Abstract
Mitochondrial diseases are primary disorders of the mitochondrial respiratory chain. They are caused by known or presumed genetic mutations in mitochondrial or nuclear genes encoding subunits of the respiratory chain or a number of nuclear genes required for: import of respiratory chain subunits into mitochondria; assembly of functional respiratory chain complexes; replication, transcription and translation of mitochondrial DNA. This complexity is reflected in the different inheritance patterns of mitochondrial diseases and considerable variability in the clinical presentations throughout life. This chapter summarises the epidemiology and presentation of mitochondrial diseases, the major clinical features and classification schemes and presents a diagnostic approach to patient with a presumed mitochondrial disease.
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Recently, a raised serum level of FGF-21 has been reported to be a very sensitive and specific biomarker for muscle-manifesting mitochondrial disease, the area under the receiver-operating curve being 0.95 [62], but this awaits further evaluation.
References
Calvo S, Jain M, Xie X, Sheth SA, Chang B, Goldberger OA et al (2006) Systematic identification of human mitochondrial disease genes through integrative genomics. Nat Genet 38(5):576–582
Vives-Bauza C, Przedborski S (2011) Mitophagy: the latest problem for Parkinson’s disease. Trends Mol Med 17(3):158–165
Chinnery PF, DiMauro S, Shanske S, Schon EA, Zeviani M, Mariotti C et al (2004) Risk of developing a mitochondrial DNA deletion disorder. Lancet 364(9434):592–596
Mazzarello P (1999) A unifying concept: the history of cell theory. Nat Cell Biol 1(1):E13–E15
Engel WK, Cunningham GG (1963) Rapid examination of muscle tissue. An improved trichrome method for fresh-frozen biopsy sections. Neurology 13:919–923
Seligman AM, Karnovsky MJ, Wasserkrug HL, Hanker JS (1968) Nondroplet ultrastructural demonstration of cytochrome oxidase activity with a polymerizing osmiophilic reagent, diaminobenzidine (DAB). J Cell Biol 38(1):1–14
Luft R, Ikkos D, Palmieri G, Ernster L, Afzelius B (1962) A case of severe hypermetabolism of nonthyroid origin with a defect in the maintenance of mitochondrial respiratory control: a correlated clinical, biochemical, and morphological study. J Clin Invest 41:1776–1804
DiMauro S, Bonilla E, Lee CP, Schotland DL, Scarpa A, Conn H et al (1976) Luft’s disease. Further biochemical and ultrastructural studies of skeletal muscle in the second case. J Neurol Sci 27(2):217–232
Shy GM, Gonatas NK (1964) Human myopathy with giant abnormal mitochondria. Science 145:493–496
Drachman DA (1968) Ophthalmoplegia plus: the neurodegenerative disorders associated with progressive external ophthalmoplegia. Arch Neurol 18(6):654–674
Kearns TP, Sayre GP (1958) Retinitis pigmentosa, external ophthalmoplegia, and complete heart block: unusual syndrome with histologic study in one of two cases. AMA Arch Ophthalmol 60(2):280–289
Olson W, Engel WK, Walsh GO, Einaugler R (1972) Oculocraniosomatic neuromuscular disease with “ragged-red” fibers. Arch Neurol 26(3):193–211
Shapira Y, Harel S, Russell A (1977) Mitochondrial encephalomyopathies: a group of neuromuscular disorders with defects in oxidative metabolism. Isr J Med Sci 13(2):161–164
Egger J, Lake BD, Wilson J (1981) Mitochondrial cytopathy. A multisystem disorder with ragged red fibres on muscle biopsy. Arch Dis Child 56(10):741–752
Anderson S, Bankier AT, Barrell BG, de Bruijn MH, Coulson AR, Drouin J et al (1981) Sequence and organization of the human mitochondrial genome. Nature 290(5806):457–465
Egger J, Wilson J (1983) Mitochondrial inheritance in a mitochondrially mediated disease. N Engl J Med 309(3):142–146
Hutchison CA, Newbold JE, Potter SS, Edgell MH (1974) Maternal inheritance of mammalian mitochondrial DNA. Nature 251(5475):536–538
Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AM et al (1988) Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science 242(4884):1427–1430
Holt IJ, Cooper JM, Morgan-Hughes JA, Harding AE (1988) Deletions of muscle mitochondrial DNA. Lancet 1(8600):1462
Goto Y, Nonaka I, Horai S (1990) A mutation in the tRNA (Leu) (UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 348(6302):651–653
Shoffner JM, Lott MT, Lezza AM, Seibel P, Ballinger SW, Wallace DC (1990) Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNA (Lys) mutation. Cell 61(6):931–937
Zeviani M, Servidei S, Gellera C, Bertini E, DiMauro S, DiDonato S (1989) An autosomal dominant disorder with multiple deletions of mitochondrial DNA starting at the D-loop region. Nature 339(6222):309–311
Goethem GV, Dermaut B, Löfgren A, Martin JJ, Broeckhoven CV (2001) Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions. Nat Genet 28(3):211–212
Kaukonen J, Juselius JK, Tiranti V, Kyttälä A, Zeviani M, Comi GP et al (2000) Role of adenine nucleotide translocator 1 in mtDNA maintenance. Science 289(5480):782–785
Nishino I, Spinazzola A, Papadimitriou A, Hammans S, Steiner I, Hahn CD et al (2000) Mitochondrial neurogastrointestinal encephalomyopathy: an autosomal recessive disorder due to thymidine phosphorylase mutations. Ann Neurol 47(6):792–800
Spelbrink JN, Li FY, Tiranti V, Nikali K, Yuan QP, Tariq M et al (2001) Human mitochondrial DNA deletions associated with mutations in the gene encoding twinkle, a phage T7 gene 4-like protein localized in mitochondria. Nat Genet 28(3):223–231
Mandel H, Szargel R, Labay V, Elpeleg O, Saada A, Shalata A et al (2001) The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA. Nat Genet 29(3):337–341
Saada A, Shaag A, Mandel H, Nevo Y, Eriksson S, Elpeleg O (2001) Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy. Nat Genet 29(3):342–344
Bourgeron T, Rustin P, Chretien D, Birch-Machin M, Bourgeois M, Viegas-Péquignot E et al (1995) Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency. Nat Genet 11(2):144–149
Ugalde C, Janssen RJ, van den Heuvel LP, Smeitink JAM, Nijtmans LGJ (2004) Differences in assembly or stability of complex I and other mitochondrial OXPHOS complexes in inherited complex I deficiency. Hum Mol Genet 13(6):659–667
Zhu Z, Yao J, Johns T, Fu K, Bie ID, Macmillan C et al (1998) SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome. Nat Genet 20(4):337–343
Papadopoulou LC, Sue CM, Davidson MM, Tanji K, Nishino I, Sadlock JE et al (1999) Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene. Nat Genet 23(3):333–337
Visapää I, Fellman V, Vesa J, Dasvarma A, Hutton JL, Kumar V et al (2002) GRACILE syndrome, a lethal metabolic disorder with iron overload, is caused by a point mutation in BCS1L. Am J Hum Genet 71(4):863–876
Miller C, Saada A, Shaul N, Shabtai N, Ben-Shalom E, Shaag A et al (2004) Defective mitochondrial translation caused by a ribosomal protein (MRPS16) mutation. Ann Neurol 56(5):734–738
Bykhovskaya Y, Casas K, Mengesha E, Inbal A, Fischel-Ghodsian N (2004) Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial myopathy and sideroblastic anemia (MLASA). Am J Hum Genet 74(6):1303–1308
Schaefer AM, Taylor RW, Turnbull DM, Chinnery PF (2004) The epidemiology of mitochondrial disorders–past, present and future. Biochim Biophys Acta 1659(2–3):115–120
Darin N, Oldfors A, Moslemi AR, Holme E, Tulinius M (2001) The incidence of mitochondrial encephalomyopathies in childhood: clinical features and morphological, biochemical, and DNA abormalities. Ann Neurol 49(3):377–383
Skladal D, Halliday J, Thorburn DR (2003) Minimum birth prevalence of mitochondrial respiratory chain disorders in children. Brain 126(Pt 8):1905–1912
Verity CM, Winstone AM, Stellitano L, Krishnakumar D, Will R, McFarland R (2010) The clinical presentation of mitochondrial diseases in children with progressive intellectual and neurological deterioration: a national, prospective, population-based study. Dev Med Child Neurol 52(5):434–440
Castro-Gago M, Blanco-Barca MO, Campos-González Y, Arenas-Barbero J, Pintos-Martínez E, Eirís-Puñal J (2006) Epidemiology of pediatric mitochondrial respiratory chain disorders in northwest Spain. Pediatr Neurol 34(3):204–211
Elliott HR, Samuels DC, Eden JA, Relton CL, Chinnery PF (2008) Pathogenic mitochondrial DNA mutations are common in the general population. Am J Hum Genet 83(2):254–260
Clark JM, Marks MP, Adalsteinsson E, Spielman DM, Shuster D, Horoupian D et al (1996) MELAS: clinical and pathologic correlations with MRI, xenon/CT, and MR spectroscopy. Neurology 46(1):223–227
Friedman SD, Shaw DWW, Ishak G, Gropman AL, Saneto RP (2010) The use of neuroimaging in the diagnosis of mitochondrial disease. Dev Disabil Res Rev 16(2):129–135
Thyagarajan D, Shanske S, Vazquez-Memije M, Vivo DD, DiMauro S (1995) A novel mitochondrial ATPase 6 point mutation in familial bilateral striatal necrosis. Ann Neurol 38(3):468–472
Yonemura K, Hasegawa Y, Kimura K, Minematsu K, Yamaguchi T (2001) Diffusion-weighted MR imaging in a case of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke like episodes. AJNR Am J Neuroradiol 22(2):269–272
Oppenheim C, Galanaud D, Samson Y, Sahel M, Dormont D, Wechsler B et al (2000) Can diffusion weighted magnetic resonance imaging help differentiate stroke from stroke-like events in MELAS? J Neurol Neurosurg Psychiatry 69(2):248–250
Haas RH, Parikh S, Falk MJ, Saneto RP, Wolf NI, Darin N et al (2007) Mitochondrial disease: a practical approach for primary care physicians. Pediatrics 120(6):1326–1333
Walker UA, Collins S, Byrne E (1996) Respiratory chain encephalomyopathies: a diagnostic classification. Eur Neurol 36(5):260–267
Wolf NI, Smeitink JAM (2002) Mitochondrial disorders: a proposal for consensus diagnostic criteria in infants and children. Neurology 59(9):1402–1405
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(9):1406–1411
DiMauro S, Bonilla E, Vivo DCD (1999) Does the patient have a mitochondrial encephalomyopathy? J Child Neurol 14(Suppl 1):S23–S35
Schwartz M, Vissing J (2002) Paternal inheritance of mitochondrial DNA. N Engl J Med 347(8):576–580
Bandelt HJ, Kong QP, Parson W, Salas A (2005) More evidence for non-maternal inheritance of mitochondrial DNA? J Med Genet 42(12):957–960
Chow SL, Rooney ZJ, Cleary MA, Clayton PT, Leonard JV (2005) The significance of elevated CSF lactate. Arch Dis Child 90(11):1188–1189
Finsterer J, Eichberger H, Jarius C (2000) Lactate-stress testing in 54 patients with mitochondriopathy. Eur Arch Psychiatry Clin Neurosci 250(1):36–39
Shaham O, Slate NG, Goldberger O, Xu Q, Ramanathan A, Souza AL et al (2010) A plasma signature of human mitochondrial disease revealed through metabolic profiling of spent media from cultured muscle cells. Proc Natl Acad Sci USA 107(4):1571–1575
Mitochondrial Medicine Society’s Committee on Diagnosis, Haas RH, Parikh S, Falk MJ, Saneto RP, Wolf NI et al (2008) The in-depth evaluation of suspected mitochondrial disease. Mol Genet Metab 94(1):16–37
Scaglia F, Towbin JA, Craigen WJ, Belmont JW, Smith EO, Neish SR et al (2004) Clinical spectrum, morbidity, and mortality in 113 pediatric patients with mitochondrial disease. Pediatrics 114(4):925–931
Rollins S, Prayson RA, McMahon JT, Cohen BH (2001) Diagnostic yield muscle biopsy in patients with clinical evidence of mitochondrial cytopathy. Am J Clin Pathol 116(3):326–330
Vasta V, Ng SB, Turner EH, Shendure J, Hahn SH (2009) Next generation sequence analysis for mitochondrial disorders. Genome Med 1(10):100
Taylor RW, Taylor GA, Morris CM, Edwardson JM, Turnbull DM (1998) Diagnosis of mitochondrial disease: assessment of mitochondrial DNA heteroplasmy in blood. Biochem Biophys Res Commun 251(3):883–887
Suomalainen A, Elo JM, Pietiläinen KH, Hakonen AH, Sevastianova K, Korpela M, Isohanni P, Marjavaara SK, Tyni T, Kiuru-Enari S,Pihko H, Darin N, Õunap K, Kluijtmans LA, Paetau A, Buzkova J, Bindoff LA, Annunen-Rasila J, Uusimaa J, Rissanen A, Yki-Järvinen H, Hirano M, Tulinius M, Smeitink J, Tyynismaa H (2011) FGF-21 as a biomarker for muscle-manifesting mitochondrial respiratory chain deficiencies: a diagnostic study. Lancet Neurol 10(9):806–818
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Thyagarajan, D. (2013). Clinical Approach to the Diagnosis of Mitochondrial Disease. In: St. John, J. (eds) Mitochondrial DNA, Mitochondria, Disease and Stem Cells. Stem Cell Biology and Regenerative Medicine. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-101-1_1
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