Abstract
Summary: Disorders of mitochondrial oxidative phosphorylation (OXPHOS) are renowned for their variability in clinical features and genetic causes. This makes it difficult to determine their true prevalence, but recent studies have documented a minimum birth prevalence of 13.1/100 000 or 1/7634 for oxidative phosphorylation disorders with onset at any age. This clearly remains an underestimate but it indicates that oxidative phosphorylation disorders can be regarded as the most common group of inborn errors of metabolism. Pathogenic mutations causing human oxidative phosphorylation disorders have now been identified in more than 30 of the 37 mitochondrial DNA genes and in more than 30 nuclear genes. Most of the nuclear gene defects cause autosomal recessive diseases, but autosomal dominant and X-linked disorders also occur. It is likely that at least another 30, and perhaps over 100, nuclear-encoded oxidative phosphorylation disorders await identification. Oxidative phosphorylation genetics are complex and there appear to be a number of common misconceptions about mitochondrial DNA mutations that may impede optimal investigation and management of patients. In our experience, mitochondrial DNA mutations are not a negligible cause of OXPHOS disorders in children but account for 20–25% of cases. Similarly, a family history suggesting maternal inheritance is the exception rather than the norm for children with mitochondrial DNA mutations, many of whom have de novo mutations. Only some mitochondrial DNA mutations disappear from cultured cells, so deficient enzyme activity in fibroblasts does not imply the presence of a nuclear defect. Finally, it is still widely thought that there are very few reproductive options that can be offered to women at risk of transmitting a mitochondrial DNA mutation. While a cautious approach is needed, there is now a consensus that prenatal diagnosis should be offered to some women, particularly those at lower recurrence risk. Preimplantation genetic diagnosis can also be an option.
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REFERENCES
Allikmets R, Raskind WH, Hutchinson A, Schueck ND, Dean M, KoellerDM(1999) Mutation of a putative mitochondrial iron transporter gene (ABC7) in X-linked sideroblastic anemia and ataxia (XLSA/A). Hum Mol Genet 8: 743–749.
Applegarth DA, Toone JR, Lowry RB (2000) Incidence of inborn errors of metabolism in British Columbia, 1969-1996. Pediatrics 105: 1–6.
Benit P, Chretien D, Kadhom N, et al (2001) Large-scale deletion and point mutations of the nuclear NDUFV1 and NDUFS1 genes in mitochondrial complex I deficiency. Am J Hum Genet 68: 1344–1352.
Benit P, Beugnot R, Chretien D, et al (2003) Mutant NDUFV2 subunit of mitochondrial complex I causes early onset hypertrophic cardiomyopathy and encephalopathy. HumMutat 21: 582–586.
Benit P, Slama A, Cartault F, et al (2004) Mutant NDUFS3 subunit of mitochondrial complex I causes Leigh syndrome. J Med Genet 41: 14–17.
Bernier FP, Boneh A, Dennett X, Chow CW, Cleary MA, Thorburn DR (2002) Diagnostic criteria for respiratory chain disorders in adults and children. Neurology 59: 1406–1411.
Bourgeron T, Rustin P, Chretien D, et al (1995) Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency. Nature Genetics 11: 144–149.
Chinnery PF, Johnson MA, Wardell TM, et al (2000a) The epidemiology of pathogenic mitochondrial DNA mutations. Ann Neurol 48: 188–193.
Chinnery PF, Thorburn DR, Samuels DC, et al (2000b) The inheritance of mitochondrial DNA heteroplasmy: random drift, selection or both? Trends Genet 16: 500–505.
Darin N, Oldfors A, Moslemi AR, Holme E, TuliniusM (2001) The incidence of mitochondrial encephalomyopathies in childhood: clinical features and morphological, biochemical, and DNA abnormalities. Ann Neurol 49: 377–383.
De Meirleir L, Seneca SH, Lissens W, et al (2004) Respiratory chain complex V deficiency due to a mutation in the assembly gene ATP12. J Med Genet 41: 120–124.
Dean NL, Battersby BJ, Ao A, Gosden RG, Tan SL, Shoubridge EA (2003) Prospect of preimplantation genetic diagnosis for heritable mitochondrial DNA diseases. Mol Hum Reprod 9: 631–638.
DiMauro S, Schon EA (2003) Mitochondrial respiratory-chain diseases. N Engl J Med 348: 2656–2668.
Gerard B, Bourgeron T, Chretien D, Rotig A, Munnich A, Rustin P (1993) Uridine preserves the expression of respiratory enzyme deficiencies in cultured fibroblasts. Eur J Pediatr 152: 270.
Haut S, Brivet M, Touati G, et al (2003) A deletion in the human QP-C gene causes a complex III deficiency resulting in hypoglycaemia and lactic acidosis. Hum Genet 113: 118–122.
Holt IJ, Harding AE, Morgan-Hughes JA (1988) Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 331: 717–719.
Holt IJ, Harding AE, Cooper JM, et al (1989) Mitochondrial myopathies: clinical and biochemical features of 30 patients with major deletions of muscle mitochondrial DNA. Ann Neurol 26: 699–708.
Jenuth JP, Peterson AC, Fu K, Shoubridge EA (1996) Random genetic drift in the female germline explains the rapid segregation of mammalian mitochondrial DNA. Nature Genetics 14: 146–151.
Kirby DM, Crawford M, Cleary MA, Dahl HHM, Dennett X, Thorburn DR (1999) Respiratory chain complex I deficiency. An underdiagnosed energy generation disorder. Neurology 52: 1255–1264.
Lamont PJ, Surtees R, Woodward CE, Leonard JV, Wood NW, Harding AE (1998) Clinical and laboratory findings in referrals for mitochondrial DNA analysis. Arch Dis Child 79: 22–27.
Lebon S, Chol M, Benit P, et al (2003) Recurrent de novo mitochondrial DNA mutations in respiratory chain deficiency. J Med Genet 40: 896–899.
Liang MH, Wong LJ (1998) Yield of mtDNA mutation analysis in 2,000 patients. Am J Med Genet 77: 395–400.
Luft R, Ikkos D, Palmieri G, Ernster L, Afzelius B (1962) A case of severe hypermetabolism of non-thyroid origin with a defect in the maintenance of mitochondrial respiratory control. A correlated clinical, biochemical and morphological study. J Clin Invest 41: 1776–1804.
Marotta R, Chin J, Quigley A, et al (2004) Diagnostic screening of mitochondrial DNA mutations in Australian adults, 1990-2001. Int Med J 34: 10–19.
McFarland R, Kirby DM, Fowler KJ, et al (2004) De novo mutations in the mitochondrial ND3 gene as a cause of infantile mitochondrial encephalopathy and complex I deficiency. Ann Neurol 55: 58–64.
Meikle PJ, Hopwood JJ, Clague AE, Carey WF (1999) Prevalence of lysosomal storage disorders. JAMA 281: 249–254.
Mootha VK, Bunkenborg J, Olsen JV, et al (2003a) Integrated analysis of protein composition, tissue diversity, and gene regulation in mouse mitochondria.Cell 115: 629–640.
Mootha VK, Lepage P, Miller K, et al (2003b) Identification of a gene causing human cytochrome c oxidase deficiency by integrative genomics. Proc Natl Acad Sci USA 100: 605–610.
Moraes CT, DiMauro S, Zeviani M, et al (1989) Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome. N Engl J Med 320: 1293–1299.
Munnich A, Rotig A, Chretien D, et al (1996) Clinical presentation of mitochondrial disorders in childhood. J Inherit Metab Dis 19: 521–527.
Online Mendelian Inheritance in Man, 2000. <http://www.ncbi.nlm.nih.gov/omim/>
Poulton J, Turnbull DM (2000) 74th ENMC international workshop: mitochondrial diseases 19-20 November 1999, Naarden, the Netherlands. Neuromuscul Disord 10: 460–462.
Rahman S, Poulton J, Marchington D, Suomalainen A (2001) Decrease of 3243 A>G mtDNA mutation from blood in MELAS syndrome: a longitudinal study. Am J Hum Genet 68: 238–240.
Robinson BH (1993) Lacticacidemia. Biochim Biophys Acta 1182: 231–244.
Schulte U (2001) Biogenesis of respiratory complex I. J Bioenerg Biomembr 33: 205–212.
Shoffner JM (1996) Maternal inheritance and the evaluation of oxidative phosphorylation diseases. Lancet 348: 1283–1288.
Shoubridge EA (2001) Nuclear genetic defects of oxidative phosphorylation. Hum Mol Genet 10: 2277–2284.
Skladal D, Halliday J, Thorburn DR (2003) Minimum birth prevalence of mitochondrial respiratory chain disorders in children. Brain 126: 1905–1912.
Smeitink JA, Loeffen JL, Triepels RH, Smeets RJ, Trijbels JM, van den Heuvel LP (1998) Nuclear genes of human complex I of the mitochondrial electron transport chain: state of the art. Hum Mol Genet 7: 1573–1579.
Special Writing Group of the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young of the American Heart Association (1992) Guidelines for the diagnosis of rheumatic fever. Jones Criteria, 1992 update. JAMA 268: 2069–2073.
Taylor SW, Fahy E, Zhang B, et al (2003) Characterization of the human heart mitochondrial proteome. Nature Biotechnology 21: 281–286.
Thorburn DR (2004) Diverse powerhouses. Nature Genetics 36: 13–14.
Thorburn DR, Dahl HHM (2001) Mitochondrial disorders: genetics, counseling, prenatal diagnosis and reproductive options. Am J Med Genet (Semin Med Genet) 106: 102–114.
Thorburn DR, Smeitink J (2001) Diagnosis of mitochondrial disorders: clinical and biochemical approach. J Inherit Metab Dis 24: 312–316.
Triepels RH, van den Heuvel LP, Trijbels JM, Smeitink JA (2001) Respiratory chain complex I deficiency. Am J Med Genet (Semin Med Genet) 106: 37–45.
Trijbels JMF, Scholte HR, Ruitenbeek W, Sengers RCA, Janssen AJM, Busch HFM (1993) Problems with the biochemical diagnosis in mitochondrial (encephalo-)myopathies. Eur J Pediatr 152: 178–184.
Walker UA, Collins S, Byrne E (1996) Respiratory chain encephalomyopathies: a diagnostic classification. Eur Neurol 36: 260–267.
Wallace DC, Singh G, Lott MT, et al (1988) Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 242: 1427–1430.
White SL, Collins VR, Wolfe R, et al (1999a) Genetic counseling and prenatal diagnosis for the mitochondrial DNA mutations at nucleotide 8993. Am J Hum Genet 65: 474–482.
White SL, Shanske S, McGill JJ, et al (1999b) Mitochondrial DNA mutations at nucleotide 8993 show a lack of tissue-or age-related variation. J Inherit Metab Dis 22: 899–914.
Zeviani M, Bertagnolio B, Uziel G (1996) Neurological presentations of mitochondrial diseases. J Inherit Metab Dis 19: 504–520.
Zhu Z, Yao J, Johns T, et al (1998) SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome. Nature Genetics 20: 337–343.
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Thorburn, D.R. Mitochondrial disorders: Prevalence, myths and advances. J Inherit Metab Dis 27, 349–362 (2004). https://doi.org/10.1023/B:BOLI.0000031098.41409.55
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DOI: https://doi.org/10.1023/B:BOLI.0000031098.41409.55