1/6. Revelation of a new mitochondrial dna mutation (G12147A) in a MELAS/MERFF phenotype.BACKGROUND: A 26-year-old man presented at onset with the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) and later with a phenotype for MELAS and myoclonic epilepsy and ragged red fiber disease (MELAS/MERRF). OBJECTIVE: To identify the possible defects in the mitochondrial genome in blood and muscle samples of the patient. DESIGN: Case study of a patient clinically exhibiting strokelike episodes and then epilepsy with myoclonic features, ataxia, and dementia. SETTING: research unit of a university hospital. MAIN OUTCOME MEASURES: Electromyographic, morphologic, and biochemical studies of muscle and molecular analysis of blood and muscle to investigate mitochondrial dna (mtDNA) size and quantity. RESULTS: Morphologically, we found abnormal mitochondrial proliferation with several cytochrome-c oxidase (COX)-negative fibers in muscle biopsy specimens; the analysis of serial sections showed a decreased immunoreactivity for the mtDNA-encoded subunits COXII and, partially, COXI. Biochemically, we found a partial and isolated COX deficiency. The complete mtDNA sequence analysis identified 3 sequence changes, 2 of which were reported polymorphisms. The remaining change, a G12147A transition in the transfer rna(His) gene, appeared to be the likely pathogenic mutation. CONCLUSIONS: Our data propose that the G12147A change, the first mutation in the transfer rna(His) gene associated with an overlapped MELAS/MERFF phenotype, is the cause of the encephalomyopathy in this patient interfering with the overall mitochondrial protein synthesis.- - - - - - - - - - ranking = 1keywords = genome (Clic here for more details about this article) |
2/6. A novel mitochondrial tRNAPhe mutation causes merrf syndrome.A woman with typical features of myoclonic epilepsy with ragged red fibers (MERRF) had a novel heteroplasmic mutation (G611A) in the mitochondrial dna tRNA phenylalanine gene. The mutation was heteroplasmic (91%) in muscle but undetectable in accessible tissues from the patient and her maternal relatives. Single-fiber PCR analysis showed that the proportion of mutant genomes was higher in cytochrome c oxidase (COX)-negative ragged red fibers (RRFs) than in COX-positive non-RRFs. This report shows that typical merrf syndrome is not always associated with tRNA lysine mutations.- - - - - - - - - - ranking = 1keywords = genome (Clic here for more details about this article) |
3/6. Mitochondrial dna deletion in a patient with mitochondrial myopathy, lactic acidosis, and stroke-like episodes (MELAS) and Fanconi's syndrome.Large-scale mitochondrial dna deletion was found in a 5-year-old girl with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and Fanconi's syndrome. Muscle biopsy disclosed ragged-red fibers and cytochrome c oxidase negative fibers. Respiratory chain studies were normal. Southern blot analysis demonstrated a 10.5-Kb heteroplasmic deletion in both muscle and blood. Deleted genomes represented 40% of total mitochondrial dna in muscle and 63% in blood. There was no evidence of point mutations characteristic of MELAS. We suggest that not only patients with progressive external ophthalmoplegia syndromes, but also those with defined syndromes [e.g., MELAS or myoclonic epilepsy and ragged-red fibers (MERRF)] without characteristic point mutations, be screened for mitochondrial dna deletions.- - - - - - - - - - ranking = 1keywords = genome (Clic here for more details about this article) |
4/6. merrf syndrome with overwhelming lactic acidosis.Myoclonic epilepsy with ragged-red fiber syndrome has been associated with a mitochondrial dna base substitution at nucleotide 8344 in the mitochondrial tRNA(Lys) gene. In several reported series, adult patients with these mutations have mild to moderate symptoms that progress slowly over many years. We describe a girl with merrf syndrome who had an unusually rapid and severe clinical course, with onset of symptoms at age 7 years and death by age 14 years of overwhelming lactic acidosis. Postmortem tissue biopsy revealed variable but generally high percentages of mutant mitochondrial genomes in multiple organ systems. Twenty-one other members of her family were tested for the mutation and had varying percentages in leukocytes.- - - - - - - - - - ranking = 1keywords = genome (Clic here for more details about this article) |
5/6. gene dosage effect in one family with myoclonic epilepsy and ragged-red fibers (MERRF).OBJECTIVES: We analyzed the percentage of mitochondrial dna (mtDNA) heteroplasmy in blood samples of 13 individuals belonging to a three family generation of myoclonic epilepsy with ragged-red fibers (MERRF) and compared the 5 affected patients and the 8 unaffected relatives. MATERIAL AND methods: dna was extracted from blood and muscle of the proband and from blood of 12 maternal relatives. A PCR restriction analysis method was used to detect the mutation. RESULTS: The proband had the complete MERRF phenotype. The phenotype in three other individuals in the maternal lineage was consistent with the merrf syndrome. The remaining were asymptomatic. The np 8344 mutation was observed in muscle and blood of the proband, and in blood from every one of 12 maternal relatives, ranging from 44% to 83% of mutated genomes. Symptomatic individuals had higher levels (P < 0.001) of mutated mtDNA than asymptomatic maternal relatives. However, high proportions of mutant genomes (up to 63%) were found in asymptomatic relatives. CONCLUSIONS: Although there seems to be a gene dosage effect in MERRF, we found no absolute relationship between the relative proportion of mutant genomes in blood and clinical severity. Factors other than gene dosage in blood may account for the differences in clinical phenotype.- - - - - - - - - - ranking = 3keywords = genome (Clic here for more details about this article) |
6/6. A double mutation (A8296G and G8363A) in the mitochondrial dna tRNA (Lys) gene associated with myoclonus epilepsy with ragged-red fibers.OBJECTIVE: To define potential pathogenic mitochondrial dna (mtDNA) point mutations in a patient with myoclonus epilepsy with ragged-red fibers (MERRF) syndrome. BACKGROUND: merrf syndrome is typically associated with point mutations in the mtDNA tRNALys gene. methods: We performed morphologic, biochemical, and genetic analysis of muscle samples from the patient and four relatives. Molecular genetic studies included sequencing, PCR, and restriction enzyme analysis on whole muscle, blood, and single muscle fibers. RESULTS: Muscle biopsy showed cytochrome c oxidase (COX), negative ragged-red fibers (RRF), and a defect of complex I of the mitochondrial respiratory chain. We found an A8296G transition and a G8363A mutation in the mtDNA tRNALYs gene. The A8296G was almost homoplasmic in muscle and blood from the propositus and his oligosymptomatic maternal relatives. The G8363A mutation was heteroplasmic and more abundant in muscle than in blood, and its proportion correlated with clinical severity. Single muscle fiber analysis showed significantly higher levels of G8363A genomes in COX-negative than in normal fibers, and almost homoplasmic levels of mutant A8296G mtDNA in both COX-negative and normal fibers. The two mutations affect highly conserved nucleotides and were not found in controls. CONCLUSIONS: The G8363A mutation is pathogenic; the co-occurrence of the A8296G mutation is of unclear significance and is likely to be a rare polymorphism.- - - - - - - - - - ranking = 1keywords = genome (Clic here for more details about this article) |