Abstract
AIMS—To clarify the phenotype-genotype relation associated with the A3243G mitochondrial DNA mutation. METHODS—Five unrelated probands harbouring the A3243G mutation but presenting different clinical phenotype were analysed. Probands include Leigh syndrome (LS3243), mitochondrial myopathy, encephalopathy, lactic acidosis and stroke like episodes (MELAS3243), progressive external ophthalmoplegia (PEO3243), and mitochondrial diabetes mellitus (MDM3243). Extensive clinical, histological, biochemical, and molecular genetic studies were performed on five families. RESULTS—All patients showed ragged red fibres (RRF), and focal cytochrome c oxidase (COX) deficiency except for the patient with MDM3243. The mutation load was highest in the proband with LS3243 (>90%), who also presented the highest proportion of RRF (68%) and COX negative fibres (10%), and severe complex I plus IV deficiency. These proportions were lower in the probands with PEO3243 and with MDM3243. CONCLUSION—The most severe clinical phenotype, LS3243, was associated with the highest proportion of the A3243G mutation as well as the most prominent histological and biochemical abnormalities.
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- Anan R., Nakagawa M., Miyata M., Higuchi I., Nakao S., Suehara M., Osame M., Tanaka H. Cardiac involvement in mitochondrial diseases. A study on 17 patients with documented mitochondrial DNA defects. Circulation. 1995 Feb 15;91(4):955–961. doi: 10.1161/01.cir.91.4.955. [DOI] [PubMed] [Google Scholar]
- Campos Y., Martin M. A., Lorenzo G., Aparicio M., Cabello A., Arenas J. Sporadic MERRF/MELAS overlap syndrome associated with the 3243 tRNA(Leu(UUR)) mutation of mitochondrial DNA. Muscle Nerve. 1996 Feb;19(2):187–190. doi: 10.1002/(SICI)1097-4598(199602)19:2<187::AID-MUS10>3.0.CO;2-S. [DOI] [PubMed] [Google Scholar]
- Ciafaloni E., Ricci E., Shanske S., Moraes C. T., Silvestri G., Hirano M., Simonetti S., Angelini C., Donati M. A., Garcia C. MELAS: clinical features, biochemistry, and molecular genetics. Ann Neurol. 1992 Apr;31(4):391–398. doi: 10.1002/ana.410310408. [DOI] [PubMed] [Google Scholar]
- Fabrizi G. M., Cardaioli E., Grieco G. S., Cavallaro T., Malandrini A., Manneschi L., Dotti M. T., Federico A., Guazzi G. The A to G transition at nt 3243 of the mitochondrial tRNALeu(UUR) may cause an MERRF syndrome. J Neurol Neurosurg Psychiatry. 1996 Jul;61(1):47–51. doi: 10.1136/jnnp.61.1.47. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Goto Y., Nonaka I., Horai S. A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature. 1990 Dec 13;348(6302):651–653. doi: 10.1038/348651a0. [DOI] [PubMed] [Google Scholar]
- Hammans S. R., Sweeney M. G., Brockington M., Lennox G. G., Lawton N. F., Kennedy C. R., Morgan-Hughes J. A., Harding A. E. The mitochondrial DNA transfer RNA(Lys)A-->G(8344) mutation and the syndrome of myoclonic epilepsy with ragged red fibres (MERRF). Relationship of clinical phenotype to proportion of mutant mitochondrial DNA. Brain. 1993 Jun;116(Pt 3):617–632. doi: 10.1093/brain/116.3.617. [DOI] [PubMed] [Google Scholar]
- Holt I. J., Harding A. E., Petty R. K., Morgan-Hughes J. A. A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. Am J Hum Genet. 1990 Mar;46(3):428–433. [PMC free article] [PubMed] [Google Scholar]
- King M. P., Koga Y., Davidson M., Schon E. A. Defects in mitochondrial protein synthesis and respiratory chain activity segregate with the tRNA(Leu(UUR)) mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. Mol Cell Biol. 1992 Feb;12(2):480–490. doi: 10.1128/mcb.12.2.480. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kishnani P. S., Van Hove J. L., Shoffner J. S., Kaufman A., Bossen E. H., Kahler S. G. Acute pancreatitis in an infant with lactic acidosis and a mutation at nucleotide 3243 in the mitochondrial DNA tRNALeu(UUR) gene. Eur J Pediatr. 1996 Oct;155(10):898–903. doi: 10.1007/BF02282842. [DOI] [PubMed] [Google Scholar]
- Koga Y., Nonaka I., Kobayashi M., Tojyo M., Nihei K. Findings in muscle in complex I (NADH coenzyme Q reductase) deficiency. Ann Neurol. 1988 Dec;24(6):749–756. doi: 10.1002/ana.410240609. [DOI] [PubMed] [Google Scholar]
- Koga Y., Nonaka I., Nakao M., Yoshino M., Tanaka M., Ozawa T., Nakase H., DiMauro S. Progressive cytochrome c oxidase deficiency in a case of Leigh's encephalomyelopathy. J Neurol Sci. 1990 Jan;95(1):63–76. doi: 10.1016/0022-510x(90)90117-6. [DOI] [PubMed] [Google Scholar]
- Lombes A., Mendell J. R., Nakase H., Barohn R. J., Bonilla E., Zeviani M., Yates A. J., Omerza J., Gales T. L., Nakahara K. Myoclonic epilepsy and ragged-red fibers with cytochrome oxidase deficiency: neuropathology, biochemistry, and molecular genetics. Ann Neurol. 1989 Jul;26(1):20–33. doi: 10.1002/ana.410260104. [DOI] [PubMed] [Google Scholar]
- Mariotti C., Savarese N., Suomalainen A., Rimoldi M., Comi G., Prelle A., Antozzi C., Servidei S., Jarre L., DiDonato S. Genotype to phenotype correlations in mitochondrial encephalomyopathies associated with the A3243G mutation of mitochondrial DNA. J Neurol. 1995 May;242(5):304–312. doi: 10.1007/BF00878873. [DOI] [PubMed] [Google Scholar]
- Matsuishi T., Yoshino M., Tokunaga O., Katafuchi Y., Yamashita F. Subacute necrotizing encephalomyelopathy (Leigh disease): report of a case with Lennox-Gastaut syndrome. Brain Dev. 1985;7(5):500–504. doi: 10.1016/s0387-7604(85)80117-0. [DOI] [PubMed] [Google Scholar]
- Mita S., Schmidt B., Schon E. A., DiMauro S., Bonilla E. Detection of "deleted" mitochondrial genomes in cytochrome-c oxidase-deficient muscle fibers of a patient with Kearns-Sayre syndrome. Proc Natl Acad Sci U S A. 1989 Dec;86(23):9509–9513. doi: 10.1073/pnas.86.23.9509. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Moraes C. T., Ciacci F., Silvestri G., Shanske S., Sciacco M., Hirano M., Schon E. A., Bonilla E., DiMauro S. Atypical clinical presentations associated with the MELAS mutation at position 3243 of human mitochondrial DNA. Neuromuscul Disord. 1993 Jan;3(1):43–50. doi: 10.1016/0960-8966(93)90040-q. [DOI] [PubMed] [Google Scholar]
- Petruzzella V., Moraes C. T., Sano M. C., Bonilla E., DiMauro S., Schon E. A. Extremely high levels of mutant mtDNAs co-localize with cytochrome c oxidase-negative ragged-red fibers in patients harboring a point mutation at nt 3243. Hum Mol Genet. 1994 Mar;3(3):449–454. doi: 10.1093/hmg/3.3.449. [DOI] [PubMed] [Google Scholar]
- Shimomura T., Kitano A., Marukawa H., Mishima K., Isoe K., Adachi Y., Takahashi K. Point mutation in platelet mitochondrial tRNA(Leu(UUR)) in patient with cluster headache. Lancet. 1994 Aug 27;344(8922):625–625. doi: 10.1016/s0140-6736(94)92015-x. [DOI] [PubMed] [Google Scholar]
- Shoffner J. M., Lott M. T., Lezza A. M., Seibel P., Ballinger S. W., Wallace D. C. Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNA(Lys) mutation. Cell. 1990 Jun 15;61(6):931–937. doi: 10.1016/0092-8674(90)90059-n. [DOI] [PubMed] [Google Scholar]
- Tatuch Y., Christodoulou J., Feigenbaum A., Clarke J. T., Wherret J., Smith C., Rudd N., Petrova-Benedict R., Robinson B. H. Heteroplasmic mtDNA mutation (T----G) at 8993 can cause Leigh disease when the percentage of abnormal mtDNA is high. Am J Hum Genet. 1992 Apr;50(4):852–858. [PMC free article] [PubMed] [Google Scholar]
- Vilarinho L., Maia C., Coelho T., Coutinho P., Santorelli F. M. Heterogeneous presentation in Leigh syndrome. J Inherit Metab Dis. 1997 Sep;20(5):704–705. doi: 10.1023/a:1005330611147. [DOI] [PubMed] [Google Scholar]
- van den Ouweland J. M., Lemkes H. H., Ruitenbeek W., Sandkuijl L. A., de Vijlder M. F., Struyvenberg P. A., van de Kamp J. J., Maassen J. A. Mutation in mitochondrial tRNA(Leu)(UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness. Nat Genet. 1992 Aug;1(5):368–371. doi: 10.1038/ng0892-368. [DOI] [PubMed] [Google Scholar]