adolescent; Adult; Aged; Cross-Sectional Studies; DNA, Mitochondrial; Female; Genotype; Headache; Humans; Male; Middle Aged; Mitochondrial Diseases; Mutation; Phenotype; Prevalence; Surveys and Questionnaires; Young Adult
PubMed: 29139113
DOI: 10.1111/head.13219 -
Urology Case Reports Jan 2019
PubMed: 30364532
DOI: 10.1016/j.eucr.2018.10.006 -
Archives of Biochemistry and Biophysics Mar 2018Myoclonic epilepsy with ragged-red fibers (MERRF) is a maternally inherited mitochondrial neuromuscular disease. We previously reported a significant decrease of mRNA...
Myoclonic epilepsy with ragged-red fibers (MERRF) is a maternally inherited mitochondrial neuromuscular disease. We previously reported a significant decrease of mRNA and protein levels of nuclear DNA-encoded carbonic anhydrase VIII (CA8) in MERRF cybrids harboring A8344G mutation in mitochondrial DNA (mtDNA). In this study, we established a reporter construct of luciferase gene-carrying hCA8 promoter containing several putative transcription factor-binding sites, including GC-box, AP-2 and TATA-binding element in the 5'flanking region of the hCA8 gene. Using a series of mutated hCA8 promoter constructs, we demonstrated that a proximal GC-box, recognized by Sp1 and other Sp family members, may be a key cis-element functioning at the promoter. Additionally, a significant increase of the hCA8 promoter activity was observed in the wild-type and mutant cybrids with over-expression of eGFP-Sp1, but no detectable increase in the CA8 protein expression. In contrast, over-expression of Flag-Sp1 and Flag-Sp4 significantly increased the hCA8 promoter activity as well as endogenous CA8 protein expression in neuron-like HEK-293 T cells. However, down-regulation of Sp1, but not Sp4, in 293 T cells revealed a significant reduction of CA8 expression, suggesting that Sp1 is a predominant transcription factor for regulation of CA8 activity. Furthermore, our data indicate that chromatin structure may be involved in the expression of hCA8 gene in MERRF cybrids. Taken together, these results suggest that Sp1 transactivates hCA8 gene through the proximal GC box element in the promoter region. The key modulator-responsive factor to the mtDNA mutation and how it may affect nuclear hCA8 gene transcription need further investigations.
Topics: Binding Sites; Biomarkers, Tumor; DNA, Mitochondrial; Gene Expression Regulation, Enzymologic; Genes, Reporter; Green Fluorescent Proteins; HEK293 Cells; HSP27 Heat-Shock Proteins; Humans; MERRF Syndrome; Models, Biological; Mutation; Promoter Regions, Genetic; Transcription Factors; Transcription, Genetic
PubMed: 29407793
DOI: 10.1016/j.abb.2018.01.012 -
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 -
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 -
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