Abstract
The classification of mitochondrial encephalomyopathies relied upon clinical, biochemical, and histological features until the discovery of mitochondrial DNA defects in 1988. Since then, an outburst of molecular genetic information has aided our understanding of the pathogenesis and the classification of these heterogeneous disorders. Novel concepts of maternal inheritance, mitochondrial DNA (mtDNA) heteroplasmy, tissue distribution, and threshold have explained many of the clinical characteristics. The discovery of point mutations, large-scale mtDNA deletions, duplications, and autosomally inherited disorders with multiple mtDNA deletions have revealed new genetic phenomena. Despite our rapidly expanding understanding of the molecular genetic defects, many questions remain to be explored to fill the gap in our knowledge of the relationship between genotype and clinical phenotype.
Similar content being viewed by others
References
Anderson, S., Bankier, A. T., Barrell, B. G., de Bruijn, M. H. L., Coulson, A. R., Drouin, J., Eperon, I. C., Nierlich, D. P., Roe, B. A., Sanger, F., Schreier, P. H., Smith, A. J. H., Staden, R., and Young, I. G. (1981).Nature (London)290 457–465.
Arnaudo, E., Dalakas, M., Shanske, S., Moraes, C. T., DiMauro, S., and Schon, E. A. (1991).Lancet 337 508–510.
Ballinger, S. W., Shoffner, J. M., Hedaya, E. V., Trounce, I., Polak, M. A., Koontz, D. A., and Wallace, D. C. (1992).Nature Genet. 1 11–15.
Bernes, S. M., Bacino, C., Prezant, T. R., Pearson, M. A., Wood, T. S., Fournier, P., and Fischel-Ghodsian, N. (1993).J. Pediatr. 123 598–602.
Bindoff, L. A., Howell, N., Poulton, J., McCullough, D. A., Morten, K. J., Lightowlers, R. N., Turnbull, D. M., and Weber, K. (1993).J. Biol. Chem. 268 19559–19564.
Bolhuis, P. A., Bleeker-Wagemakers, E. M., Ponne, N. J., Van Schoonveld, M. J., Westerveld, A., Van den Bogert, C., and Tabak, H. F. (1990).Biochem. Biophys. Res. Commun. 170 994–997.
Brown, M. D., Torroni, A., Shoffner, J. M., and Wallace, D. C. (1992a).Am. J. Hum. Genet. 51 446–447.
Brown, M. D., Voljavec, A. S., Lott, M. T., MacDonald, I., and Wallace, D. C. (1992b).FASEB J. 6 2791–2799.
Brown, M. D., Voljavec, A. S., Lott, M. T., Torroni, A., Yang, C.-C., and Wallace, D. C. (1992c).Genetics 130 163–173.
Bu, X., and Rotter, J. I. (1991).Proc. Natl. Acad. Sci. USA 88 8198–8202.
Ciafaloni, E., Ricci, E., Shanske, S., Moraes, C. T., Silvestri, G., Hirano, M., Simonetti, S., Angelini, C., Donati, A., Garcia, C., Martinuzzi, A., Mosewich, R., Servidei, S., Zammarchi, E., Bonilla, E., DeVivo, D. C., Rowland, L. P., Schon, E. A., and DiMauro, S. (1992).Ann. Neurol. 31 391–398.
Ciafaloni, E., Santorelli, F. M., Shanske, S., Deonna, T., Roulet, E., Janzer, C., Pescia, G., and DiMauro, S. (1993).J. Pediatr. 122 419–422.
Dalakas, M., Illa, I., Pezeshkpour, G. H., Laukaitis, J. P., Cohen, B., and Griffin, J. L. (1990).N. Engl. J. Med. 322 1098–1105.
de Vries, d. D., van Engelen, B. G. M., Gabreëls, F. J. M., Ruitenbeek, W., and van Oost, B. A. (1993).Ann. Neurol. 34 410–412.
Dunbar, D. R., Moonie, P. A., Swingler, R. J., Davidson, D., Roberts, R., and Holt, I. J. (1993).Hum. Mol. Genet. 2 1619–1624.
Fukuhara, N., Tokigushi, S., Shirakawa, K., and Tsubaki, T. (1980).J. Neurol. Sci. 47 117–133.
Gerbitz, K. D., Paprotta, A., Jaksch, M., Zierz, S., and Drechsel, J. (1993).FEBS Lett. 321 194–196.
Giles, R. E., Blanc, H., Cann, H. M., and Wallace, D. C. (1980).Proc. Natl. Acad. Sci. USA 77 6715–6719.
Goto, Y.-I., Nonaka, I., and Horai, S. (1990).Nature (London)348 651–653.
Goto, Y.-I., Nonaka, I., and Horai, S. (1991).Biochim. Biophys. Acta 1097 238–240.
Goto, Y.-I., Horai, S., Matsuoka, T., Koga, Y., Nihei, K., Kobayashi, M., and Nonaka, I. (1992a).Neurology 42 545–550.
Goto, Y.-I., Tojo, M., Tohyama, J., Horai, S., and Nonaka, I. (1992b).Ann. Neurol. 31 672–675.
Hartzog, P. E., and Cain, B. D. (1993).J. Biol. Chem. 268 12250–12252.
Hasegawa, H., Matsuoka, T., Goto, Y.-i., and Nonaka, I. (1991).Ann. Neurol. 29 601–605.
Hirano, M., Ricci, E., Koenigsberger, M. R., Defendini, R., Pavlakis, S. G., DeVivo, D. C., DiMauro, S., and Rowland, L. P. (1992).Neuromusc. Disord. 2 125–135.
Holme, E., Larsson, N.-G., Oldfors, A., Tulinius, M., Sahlin, P., and Stenman, G. (1993).Am. J. Hum. Genet. 52 551–556.
Holt, I. J., Harding, A. E., and Morgan-Hughes, J. A. (1988).Nature (London)331 717–719.
Holt, I. J., Harding, A. E., and Morgan-Hughes, J. A. (1989).Nucleic Acids Res. 17 4465–4469.
Holt, I. J., Harding, A. E., Petty, R. K. H., and Morgan-Hughes, J. A. (1990).Am. J. Hum. Genet. 46 428–433.
Howell, N., Kubacka, I., Xu, M., and McCullough, D. A. (1991).Am. J. Hum. Genet. 48 935–942.
Howell, N., McCullough, D., and Bodis-Wollner, I. (1992).Am. J. Hum. Genet. 50 443–446.
Huoponen, K., Vilkki, J., Aula, P., Nikoskelain, E. K., and Savontaus, M.-L. (1991).Am. J. Hum. Genet. 48 1147–1153.
Hutchin, T., Haworth, I., Higashi, K., Fischel-Ghodsian, N., Stoneking, M., Saha, N., Arnos, C., and Cortopassi, G. (1993).Nucleic Acids Res. 21 4174–4179.
Johns, D. R., and Berman, J. (1991).Biochem. Biophys. Res. Commun. 174 1324–1330.
Johns, D. R., and Hurko, O. (1991).Lancet 337 927–928.
Johns, D. R., and Neufeld, M. J. (1991).Biochem. Biophys. Res. Commun. 181 1358–1364.
Johns, D. R., Neufeld, M. J., and Park, R. D. (1992).Biochem. Biophys. Res. Commun. 187 1551–1557.
Kadowaki, H., Tobe, K., Mori, Y., Sakura, H., Sakuta, R., Nonaka, I., Hagura, R., Yazaki, Y., Akanuma, Y., and Kadowaki, T. (1993).Lancet 341 893–894.
Kearns, T. P., and Sayre, G. P. (1958).Arch Ophthalmol. 60 280–289.
Kobayashi, Y., Momoi, M. Y., Tominaga, K., Momoi, T., Nihei, K., Yanagisawa, M., Kagawa, Y., and Ohta, S. (1990).Biochem. Biophys. Res. Commun. 173 816–822.
Larsson, N.-G., Andersen, O., Holme, E., Oldfors, A., and Wahlstrom, J. (1991).Ann. Neurol. 30 701–708.
Lauber, J., Marsac, C., Kadenbach, B., and Seibel, P. (1991).Nucleic Acids Res. 19 1393–1397.
Lertrit, P., Noer, A. S., Jean-Francois, M. J. B., Kapsa, R., Dennett, X., Thyagarajan, D., Lethlean, K., Byrne, E., and Marzuki, S. (1992).Am. J. Hum. Genet. 51 457–468.
Mackey, D., and Howell, N. (1992).Am. J. Hum. Genet. 51 1218–1228.
Matthews, P. M., Tampieri, D., Berkovic, S. F., Andermann, F., Silver, K., Chityat, D., and Arnold, D. L. (1991).Neurology 41 1043–1046.
McShane, M. A., Hammans, S. R., Sweeney, M., Holt, I. J., Beattie, T. J., Brett, E. M., and Harding, A. E. (1991).Am. J. Hum. Genet. 48 39–42.
Mita, S., Rizzuto, R., Moraes, C. T., Shanske, S., Arnaudo, E., Fabrizi, G., Koga, Y., DiMauro, S., and Schon, E. A. (1990).Nucleic Acids Res. 18 561–567.
Moraes, C. T., DiMauro, S., Zeviani, M., Lombes, A., Shanske, S., Miranda, A. F., Nakase, H., Bonilla, E., Wernec, L. C., Servidei, S., Nonaka, I., Koga, Y., Spiro, A., Brownell, K. W., Schmidt, B., Schotland, D. L., Zupanc, M. D., DeVivo, D. C., Schon, E. A., and Rowland, L. P. (1989).N. Engl. J. Med. 320 1293–1299.
Moraes, C. T., Shanske, S., Tritschler, H.-J., Aprille, J. R., Andreetta, F., Bonilla, E., Schon, E., and DiMauro, S. (1991).Am. J. Hum. Gen. 48 492–501.
Moraes, C. T., Ciacci, F., Bonilla, E., Ionasescu, V., Schon, E. A., and DiMauro, S. (1993a).Nature Genet. 4 284–288.
Moraes, C. T., Ciacci, F., Bonilla, E., Jansen, C., Hirano, M., Rao, N., Lovelace, R. E., Rowland, L. P., Schon, E. A., and DiMauro, S. (1993b).J. Clin. Invest. 92 2906–2915.
Moraes, C. T., Ciacci, F., Silvestri, G., Shanske, S., Sciacco, M., Hirano, M., Schon, E. A., Bonilla, E., and DiMauro, S. (1993c).Neuromusc. Disord. 3 43–50.
Morten, K. J., Cooper, J. M., Brown, G. K., Lake, B. D., Pike, D., and Poulton, J. (1993).Hum. Mol. Genet. 2 2081–2087.
Nikoskelainen, E. K., Savontaus, M., Wanne, O. P., Katila, M. J., and Nummelin, K. U. (1987).Arch. Ophthalmol. 105 665–671.
Ohama, E., Ohara, S., Ikuta, K., Tanaka, K., Nishizawa, M., and Miyatake, T. (1987).Acta Neuropathol. 74 226–233.
Onishi, H., Inoue, K., Osaka, H., Kimura, S., Nagatomo, H., Hanihara, T., Kawamoto, S., Okuda, K., Yamada, Y., and Kosaka, K. (1993).J. Neurol. Sci. 114 205–208.
Ozawa, T., Tanaka, M., Sugiyama, S., Ino, H., Hattori, K., Ohbayashi, T., Ito, T., Deguchi, H., Kawamura, K., Nakane, Y., and Hashiba, K. (1991).Biochem. Biophys. Res. Commun. 177 518–525.
Pearson, H. A., Lobel, J. S., Kocoshis, S. A., Naiman, J. L., Windmiller, J., Lammi, A. T., Hoffman, R., and Marsh, J. C. (1979).J. Pediatr. 95 976–984.
Poulton, J., Deadman, M. E., and Gardiner, R. M. (1989a).Lancet 1 236–240.
Poulton, J., Deadman, M. E., and Gardiner, R. M. (1989b).Nucleic Acids Res. 17 10223–10229.
Poulton, J., Deadman, M. E., Bindoff, L., Morten, K., Land, J., and Brown, G. (1993).Hum. Mol. Genet. 2 23–30.
Prezant, T. R., Agapian, J. V., Bohlman, M. C., Bu, X., Oztas, S., Qiu, W.-Q., Arnos, K. S., Cortopassi, G. A., Jaber, L., Rotter, J. I., Shohat, M., and Fischel-Ghodsian, N. (1993).Nature Genet. 4 289–294.
Reardon, W., Ross, R. J., Sweeney, M. G., Luxon, L. M., Harding, A. E., and Trembath, R. C. (1992).Lancet 340 1376–1379.
Remes, A. M., Majamaa, K., Herva, R., and Hassinen, I. E. (1993).Neurology 43 1015–1020.
Rötig, A., Cormier, V., Koll, F., Mize, C. E., Saudubray, J.-M., Veerman, A., Pearson, H. A., and Munnich, A. (1991).Genomics 10 502–504.
Rötig, A., Bessis, J.-L., Romero, N., Cormier, V., Saudubray, J.-M., Narcy, P., Lenoir, G., Rustin, P., and Munnich, A. (1992).Am. J. Hum. Genet. 50 364–370.
Rowland, L. P., Hays, A. P., DiMauro, S., DeVivo, D. C., and Behrens, M. (1983). InMitochondrial Pathology in Muscle Diseases (Cerri, C., and Scarlato, G., eds.), Piccin Editore, Padua, pp. 141–158.
Sakuta, R., Goto, Y.-I., Nonaka, I., and Horai, S. (1993).Am. J. Hum. Genet. 53 964–965.
Santorelli, F., Shanske, S., Macaya, A., DeVivo, D. C., and DiMauro, S. (1993).Ann. Neurol. 34 827–834.
Santorelli, F. M., Shanske, S., Jain, K. D., Tick, D., Schon, E. A., and DiMauro, S. (1994).Neurology, in press.
Satoh, M., and Kuroiwa, T. (1991).Exp. Cell Res. 196 137–140.
Schon, E. A., Rizzuto, R., Moraes, C. T., Nakase, H., Zeviani, M., and DiMauro, S. (1989).Science 244 346–349.
Servidei, S., Zeviani, M., Manfredi, G., Ricci, E., Silvestri, G., Bertini, E., Gellera, C., DiMauro, S., DiDonato, S., and Tonali, P. (1991).Neurology 41 1053–1059.
Shoffner, J. M., Lott, M. T., Lezza, A. M. S., Seibel, P., Ballinger, S. W., and Wallace, D. C. (1990).Cell 61 931–937.
Shoffner, J. M., Fernhoff, P. M., Krawiecki, N. S., Caplan, D. B., Holt, P. J., Koontz, D. A., Takei, Y., Newman, N. J., Ortiz, R. G., Polak, M., Ballinger, S. W., Lott, M. T., and Wallace, D. C. (1992).Neurology 42 2168–2174.
Silvestri, G., Moraes, C. T., Shanske, S., Oh, S. J., and DiMauro, S. (1992).Am. J. Hum. Genet. 51 1213–1217.
Silvestri, G., Ciafaloni, E., Santorelli, F. M., Shanske, S., Servidei, S., Graf, W. D., Sumi, M., and DiMauro, S. (1993a).Neurology 43 1200–1206.
Silvestri, G., Santorelli, F. M., Shanske, S., Whitley, C. B., Schimmenti, L. A., Smith, S. A., and DiMauro, S. (1993b).Hum. Mutat.,3 37–43.
Simpson, M. V., Chin, C. D., Keilbaugh, S. A., Lin, T.-S., and Prusoff, W. H. (1989).Biochem. Pharmacol. 38 1033–1036.
Sweeney, M. G., Bundey, S., Brockington, M., Poulton, J. R., Weiner, J. B., and Harding, A. E. (1993).Q. J. Med.,86 709–713.
Taniike, M., Fukushima, H., Yanagihara, I., Tsukamoto, H., Tanaka, J., Fujimura, H., Nagai, T., Sano, T., Yamaoka, K., Inui, K., and Okada, S. (1992).Biochem. Biophys. Res. Commun. 186 47–53.
Tatuch, Y., Christodoulou, J., Feigenbaum, A., Clarke, J. T. R., Wherret, J., Smith, C., Rudd, N., Petrova-Benedict, R., and Robinson, B. H. (1992).Am. J. Hum. Genet. 50 852–858.
Tritschler, H-J., Andreetta, F., Moraes, C. T., Bonilla, E., Arnaudo, E., Danon, M. J., Glass, S., Zelaya, B. M., Vamos, E., Telerman-Toppet, N., Kadenbach, B., DiMauro, S., and Schon, E. A. (1992).Neurology 42 209–217.
van den Ouweland, J. M. W., Bruining, G. J., Lindhout, D., Wit, J.-M., Veldhuyzen, B. F. E., and Maassen, J. A. (1992a).Nucleic Acids Res. 20 679–682.
van den Ouweland, J. M. W., Lemkes, H. H. P. J., Ruitenbeek, W., Sandkuijl, L. A., de Vijlder, M. F., Struyvenberg, P. A. A., van de Kamp, J. J. P., and Maassen, J. A. (1992b).Nature Genet. 1 368–371.
Vilkki, J., Ott, J., Savontaus, M.-L., Aula, P., and Nikoskelainen, E. K. (1991).Am. J. Hum. Genet. 48 486–491.
Wallace, D. C. (1992).Annu. Rev. Biochem. 61 1175–1212.
Wallace, D. C., Singh, G., Lott, M. T., Hodge, J. A., Schurr, T. G., Lezza, A. M. S., Elsas II, L. J., and Nikoskelainen, E. K. (1988).Science 242 1427–1430.
Yoneda, M., Tanno, Y., Horai, S., Ozawa, T., Miyatake, T., and Tsuji, S. (1990).Biochem. Int. 21 789–796.
Yoon, K. L., Aprille, J. R., and Ernst, S. G. (1991).Biochem. Biophys. Res. Commun. 176 1112–1115.
Zeviani, M., Moraes, C. T., DiMauro, S., Nakase, H., Bonilla, E., Schon, E. A., and Rowland, L. P. (1988).Neurology 38 1339–1346.
Zeviani, M., Servidei, S., Gellera, C., Bertini, E., DiMauro, S., and DiDonato, S. (1989).Nature (London)339 309–311.
Zeviani, M., Bresolin, N., Gellera, C., Bordoni, A., Pannacci, M., Amati, P., Moggio, M., Servidei, S., Scarlato, G., and DiDonato, S. (1990).Am. J. Hum. Genet. 47 904–914.
Zeviani, M., Gellera, C., Antozzi, C., Rimoldi, M., Morandi, L., Villani, F., Tiranti, V., and DiDonato, S. (1991).Lancet 338 143–147.
Zeviani, M., Muntoni, F., Savarese, N., Serra, G., Tiranti, V., Carrara, F., Mariotti, C., and DiDonato, S. (1993).Eur. J. Hum. Genet. 1 80–87.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Schon, E.A., Hirano, M. & DiMauro, S. Mitochondrial encephalomyopathies: Clinical and molecular analysis. J Bioenerg Biomembr 26, 291–299 (1994). https://doi.org/10.1007/BF00763100
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00763100