UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Mitochondrial myopathies: Clinical features and diagnosis

Author
Erin O'Ferrall, MD
Section Editors
Jeremy M Shefner, MD, PhD
Sihoun Hahn, MD, PhD
Deputy Editor
John F Dashe, MD, PhD

INTRODUCTION

Mitochondrial diseases present with a wide range of clinical expression. Organ systems relying most on aerobic metabolism are preferentially affected and involvement of the nervous system is common. When skeletal muscle is affected, either alone or with central nervous system disease, the term mitochondrial myopathy is used.

The epidemiology, clinical manifestations, and diagnosis of the mitochondrial myopathies are discussed in this topic review. Treatment is discussed elsewhere. (See "Mitochondrial myopathies: Treatment".)

BACKGROUND

Mitochondria are the cellular organelles responsible for oxidative phosphorylation, which produces energy in the form of adenosine triphosphate (ATP). Mitochondrial diseases can be divided into the following categories based on the primary genetic defect (table 1):

Respiratory chain proteins

Respiratory chain ancillary proteins

                           

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Nov 2016. | This topic last updated: Thu Nov 03 00:00:00 GMT+00:00 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
References
Top
  1. Scheffler IE. A century of mitochondrial research: achievements and perspectives. Mitochondrion 2001; 1:3.
  2. DiMauro S. Mitochondrial myopathies. Curr Opin Rheumatol 2006; 18:636.
  3. DiMauro S, Hirano M. Mitochondrial encephalomyopathies: an update. Neuromuscul Disord 2005; 15:276.
  4. DiMauro S, Schon EA, Carelli V, Hirano M. The clinical maze of mitochondrial neurology. Nat Rev Neurol 2013; 9:429.
  5. Darin N, Oldfors A, Moslemi AR, et al. The incidence of mitochondrial encephalomyopathies in childhood: clinical features and morphological, biochemical, and DNA abnormalities. Ann Neurol 2001; 49:377.
  6. García-Cazorla A, De Lonlay P, Nassogne MC, et al. Long-term follow-up of neonatal mitochondrial cytopathies: a study of 57 patients. Pediatrics 2005; 116:1170.
  7. 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.
  8. Elliott HR, Samuels DC, Eden JA, et al. Pathogenic mitochondrial DNA mutations are common in the general population. Am J Hum Genet 2008; 83:254.
  9. Skladal D, Halliday J, Thorburn DR. Minimum birth prevalence of mitochondrial respiratory chain disorders in children. Brain 2003; 126:1905.
  10. Arpa J, Cruz-Martínez A, Campos Y, et al. Prevalence and progression of mitochondrial diseases: a study of 50 patients. Muscle Nerve 2003; 28:690.
  11. Thorburn DR. Mitochondrial disorders: prevalence, myths and advances. J Inherit Metab Dis 2004; 27:349.
  12. Fattal O, Link J, Quinn K, et al. Psychiatric comorbidity in 36 adults with mitochondrial cytopathies. CNS Spectr 2007; 12:429.
  13. Inczedy-Farkas G, Remenyi V, Gal A, et al. Psychiatric symptoms of patients with primary mitochondrial DNA disorders. Behav Brain Funct 2012; 8:9.
  14. Giordano C, Pichiorri F, Blakely EL, et al. Isolated distal myopathy of the upper limbs associated with mitochondrial DNA depletion and polymerase gamma mutations. Arch Neurol 2010; 67:1144.
  15. Andreu AL, Bruno C, Dunne TC, et al. A nonsense mutation (G15059A) in the cytochrome b gene in a patient with exercise intolerance and myoglobinuria. Ann Neurol 1999; 45:127.
  16. Massie R, Wong LJ, Milone M. Exercise intolerance due to cytochrome b mutation. Muscle Nerve 2010; 42:136.
  17. Massie R, Wang J, Chen LC, et al. Mitochondrial myopathy due to novel missense mutation in the cytochrome c oxidase 1 gene. J Neurol Sci 2012; 319:158.
  18. McFarland R, Taylor RW, Chinnery PF, et al. A novel sporadic mutation in cytochrome c oxidase subunit II as a cause of rhabdomyolysis. Neuromuscul Disord 2004; 14:162.
  19. Horváth R, Schoser BG, Müller-Höcker J, et al. Mutations in mtDNA-encoded cytochrome c oxidase subunit genes causing isolated myopathy or severe encephalomyopathy. Neuromuscul Disord 2005; 15:851.
  20. Emmanuele V, Sotiriou E, Shirazi M, et al. Recurrent myoglobinuria in a sporadic patient with a novel mitochondrial DNA tRNA(Ile) mutation. J Neurol Sci 2011; 303:39.
  21. Quinzii CM, Hirano M. Coenzyme Q and mitochondrial disease. Dev Disabil Res Rev 2010; 16:183.
  22. Béhin A, Jardel C, Claeys KG, et al. Adult cases of mitochondrial DNA depletion due to TK2 defect: an expanding spectrum. Neurology 2012; 78:644.
  23. Yamashita S, Nishino I, Nonaka I, Goto Y. Genotype and phenotype analyses in 136 patients with single large-scale mitochondrial DNA deletions. J Hum Genet 2008; 53:598.
  24. Yu Wai Man CY, Smith T, Chinnery PF, et al. Assessment of visual function in chronic progressive external ophthalmoplegia. Eye (Lond) 2006; 20:564.
  25. Schoser BG, Pongratz D. Extraocular mitochondrial myopathies and their differential diagnoses. Strabismus 2006; 14:107.
  26. Milone M, Massie R. Polymerase gamma 1 mutations: clinical correlations. Neurologist 2010; 16:84.
  27. Milone M, Benarroch EE, Wong LJ. POLG-related disorders: defects of the nuclear and mitochondrial genome interaction. Neurology 2011; 77:1847.
  28. Pitceathly RD, Smith C, Fratter C, et al. Adults with RRM2B-related mitochondrial disease have distinct clinical and molecular characteristics. Brain 2012; 135:3392.
  29. Ronchi D, Garone C, Bordoni A, et al. Next-generation sequencing reveals DGUOK mutations in adult patients with mitochondrial DNA multiple deletions. Brain 2012; 135:3404.
  30. Pfeffer G, Gorman GS, Griffin H, et al. Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance. Brain 2014; 137:1323.
  31. Melberg A, Moslemi AR, Palm O, et al. A patient with two mitochondrial DNA mutations causing PEO and LHON. Eur J Med Genet 2009; 52:47.
  32. Chuenkongkaew WL, Lertrit P, Limwongse C, et al. An unusual family with Leber's hereditary optic neuropathy and facioscapulohumeral muscular dystrophy. Eur J Neurol 2005; 12:388.
  33. Newman NJ, Lott MT, Wallace DC. The clinical characteristics of pedigrees of Leber's hereditary optic neuropathy with the 11778 mutation. Am J Ophthalmol 1991; 111:750.
  34. Gibson K, Halliday JL, Kirby DM, et al. Mitochondrial oxidative phosphorylation disorders presenting in neonates: clinical manifestations and enzymatic and molecular diagnoses. Pediatrics 2008; 122:1003.
  35. Rubio-Gozalbo ME, Dijkman KP, van den Heuvel LP, et al. Clinical differences in patients with mitochondriocytopathies due to nuclear versus mitochondrial DNA mutations. Hum Mutat 2000; 15:522.
  36. Skladal D, Sudmeier C, Konstantopoulou V, et al. The clinical spectrum of mitochondrial disease in 75 pediatric patients. Clin Pediatr (Phila) 2003; 42:703.
  37. Labarthe F, Dobbelaere D, Devisme L, et al. Clinical, biochemical and morphological features of hepatocerebral syndrome with mitochondrial DNA depletion due to deoxyguanosine kinase deficiency. J Hepatol 2005; 43:333.
  38. Rahman S, Hargreaves I, Clayton P, Heales S. Neonatal presentation of coenzyme Q10 deficiency. J Pediatr 2001; 139:456.
  39. Cormier-Daire V, Chretien D, Rustin P, et al. Neonatal and delayed-onset liver involvement in disorders of oxidative phosphorylation. J Pediatr 1997; 130:817.
  40. Yaplito-Lee J, Weintraub R, Jamsen K, et al. Cardiac manifestations in oxidative phosphorylation disorders of childhood. J Pediatr 2007; 150:407.
  41. Goldenberg A, Ngoc LH, Thouret MC, et al. Respiratory chain deficiency presenting as congenital nephrotic syndrome. Pediatr Nephrol 2005; 20:465.
  42. Götz A, Isohanni P, Pihko H, et al. Thymidine kinase 2 defects can cause multi-tissue mtDNA depletion syndrome. Brain 2008; 131:2841.
  43. Alberio S, Mineri R, Tiranti V, Zeviani M. Depletion of mtDNA: syndromes and genes. Mitochondrion 2007; 7:6.
  44. Rötig A. Renal disease and mitochondrial genetics. J Nephrol 2003; 16:286.
  45. Morris AA, Taylor RW, Birch-Machin MA, et al. Neonatal Fanconi syndrome due to deficiency of complex III of the respiratory chain. Pediatr Nephrol 1995; 9:407.
  46. Artuch R, Salviati L, Jackson S, et al. Coenzyme Q10 deficiencies in neuromuscular diseases. Adv Exp Med Biol 2009; 652:117.
  47. Zeviani M, Peterson P, Servidei S, et al. Benign reversible muscle cytochrome c oxidase deficiency: a second case. Neurology 1987; 37:64.
  48. Horvath R, Kemp JP, Tuppen HA, et al. Molecular basis of infantile reversible cytochrome c oxidase deficiency myopathy. Brain 2009; 132:3165.
  49. Wolny S, McFarland R, Chinnery P, Cheetham T. Abnormal growth in mitochondrial disease. Acta Paediatr 2009; 98:553.
  50. Barth PG, Valianpour F, Bowen VM, et al. X-linked cardioskeletal myopathy and neutropenia (Barth syndrome): an update. Am J Med Genet A 2004; 126A:349.
  51. Visapää 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.
  52. Chinnery PF, Turnbull DM. Epidemiology and treatment of mitochondrial disorders. Am J Med Genet 2001; 106:94.
  53. Kärppä M, Herva R, Moslemi AR, et al. Spectrum of myopathic findings in 50 patients with the 3243A>G mutation in mitochondrial DNA. Brain 2005; 128:1861.
  54. Finsterer J. Leigh and Leigh-like syndrome in children and adults. Pediatr Neurol 2008; 39:223.
  55. Lee HF, Tsai CR, Chi CS, et al. Leigh syndrome: clinical and neuroimaging follow-up. Pediatr Neurol 2009; 40:88.
  56. Rahman S, Blok RB, Dahl HH, et al. Leigh syndrome: clinical features and biochemical and DNA abnormalities. Ann Neurol 1996; 39:343.
  57. Staley KJ, Sims KB, Grant PE, Hedley-Whyte ET. Case records of the Massachusetts General Hospital. Case 28-2008. An 8-day-old infant with congenital deafness, lethargy, and hypothermia. N Engl J Med 2008; 359:1156.
  58. Lake NJ, Compton AG, Rahman S, Thorburn DR. Leigh syndrome: One disorder, more than 75 monogenic causes. Ann Neurol 2016; 79:190.
  59. Pavlakis SG, Phillips PC, DiMauro S, et al. Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes: a distinctive clinical syndrome. Ann Neurol 1984; 16:481.
  60. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 39-1998. A 13-year-old girl with a relapsing-remitting neurologic disorder. N Engl J Med 1998; 339:1914.
  61. Montagna P, Gallassi R, Medori R, et al. MELAS syndrome: characteristic migrainous and epileptic features and maternal transmission. Neurology 1988; 38:751.
  62. Ohno K, Isotani E, Hirakawa K. MELAS presenting as migraine complicated by stroke: case report. Neuroradiology 1997; 39:781.
  63. Lee HN, Eom S, Kim SH, et al. Epilepsy Characteristics and Clinical Outcome in Patients With Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS). Pediatr Neurol 2016.
  64. Koenig MK, Emrick L, Karaa A, et al. Recommendations for the Management of Strokelike Episodes in Patients With Mitochondrial Encephalomyopathy, Lactic Acidosis, and Strokelike Episodes. JAMA Neurol 2016; 73:591.
  65. Kaufmann P, Engelstad K, Wei Y, et al. Natural history of MELAS associated with mitochondrial DNA m.3243A>G genotype. Neurology 2011; 77:1965.
  66. Hirano M, Ricci E, Koenigsberger MR, et al. Melas: an original case and clinical criteria for diagnosis. Neuromuscul Disord 1992; 2:125.
  67. Dimauro S, Tay S, Mancuso M. Mitochondrial encephalomyopathies: diagnostic approach. Ann N Y Acad Sci 2004; 1011:217.
  68. Dickerson BC, Holtzman D, Grant PE, Tian D. Case records of the Massachusetts General Hospital. Case 36-2005. A 61-year-old woman with seizure, disturbed gait, and altered mental status. N Engl J Med 2005; 353:2271.
  69. DiMauro S, Hirano M. MERRF. GeneReviews. www.ncbi.nlm.nih.gov/books/NBK1520/ (Accessed on June 18, 2015).
  70. Kadowaki T, Kadowaki H, Mori Y, et al. A subtype of diabetes mellitus associated with a mutation of mitochondrial DNA. N Engl J Med 1994; 330:962.
  71. Donovan LE, Severin NE. Maternally inherited diabetes and deafness in a North American kindred: tips for making the diagnosis and review of unique management issues. J Clin Endocrinol Metab 2006; 91:4737.
  72. Murphy R, Turnbull DM, Walker M, Hattersley AT. Clinical features, diagnosis and management of maternally inherited diabetes and deafness (MIDD) associated with the 3243A>G mitochondrial point mutation. Diabet Med 2008; 25:383.
  73. Guillausseau PJ, Massin P, Dubois-LaForgue D, et al. Maternally inherited diabetes and deafness: a multicenter study. Ann Intern Med 2001; 134:721.
  74. 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.
  75. Shoffner JM. Mitochondrial neurogastrointestinal encephalopathy disease. GeneReviews. www.ncbi.nlm.nih.gov/books/NBK1179/ (Accessed on February 11, 2011).
  76. Giordano C, Sebastiani M, De Giorgio R, et al. Gastrointestinal dysmotility in mitochondrial neurogastrointestinal encephalomyopathy is caused by mitochondrial DNA depletion. Am J Pathol 2008; 173:1120.
  77. 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.
  78. Teitelbaum JE, Berde CB, Nurko S, et al. Diagnosis and management of MNGIE syndrome in children: case report and review of the literature. J Pediatr Gastroenterol Nutr 2002; 35:377.
  79. Garone C, Tadesse S, Hirano M. Clinical and genetic spectrum of mitochondrial neurogastrointestinal encephalomyopathy. Brain 2011; 134:3326.
  80. Shaibani A, Shchelochkov OA, Zhang S, et al. Mitochondrial neurogastrointestinal encephalopathy due to mutations in RRM2B. Arch Neurol 2009; 66:1028.
  81. Holt IJ, Harding AE, Petty RK, Morgan-Hughes JA. A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. Am J Hum Genet 1990; 46:428.
  82. Uziel G, Moroni I, Lamantea E, et al. Mitochondrial disease associated with the T8993G mutation of the mitochondrial ATPase 6 gene: a clinical, biochemical, and molecular study in six families. J Neurol Neurosurg Psychiatry 1997; 63:16.
  83. White SL, Collins VR, Wolfe R, et al. Genetic counseling and prenatal diagnosis for the mitochondrial DNA mutations at nucleotide 8993. Am J Hum Genet 1999; 65:474.
  84. DiMauro S, Hirano M. Mitochondrial DNA deletion syndromes. GeneReviews. www.ncbi.nlm.nih.gov/books/NBK1203/ (Accessed on June 18, 2015).
  85. Hargreaves IP. Coenzyme Q10 as a therapy for mitochondrial disease. Int J Biochem Cell Biol 2014; 49:105.
  86. Emmanuele V, López LC, Berardo A, et al. Heterogeneity of coenzyme Q10 deficiency: patient study and literature review. Arch Neurol 2012; 69:978.
  87. 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.
  88. McFarland R, Taylor RW, Turnbull DM. The neurology of mitochondrial DNA disease. Lancet Neurol 2002; 1:343.
  89. Nardin RA, Johns DR. Mitochondrial dysfunction and neuromuscular disease. Muscle Nerve 2001; 24:170.
  90. Cohen BH. Neuromuscular and systemic presentations in adults: diagnoses beyond MERRF and MELAS. Neurotherapeutics 2013; 10:227.
  91. Taylor RW, Schaefer AM, Barron MJ, et al. The diagnosis of mitochondrial muscle disease. Neuromuscul Disord 2004; 14:237.
  92. 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.
  93. 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.
  94. Suomalainen A, Elo JM, Pietiläinen KH, et al. FGF-21 as a biomarker for muscle-manifesting mitochondrial respiratory chain deficiencies: a diagnostic study. Lancet Neurol 2011; 10:806.
  95. Davis RL, Liang C, Edema-Hildebrand F, et al. Fibroblast growth factor 21 is a sensitive biomarker of mitochondrial disease. Neurology 2013; 81:1819.
  96. Haas RH, Parikh S, Falk MJ, et al. Mitochondrial disease: a practical approach for primary care physicians. Pediatrics 2007; 120:1326.
  97. Milone M, Wong LJ. Diagnosis of mitochondrial myopathies. Mol Genet Metab 2013; 110:35.
  98. Hirano M, Garone C, Quinzii CM. CoQ(10) deficiencies and MNGIE: two treatable mitochondrial disorders. Biochim Biophys Acta 2012; 1820:625.
  99. Friedman SD, Shaw DW, Ishak G, et al. The use of neuroimaging in the diagnosis of mitochondrial disease. Dev Disabil Res Rev 2010; 16:129.
  100. Tarnopolsky MA, Raha S. Mitochondrial myopathies: diagnosis, exercise intolerance, and treatment options. Med Sci Sports Exerc 2005; 37:2086.
  101. Lindholm H, Löfberg M, Somer H, et al. Abnormal blood lactate accumulation after exercise in patients with multiple mitochondrial DNA deletions and minor muscular symptoms. Clin Physiol Funct Imaging 2004; 24:109.
  102. Sarnat HB, Marín-García J. Pathology of mitochondrial encephalomyopathies. Can J Neurol Sci 2005; 32:152.
  103. Engel AG. The muscle biopsy. In: Myology, 3rd ed, Engel AG, Franzini-Armstrong C (Eds), McGraw-Hill, New York 2004. p.681-690.
  104. Bernier FP, Boneh A, Dennett X, et al. Diagnostic criteria for respiratory chain disorders in adults and children. Neurology 2002; 59:1406.