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Mitochondrial Myopathies and Related Diseases

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Myopathology

Abstract

Mitochondria are specialized cell organelles present in eukaryotes and postulated to have evolved from free-living bacteria approximately two billion years ago [1]. The primary function of mitochondria is energy production through oxidative phosphorylation (OXPHOS). Other than OXPHOS, mitochondria play key roles in Ca2+ homeostasis, apoptosis, etc. [2, 3]. Each mitochondrion has two membranes (outer and inner), an intermembranous space (between the two membranes) and a matrix (bound on all sides by the inner membrane). The cristae are parallel folds of inner membrane that protrude into the matrix. The outer membrane contains pores that are permissive to molecules <5 kDa and, a large multi-subunit protein complex called translocase that recognizes mitochondrial signal sequences on proteins >5 kDa and allows these large molecules to pass through. The inner membrane harbors all the proteins of the OXPHOS. The tips of the cristae contain ATP synthase complex. The mitochondria are peculiar among the cell organelles because they contain DNA (mtDNA). By virtue of mtDNA, the mitochondria are able to self-replicate and synthesize proteins for the normal functioning of OXPHOS. Most of the proteins required for the normal functioning of OXPHOS are encoded by the nuclear DNA (nDNA) genes (i.e., not encoded by the mtDNA genes) and imported via the pores or translocase present in the outer mitochondrial membrane. Mitochondrial myopathies can result from structural and/or functional defects in mitochondria or nDNA-encoded mitochondrial proteins [4, 5].

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References

  1. Keeling PJ, McCutcheon JP. Endosymbiosis: the feeling is not mutual. J Theor Biol. 2017;434:75–9.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Hopper RK, Carroll S, Aponte AM, et al. Mitochondrial matrix phosphoproteome: effect of extra mitochondrial calcium. Biochemistry. 2006;45:2524–36.

    Article  CAS  PubMed  Google Scholar 

  3. Wang C, Youle RJ. The role of mitochondria in apoptosis. Annu Rev Genet. 2009;43:95–118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Schaefer AM, Taylor RW, Turnbull DM, Chinnery PF. The epidemiology of mitochondrial disorders—past, present and future. Biochim Biophys Acta. 2004;1659:115–20.

    Article  CAS  PubMed  Google Scholar 

  5. Gorman GS, Schaefer AM, Ng Y, et al. Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease. Ann Neurol. 2015;77:753–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Anderson S, Bankier AT, Barrell BG, et al. Sequence and organization of the human mitochondrial genome. Nature. 1981;290:457–65.

    Article  CAS  PubMed  Google Scholar 

  7. Calvo SE, Clauser KR, Mootha VK. MitoCarta2.0: an updated inventory of mammalian mitochondrial proteins. Nucleic Acids Res. 2016;44:D1251–7.

    Article  CAS  PubMed  Google Scholar 

  8. Giles RE, Blanc H, Cann HM, et al. Maternal inheritance of human mitochondrial DNA. Proc Natl Acad Sci U S A. 1980;77:6715–9.

    Article  CAS  Google Scholar 

  9. Breton S, Stewart DT. Atypical mitochondrial inheritance patterns in eukaryotes. Genome. 2015;58:423–31.

    Article  CAS  PubMed  Google Scholar 

  10. Sato M, Sato K. Maternal inheritance of mitochondrial DNA by diverse mechanisms to eliminate paternal mitochondrial DNA. Biochim Biophys Acta. 2013;1833:1979–84.

    Article  CAS  PubMed  Google Scholar 

  11. Esterhuizen K, van der Westhuizen FH, Louw R. Metabolomics of mitochondrial disease. Mitochondrion. 2017;35:97–110.

    Article  CAS  PubMed  Google Scholar 

  12. Fearnley IM, Carroll J, Walker JE. Proteomic analysis of the subunit composition of complex I (NADH:ubiquinone oxidoreductase) from bovine heart mitochondria. Methods Mol Biol. 2007;357:103–25.

    CAS  PubMed  Google Scholar 

  13. Carroll J, Fearnley IM, Shannon RJ, et al. Analysis of the subunit composition of complex I from bovine heart mitochondria. Mol Cell Proteomics. 2003;2:117–26.

    Google Scholar 

  14. Vogel RO, Smeitink JA, Nijtmans LG. Human mitochondrial complex I assembly: a dynamic and versatile process. Biochim Biophys Acta. 2007;1767:1215–27.

    Article  CAS  PubMed  Google Scholar 

  15. McFarland R, Kirby DM, Fowler KJ, et al. De novo mutations in the mitochondrial ND3 gene as a cause of infantile mitochondrial encephalopathy and complex I deficiency. Ann Neurol. 2004;55:58–64.

    Article  CAS  PubMed  Google Scholar 

  16. Kirby DM, Salemi R, Sugiana C, et al. NDUFS6 mutations are a novel cause of lethal neonatal mitochondrial complex I deficiency. J Clin Investig. 2004;114:837–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Swalwell H, Kirby DM, Blakely EL, et al. Respiratory chain complex I deficiency caused by mitochondrial DNA mutations. Eur J Hum Genet. 2011;19:769–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Janssen RJ, Nijtmans LG, van den Heuvel LP, et al. Mitochondrial complex I: structure, function and pathology. J Inherit Metab Dis. 2006;29:499–515.

    Article  CAS  PubMed  Google Scholar 

  19. Pitkanen S, Feigenbaum A, Laframboise R, et al. NADH-coenzyme Q reductase (complex I) deficiency: heterogeneity in phenotype and biochemical findings. J Inherit Metab Dis. 1996;19:675–86.

    Article  CAS  PubMed  Google Scholar 

  20. Kirby DM, Crawford M, Cleary MA, et al. Respiratory chain complex I deficiency: an underdiagnosed energy generation disorder. Neurology. 1999;52:1255–64.

    Article  CAS  PubMed  Google Scholar 

  21. Loeffen JL, Smeitink JA, Trijbels JM, et al. Isolated complex I deficiency in children: clinical, biochemical and genetic aspects. Hum Mutat. 2000;15:123–34.

    Article  CAS  PubMed  Google Scholar 

  22. Bugiani M, Invernizzi F, Alberio S, et al. Clinical and molecular findings in children with complex I deficiency. Biochim Biophys Acta. 2004;1659:136–47.

    Article  CAS  PubMed  Google Scholar 

  23. Fernandez-Moreira D, Ugalde C, Smeets R, et al. X-linked NDUFA1 gene mutations associated with mitochondrial encephalomyopathy. Ann Neurol. 2007;61:73–83.

    Article  CAS  PubMed  Google Scholar 

  24. Potluri P, Davila A, Ruiz-Pesini E, et al. A novel NDUFA1 mutation leads to a progressive mitochondrial complex I-specific neurodegenerative disease. Mol Genet Metab. 2009;96:189–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ravera S, Vaccaro D, Cuccarolo P, et al. Mitochondrial respiratory chain Complex I defects in Fanconi anemia complementation group A. Biochimie. 2013;95:1828–37.

    Article  CAS  PubMed  Google Scholar 

  26. Mayr JA, Bodamer O, Haack TB, et al. Heterozygous mutation in the X chromosomal NDUFA1 gene in a girl with complex I deficiency. Mol Genet Metab. 2011;103:358–61.

    Article  CAS  PubMed  Google Scholar 

  27. Sun F, Huo X, Zhai Y, et al. Crystal structure of mitochondrial respiratory membrane protein complex II. Cell. 2005;121:1043–57.

    Article  CAS  PubMed  Google Scholar 

  28. Ackrell BA. Cytopathies involving mitochondrial complex II. Mol Asp Med. 2002;23:369–84.

    Article  CAS  Google Scholar 

  29. Jain-Ghai S, Cameron JM, Al Maawali A, et al. Complex II deficiency--a case report and review of the literature. Am J Med Genet A. 2013;161A:285–94.

    Article  PubMed  Google Scholar 

  30. Vladutiu GD, Heffner RR. Succinate dehydrogenase deficiency. Arch Pathol Lab Med. 2000;124:1755–8.

    CAS  PubMed  Google Scholar 

  31. Vazquez-Acevedo M, Antaramian A, Corona N, et al. Subunit structures of purified beef mitochondrial cytochrome bc1 complex from liver and heart. J Bioenerg Biomembr. 1993;25:401–10.

    Google Scholar 

  32. Benit P, Lebon S, Rustin P. Respiratory-chain diseases related to complex III deficiency. Biochim Biophys Acta. 2009;1793:181–5.

    Article  CAS  PubMed  Google Scholar 

  33. Zhang T, Hong F, Qian G, et al. Analysis of UQCRB gene mutation in a child with mitochondrial complex III deficiency. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2017;34:382–6.

    PubMed  Google Scholar 

  34. Barel O, Shorer Z, Flusser H, et al. Mitochondrial complex III deficiency associated with a homozygous mutation in UQCRQ. Am J Hum Genet. 2008;82:1211–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Miyake N, Yano S, Sakai C, et al. Mitochondrial complex III deficiency caused by a homozygous UQCRC2 mutation presenting with neonatal-onset recurrent metabolic decompensation. Hum Mutat. 2013;34:446–52.

    Article  CAS  PubMed  Google Scholar 

  36. Gaignard P, Menezes M, Schiff M, et al. Mutations in CYC1, encoding cytochrome c1 subunit of respiratory chain complex III, cause insulin-responsive hyperglycemia. Am J Hum Genet. 2013;93:384–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wanschers BF, Szklarczyk R, van den Brand MA, et al. A mutation in the human CBP4 ortholog UQCC3 impairs complex III assembly, activity and cytochrome b stability. Hum Mol Genet. 2014;23:6356–65.

    Article  CAS  PubMed  Google Scholar 

  38. Mancuso M, Filosto M, Stevens JC, et al. Mitochondrial myopathy and complex III deficiency in a patient with a new stop-codon mutation (G339X) in the cytochrome b gene. J Neurol Sci. 2003;209:61–3.

    Article  CAS  PubMed  Google Scholar 

  39. Munnich A, Rustin P. Clinical spectrum and diagnosis of mitochondrial disorders. Am J Med Genet. 2001;106:4–17.

    Article  CAS  PubMed  Google Scholar 

  40. Blakely EL, Mitchell AL, Fisher N, et al. A mitochondrial cytochrome b mutation causing severe respiratory chain enzyme deficiency in humans and yeast. FEBS J. 2005;272:3583–92.

    Article  CAS  PubMed  Google Scholar 

  41. Fragaki K, Procaccio V, Bannwarth S, et al. A neonatal polyvisceral failure linked to a de novo homoplasmic mutation in the mitochondrially encoded cytochrome b gene. Mitochondrion. 2009;9:346–52.

    Article  CAS  PubMed  Google Scholar 

  42. Ghezzi D, Arzuffi P, Zordan M, et al. Mutations in TTC19 cause mitochondrial complex III deficiency and neurological impairment in humans and flies. Nat Genet. 2011;43:259–63.

    Article  CAS  PubMed  Google Scholar 

  43. Morino H, Miyamoto R, Ohnishi S, et al. Exome sequencing reveals a novel TTC19 mutation in an autosomal recessive spinocerebellar ataxia patient. BMC Neurol. 2014;14:5.

    Google Scholar 

  44. Ardissone A, Granata T, Legati A, et al. Mitochondrial Complex III deficiency caused by TTC19 defects: report of a novel mutation and review of literature. JIMD Rep. 2015;22:115–20.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Mordaunt DA, Jolley A, Balasubramaniam S, et al. Phenotypic variation of TTC19-deficient mitochondrial complex III deficiency: a case report and literature review. Am J Med Genet A. 2015;167:1330–6.

    Article  PubMed  Google Scholar 

  46. Tucker EJ, Wanschers BF, Szklarczyk R, et al. Mutations in the UQCC1-interacting protein, UQCC2, cause human complex III deficiency associated with perturbed cytochrome b protein expression. PLoS Genet. 2013;9:e1004034.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Invernizzi F, Tigano M, Dallabona C, et al. A homozygous mutation in LYRM7/MZM1L associated with early onset encephalopathy, lactic acidosis, and severe reduction of mitochondrial complex III activity. Hum Mutat. 2013;34:1619–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Dallabona C, Abbink TE, Carrozzo R, et al. LYRM7 mutations cause a multifocal cavitating leukoencephalopathy with distinct MRI appearance. Brain. 2016;139:782–94.

    Article  PubMed  Google Scholar 

  49. Al-Owain M, Colak D, Albakheet A, et al. Clinical and biochemical features associated with BCS1L mutation. J Inherit Metab Dis. 2013;36:813–20.

    Article  CAS  PubMed  Google Scholar 

  50. Jackson CB, Bauer MF, Schaller A, et al. A novel mutation in BCS1L associated with deafness, tubulopathy, growth retardation and microcephaly. Eur J Pediatr. 2016;175:517–25.

    Article  CAS  PubMed  Google Scholar 

  51. Ramos-Arroyo MA, Hualde J, Ayechu A, et al. Clinical and biochemical spectrum of mitochondrial complex III deficiency caused by mutations in the BCS1L gene. Clin Genet. 2009;75:585–7.

    Article  CAS  PubMed  Google Scholar 

  52. Gil-Borlado MC, Gonzalez-Hoyuela M, Blazquez A, et al. Pathogenic mutations in the 5′ untranslated region of BCS1L mRNA in mitochondrial complex III deficiency. Mitochondrion. 2009;9:299–305.

    Article  CAS  PubMed  Google Scholar 

  53. Blazquez A, Gil-Borlado MC, Moran M, et al. Infantile mitochondrial encephalomyopathy with unusual phenotype caused by a novel BCS1L mutation in an isolated complex III-deficient patient. Neuromuscul Disord. 2009;19:143–6.

    Article  PubMed  Google Scholar 

  54. Fernandez-Vizarra E, Bugiani M, Goffrini P, et al. Impaired complex III assembly associated with BCS1L gene mutations in isolated mitochondrial encephalopathy. Hum Mol Genet. 2007;16:1241–52.

    Article  CAS  PubMed  Google Scholar 

  55. Falco M, Franze A, Iossa S, et al. Novel compound heterozygous mutations in BCS1L gene causing Bjornstad syndrome in two siblings. Am J Med Genet A. 2017;173:1348–52.

    Article  CAS  PubMed  Google Scholar 

  56. Visapaa I, Fellman V, Vesa J, et al. GRACILE syndrome, a lethal metabolic disorder with iron overload, is caused by a point mutation in BCS1L. Am J Hum Genet. 2002;71:863–76.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Schagger H, de Coo R, Bauer MF, et al. Significance of respirasomes for the assembly/stability of human respiratory chain complex I. J Biol Chem. 2004;279:36349–53.

    Article  CAS  PubMed  Google Scholar 

  58. Zhen X, Wu B, Wang J, et al. Increased incidence of mitochondrial cytochrome C oxidase 1 gene mutations in patients with primary ovarian insufficiency. PLoS One. 2015;10:e0132610.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Debray FG, Seneca S, Gonce M, et al. Mitochondrial encephalomyopathy with cytochrome c oxidase deficiency caused by a novel mutation in the MTCO1 gene. Mitochondrion. 2014;17:101–5.

    Article  CAS  PubMed  Google Scholar 

  60. Baklouti-Gargouri S, Ghorbel M, Ben Mahmoud A, et al. A novel m.6307A>G mutation in the mitochondrial COXI gene in asthenozoospermic infertile men. Mol Reprod Dev. 2013;80:581–7.

    Article  CAS  PubMed  Google Scholar 

  61. Herrero-Martin MD, Pineda M, Briones P, et al. A new pathologic mitochondrial DNA mutation in the cytochrome oxidase subunit I (MT-CO1). Hum Mutat. 2008;29:E112–22.

    Article  PubMed  Google Scholar 

  62. Varlamov DA, Kudin AP, Vielhaber S, et al. Metabolic consequences of a novel missense mutation of the mtDNA CO I gene. Hum Mol Genet. 2002;11:1797–805.

    Article  CAS  PubMed  Google Scholar 

  63. Gattermann N, Retzlaff S, Wang YL, et al. Heteroplasmic point mutations of mitochondrial DNA affecting subunit I of cytochrome c oxidase in two patients with acquired idiopathic sideroblastic anemia. Blood. 1997;90:4961–72.

    CAS  PubMed  Google Scholar 

  64. Mkaouar-Rebai E, Ben Mahmoud A, Chamkha I, et al. A novel MT-CO2 m.8249G>A pathogenic variation and the MT-TW m.5521G>A mutation in patients with mitochondrial myopathy. Mitochondrial DNA. 2014;25:394–9.

    Article  CAS  PubMed  Google Scholar 

  65. Liu CS, Cheng WL, Chen YY, et al. High prevalence of the COII/tRNA(Lys) intergenic 9-bp deletion in mitochondrial DNA of Taiwanese patients with MELAS or MERRF syndrome. Ann N Y Acad Sci. 2005;1042:82–7.

    Article  CAS  PubMed  Google Scholar 

  66. Tabebi M, Charfi N, Kallabi F, et al. Whole mitochondrial genome screening of a family with maternally inherited diabetes and deafness (MIDD) associated with retinopathy: A putative haplotype associated to MIDD and a novel MT-CO2 m.8241T>G mutation. J Diabetes Complicat. 2017;31:253–9.

    Article  Google Scholar 

  67. Siwar BG, Myriam G, Afif BM, et al. Two novel mutations in COII and tRNA(His) mitochondrial genes in asthenozoospermic infertiles men. Biochem Biophys Res Commun. 2014;450:610–5.

    Article  CAS  PubMed  Google Scholar 

  68. Gutierrez Cortes N, Pertuiset C, Dumon E, et al. Novel mitochondrial DNA mutations responsible for maternally inherited nonsyndromic hearing loss. Hum Mutat. 2012;33:681–9.

    Article  CAS  PubMed  Google Scholar 

  69. Horvath R, Schoser BG, Muller-Hocker J, et al. Mutations in mtDNA-encoded cytochrome c oxidase subunit genes causing isolated myopathy or severe encephalomyopathy. Neuromuscul Disord. 2005;15:851–7.

    Article  PubMed  Google Scholar 

  70. Mughal IA, Irfan A, Hameed A, et al. Sperm mitochondrial DNA 15bp deletion of cytochrome c oxidase subunit III is significantly associated with human male infertility in Pakistan. J Pak Med Assoc. 2016;66:3–7.

    Google Scholar 

  71. Baklouti-Gargouri S, Ghorbel M, Ben Mahmoud A, et al. Identification of a novel m.9588G > a missense mutation in the mitochondrial COIII gene in asthenozoospermic Tunisian infertile men. J Assist Reprod Genet. 2014;31:595–600.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Marotta R, Chin J, Kirby DM, et al. Novel single base pair COX III subunit deletion of mitochondrial DNA associated with rhabdomyolysis. J Clin Neurosci. 2011;18:290–2.

    Article  CAS  PubMed  Google Scholar 

  73. Keightley JA, Hoffbuhr KC, Burton MD, et al. A microdeletion in cytochrome c oxidase (COX) subunit III associated with COX deficiency and recurrent myoglobinuria. Nat Genet. 1996;12:410–6.

    Article  CAS  PubMed  Google Scholar 

  74. Markaryan A, Nelson EG, Hinojosa R. Major arc mitochondrial DNA deletions in cytochrome c oxidase-deficient human cochlear spiral ganglion cells. Acta Otolaryngol. 2010;130:780–7.

    Article  CAS  PubMed  Google Scholar 

  75. Choi BO, Hwang JH, Kim J, et al. A MELAS syndrome family harboring two mutations in mitochondrial genome. Exp Mol Med. 2008;40:354–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Mkaouar-Rebai E, Ellouze E, Chamkha I, et al. Molecular-clinical correlation in a family with a novel heteroplasmic Leigh syndrome missense mutation in the mitochondrial cytochrome c oxidase III gene. J Child Neurol. 2011;26:12–20.

    Article  PubMed  Google Scholar 

  77. Tabebi M, Mkaouar-Rebai E, Mnif M, et al. A novel mutation MT-COIII m.9267G>C and MT-COI m.5913G>A mutation in mitochondrial genes in a Tunisian family with maternally inherited diabetes and deafness (MIDD) associated with severe nephropathy. Biochem Biophys Res Commun. 2015;459:353–60.

    Article  CAS  PubMed  Google Scholar 

  78. Inagaki Y, Mashima Y, Fuse N, et al. Mitochondrial DNA mutations with Leber’s hereditary optic neuropathy in Japanese patients with open-angle glaucoma. Jpn J Ophthalmol. 2006;50:128–34.

    Article  CAS  PubMed  Google Scholar 

  79. Abu-Libdeh B, Douiev L, Amro S, et al. Mutation in the COX4I1 gene is associated with short stature, poor weight gain and increased chromosomal breaks, simulating Fanconi anemia. Eur J Hum Genet. 2017;25:1142–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Shteyer E, Saada A, Shaag A, et al. Exocrine pancreatic insufficiency, dyserythropoeitic anemia, and calvarial hyperostosis are caused by a mutation in the COX4I2 gene. Am J Hum Genet. 2009;84:412–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Baertling F, Al-Murshedi F, Sanchez-Caballero L, et al. Mutation in mitochondrial complex IV subunit COX5A causes pulmonary arterial hypertension, lactic acidemia, and failure to thrive. Hum Mutat. 2017;38:692–703.

    Article  CAS  PubMed  Google Scholar 

  82. Abdulhag UN, Soiferman D, Schueler-Furman O, et al. Mitochondrial complex IV deficiency, caused by mutated COX6B1, is associated with encephalomyopathy, hydrocephalus and cardiomyopathy. Eur J Hum Genet. 2015;23:159–64.

    Article  CAS  PubMed  Google Scholar 

  83. Massa V, Fernandez-Vizarra E, Alshahwan S, et al. Severe infantile encephalomyopathy caused by a mutation in COX6B1, a nucleus-encoded subunit of cytochrome c oxidase. Am J Hum Genet. 2008;82:1281–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Indrieri A, van Rahden VA, Tiranti V, et al. Mutations in COX7B cause microphthalmia with linear skin lesions, an unconventional mitochondrial disease. Am J Hum Genet. 2012;91:942–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Hallmann K, Kudin AP, Zsurka G, et al. Loss of the smallest subunit of cytochrome c oxidase, COX8A, causes Leigh-like syndrome and epilepsy. Brain. 2016;139:338–45.

    Article  PubMed  Google Scholar 

  86. Valnot I, von Kleist-Retzow JC, Barrientos A, et al. A mutation in the human heme A:farnesyltransferase gene (COX10 ) causes cytochrome c oxidase deficiency. Hum Mol Genet. 2000;9:1245–9.

    Article  CAS  PubMed  Google Scholar 

  87. Coenen MJ, van den Heuvel LP, Ugalde C, et al. Cytochrome C oxidase biogenesis in a patient with a mutation in COX10 gene. Ann Neurol. 2004;56:560–4.

    Article  CAS  PubMed  Google Scholar 

  88. Reiter LT, Murakami T, Koeuth T, et al. The human COX10 gene is disrupted during homologous recombination between the 24 kb proximal and distal CMT1A-REPs. Hum Mol Genet. 1997;6:1595–603.

    Article  CAS  PubMed  Google Scholar 

  89. Weraarpachai W, Sasarman F, Nishimura T, et al. Mutations in C12orf62, a factor that couples COX I synthesis with cytochrome c oxidase assembly, cause fatal neonatal lactic acidosis. Am J Hum Genet. 2012;90:142–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Oquendo CE, Antonicka H, Shoubridge EA, et al. Functional and genetic studies demonstrate that mutation in the COX15 gene can cause Leigh syndrome. J Med Genet. 2004;41:540–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Antonicka H, Mattman A, Carlson CG, et al. Mutations in COX15 produce a defect in the mitochondrial heme biosynthetic pathway, causing early-onset fatal hypertrophic cardiomyopathy. Am J Hum Genet. 2003;72:101–14.

    Article  CAS  PubMed  Google Scholar 

  92. Piekutowska-Abramczuk D, Popowska E, Pronicki M, et al. High prevalence of SURF1 c.845_846delCT mutation in Polish Leigh patients. Eur J Paediatr Neurol. 2009;13:146–53.

    Article  PubMed  Google Scholar 

  93. Pronicki M, Matyja E, Piekutowska-Abramczuk D, et al. Light and electron microscopy characteristics of the muscle of patients with SURF1 gene mutations associated with Leigh disease. J Clin Pathol. 2008;61:460–6.

    Article  CAS  PubMed  Google Scholar 

  94. Salviati L, Freehauf C, Sacconi S, et al. Novel SURF1 mutation in a child with subacute encephalopathy and without the radiological features of Leigh Syndrome. Am J Med Genet A. 2004;128A:195–8.

    Article  PubMed  Google Scholar 

  95. Moslemi AR, Tulinius M, Darin N, et al. SURF1 gene mutations in three cases with Leigh syndrome and cytochrome c oxidase deficiency. Neurology. 2003;61:991–3.

    Article  CAS  PubMed  Google Scholar 

  96. Piekutowska-Abramczuk D, Magner M, Popowska E, et al. SURF1 missense mutations promote a mild Leigh phenotype. Clin Genet. 2009;76:195–204.

    Article  CAS  PubMed  Google Scholar 

  97. Bundschuh FA, Hannappel A, Anderka O, et al. Surf1, associated with Leigh syndrome in humans, is a heme-binding protein in bacterial oxidase biogenesis. J Biol Chem. 2009;284:25735–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Lee IC, El-Hattab AW, Wang J, et al. SURF1-associated Leigh syndrome: a case series and novel mutations. Hum Mutat. 2012;33:1192–200.

    Article  CAS  PubMed  Google Scholar 

  99. Tanigawa J, Kaneko K, Honda M, et al. Two Japanese patients with Leigh syndrome caused by novel SURF1 mutations. Brain Dev. 2012;34:861–5.

    Article  PubMed  Google Scholar 

  100. Valnot I, Osmond S, Gigarel N, et al. Mutations of the SCO1 gene in mitochondrial cytochrome c oxidase deficiency with neonatal-onset hepatic failure and encephalopathy. Am J Hum Genet. 2000;67:1104–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Wakazono T, Miyake M, Yamashiro K, et al. Association between SCO2 mutation and extreme myopia in Japanese patients. Jpn J Ophthalmol. 2016;60:319–25.

    Article  CAS  PubMed  Google Scholar 

  102. Sambuughin N, Liu X, Bijarnia S, et al. Exome sequencing reveals SCO2 mutations in a family presented with fatal infantile hyperthermia. J Hum Genet. 2013;58:226–8.

    Article  CAS  PubMed  Google Scholar 

  103. Jaksch M, Horvath R, Horn N, et al. Homozygosity (E140K) in SCO2 causes delayed infantile onset of cardiomyopathy and neuropathy. Neurology. 2001;57:1440–6.

    Article  CAS  PubMed  Google Scholar 

  104. Pronicki M, Kowalski P, Piekutowska-Abramczuk D, et al. A homozygous mutation in the SCO2 gene causes a spinal muscular atrophy like presentation with stridor and respiratory insufficiency. Eur J Paediatr Neurol. 2010;14:253–60.

    Article  PubMed  Google Scholar 

  105. Szymanska-Debinska T, Karkucinska-Wieckowska A, Piekutowska-Abramczuk D, et al. Leigh disease due to SCO2 mutations revealed at extended autopsy. J Clin Pathol. 2015;68:397–9.

    Article  CAS  PubMed  Google Scholar 

  106. Tran-Viet KN, Powell C, Barathi VA, et al. Mutations in SCO2 are associated with autosomal-dominant high-grade myopia. Am J Hum Genet. 2013;92:820–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Verdijk RM, de Krijger R, Schoonderwoerd K, et al. Phenotypic consequences of a novel SCO2 gene mutation. Am J Med Genet A. 2008;146A:2822–7.

    Article  CAS  PubMed  Google Scholar 

  108. Vesela K, Hulkova H, Hansikova H, et al. Structural analysis of tissues affected by cytochrome c oxidase deficiency due to mutations in the SCO2 gene. APMIS. 2008;116:41–9.

    Article  PubMed  Google Scholar 

  109. Debray FG, Morin C, Janvier A, et al. LRPPRC mutations cause a phenotypically distinct form of Leigh syndrome with cytochrome c oxidase deficiency. J Med Genet. 2011;48:183–9.

    Article  CAS  PubMed  Google Scholar 

  110. Olahova M, Hardy SA, Hall J, et al. LRPPRC mutations cause early-onset multisystem mitochondrial disease outside of the French-Canadian population. Brain. 2015;138:3503–19.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Seeger J, Schrank B, Pyle A, et al. Clinical and neuropathological findings in patients with TACO1 mutations. Neuromuscul Disord. 2010;20:720–4.

    Article  PubMed  Google Scholar 

  112. Weraarpachai W, Antonicka H, Sasarman F, et al. Mutation in TACO1, encoding a translational activator of COX I, results in cytochrome c oxidase deficiency and late-onset Leigh syndrome. Nat Genet. 2009;41:833–7.

    Article  CAS  PubMed  Google Scholar 

  113. Ghezzi D, Saada A, D'Adamo P, et al. FASTKD2 nonsense mutation in an infantile mitochondrial encephalomyopathy associated with cytochrome c oxidase deficiency. Am J Hum Genet. 2008;83:415–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Jonckheere AI, Renkema GH, Bras M, et al. A complex V ATP5A1 defect causes fatal neonatal mitochondrial encephalopathy. Brain. 2013;136:1544–54.

    Article  PubMed  Google Scholar 

  115. Mayr JA, Havlickova V, Zimmermann F, et al. Mitochondrial ATP synthase deficiency due to a mutation in the ATP5E gene for the F1 epsilon subunit. Hum Mol Genet. 2010;19:3430–9.

    Article  CAS  PubMed  Google Scholar 

  116. Gelfand JM, Duncan JL, Racine CA, et al. Heterogeneous patterns of tissue injury in NARP syndrome. J Neurol. 2011;258:440–8.

    Article  PubMed  Google Scholar 

  117. Jackson CB, Hahn D, Schroter B, et al. A novel mitochondrial ATP6 frameshift mutation causing isolated complex V deficiency, ataxia and encephalomyopathy. Eur J Med Genet. 2017;60:345–51.

    Article  PubMed  Google Scholar 

  118. Alila-Fersi O, Chamkha I, Majdoub I, et al. Co segregation of the m.1555A>G mutation in the MT-RNR1 gene and mutations in MT-ATP6 gene in a family with dilated mitochondrial cardiomyopathy and hearing loss: A whole mitochondrial genome screening. Biochem Biophys Res Commun. 2017;484:71–8.

    Article  CAS  PubMed  Google Scholar 

  119. Lopez-Gallardo E, Emperador S, Solano A, et al. Expanding the clinical phenotypes of MT-ATP6 mutations. Hum Mol Genet. 2014;23:6191–200.

    Article  CAS  PubMed  Google Scholar 

  120. Honzik T, Tesarova M, Vinsova K, et al. Different laboratory and muscle biopsy findings in a family with an m.8851T>C mutation in the mitochondrial MTATP6 gene. Mol Genet Metab. 2013;108:102–5.

    Article  CAS  PubMed  Google Scholar 

  121. Synofzik M, Schicks J, Wilhelm C,et al. Charcot-Marie-Tooth hereditary neuropathy due to a mitochondrial ATP6 mutation. Eur J Neurol. 2012;19:e114–6.

    Article  PubMed  Google Scholar 

  122. Pitceathly RD, Murphy SM, Cottenie E, et al. Genetic dysfunction of MT-ATP6 causes axonal Charcot-Marie-Tooth disease. Neurology. 2012;79:1145–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Kara B, Arikan M, Maras H, et al. Whole mitochondrial genome analysis of a family with NARP/MILS caused by m.8993T>C mutation in the MT-ATP6 gene. Mol Genet Metab. 2012;107:389–93.

    Article  CAS  PubMed  Google Scholar 

  124. Song S, Pursell ZF, Copeland WC, et al. DNA precursor asymmetries in mammalian tissue mitochondria and possible contribution to mutagenesis through reduced replication fidelity. Proc Natl Acad Sci U S A. 2005;102:4990–5.

    Article  CAS  Google Scholar 

  125. Da Pozzo P, Cardaioli E, Rubegni A, et al. Novel POLG mutations and variable clinical phenotypes in 13 Italian patients. Neurol Sci. 2017;38:563–70.

    Article  PubMed  Google Scholar 

  126. Rajakulendran S, Pitceathly RD, Taanman JW, et al. A Clinical, Neuropathological and Genetic Study of Homozygous A467T POLG-Related Mitochondrial Disease. PLoS One. 2016;11:e0145500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Bereau M, Anheim M, Echaniz-Laguna A, et al. The wide POLG-related spectrum: An integrated view. J Neurol Sci. 2016;368:70–6.

    Article  CAS  PubMed  Google Scholar 

  128. Siibak T, Clemente P, Bratic A, et al. A multi-systemic mitochondrial disorder due to a dominant p.Y955H disease variant in DNA polymerase gamma. Hum Mol Genet. 2017;26:2515–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Delgado-Alvarado M, de la Riva P, Jimenez-Urbieta H, et al. Parkinsonism, cognitive deficit and behavioural disturbance caused by a novel mutation in the polymerase gamma gene. J Neurol Sci. 2015;350:93–7.

    Article  CAS  PubMed  Google Scholar 

  130. Longley MJ, Clark S, Yu Wai Man C, et al. Mutant POLG2 disrupts DNA polymerase gamma subunits and causes progressive external ophthalmoplegia. Am J Hum Genet. 2006;78:1026–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Varma H, Faust PL, Iglesias AD, et al. Whole exome sequencing identifies a homozygous POLG2 missense variant in an infant with fulminant hepatic failure and mitochondrial DNA depletion. Eur J Med Genet. 2016;59:540–5.

    Article  PubMed  PubMed Central  Google Scholar 

  132. Thompson K, Majd H, Dallabona C, et al. Recurrent De Novo Dominant Mutations in SLC25A4 cause severe early-onset mitochondrial disease and loss of mitochondrial DNA copy number. Am J Hum Genet. 2016;99:860–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Bakker HD, Scholte HR, Van den Bogert C, et al. Deficiency of the adenine nucleotide translocator in muscle of a patient with myopathy and lactic acidosis: a new mitochondrial defect. Pediatr Res. 1993;33:412–7.

    CAS  PubMed  Google Scholar 

  134. Demain LA, Urquhart JE, O'Sullivan J, et al. Expanding the genotypic spectrum of Perrault syndrome. Clin Genet. 2017;91:302–12.

    Article  CAS  PubMed  Google Scholar 

  135. Baloh RH, Salavaggione E, Milbrandt J, et al. Familial parkinsonism and ophthalmoplegia from a mutation in the mitochondrial DNA helicase twinkle. Arch Neurol. 2007;64:998–1000.

    Article  PubMed  Google Scholar 

  136. Rivera H, Blazquez A, Carretero J, et al. Mild ocular myopathy associated with a novel mutation in mitochondrial twinkle helicase. Neuromuscul Disord. 2007;17:677–80.

    Article  PubMed  Google Scholar 

  137. Vandenberghe W, Van Laere K, Debruyne F, et al. Neurodegenerative Parkinsonism and progressive external ophthalmoplegia with a Twinkle mutation. Mov Disord. 2009;24:308–9.

    Article  PubMed  Google Scholar 

  138. Oldak M, Ozieblo D, Pollak A, et al. Novel neuro-audiological findings and further evidence for TWNK involvement in Perrault syndrome. J Transl Med. 2017;15:25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Dimmock D, Tang LY, Schmitt ES, et al. Quantitative evaluation of the mitochondrial DNA depletion syndrome. Clin Chem. 2010;56:1119–27.

    Article  CAS  PubMed  Google Scholar 

  140. Lonnqvist T, Paetau A, Valanne L, et al. Recessive twinkle mutations cause severe epileptic encephalopathy. Brain. 2009;132:1553–62.

    Article  PubMed  Google Scholar 

  141. Hakonen AH, Isohanni P, Paetau A, et al. Recessive Twinkle mutations in early onset encephalopathy with mtDNA depletion. Brain. 2007;130:3032–40.

    Article  PubMed  Google Scholar 

  142. Sarzi E, Goffart S, Serre V, et al. Twinkle helicase (PEO1) gene mutation causes mitochondrial DNA depletion. Ann Neurol. 2007;62:579–87.

    Article  CAS  PubMed  Google Scholar 

  143. Tyynismaa H, Ylikallio E, Patel M, et al. A heterozygous truncating mutation in RRM2B causes autosomal-dominant progressive external ophthalmoplegia with multiple mtDNA deletions. Am J Hum Genet. 2009;85:290–5.

    Article  CAS  PubMed  Google Scholar 

  144. Pitceathly RD, Fassone E, Taanman JW, et al. Kearns-Sayre syndrome caused by defective R1/p53R2 assembly. J Med Genet. 2011;48:610–7.

    Article  CAS  PubMed  Google Scholar 

  145. Bornstein B, Area E, Flanigan KM, et al. Mitochondrial DNA depletion syndrome due to mutations in the RRM2B gene. Neuromuscul Disord. 2008;18:453–9.

    Article  PubMed  PubMed Central  Google Scholar 

  146. Shaibani A, Shchelochkov OA, Zhang S, et al. Mitochondrial neurogastrointestinal encephalopathy due to mutations in RRM2B. Arch Neurol. 2009;66:1028–32.

    Article  PubMed  PubMed Central  Google Scholar 

  147. Fratter C, Raman P, Alston CL, et al. RRM2B mutations are frequent in familial PEO with multiple mtDNA deletions. Neurology. 2011;76:2032–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Alston CL, Schaefer AM, Raman P, et al. Late-onset respiratory failure due to TK2 mutations causing multiple mtDNA deletions. Neurology. 2013;81:2051–3.

    Article  PubMed  PubMed Central  Google Scholar 

  149. Chanprasert S, Wang J, Weng SW, et al. Molecular and clinical characterization of the myopathic form of mitochondrial DNA depletion syndrome caused by mutations in the thymidine kinase (TK2) gene. Mol Genet Metab. 2013;110:153–61.

    Article  CAS  PubMed  Google Scholar 

  150. Blakely E, He L, Gardner JL, et al. Novel mutations in the TK2 gene associated with fatal mitochondrial DNA depletion myopathy. Neuromuscul Disord. 2008;18:557–60.

    Article  PubMed  Google Scholar 

  151. Camara Y, Carreno-Gago L, Martin MA, et al. Severe TK2 enzyme activity deficiency in patients with mild forms of myopathy. Neurology. 2015;84:2286–8.

    Article  PubMed  Google Scholar 

  152. Couser NL, Marchuk DS, Smith LD, et al. Co-occurring down syndrome and SUCLA2-related mitochondrial depletion syndrome. Am J Med Genet A. 2017;173:2720–4.

    Article  CAS  PubMed  Google Scholar 

  153. Elpeleg O, Miller C, Hershkovitz E, et al. Deficiency of the ADP-forming succinyl-CoA synthase activity is associated with encephalomyopathy and mitochondrial DNA depletion. Am J Hum Genet. 2005;76:1081–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Ostergaard E. Disorders caused by deficiency of succinate-CoA ligase. J Inherit Metab Dis. 2008;31:226–9.

    Article  CAS  PubMed  Google Scholar 

  155. Navarro-Sastre A, Tort F, Garcia-Villoria J, et al. Mitochondrial DNA depletion syndrome: new descriptions and the use of citrate synthase as a helpful tool to better characterise the patients. Mol Genet Metab. 2012;107:409–15.

    Article  CAS  PubMed  Google Scholar 

  156. Matilainen S, Isohanni P, Euro L, et al. Mitochondrial encephalomyopathy and retinoblastoma explained by compound heterozygosity of SUCLA2 point mutation and 13q14 deletion. Eur J Hum Genet. 2015;23:325–30.

    Article  CAS  PubMed  Google Scholar 

  157. Jaberi E, Chitsazian F, Ali Shahidi G, et al. The novel mutation p.Asp251Asn in the beta-subunit of succinate-CoA ligase causes encephalomyopathy and elevated succinylcarnitine. J Hum Genet. 2013;58:526–30.

    Article  CAS  PubMed  Google Scholar 

  158. Gaier ED, Boudreault K, Nakata I, et al. Diagnostic genetic testing for patients with bilateral optic neuropathy and comparison of clinical features according to OPA1 mutation status. Mol Vis. 2017;23:548–60.

    PubMed  PubMed Central  Google Scholar 

  159. Spiegel R, Saada A, Flannery PJ, et al. Fatal infantile mitochondrial encephalomyopathy, hypertrophic cardiomyopathy and optic atrophy associated with a homozygous OPA1 mutation. J Med Genet. 2016;53:127–31.

    Article  CAS  PubMed  Google Scholar 

  160. Hayashi T, Sasano H, Katagiri S, et al. Heterozygous deletion of the OPA1 gene in patients with dominant optic atrophy. Jpn J Ophthalmol. 2017;61:395–401.

    Article  CAS  PubMed  Google Scholar 

  161. Liskova P, Tesarova M, Dudakova L, et al. OPA1 analysis in an international series of probands with bilateral optic atrophy. Acta Ophthalmol. 2017;95:363–9.

    Article  CAS  PubMed  Google Scholar 

  162. Carelli V, Musumeci O, Caporali L, et al. Syndromic parkinsonism and dementia associated with OPA1 missense mutations. Ann Neurol. 2015;78:21–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Zsurka G, Hampel KG, Nelson I, et al. Severe epilepsy as the major symptom of new mutations in the mitochondrial tRNA(Phe) gene. Neurology. 2010;74:507–12.

    Article  CAS  PubMed  Google Scholar 

  164. Moslemi AR, Lindberg C, Toft J, et al. A novel mutation in the mitochondrial tRNA(Phe) gene associated with mitochondrial myopathy. Neuromuscul Disord. 2004;14:46–50.

    Article  PubMed  Google Scholar 

  165. Charif M, Titah SM, Roubertie A, et al. Optic neuropathy, cardiomyopathy, cognitive disability in patients with a homozygous mutation in the nuclear MTO1 and a mitochondrial MT-TF variant. Am J Med Genet A. 2015;167A:2366–74.

    Article  CAS  PubMed  Google Scholar 

  166. DiMauro S, Hirano M. MERRF. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews((R)). Seattle: University of Washington; 1993.

    Google Scholar 

  167. DiMauro S, Hirano M. MELAS. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews((R)). Seattle: University of Washington; 1993.

    Google Scholar 

  168. Chinnery PF. Mitochondrial Disorders Overview. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews((R)). Seattle: University of Washington; 1993.

    Google Scholar 

  169. Guo L, Yuan Y, Bi R. Mitochondrial DNA mutation m.5512A>G in the acceptor-stem of mitochondrial tRNA(Trp) causing maternally inherited essential hypertension. Biochem Biophys Res Commun. 2016;479:800–7.

    Article  CAS  PubMed  Google Scholar 

  170. Duff RM, Shearwood AM, Ermer J, et al. A mutation in MT-TW causes a tRNA processing defect and reduced mitochondrial function in a family with Leigh syndrome. Mitochondrion. 2015;25:113–9.

    Article  CAS  PubMed  Google Scholar 

  171. Mkaouar-Rebai E, Chamkha I, Kammoun F, et al. Two new mutations in the MT-TW gene leading to the disruption of the secondary structure of the tRNA(Trp) in patients with Leigh syndrome. Mol Genet Metab. 2009;97:179–84.

    Article  CAS  PubMed  Google Scholar 

  172. Wang M, Peng Y, Zheng J, et al. A deafness-associated tRNAAsp mutation alters the m1G37 modification, aminoacylation and stability of tRNAAsp and mitochondrial function. Nucleic Acids Res. 2016;44:10974–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Martin-Jimenez R, Martin-Hernandez E, Cabello A, et al. Clinical and cellular consequences of the mutation m.12300G>A in the mitochondrial tRNA(Leu(CUN)) gene. Mitochondrion. 2012;12:288–93.

    Article  CAS  PubMed  Google Scholar 

  174. Cardaioli E, Da Pozzo P, Malfatti E, et al. Chronic progressive external ophthalmoplegia: a new heteroplasmic tRNA(Leu(CUN)) mutation of mitochondrial DNA. J Neurol Sci. 2008;272:106–9.

    Article  CAS  PubMed  Google Scholar 

  175. Jiang Y, Ellis T, Greenlee AR. Genotyping Parkinson disease-associated mitochondrial polymorphisms. Clin Med Res. 2004;2:99–106.

    Article  PubMed  PubMed Central  Google Scholar 

  176. Kato T, Nishigaki Y, Noguchi Y, et al. Extensive and rapid screening for major mitochondrial DNA point mutations in patients with hereditary hearing loss. J Hum Genet. 2010;55:147–54.

    Article  CAS  PubMed  Google Scholar 

  177. Fraidakis MJ, Jardel C, Allouche S, et al. Phenotypic diversity associated with the MT-TV gene m.1644G>A mutation, a matter of quantity. Mitochondrion. 2014;15:34–9.

    Article  CAS  PubMed  Google Scholar 

  178. Menotti F, Brega A, Diegoli M, et al. A novel mtDNA point mutation in tRNA(Val) is associated with hypertrophic cardiomyopathy and MELAS. Ital Heart J. 2004;5:460–5.

    Google Scholar 

  179. Xu Y, Chen X, Huang H, et al. The mitochondrial tRNA(Ala) T5655C mutation may modulate the phenotypic expression of tRNA(Met) and tRNA(Gln) A4401G mutation in a Han Chinese family with essential hypertension. Int Heart J. 2017;58:95–9.

    Google Scholar 

  180. Jiang P, Wang M, Xue L, et al. A hypertension-associated tRNAAla mutation alters tRNA metabolism and mitochondrial function. Mol Cell Biol. 2016;36:1920–30.

    Article  PubMed  PubMed Central  Google Scholar 

  181. Gamba J, Kiyomoto BH, de Oliveira AS, et al. The mutations m.5628T>C and m.8348A>G in single muscle fibers of a patient with chronic progressive external ophthalmoplegia. J Neurol Sci. 2012;320:131–5.

    Article  CAS  PubMed  Google Scholar 

  182. Lehmann D, Schubert K, Joshi PR, et al. Pathogenic mitochondrial mt-tRNA(Ala) variants are uniquely associated with isolated myopathy. Eur J Hum Genet. 2015;23:1735–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Altmann J, Buchner B, Nadaj-Pakleza A, et al. Expanded phenotypic spectrum of the m.8344A>G “MERRF” mutation: data from the German mitoNET registry. J Neurol. 2016;263:961–72.

    Article  CAS  PubMed  Google Scholar 

  184. Virgilio R, Ronchi D, Bordoni A, et al. Mitochondrial DNA G8363A mutation in the tRNA Lys gene: clinical, biochemical and pathological study. J Neurol Sci. 2009;281:85–92.

    Article  CAS  PubMed  Google Scholar 

  185. Molnar MJ, Perenyi J, Siska E, et al. The typical MERRF (A8344G) mutation of the mitochondrial DNA associated with depressive mood disorders. J Neurol. 2009;256:264–5.

    Article  PubMed  Google Scholar 

  186. Zaganas I, Latsoudis H, Papadaki E, et al. A8344G tRNALys mutation associated with recurrent brain stem stroke-like episodes. J Neurol. 2009;256:271–3.

    Article  PubMed  Google Scholar 

  187. Blakely EL, Swalwell H, Petty RK, et al. Sporadic myopathy and exercise intolerance associated with the mitochondrial 8328G>A tRNALys mutation. J Neurol. 2007;254:1283–5.

    Article  CAS  PubMed  Google Scholar 

  188. van de Glind G, de Vries M, Rodenburg R, et al. Resting muscle pain as the first clinical symptom in children carrying the MTTK A8344G mutation. Eur J Paediatr Neurol. 2007;11:243–6.

    Google Scholar 

  189. Gambello MJ, Bai RK, Chen TJ, et al. Exercise intolerance associated with a novel 8300T>C mutation in mitochondrial transfer RNAlys. Muscle Nerve. 2006;34:437–43.

    Article  CAS  Google Scholar 

  190. Nakamura M, Yabe I, Sudo A, et al. MERRF/MELAS overlap syndrome: a double pathogenic mutation in mitochondrial tRNA genes. J Med Genet. 2010;47:659–64.

    Article  CAS  PubMed  Google Scholar 

  191. Fan H, Civalier C, Booker JK, et al. Detection of common disease-causing mutations in mitochondrial DNA (mitochondrial encephalomyopathy, lactic acidosis with stroke-like episodes MTTL1 3243 A>G and myoclonic epilepsy associated with ragged-red fibers MTTK 8344A>G) by real-time polymerase chain reaction. J Mol Diagn. 2006;8:277–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Mezghani N, Mkaouar-Rebai E, Mnif M, et al. The heteroplasmic m.14709T>C mutation in the tRNA(Glu) gene in two Tunisian families with mitochondrial diabetes. J Diabetes Complicat. 2010;24:270–7.

    Article  Google Scholar 

  193. Meulemans A, Seneca S, Smet J, et al. A new family with the mitochondrial tRNAGLU gene mutation m.14709T>C presenting with hydrops fetalis. Eur J Paediatr Neurol. 2007;11:17–20.

    Article  PubMed  Google Scholar 

  194. Uusimaa J, Finnila S, Remes AM, et al. Molecular epidemiology of childhood mitochondrial encephalomyopathies in a Finnish population: sequence analysis of entire mtDNA of 17 children reveals heteroplasmic mutations in tRNAArg, tRNAGlu, and tRNALeu(UUR) genes. Pediatrics. 2004;114:443–50.

    Article  PubMed  Google Scholar 

  195. Zhou M, Wang M, Xue L, et al. A hypertension-associated mitochondrial DNA mutation alters the tertiary interaction and function of tRNA(Leu(UUR)). J Biol Chem. 2017;292:13934–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Zhu J, Yang P, Liu X, et al. The clinical characteristics of patients with mitochondrial tRNA Leu(UUR)m.3243A > G mutation: compared with type 1 diabetes and early onset type 2 diabetes. J Diabetes Complicat. 2017;31:1354–9.

    Article  Google Scholar 

  197. Ng YS, Feeney C, Schaefer AM, et al. Pseudo-obstruction, stroke, and mitochondrial dysfunction: A lethal combination. Ann Neurol. 2016;80:686–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Prasad M, Narayan B, Prasad AN, et al. MELAS: A Multigenerational Impact of the MTTL1 A3243G MELAS Mutation. Can J Neurol Sci. 2014;41:210–9.

    Article  CAS  PubMed  Google Scholar 

  199. Liu K, Zhao H, Ji K, et al. MERRF/MELAS overlap syndrome due to the m.3291T>C mutation. Metab Brain Dis. 2014;29:139–44.

    Article  CAS  PubMed  Google Scholar 

  200. de Laat P, Smeitink JA, Janssen MC, et al. Mitochondrial retinal dystrophy associated with the m.3243A>G mutation. Ophthalmology. 2013;120:2684–96.

    Article  PubMed  Google Scholar 

  201. Nesbitt V, Pitceathly RD, Turnbull DM, et al. The UK MRC mitochondrial disease patient cohort study: clinical phenotypes associated with the m.3243A>G mutation--implications for diagnosis and management. J Neurol Neurosurg Psychiatry. 2013;84:936–8.

    Article  PubMed  Google Scholar 

  202. Garcia-Lozano JR, Mir P, Alberca R, et al. Mitochondrial DNA A4336G mutation in Alzheimer's and Parkinson's diseases. Eur Neurol. 2002;48:34–6.

    Article  CAS  PubMed  Google Scholar 

  203. Ding Y, Li Y, You J, et al. Mitochondrial tRNA(Glu) A14693G variant may modulate the phenotypic manifestation of deafness-associated 12S rRNA A1555G mutation in a Han Chinese family. J Genet Genomics. 2009;36:241–50.

    Article  CAS  PubMed  Google Scholar 

  204. Zhang Y, Zhang JJ, Ji YC, et al. The mitochondrial tRNA(Thr) A15951G mutation may be associated with Leber’s hereditary optic neuropathy in two Chinese families. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2011;28:501–6.

    PubMed  Google Scholar 

  205. Momiyama Y, Furutani M, Suzuki Y, et al. A mitochondrial DNA variant associated with left ventricular hypertrophy in diabetes. Biochem Biophys Res Commun. 2003;312:858–64.

    Article  CAS  PubMed  Google Scholar 

  206. Jackson CB, Neuwirth C, Hahn D, et al. Novel mitochondrial tRNA(Ile) m.4282A>G gene mutation leads to chronic progressive external ophthalmoplegia plus phenotype. Br J Ophthalmol. 2014;98:1453–9.

    Article  PubMed  Google Scholar 

  207. Martikainen MH, Kytovuori L, Majamaa K. Juvenile parkinsonism, hypogonadism and Leigh-like MRI changes in a patient with m.4296G>A mutation in mitochondrial DNA. Mitochondrion. 2013;13:83–6.

    Article  CAS  PubMed  Google Scholar 

  208. Cox R, Platt J, Chen LC, et al. Leigh syndrome caused by a novel m.4296G>A mutation in mitochondrial tRNA isoleucine. Mitochondrion. 2012;12:258–61.

    Article  CAS  PubMed  Google Scholar 

  209. Wang S, Li R, Fettermann A, et al. Maternally inherited essential hypertension is associated with the novel 4263A>G mutation in the mitochondrial tRNAIle gene in a large Han Chinese family. Circ Res. 2011;108:862–70.

    Article  CAS  PubMed  Google Scholar 

  210. Schaller A, Desetty R, Hahn D, et al. Impairment of mitochondrial tRNAIle processing by a novel mutation associated with chronic progressive external ophthalmoplegia. Mitochondrion. 2011;11:488–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Mahjoub S, Sternberg D, Boussaada R, et al. A novel mitochondrial DNA tRNAIle (m.4322dupC) mutation associated with idiopathic dilated cardiomyopathy. Diagn Mol Pathol. 2007;16:238–42.

    Article  CAS  PubMed  Google Scholar 

  212. Smits BW, Hol FA, van den Heuvel LP, et al. Chronic progressive external ophthalmoplegia caused by an m.4267A > G mutation in the mitochondrial tRNAIle. J Neurol. 2007;254:1614–5.

    Article  PubMed  Google Scholar 

  213. Wang F, Huang GD, Tian H, et al. Point mutations in KAL1 and the mitochondrial gene MT-tRNA(cys) synergize to produce Kallmann syndrome phenotype. Sci Rep. 2015;5:13050.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Roos S, Darin N, Kollberg G, et al. A novel mitochondrial tRNA Arg mutation resulting in an anticodon swap in a patient with mitochondrial encephalomyopathy. Eur J Hum Genet. 2013;21:571–3.

    Article  CAS  PubMed  Google Scholar 

  215. Gong S, Peng Y, Jiang P, et al. A deafness-associated tRNAHis mutation alters the mitochondrial function, ROS production and membrane potential. Nucleic Acids Res. 2014;42:8039–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Lu Z, Chen H, Meng Y, et al. The tRNAMet 4435A>G mutation in the mitochondrial haplogroup G2a1 is responsible for maternally inherited hypertension in a Chinese pedigree. Eur J Hum Genet. 2011;19:1181–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Gotz A, Isohanni P, Liljestrom B, et al. Fatal neonatal lactic acidosis caused by a novel de novo mitochondrial G7453A tRNA-Serine ((UCN)) mutation. Pediatr Res. 2012;72:90–4.

    Article  CAS  PubMed  Google Scholar 

  218. Labay V, Garrido G, Madeo AC, et al. Haplogroup analysis supports a pathogenic role for the 7510T>C mutation of mitochondrial tRNA(Ser(UCN)) in sensorineural hearing loss. Clin Genet. 2008;73:50–4.

    Article  CAS  PubMed  Google Scholar 

  219. Lindberg C, Moslemi AR, Oldfors A. MELAS syndrome in a patient with a point mutation in MTTS1. Acta Neurol Scand. 2008;117:128–32.

    CAS  PubMed  Google Scholar 

  220. Bidooki S, Jackson MJ, Johnson MA, et al. Sporadic mitochondrial myopathy due to a new mutation in the mitochondrial tRNASer(UCN) gene. Neuromuscul Disord. 2004;14:417–20.

    Article  PubMed  Google Scholar 

  221. Chen DY, Zhu WD, Chai YC, et al. Mutation in PCDH15 may modify the phenotypic expression of the 7511T>C mutation in MT-TS1 in a Chinese Han family with maternally inherited nonsyndromic hearing loss. Int J Pediatr Otorhinolaryngol. 2015;79:1654–7.

    Article  PubMed  Google Scholar 

  222. Subathra M, Selvakumari M, Ramesh A, et al. Complete mitochondrial genome analysis and clinical documentation of a five-generational Indian family with mitochondrial 1555A>G mutation and postlingual hearing loss. Ann Hum Genet. 2014;78:217–34.

    Article  CAS  PubMed  Google Scholar 

  223. Barbarino JM, McGregor TL, Altman RB, et al. PharmGKB summary: very important pharmacogene information for MT-RNR1. Pharmacogenet Genomics. 2016;26:558–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Aoyama C, Liao H, Ishidate K. Structure and function of choline kinase isoforms in mammalian cells. Prog Lipid Res. 2004;43:266–81.

    Article  CAS  PubMed  Google Scholar 

  225. Wu G, Vance DE. Choline kinase and its function. Biochem Cell Biol. 2010;88:559–64.

    Article  CAS  PubMed  Google Scholar 

  226. Mitsuhashi S, Ohkuma A, Talim B, et al. A congenital muscular dystrophy with mitochondrial structural abnormalities caused by defective de novo phosphatidylcholine biosynthesis. Am J Hum Genet. 2011;88:845–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Oliveira J, Negrao L, Fineza I, et al. New splicing mutation in the choline kinase beta (CHKB) gene causing a muscular dystrophy detected by whole-exome sequencing. J Hum Genet. 2015;60:305–12.

    Article  CAS  PubMed  Google Scholar 

  228. Mitsuhashi S, Nishino I. Megaconial congenital muscular dystrophy due to loss-of-function mutations in choline kinase beta. Curr Opin Neurol. 2013;26:536–43.

    Article  CAS  PubMed  Google Scholar 

  229. Nishino I, Kobayashi O, Goto Y, et al. A new congenital muscular dystrophy with mitochondrial structural abnormalities. Muscle Nerve. 1998;21:40–7.

    Article  CAS  PubMed  Google Scholar 

  230. Haliloglu G, Talim B, Sel CG, et al. Clinical characteristics of megaconial congenital muscular dystrophy due to choline kinase beta gene defects in a series of 15 patients. J Inherit Metab Dis. 2015;38:1099–108.

    Article  CAS  PubMed  Google Scholar 

  231. Vanlander AV, Muino Mosquera L, Panzer J, et al. Megaconial muscular dystrophy caused by mitochondrial membrane homeostasis defect, new insights from skeletal and heart muscle analyses. Mitochondrion. 2016;27:32–8.

    Article  CAS  PubMed  Google Scholar 

  232. Mitochondrial Medicine Society's Committee on Diagnosis, Haas RH, Parikh S, et al. The in-depth evaluation of suspected mitochondrial disease. Mol Genet Metab. 2008;94:16–37.

    Article  CAS  Google Scholar 

  233. Wolf NI, Smeitink JA. Mitochondrial disorders: a proposal for consensus diagnostic criteria in infants and children. Neurology. 2002;59:1402–5.

    Article  PubMed  Google Scholar 

  234. Milone M, Wong LJ. Diagnosis of mitochondrial myopathies. Mol Genet Metab. 2013;110:35–41.

    Article  CAS  PubMed  Google Scholar 

  235. Coon KD, Valla J, Szelinger S, et al. Quantitation of heteroplasmy of mtDNA sequence variants identified in a population of AD patients and controls by array-based resequencing. Mitochondrion. 2006;6:194–210.

    Article  CAS  PubMed  Google Scholar 

  236. Moraes CT, Atencio DP, Oca-Cossio J, et al. Techniques and pitfalls in the detection of pathogenic mitochondrial DNA mutations. J Mol Diagn. 2003;5:197–208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Parikh S, Goldstein A, Koenig MK, et al. Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med. 2015;17:689–701.

    Article  CAS  PubMed  Google Scholar 

  238. Vincent AE, Ng YS, White K, et al. The spectrum of mitochondrial ultrastructural defects in mitochondrial myopathy. Sci Rep. 2016;6:30610.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Mun JY, Jung MK, Kim SH, et al. Ultrastructural changes in skeletal muscle of infants with mitochondrial respiratory chain complex I defects. J Clin Neurol. 2017;13:359–65.

    Article  PubMed  PubMed Central  Google Scholar 

  240. Kyriacou K, Kyriakides T. Mitochondrial encephalomyopathies: a review of routine morphological diagnostic methods with emphasis on the role of electron microscopy. J Submicrosc Cytol Pathol. 2006;38:201–8.

    CAS  PubMed  Google Scholar 

  241. Punsoni M, Mangray S, Lombardo KA, et al. Succinate dehydrogenase B (SDHB) immunohistochemistry for the evaluation of muscle biopsies. Appl Immunohistochem Mol Morphol. 2017;25:645–50.

    Article  CAS  Google Scholar 

  242. Rocha MC, Grady JP, Grunewald A, et al. A novel immunofluorescent assay to investigate oxidative phosphorylation deficiency in mitochondrial myopathy: understanding mechanisms and improving diagnosis. Sci Rep. 2015;5:15037.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Tanaka M, Nishikimi M, Suzuki H, et al. Deficiency of subunits of complex I or IV in mitochondrial myopathies: immunochemical and immunohistochemical study. J Inherit Metab Dis. 1987;10:284–8.

    Article  CAS  PubMed  Google Scholar 

  244. Morgan-Hughes JA, Schapira AH, Cooper JM, et al. The molecular pathology of respiratory-chain dysfunction in human mitochondrial myopathies. Biochim Biophys Acta. 1990;1018:217–22.

    Article  CAS  Google Scholar 

  245. Takamiya S, Yanamura W, Capaldi RA, et al. Mitochondrial myopathies involving the respiratory chain: a biochemical analysis. Ann N Y Acad Sci. 1986;488:33–43.

    Article  CAS  PubMed  Google Scholar 

  246. Bindoff LA, Turnbull DM. Defects of the respiratory chain. Bailliere Clin Endocrinol Metab. 1990;4:583–619.

    Article  CAS  Google Scholar 

  247. Bernier FP, Boneh A, Dennett X, et al. Diagnostic criteria for respiratory chain disorders in adults and children. Neurology. 2002;59:1406–11.

    Article  CAS  PubMed  Google Scholar 

  248. Smeitink J, van den Heuvel L, DiMauro S. The genetics and pathology of oxidative phosphorylation. Nat Rev Genet. 2001;2:342–52.

    Article  CAS  PubMed  Google Scholar 

  249. Wong LJ, Scaglia F, Graham BH, et al. Current molecular diagnostic algorithm for mitochondrial disorders. Mol Genet Metab. 2010;100:111–7.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

    Balan Louis Gaspar & Rakesh Kumar Vasishta

  2. Division of Neuropathology, Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

    Bishan Dass Radotra

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  1. Balan Louis Gaspar
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Gaspar, B.L., Vasishta, R.K., Radotra, B.D. (2019). Mitochondrial Myopathies and Related Diseases. In: Myopathology. Springer, Singapore. https://doi.org/10.1007/978-981-13-1462-9_10

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