Segregation and manifestations of the mtDNA tRNA(Lys) A-->G(8344) mutation of myoclonus epilepsy and ragged-red fibers (MERRF) syndrome.

We have studied the segregation and manifestations of the tRNA(Lys) A-->G(8344) mutation of mtDNA. Three unrelated patients with myoclonus epilepsy and ragged-red fibers (MERRF) syndrome were investigated, along with 30 of their maternal relatives. Mutated mtDNA was not always found in the offspring of women carrying the tRNA(Lys) mutation. Four women had 10%-33% of mutated mtDNA in lymphocytes, and no mutated mtDNA was found in 7 of their 14 investigated children. The presence of mutated mtDNA was excluded at a level of 3:1,000. Five women had a proportion of 43%-73% mutated mtDNA in lymphocytes, and mutated mtDNA was found in all their 12 investigated children. This suggests that the risk for transmission of mutated mtDNA to the offspring increases if high levels are present in the mother and that, above a threshold level of 35%-40%, it is very likely that transmission will occur to all children. The three patients with MERRF syndrome had, in muscle, both 94%-96% mutated mtDNA and biochemical and histochemical evidence of a respiratory-chain dysfunction. Four relatives had a proportion of 61%-92% mutated mtDNA in muscle, and biochemical measurements showed a normal respiratory-chain function in muscle in all cases. These findings suggest that > 92% of mtDNA with the tRNA(Lys) mutation in muscle is required to cause a respiratory-chain dysfunction that can be detected by biochemical methods. There was a positive correlation between the levels of mtDNA with the tRNA(Lys) mutation in lymphocytes and the levels in muscle, in all nine investigated cases. The levels of mutated mtDNA were higher in muscle than in lymphocytes in all cases. In two of the patients with MERRF syndrome, muscle specimens were obtained at different times. In both cases, biochemical measurements revealed a deteriorating respiratory-chain function, and in one case a progressive increase in the amount of cytochrome c oxidase-deficient muscle fibers was found.

[1]  E. Holme,et al.  Multiple symmetric lipomas with high levels of mtDNA with the tRNA(Lys) A-->G(8344) mutation as the only manifestation of disease in a carrier of myoclonus epilepsy and ragged-red fibers (MERRF) syndrome. , 1993, American journal of human genetics.

[2]  E. Holme,et al.  Mitochondrial DNA deletions and cytochrome c oxidase deficiency in muscle fibres , 1992, Journal of the Neurological Sciences.

[3]  D. Wallace.  Mitochondrial genetics: a paradigm for aging and degenerative diseases? , 1992, Science.

[4]  E. Holme,et al.  Leber's hereditary optic neuropathy and complex I deficiency in muscle , 1991, Annals of neurology.

[5]  R. Kapsa,et al.  A tRNA(Lys) mutation in the mtDNA is the causal genetic lesion underlying myoclonic epilepsy and ragged-red fiber (MERRF) syndrome. , 1991, American journal of human genetics.

[6]  N. Romero,et al.  Genetic biochemical and pathophysiological characterization of a familial mitochondrial encephalomyopathy (MERRF) , 1991, Journal of the Neurological Sciences.

[7]  S. Tsuji,et al.  Quantitation of mitochondrial DNA carrying tRNALys mutation in MERRF patients. , 1991, Biochemical and biophysical research communications.

[8]  E. Shoubridge,et al.  Clinical spectrum of mitochondrial DNA mutation at base pair 8344 , 1991, The Lancet.

[9]  E. Holme,et al.  Mitochondrial encephalomyopathies in childhood. I. Biochemical and morphologic investigations. , 1991, The Journal of pediatrics.

[10]  E. Holme,et al.  Mitochondrial encephalomyopathies in childhood. II. Clinical manifestations and syndromes. , 1991, The Journal of pediatrics.

[11]  N. Bresolin,et al.  In vitro genetic transfer of protein synthesis and respiration defects to mitochondrial DNA-less cells with myopathy-patient mitochondria. , 1991, Molecular and cellular biology.

[12]  N. Bresolin,et al.  Rapid detection of the A----G(8344) mutation of mtDNA in Italian families with myoclonus epilepsy and ragged-red fibers (MERRF). , 1991, American journal of human genetics.

[13]  I. Nonaka,et al.  A mutation in the tRNALeu(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies , 1990, Nature.

[14]  E. Holme,et al.  Progressive Increase of the Mutated Mitochondrial DNA Fraction in Kearns-Sayre Syndrome , 1990, Pediatric Research.

[15]  S. Tsuji,et al.  A common mitochondrial DNA mutation in the t-RNA(Lys) of patients with myoclonus epilepsy associated with ragged-red fibers. , 1990, Biochemistry international.

[16]  M. Savontaus,et al.  Segregation of mitochondrial genomes in a heteroplasmic lineage with Leber hereditary optic neuroretinopathy. , 1990, American journal of human genetics.

[17]  D. Wallace,et al.  Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNALys mutation , 1990, Cell.

[18]  A. Harding,et al.  A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. , 1990, American journal of human genetics.

[19]  S. Dimauro,et al.  Detection of "deleted" mitochondrial genomes in cytochrome-c oxidase-deficient muscle fibers of a patient with Kearns-Sayre syndrome. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[20]  E. Shoubridge,et al.  Myoclonus epilepsy and ragged-red fibres (MERRF). 1. A clinical, pathological, biochemical, magnetic resonance spectrographic and positron emission tomographic study. , 1989, Brain : a journal of neurology.

[21]  W. Hauswirth,et al.  Rapid segregation of heteroplasmic bovine mitochondria. , 1989, Nucleic acids research.

[22]  S. Dimauro,et al.  Myoclonic epilepsy and ragged‐red fibers with cytochrome oxidase deficiency: Neuropathology, biochemistry, and molecular genetics , 1989, Annals of neurology.

[23]  C. Epstein,et al.  Familial mitochondrial encephalomyopathy (MERRF): Genetic, pathophysiological, and biochemical characterization of a mitochondrial DNA disease , 1988, Cell.

[24]  D. Wallace,et al.  Maternally inherited mitochondrial myopathy and myoclonic epilepsy , 1985, Annals of neurology.

[25]  F. Sanger,et al.  Sequence and organization of the human mitochondrial genome , 1981, Nature.

[26]  H. Cann,et al.  Maternal inheritance of human mitochondrial DNA. , 1980, Proceedings of the National Academy of Sciences of the United States of America.

[27]  T. Tsubaki,et al.  Myoclonus epilepsy associated with ragged-red fibres (mitochondrial abnormalities): Disease entity or a syndrome? Light- and electron-microscopic studies of two cases and review of literature , 1980, Journal of the Neurological Sciences.

[28]  R. E. Pershman.  [On myoclonic epilepsy]. , 1949, Nevropatologiia i psikhiatriia.