Diagnosis and management of mitochondrial disease: A consensus statement from the Mitochondrial Medicine Society

Genetics in Medicine

Volumn 17, Issue 9, 2015, Pages 689-701

  Parikh, Sumit ^a   Goldstein, Amy ^b   Koenig, Mary Kay ^c   Scaglia, Fernando ^d   Enns, Gregory M ^e   Saneto, Russell ^f   Anselm, Irina ^g   Cohen, Bruce H ^h   Falk, Marni J ⁱ   Greene, Carol ^j   Gropman, Andrea L ^k   Haas, Richard ^l   Hirano, Michio ^m   Morgan, Phil ⁿ   Sims, Katherine ^o   Tarnopolsky, Mark ^p   Van Hove, Johan L K ^q   Wolfe, Lynne ^r   DiMauro, Salvatore ^s  

^a LERNER RESEARCH INSTITUTE   (United States)

^b CHILDREN S HOSPITAL OF PITTSBURGH   (United States)

^c UNIVERSITY OF TEXAS MEDICAL SCHOOL   (United States)

^d TEXAS CHILDREN S HOSPITAL   (United States)

^e LUCILE PACKARD CHILDREN S HOSPITAL   (United States)

^f UNIVERSITY OF WASHINGTON   (United States)

^g BOSTON CHILDREN S HOSPITAL   (United States)

^h AKRON CHILDREN'S HOSPITAL   (United States)

ⁱ UNIVERSITY OF PENNSYLVANIA   (United States)

^j UNIVERSITY OF MARYLAND MEDICAL CENTER   (United States)

^k GEORGE WASHINGTON UNIVERSITY   (United States)

^l RADY CHILDREN'S HOSPITAL   (United States)

^m Department of Neurology ^*  (United States)

ⁿ SEATTLE CHILDREN S HOSPITAL   (United States)

^o MASSACHUSETTS GENERAL HOSPITAL   (United States)

^p MCMASTER UNIVERSITY   (Canada)

^q CHILDREN S HOSPITAL   (United States)

^r NATIONAL INSTITUTES OF HEALTH   (United States)

^s NewYork Presbyterian Hospital   (United States)

more..

Author keywords

Consensus criteria; Delphi method; mitochondrial disease; mitochondrial medicine; Mitochondrial Medicine Society

Indexed keywords

5 METHYLTETRAHYDROFOLIC ACID; ALBUMIN; AMINOTRANSFERASE; ARGININE; CARNITINE; CITRULLINE; CREATINE KINASE; CYTOCHROME C OXIDASE; FUMARIC ACID; LACTIC ACID; MALIC ACID; MITOCHONDRIAL DNA; MUSCLE RELAXANT AGENT; NARCOTIC AGENT; PYRUVIC ACID; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE DEHYDROGENASE (UBIQUINONE); SUCCINATE DEHYDROGENASE (UBIQUINONE); UBIDECARENONE; UBIQUINOL CYTOCHROME C REDUCTASE; URIC ACID; VITAMIN; XENOBIOTIC AGENT;

ACUTE DISEASE; AMINO ACID ANALYSIS; ANESTHESIA; BLOOD ANALYSIS; CEREBROSPINAL FLUID ANALYSIS; CEREBROVASCULAR ACCIDENT; CLINICAL PRACTICE; COMPUTER ASSISTED TOMOGRAPHY; DELPHI STUDY; DISORDERS OF MITOCHONDRIAL FUNCTIONS; DNA DETERMINATION; EVIDENCE BASED MEDICINE; EXERCISE; FATTY ACID OXIDATION; FOLIC ACID DEFICIENCY; GENOME ANALYSIS; HETEROPLASMY; HUMAN; LACTATE BLOOD LEVEL; LIVER DYSFUNCTION; MELAS SYNDROME; MITOCHONDRIAL DNA DEPLETION; MITOCHONDRIAL DNA DEPLETION SYNDROME; MITOCHONDRIAL GENOME; MUSCLE BIOPSY; NEUROIMAGING; NONHUMAN; NUCLEAR MAGNETIC RESONANCE IMAGING; POINT MUTATION; RESPIRATION DEPRESSION; REVIEW; RHABDOMYOLYSIS; URINALYSIS; VITAMIN SUPPLEMENTATION; CONSENSUS; MITOCHONDRIAL DISEASES; TREATMENT OUTCOME;

CONSENSUS; DELPHI TECHNIQUE; EVIDENCE-BASED MEDICINE; HUMANS; MITOCHONDRIAL DISEASES; TREATMENT OUTCOME;

EID: 84940939416     PISSN: 10983600     EISSN: 15300366     Source Type: Journal    
DOI: 10.1038/gim.2014.177     Document Type: Review

References (164)

1. Chinnery PF. Mitochondrial disorders overview. In: Pagon RA, Adam MP, Ardinger HH, et al. (eds). GeneReviews. University of Washington: Seattle, WA, 1993-2014.
2. Parikh S, Goldstein A, Koenig MK, et al. Practice patterns of mitochondrial disease physicians in North America. Part 1: diagnostic and clinical challenges. Mitochondrion 2014;14:26-33.
3. Haas RH, Parikh S, Falk MJ, et al. The in-depth evaluation of suspected mitochondrial disease. Mol Genet Metab 2008;94:16-37.
4. Vafai SB, Mootha VK. Mitochondrial disorders as windows into an ancient organelle. Nature 2012;491:374-383.
5. Pfeffer G, Horvath R, Klopstock T, et al. New treatments for mitochondrial disease-no time to drop our standards. Nat Rev Neurol 2013;9:474-481.
6. Calvo SE, Compton AG, Hershman SG, et al. Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing. Sci Transl Med 2012;4:118ra10.
7. Linstone HA, Turoff M. The Delphi Method: Techniques and Applications. Addison-Wesley: Reading, MA, 1975.
8. Arnold GL, Koeberl DD, Matern D, et al. A Delphi-based consensus clinical practice protocol for the diagnosis and management of 3-methylcrotonyl CoA carboxylase deficiency. Mol Genet Metab 2008;93:363-370.
9. Arnold GL, Van Hove J, Freedenberg D, et al. A Delphi clinical practice protocol for the management of very long chain acyl-CoA dehydrogenase deficiency. Mol Genet Metab 2009;96:85-90.
10. Tarnopolsky M, Stevens L, MacDonald JR, et al. Diagnostic utility of a modified forearm ischemic exercise test and technical issues relevant to exercise testing. Muscle Nerve 2003;27:359-366.
11. Suomalainen A, Elo JM, Pietiläinen KH, et al. FGF-21 as a biomarker for musclemanifesting mitochondrial respiratory chain deficiencies: A diagnostic study. Lancet Neurol 2011;10:806-818.
12. Davis RL, Liang C, Edema-Hildebrand F, Riley C, Needham M, Sue CM. Fibroblast growth factor 21 is a sensitive biomarker of mitochondrial disease. Neurology 2013;81:1819-1826.
13. Debray FG, Mitchell GA, Allard P, Robinson BH, Hanley JA, Lambert M. Diagnostic accuracy of blood lactate-to-pyruvate molar ratio in the differential diagnosis of congenital lactic acidosis. Clin Chem 2007;53: 916-921.
14. Finsterer J. Cerebrospinal-fluid lactate in adult mitochondriopathy with and without encephalopathy. Acta Med Austriaca 2001;28:152-155.
15. Chow SL, Rooney ZJ, Cleary MA, Clayton PT, Leonard JV. The significance of elevated CSF lactate. Arch Dis Child 2005;90:1188-1189.
16. Barshop BA. Metabolomic approaches to mitochondrial disease: correlation of urine organic acids. Mitochondrion 2004;4:521-527.
17. Patel KP, O'Brien TW, Subramony SH, Shuster J, Stacpoole PW. The spectrum of pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic features in 371 patients. Mol Genet Metab 2012;106:385-394.
18. Wortmann SB, Rodenburg RJ, Jonckheere A, et al. Biochemical and genetic analysis of 3-methylglutaconic aciduria type IV: A diagnostic strategy. Brain 2009;132(Pt 1):136-146.
19. Barshop BA, Nyhan WL, Naviaux RK, McGowan KA, Friedlander M, Haas RH. Kearns-Sayre syndrome presenting as 2-oxoadipic aciduria. Mol Genet Metab 2000;69:64-68.
20. Sakamoto O, Ohura T, Murayama K, et al. Neonatal lactic acidosis with methylmalonic aciduria due to novel mutations in the SUCLG1 gene. Pediatr Int 2011;53:921-925.
21. Su B, Ryan RO. Metabolic biology of 3-methylglutaconic acid-uria: A new perspective. J Inherit Metab Dis 2014;37:359-368.
22. Marsden D, Nyhan WL, Barshop BA. Creatine kinase and uric acid: early warning for metabolic imbalance resulting from disorders of fatty acid oxidation. Eur J Pediatr 2001;160:599-602.
23. 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;110:153-161.
24. Finsterer J. Hematological manifestations of primary mitochondrial disorders. Acta Haematol 2007;118:88-98.
25. Hargreaves IP, Sheena Y, Land JM, Heales SJ. Glutathione deficiency in patients with mitochondrial disease: Implications for pathogenesis and treatment. J Inherit Metab Dis 2005;28:81-88.
26. Atkuri KR, Cowan TM, Kwan T, et al. Inherited disorders affecting mitochondrial function are associated with glutathione deficiency and hypocitrullinemia. Proc Natl Acad Sci USA 2009;106:3941-3945.
27. Ramaekers V, Sequeira JM, Quadros EV. Clinical recognition and aspects of the cerebral folate deficiency syndromes. Clin Chem Lab Med 2013; 51:497-511.
28. Allen RJ, DiMauro S, Coulter DL, Papadimitriou A, Rothenberg SP. Kearns-Sayre syndrome with reduced plasma and cerebrospinal fluid folate. Ann Neurol 1983;13:679-682.
29. Dougados M, Zittoun J, Laplane D, Castaigne P. Folate metabolism disorder in Kearns-Sayre syndrome. Ann Neurol 1983;13:687.
30. Serrano M, García-Silva MT, Martin-Hernandez E, et al. Kearns-Sayre syndrome: cerebral folate deficiency, MRI findings and new cerebrospinal fluid biochemical features. Mitochondrion 2010;10:429-432.
31. Tondo M, Málaga I, O'Callaghan M, et al. Biochemical parameters to assess choroid plexus dysfunction in Kearns-Sayre syndrome patients. Mitochondrion 2011;11:867-870.
32. Pineda M, Ormazabal A, López-Gallardo E, et al. Cerebral folate deficiency and leukoencephalopathy caused by a mitochondrial DNA deletion. Ann Neurol 2006;59:394-398.
33. Hasselmann O, Blau N, Ramaekers VT, Quadros EV, Sequeira JM, Weissert M. Cerebral folate deficiency and CNS inflammatory markers in Alpers disease. Mol Genet Metab 2010;99:58-61.
34. Ramaekers VT, Weis J, Sequeira JM, Quadros EV, Blau N. Mitochondrial complex I encephalomyopathy and cerebral 5-methyltetrahydrofolate deficiency. Neuropediatrics 2007;38:184-187.
35. 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.
36. Moraes CT, Atencio DP, Oca-Cossio J, Diaz F. Techniques and pitfalls in the detection of pathogenic mitochondrial DNA mutations. J Mol Diagn 2003;5:197-208.
37. Zhou S, Kassauei K, Cutler DJ, et al. An oligonucleotide microarray for high-throughput sequencing of the mitochondrial genome. J Mol Diagn 2006;8:476-482.
38. McCormick E, Place E, Falk MJ. Molecular genetic testing for mitochondrial disease: from one generation to the next. Neurotherapeutics 2013;10:251-261.
39. Cui H, Li F, Chen D, et al. Comprehensive next-generation sequence analyses of the entire mitochondrial genome reveal new insights into the molecular diagnosis of mitochondrial DNA disorders. Genet Med 2013;15:388-394.
40. de Laat P, Koene S, van den Heuvel LP, Rodenburg RJ, Janssen MC, Smeitink JA. Clinical features and heteroplasmy in blood, urine and saliva in 34 Dutch families carrying the m. 3243A G mutation. J Inherit Metab Dis 2012;35:1059-1069.
41. McDonnell MT, Schaefer AM, Blakely EL, et al. Noninvasive diagnosis of the 3243A G mitochondrial DNA mutation using urinary epithelial cells. Eur J Hum Genet 2004;12:778-781.
42. Whittaker RG, Blackwood JK, Alston CL, et al. Urine heteroplasmy is the best predictor of clinical outcome in the m. 3243AG mtDNA mutation. Neurology 2009;72:568-569.
43. Chinault AC, Shaw CA, Brundage EK, Tang LY, Wong LJ. Application of dualgenome oligonucleotide array-based comparative genomic hybridization to the molecular diagnosis of mitochondrial DNA deletion and depletion syndromes. Genet Med 2009;11:518-526.
44. Wong LJ, Dimmock D, Geraghty MT, et al. Utility of oligonucleotide array-based comparative genomic hybridization for detection of target gene deletions. Clin Chem 2008;54:1141-1148.
45. Wong LJ. Next generation molecular diagnosis of mitochondrial disorders. Mitochondrion 2013;13:379-387.
46. Zhang W, Cui H, Wong LJ. Comprehensive one-step molecular analyses of mitochondrial genome by massively parallel sequencing. Clin Chem 2012;58:1322-1331.
47. Cohen BH, Naviaux RK. The clinical diagnosis of POLG disease and other mitochondrial DNA depletion disorders. Methods 2010;51:364-373.
48. El-Hattab AW, Scaglia F, Craigen WJ, Wong LJC. MPV17-related hepatocerebral mitochondrial DNA depletion syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al., (eds). GeneReviews. University of Washington: Seattle, WA, 1993-2014.
49. Dimmock D, Tang LY, Schmitt ES, Wong LJ. Quantitative evaluation of the mitochondrial DNA depletion syndrome. Clin Chem 2010;56:1119-1127.
50. Falk MJ, Pierce EA, Consugar M, et al. Mitochondrial disease genetic diagnostics: optimized whole-exome analysis for all MitoCarta nuclear genes and the mitochondrial genome. Discov Med 2012;14:389-399.
51. Gerards M, Kamps R, van Oevelen J, et al. Exome sequencing reveals a novel Moroccan founder mutation in SLC19A3 as a new cause of early-childhood fatal Leigh syndrome. Brain 2013;136(Pt 3):882-890.
52. Kevelam SH, Bugiani M, Salomons GS, et al. Exome sequencing reveals mutated SLC19A3 in patients with an early-infantile, lethal encephalopathy. Brain 2013;136(Pt 5):1534-1543.
53. Lamperti C, Fang M, Invernizzi F, et al. A novel homozygous mutation in SUCLA2 gene identified by exome sequencing. Mol Genet Metab 2012;107:403-408.
54. Pierson TM, Adams D, Bonn F, et al. Whole-exome sequencing identifies homozygous AFG3L2 mutations in a spastic ataxia-neuropathy syndrome linked to mitochondrial m-AAA proteases. PLoS Genet 2011;7:e1002325.
55. 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;58:226-228.
56. Takata A, Kato M, Nakamura M, et al. Exome sequencing identifies a novel missense variant in RRM2B associated with autosomal recessive progressive external ophthalmoplegia. Genome Biol 2011;12:R92.
57. Craigen WJ, Graham BH, Wong LJ, Scaglia F, Lewis RA, Bonnen PE. Exome sequencing of a patient with suspected mitochondrial disease reveals a likely multigenic etiology. BMC Med Genet 2013;14:83.
58. DiMauro S, Schon EA, Carelli V, Hirano M. The clinical maze of mitochondrial neurology. Nat Rev Neurol 2013;9:429-444.
59. Molleston JP, Sokol RJ, Karnsakul W, et al.; Childhood Liver Disease Research Education Network (ChiLDREN). Evaluation of the child with suspected mitochondrial liver disease. J Pediatr Gastroenterol Nutr 2013;57:269-276.
60. Hazard FK, Ficicioglu CH, Ganesh J, Ruchelli ED. Liver pathology in infantile mitochondrial DNA depletion syndrome. Pediatr Dev Pathol 2013;16: 415-424.
61. Walker UA, Collins S, Byrne E. Respiratory chain encephalomyopathies: A diagnostic classification. Eur Neurol 1996;36:260-267.
62. Bernier FP, Boneh A, Dennett X, Chow CW, Cleary MA, Thorburn DR. Diagnostic criteria for respiratory chain disorders in adults and children. Neurology 2002;59:1406-1411.
63. Rubio-Gozalbo ME, Sengers RC, Trijbels JM, et al. A prognostic index as diagnostic strategy in children suspected of mitochondriocytopathy. Neuropediatrics 2000;31:114-121.
64. Wolf NI, Smeitink JA. Mitochondrial disorders: A proposal for consensus diagnostic criteria in infants and children. Neurology 2002;59:1402-1405.
65. Morava E, van den Heuvel L, Hol F, et al. Mitochondrial disease criteria: diagnostic applications in children. Neurology 2006;67:1823-1826.
66. Westover JB, Goodman SI, Frerman FE. Binding, hydration, and decarboxylation of the reaction intermediate glutaconyl-coenzyme A by human glutaryl-CoA dehydrogenase. Biochemistry 2001;40:14106-14114.
67. Gempel K, Topaloglu H, Talim B, et al. The myopathic form of coenzyme Q10 deficiency is caused by mutations in the electron-transferring-flavoprotein dehydrogenase (ETFDH) gene. Brain 2007;130(Pt 8):2037-2044.
68. Laforêt P, Acquaviva-Bourdain C, Rigal O, et al. Diagnostic assessment and long-term follow-up of 13 patients with very long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency. Neuromuscul Disord 2009;19:324-329.
69. Matsuoka T, Maeda H, Goto Y, Nonaka I. Muscle coenzyme Q10 in mitochondrial encephalomyopathies. Neuromuscul Disord 1991;1:443-447.
70. Sacconi S, Trevisson E, Salviati L, et al. Coenzyme Q10 is frequently reduced in muscle of patients with mitochondrial myopathy. Neuromuscul Disord 2010;20:44-48.
71. Rahman S, Clarke CF, Hirano M. 176th ENMC International Workshop: diagnosis and treatment of coenzyme Q10 deficiency. Neuromuscul Disord 2012;22:76-86.
72. Goldenthal MJ, Kuruvilla T, Damle S, et al. Non-invasive evaluation of buccal respiratory chain enzyme dysfunction in mitochondrial disease: comparison with studies in muscle biopsy. Mol Genet Metab 2012;105:457-462.
73. Van Goethem G, Luoma P, Rantamäki M, et al. POLG mutations in neurodegenerative disorders with ataxia but no muscle involvement. Neurology 2004;63:1251-1257.
74. de Vries MC, Rodenburg RJ, Morava E, et al. Normal biochemical analysis of the oxidative phosphorylation (OXPHOS) system in a child with POLG mutations: A cautionary note. J Inherit Metab Dis 2008;31(suppl 2):S299-S302.
75. Horvath R, Hudson G, Ferrari G, et al. Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene. Brain 2006;129(Pt 7):1674-1684.
76. Mandel H, Szargel R, Labay V, et al. The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA. Nat Genet 2001;29:337-341.
77. Spinazzola A, Viscomi C, Fernandez-Vizarra E, et al. MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion. Nat Genet 2006;38:570-575.
78. van den Heuvel LP, Smeitink JA, Rodenburg RJ. Biochemical examination of fibroblasts in the diagnosis and research of oxidative phosphorylation (OXPHOS) defects. Mitochondrion 2004;4:395-401.
79. Sue CM, Crimmins DS, Soo YS, et al. Neuroradiological features of six kindreds with MELAS tRNA(Leu) A2343G point mutation: Implications for pathogenesis. J Neurol Neurosurg Psychiatry 1998;65:233-240.
80. Ito H, Mori K, Kagami S. Neuroimaging of stroke-like episodes in MELAS. Brain Dev 2011;33:283-288.
81. Saneto RP, Friedman SD, Shaw DW. Neuroimaging of mitochondrial disease. Mitochondrion 2008;8:396-413.
82. Hirano M, Silvestri G, Blake DM, et al. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): clinical, biochemical, and genetic features of an autosomal recessive mitochondrial disorder. Neurology 1994;44:721-727.
83. Nishino I, Spinazzola A, Papadimitriou A, et al. Mitochondrial neurogastrointestinal encephalomyopathy: An autosomal recessive disorder due to thymidine phosphorylase mutations. Ann Neurol 2000;47:792-800.
84. Valanne L, Ketonen L, Majander A, Suomalainen A, Pihko H. Neuroradiologic findings in children with mitochondrial disorders. AJNR Am J Neuroradiol 1998;19:369-377.
85. Savoiardo M, Zeviani M, Uziel G, Farina L. MRI in Leigh syndrome with SURF1 gene mutation. Ann Neurol 2002;51:138-139.
86. Leshinsky-Silver E, Lebre AS, Minai L, et al. NDUFS4 mutations cause Leigh syndrome with predominant brainstem involvement. Mol Genet Metab 2009;97:185-189.
87. Yi? U, Seneca S, Dirik E, et al. Unusual findings in Leigh syndrome caused by T8993C mutation. Eur J Paediatr Neurol 2009;13:550-552.
88. Namavar Y, Barth PG, Poll-The BT, Baas F. Classification, diagnosis and potential mechanisms in pontocerebellar hypoplasia. Orphanet J Rare Dis 2011;6:50.
89. Carrozzo R, Dionisi-Vici C, Steuerwald U, et al. SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness. Brain 2007;130(Pt 3):862-874.
90. Kevelam SH, Rodenburg RJ, Wolf NI, et al. NUBPL mutations in patients with complex I deficiency and a distinct MRI pattern. Neurology 2013;80: 1577-1583.
91. Yu-Wai-Man P, Griffiths PG, Gorman GS, et al. Multi-system neurological disease is common in patients with OPA1 mutations. Brain 2010;133(Pt 3):771-786.
92. Chu BC, Terae S, Takahashi C, et al. MRI of the brain in the Kearns-Sayre syndrome: report of four cases and a review. Neuroradiology 1999;41: 759-764.
93. Lerman-Sagie T, Leshinsky-Silver E, Watemberg N, Luckman Y, Lev D. White matter involvement in mitochondrial diseases. Mol Genet Metab 2005;84: 127-136.
94. Ito S, Shirai W, Asahina M, Hattori T. Clinical and brain MR imaging features focusing on the brain stem and cerebellum in patients with myoclonic epilepsy with ragged-red fibers due to mitochondrial A8344G mutation. AJNR Am J Neuroradiol 2008;29:392-395.
95. Orcesi S, Gorni K, Termine C, et al. Bilateral putaminal necrosis associated with the mitochondrial DNA A8344G myoclonus epilepsy with ragged red fibers (MERRF) mutation: An infantile case. J Child Neurol 2006;21:79-82.
96. Scheper GC, van der Klok T, van Andel RJ, et al. Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation. Nat Genet 2007;39:534-539.
97. Steenweg ME, Ghezzi D, Haack T, et al. Leukoencephalopathy with thalamus and brainstem involvement and high lactate 'LTBL' caused by EARS2 mutations. Brain 2012;135(Pt 5):1387-1394.
98. Bayat V, Thiffault I, Jaiswal M, et al. Mutations in the mitochondrial methionyltRNA synthetase cause a neurodegenerative phenotype in flies and a recessive ataxia (ARSAL) in humans. PLoS Biol 2012;10:e1001288.
99. Sproule DM, Kaufmann P. Mitochondrial encephalopathy, lactic acidosis, and strokelike episodes: basic concepts, clinical phenotype, and therapeutic management of MELAS syndrome. Ann NY Acad Sci 2008;1142:133-158.
100. Naini A, Kaufmann P, Shanske S, Engelstad K, De Vivo DC, Schon EA. Hypocitrullinemia in patients with MELAS: An insight into the "MELAS paradox". J Neurol Sci 2005;229-230:187-193.
101. Green DJ, Maiorana A, O'Driscoll G, Taylor R. Effect of exercise training on endothelium-derived nitric oxide function in humans. J Physiol 2004;561(Pt 1):1-25.
102. Koga Y, Akita Y, Nishioka J, et al. L-arginine improves the symptoms of strokelike episodes in MELAS. Neurology 2005;64:710-712.
103. El-Hattab AW, Hsu JW, Emrick LT, et al. Restoration of impaired nitric oxide production in MELAS syndrome with citrulline and arginine supplementation. Mol Genet Metab 2012;105:607-614.
104. Koga Y, Akita Y, Nishioka J, et al. MELAS and L-arginine therapy. Mitochondrion 2007;7:133-139.
105. El-Hattab AW, Emrick LT, Chanprasert S, Craigen WJ, Scaglia F. Mitochondria: role of citrulline and arginine supplementation in MELAS syndrome. Int J Biochem Cell Biol 2014;48:85-91.
106. Wenz T, Diaz F, Hernandez D, Moraes CT. Endurance exercise is protective for mice with mitochondrial myopathy. J Appl Physiol (1985) 2009;106: 1712-1719.
107. Safdar A, Bourgeois JM, Ogborn DI, et al. Endurance exercise rescues progeroid aging and induces systemic mitochondrial rejuvenation in mtDNA mutator mice. Proc Natl Acad Sci USA 2011;108:4135-4140.
108. Taivassalo T, De Stefano N, Argov Z, et al. Effects of aerobic training in patients with mitochondrial myopathies. Neurology 1998;50:1055-1060.
109. Taivassalo T, Shoubridge EA, Chen J, et al. Aerobic conditioning in patients with mitochondrial myopathies: physiological, biochemical, and genetic effects. Ann Neurol 2001;50:133-141.
110. Taivassalo T, Gardner JL, Taylor RW, et al. Endurance training and detraining in mitochondrial myopathies due to single large-scale mtDNA deletions. Brain 2006;129(Pt 12):3391-3401.
111. Cejudo P, Bautista J, Montemayor T, et al. Exercise training in mitochondrial myopathy: A randomized controlled trial. Muscle Nerve 2005;32:342-350.
112. Jeppesen TD, Schwartz M, Olsen DB, et al. Aerobic training is safe and improves exercise capacity in patients with mitochondrial myopathy. Brain 2006;129(Pt 12):3402-3412.
113. Jeppesen TD, Dunø M, Schwartz M, et al. Short-and long-term effects of endurance training in patients with mitochondrial myopathy. Eur J Neurol 2009;16:1336-1339.
114. Siciliano G, Simoncini C, Lo Gerfo A, Orsucci D, Ricci G, Mancuso M. Effects of aerobic training on exercise-related oxidative stress in mitochondrial myopathies. Neuromuscul Disord 2012;22(suppl 3):S172-7.
115. Lima FD, Stamm DN, Della-Pace ID, et al. Swimming training induces liver mitochondrial adaptations to oxidative stress in rats submitted to repeated exhaustive swimming bouts. PLoS One 2013;8:e55668.
116. Bates MG, Newman JH, Jakovljevic DG, et al. Defining cardiac adaptations and safety of endurance training in patients with m. 3243AG-related mitochondrial disease. Int J Cardiol 2013;168:3599-3608.
117. Driessen J, Willems S, Dercksen S, Giele J, van der Staak F, Smeitink J. Anesthesia-related morbidity and mortality after surgery for muscle biopsy in children with mitochondrial defects. Paediatr Anaesth 2007;17:16-21.
118. Kitoh T, Mizuno K, Otagiri T, Ichinose A, Sasao J, Goto H. Anesthetic management for a patient with Kearns-Sayre syndrome. Anesth Analg 1995;80:1240-1242.
119. Cheam EW, Critchley LA. Anesthesia for a child with complex I respiratory chain enzyme deficiency. J Clin Anesth 1998;10:524-527.
120. Footitt EJ, Sinha MD, Raiman JA, Dhawan A, Moganasundram S, Champion MP. Mitochondrial disorders and general anaesthesia: A case series and review. Br J Anaesth 2008;100:436-441.
121. Casta A, Quackenbush EJ, Houck CS, Korson MS. Perioperative white matter degeneration and death in a patient with a defect in mitochondrial oxidative phosphorylation. Anesthesiology 1997;87:420-425.
122. Cooper MA, Fox R. Anesthesia for corrective spinal surgery in a patient with Leigh's disease. Anesth Analg 2003;97:1539-1541.
123. Grattan-Smith PJ, Shield LK, Hopkins IJ, Collins KJ. Acute respiratory failure precipitated by general anesthesia in Leigh's syndrome. J Child Neurol 1990;5:137-141.
124. Cohen PJ. Effect of anesthetics on mitochondrial function. Anesthesiology 1973;39:153-164.
125. Harris RA, Munroe J, Farmer B, Kim KC, Jenkins P. Action of halothane upon mitochondrial respiration. Arch Biochem Biophys 1971;142:435-444.
126. Nahrwold ML, Cohen PJ. Additive effect of nitrous oxide and halothane on mitochondrial function. Anesthesiology 1973;39:534-536.
127. Miró O, Barrientos A, Alonso JR, et al. Effects of general anaesthetic procedures on mitochondrial function of human skeletal muscle. Eur J Clin Pharmacol 1999;55:35-41.
128. Nahrwold ML, Cohen PJ. The effects of forane and fluroxene on mitochondrial respiration: correlation with lipid solubility and in-vivo potency. Anesthesiology 1973;38:437-444.
129. Devin A, Nogueira V, Avéret N, Leverve X, Rigoulet M. Profound effects of the general anesthetic etomidate on oxidative phosphorylation without effects on their yield. J Bioenerg Biomembr 2006;38:137-142.
130. Markham A, Cameron I, White SJ. The effect of ketamine hydrochloride, a non-barbiturate parenteral anaesthetic on oxidative phosphorylation in rat liver mitochondria. Biochem Pharmacol 1981;30:2165-2168.
131. Rigoulet M, Devin A, Avéret N, Vandais B, Guérin B. Mechanisms of inhibition and uncoupling of respiration in isolated rat liver mitochondria by the general anesthetic 2, 6-diisopropylphenol. Eur J Biochem 1996;241:280-285.
132. Acco A, Comar JF, Bracht A. Metabolic effects of propofol in the isolated perfused rat liver. Basic Clin Pharmacol Toxicol 2004;95:166-174.
133. Farag E, Deboer G, Cohen BH, Niezgoda J. Metabolic acidosis due to propofol infusion. Anesthesiology 2005;102:697-8; author response 698.
134. Vanlander AV, Jorens PG, Smet J, et al. Inborn oxidative phosphorylation defect as risk factor for propofol infusion syndrome. Acta Anaesthesiol Scand 2012;56:520-525.
135. Mtaweh H, Bayir H, Kochanek PM, Bell MJ. Effect of a single dose of propofol and lack of dextrose administration in a child with mitochondrial disease: A case report. J Child Neurol 2013;29:NP40-NP46.
136. Gegenava GP, Chistiakov VV. Effect of morphine in vitro on the oxidative phosphorylation in rat liver mitochondria. Biull Eksp Biol Med 1975;80:77-79.
137. Moussa TA, el-Beih ZM. Effects of morphine on the Golgi apparatus and mitochondria of mammalian neurones. Cellule 1972;69:191-203.
138. Chinnery PF, Turnbull DM. Epidemiology and treatment of mitochondrial disorders. Am J Med Genet 2001;106:94-101.
139. Dimauro S, Mancuso M, Naini A. Mitochondrial encephalomyopathies: therapeutic approach. Ann NY Acad Sci 2004;1011:232-245.
140. DiMauro S, Hirano M, Schon EA. Approaches to the treatment of mitochondrial diseases. Muscle Nerve 2006;34:265-283.
141. Mahoney DJ, Parise G, Tarnopolsky MA. Nutritional and exercise-based therapies in the treatment of mitochondrial disease. Curr Opin Clin Nutr Metab Care 2002;5:619-629.
142. Marriage BJ, Clandinin MT, Macdonald IM, Glerum DM. Cofactor treatment improves ATP synthetic capacity in patients with oxidative phosphorylation disorders. Mol Genet Metab 2004;81:263-272.
143. Tarnopolsky MA, Raha S. Mitochondrial myopathies: diagnosis, exercise intolerance, and treatment options. Med Sci Sports Exerc 2005;37:2086-2093.
144. Tarnopolsky MA. The mitochondrial cocktail: rationale for combined nutraceutical therapy in mitochondrial cytopathies. Adv Drug Deliv Rev 2008;60:1561-1567.
145. Kerr DS. Review of clinical trials for mitochondrial disorders: 1997-2012. Neurotherapeutics 2013;10:307-319.
146. Parikh S, Goldstein A, Koenig MK, et al. Practice patterns of mitochondrial disease physicians in North America. Part 2: treatment, care and management. Mitochondrion 2013;13:681-687.
147. Pfeffer G, Majamaa K, Turnbull DM, Thorburn D, Chinnery PF. Treatment for mitochondrial disorders. Cochrane Database Syst Rev 2012;4:CD004426.
148. Haas RH. The evidence basis for coenzyme Q therapy in oxidative phosphorylation disease. Mitochondrion 2007(suppl 7):S136-S145.
149. Rodriguez MC, MacDonald JR, Mahoney DJ, Parise G, Beal MF, Tarnopolsky MA. Beneficial effects of creatine, CoQ10, and lipoic acid in mitochondrial disorders. Muscle Nerve 2007;35:235-242.
150. Glover EI, Martin J, Maher A, Thornhill RE, Moran GR, Tarnopolsky MA. A randomized trial of coenzyme Q10 in mitochondrial disorders. Muscle Nerve 2010;42:739-748.
151. Marin SE, Mesterman R, Robinson B, Rodenburg RJ, Smeitink J, Tarnopolsky MA. Leigh syndrome associated with mitochondrial complex I deficiency due to novel mutations in NDUFV1 and NDUFS2. Gene 2013;516:162-167.
152. Bernsen PL, Gabreëls FJ, Ruitenbeek W, Hamburger HL. Treatment of complex I deficiency with riboflavin. J Neurol Sci 1993;118:181-187.
153. Penn AM, Lee JW, Thuillier P, et al. MELAS syndrome with mitochondrial tRNA(Leu)(UUR) mutation: correlation of clinical state, nerve conduction, and muscle 31P magnetic resonance spectroscopy during treatment with nicotinamide and riboflavin. Neurology 1992;42:2147-2152.
154. Artuch R, Vilaseca MA, Pineda M. Biochemical monitoring of the treatment in paediatric patients with mitochondrial disease. J Inherit Metab Dis 1998;21:837-845.
155. Ribas GS, Vargas CR, Wajner M. L-carnitine supplementation as a potential antioxidant therapy for inherited neurometabolic disorders. Gene 2014;533:469-476.
156. Zaffanello M, Zamboni G. Therapeutic approach in a case of Pearson's syndrome. Minerva Pediatr 2005;57:143-146.
157. Mermigkis C, Bouloukaki I, Mastorodemos V, et al. Medical treatment with thiamine, coenzyme Q, vitamins E and C, and carnitine improved obstructive sleep apnea in an adult case of Leigh disease. Sleep Breath 2013;17: 1129-1135.
158. DiMauro S, Hirano M. Mitochondrial DNA deletion syndromes. In: Pagon RA, Adam MP, Ardinger HH, et al. (eds). GeneReviews. University of Washington: Seattle, WA, 1993-2014.
159. Chen X, Thorburn DR, Wong LJ, et al. Quality improvement of mitochondrial respiratory chain complex enzyme assays using Caenorhabditis elegans. Genet Med 2011;13:794-799.
160. Rodenburg RJ, Schoonderwoerd GC, Tiranti V, et al. A multi-center comparison of diagnostic methods for the biochemical evaluation of suspected mitochondrial disorders. Mitochondrion 2013;13:36-43.
161. Rustin P, Chretien D, Bourgeron T, et al. Biochemical and molecular investigations in respiratory chain deficiencies. Clin Chim Acta 1994;228:35-51.
162. Thorburn DR, Sugiana C, Salemi R, et al. Biochemical and molecular diagnosis of mitochondrial respiratory chain disorders. Biochim Biophys Acta 2004;1659:121-128.
163. Abadi A, Glover EI, Isfort RJ, et al. Limb immobilization induces a coordinate down-regulation of mitochondrial and other metabolic pathways in men and women. PLoS One 2009;4:e6518.
164. Rahman S, Poulton J. Diagnosis of mitochondrial DNA depletion syndromes. Arch Dis Child 2009;94:3-5.