UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate®

线粒体肌病：临床特征与诊断

Authors
Angela Genge, MD
Rami Massie, MD
Section Editor
Jeremy M Shefner, MD, PhD
Deputy Editor
John F Dashe, MD, PhD
Translators
林洁, 主治医师

引言

线粒体是一种负责氧化磷酸化的细胞器，氧化磷酸化会产生三磷酸腺苷(adenosine triphosphate, ATP)，为细胞提供能量。这一过程由位于线粒体内膜上的呼吸链完成。此外，线粒体还有其他功能，包括丙酮酸氧化、三羧酸循环、脂肪酸氧化，以及氨基酸代谢，这些作用均发生于线粒体基质内。尽管上述任何途径中的异常，理论上都可称为线粒体病，但传统上，只有呼吸链缺陷导致氧化磷酸化损害才认为是原发性线粒体病。 (参见“线粒体的结构、功能和遗传学”)

线粒体病是一组线粒体呼吸链的病理性功能障碍引起疾病，具有多种临床表现。优先影响主要依赖有氧代谢的器官系统，一般来说神经系统受累(被称为线粒体脑肌病)常见。当骨骼肌受累时，无论伴或不伴中枢神经系统受累，都称为线粒体肌病。

本专题将讨论线粒体肌病的流行病学、临床表现及其诊断。对线粒体肌病的治疗将在别处讨论。 (参见“线粒体肌病：治疗”)

流行病学

虽然线粒体病一度被视为罕见疾病，但累积的证据提示该病相对常见。

  • 一项基于人群的研究对1984-1999年间瑞典西部所有儿科健康记录进行了回顾，发现学龄前儿童中线粒体脑肌病的发病率为1/11,000[1]。16岁以下儿童的时点患病率为1/21,000。由于这些疾病在童年期的死亡率较高[2]，婴儿期发病患者的中位生存期为12岁[1]。这也解释了其时点患病率较预期的慢性疾病时点患病率相对更低的原因。该研究采用了严格的纳入标准，并得出结论认为：研究结果为实际发病率与患病率的最低估计值。研究中，32例儿童中除1例外均出现肌肉受累，表明线粒体肌病的发病率与患病率仅略低于所报道的线粒体脑肌病。
  • 一项来自英格兰东北部的青少年与成人(16-65岁)线粒体病的报道发现，该病的时点患病率为每10万人中6.6例(或1/15,200)[3]。研究人员基于接受转诊治疗患者估计该数据仅为实际患病率的1/3。未报道肌病的具体数值。一半患者被诊断为Leber遗传性视神经病(Leber hereditary optic neuropathy, LHON)，该病一般不会存在由明显的肌病表现。上文引述的瑞典报道中，仅3%的患者出现了LHON。
  • 来自英格兰东北部的同一组研究人员对3168个新生儿脐带血样本进行10个常见线粒体DNA点突变筛查，发现线粒体DNA点突变的患病率高于1/200[4]。然而，由于可变的异质性，某些突变决不会在临床上表达。
  • 澳大利亚的一项研究估计，原发性线粒体病的最低出生患病率为每10万例出生婴儿中有6.2例[5]。
  • 西班牙的一项研究估计，14岁以上人群中线粒体病的患病率为每10万人中有5.7例[6]。在接受检查的患者中，电生理学分析在80%的患者中检测到肌病征象，在22%的患者中检测到神经病变。

                      

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: 2017-06 . | This topic last updated: 2017-02-01.
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 ©2017 UpToDate, Inc.
References
Top
  1. 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.
  2. 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.
  3. Chinnery PF, Johnson MA, Wardell TM, et al. The epidemiology of pathogenic mitochondrial DNA mutations. Ann Neurol 2000; 48:188.
  4. 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.
  5. Skladal D, Halliday J, Thorburn DR. Minimum birth prevalence of mitochondrial respiratory chain disorders in children. Brain 2003; 126:1905.
  6. 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.
  7. Thorburn DR. Mitochondrial disorders: prevalence, myths and advances. J Inherit Metab Dis 2004; 27:349.
  8. DiMauro S, Hirano M. Mitochondrial encephalomyopathies: an update. Neuromuscul Disord 2005; 15:276.
  9. DiMauro S. Mitochondrial myopathies. Curr Opin Rheumatol 2006; 18:636.
  10. Yu Wai Man CY, Smith T, Chinnery PF, et al. Assessment of visual function in chronic progressive external ophthalmoplegia. Eye (Lond) 2006; 20:564.
  11. Schoser BG, Pongratz D. Extraocular mitochondrial myopathies and their differential diagnoses. Strabismus 2006; 14:107.
  12. Milone M, Massie R. Polymerase gamma 1 mutations: clinical correlations. Neurologist 2010; 16:84.
  13. Milone M, Benarroch EE, Wong LJ. POLG-related disorders: defects of the nuclear and mitochondrial genome interaction. Neurology 2011; 77:1847.
  14. Pitceathly RD, Smith C, Fratter C, et al. Adults with RRM2B-related mitochondrial disease have distinct clinical and molecular characteristics. Brain 2012; 135:3392.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. Berardo A, DiMauro S, Hirano M. A diagnostic algorithm for metabolic myopathies. Curr Neurol Neurosci Rep 2010; 10:118.
  20. 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.
  21. Filosto M, Tonin P, Vattemi G, et al. The role of muscle biopsy in investigating isolated muscle pain. Neurology 2007; 68:181.
  22. 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.
  23. 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.
  24. Skladal D, Sudmeier C, Konstantopoulou V, et al. The clinical spectrum of mitochondrial disease in 75 pediatric patients. Clin Pediatr (Phila) 2003; 42:703.
  25. 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.
  26. Rahman S, Hargreaves I, Clayton P, Heales S. Neonatal presentation of coenzyme Q10 deficiency. J Pediatr 2001; 139:456.
  27. 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.
  28. Yaplito-Lee J, Weintraub R, Jamsen K, et al. Cardiac manifestations in oxidative phosphorylation disorders of childhood. J Pediatr 2007; 150:407.
  29. Goldenberg A, Ngoc LH, Thouret MC, et al. Respiratory chain deficiency presenting as congenital nephrotic syndrome. Pediatr Nephrol 2005; 20:465.
  30. Götz A, Isohanni P, Pihko H, et al. Thymidine kinase 2 defects can cause multi-tissue mtDNA depletion syndrome. Brain 2008; 131:2841.
  31. Alberio S, Mineri R, Tiranti V, Zeviani M. Depletion of mtDNA: syndromes and genes. Mitochondrion 2007; 7:6.
  32. Rötig A. Renal disease and mitochondrial genetics. J Nephrol 2003; 16:286.
  33. 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.
  34. Artuch R, Salviati L, Jackson S, et al. Coenzyme Q10 deficiencies in neuromuscular diseases. Adv Exp Med Biol 2009; 652:117.
  35. Zeviani M, Peterson P, Servidei S, et al. Benign reversible muscle cytochrome c oxidase deficiency: a second case. Neurology 1987; 37:64.
  36. Horvath R, Kemp JP, Tuppen HA, et al. Molecular basis of infantile reversible cytochrome c oxidase deficiency myopathy. Brain 2009; 132:3165.
  37. Wolny S, McFarland R, Chinnery P, Cheetham T. Abnormal growth in mitochondrial disease. Acta Paediatr 2009; 98:553.
  38. 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.
  39. 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.
  40. Chinnery PF, Turnbull DM. Epidemiology and treatment of mitochondrial disorders. Am J Med Genet 2001; 106:94.
  41. 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.
  42. Finsterer J. Leigh and Leigh-like syndrome in children and adults. Pediatr Neurol 2008; 39:223.
  43. Rahman S, Blok RB, Dahl HH, et al. Leigh syndrome: clinical features and biochemical and DNA abnormalities. Ann Neurol 1996; 39:343.
  44. 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.
  45. 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.
  46. 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.
  47. Montagna P, Gallassi R, Medori R, et al. MELAS syndrome: characteristic migrainous and epileptic features and maternal transmission. Neurology 1988; 38:751.
  48. Ohno K, Isotani E, Hirakawa K. MELAS presenting as migraine complicated by stroke: case report. Neuroradiology 1997; 39:781.
  49. Kaufmann P, Engelstad K, Wei Y, et al. Natural history of MELAS associated with mitochondrial DNA m.3243A>G genotype. Neurology 2011; 77:1965.
  50. Hirano M, Ricci E, Koenigsberger MR, et al. Melas: an original case and clinical criteria for diagnosis. Neuromuscul Disord 1992; 2:125.
  51. Dimauro S, Tay S, Mancuso M. Mitochondrial encephalomyopathies: diagnostic approach. Ann N Y Acad Sci 2004; 1011:217.
  52. 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.
  53. DiMauro S, Hirano M. MERRF. GeneReviews. www.ncbi.nlm.nih.gov/books/NBK1520/ (Accessed on June 18, 2015).
  54. 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.
  55. 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.
  56. 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.
  57. Guillausseau PJ, Massin P, Dubois-LaForgue D, et al. Maternally inherited diabetes and deafness: a multicenter study. Ann Intern Med 2001; 134:721.
  58. 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.
  59. Shoffner JM. Mitochondrial neurogastrointestinal encephalopathy disease. GeneReviews. www.ncbi.nlm.nih.gov/books/NBK1179/ (Accessed on February 11, 2011).
  60. 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.
  61. 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.
  62. 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.
  63. Shaibani A, Shchelochkov OA, Zhang S, et al. Mitochondrial neurogastrointestinal encephalopathy due to mutations in RRM2B. Arch Neurol 2009; 66:1028.
  64. 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.
  65. 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.
  66. 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.
  67. DiMauro S, Hirano M. Mitochondrial DNA deletion syndromes. GeneReviews. www.ncbi.nlm.nih.gov/books/NBK1203/ (Accessed on June 18, 2015).
  68. 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.
  69. Taylor RW, Schaefer AM, Barron MJ, et al. The diagnosis of mitochondrial muscle disease. Neuromuscul Disord 2004; 14:237.
  70. Chinnery PF. Mitochondrial disorders overview. GeneReviews. www.ncbi.nlm.nih.gov/books/NBK1224/ (Accessed on February 11, 2011).
  71. McFarland R, Taylor RW, Turnbull DM. The neurology of mitochondrial DNA disease. Lancet Neurol 2002; 1:343.
  72. Haas RH, Parikh S, Falk MJ, et al. Mitochondrial disease: a practical approach for primary care physicians. Pediatrics 2007; 120:1326.
  73. 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.
  74. Turnbull D. A new biomarker for mitochondrial disease. Lancet Neurol 2011; 10:777.
  75. 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.
  76. Jackson MJ, Schaefer JA, Johnson MA, et al. Presentation and clinical investigation of mitochondrial respiratory chain disease. A study of 51 patients. Brain 1995; 118 ( Pt 2):339.
  77. Robinson BH. Cell culture studies on patients with mitochondrial diseases: molecular defects in pyruvate dehydrogenase. J Bioenerg Biomembr 1988; 20:313.
  78. Tarnopolsky MA, Raha S. Mitochondrial myopathies: diagnosis, exercise intolerance, and treatment options. Med Sci Sports Exerc 2005; 37:2086.
  79. 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.
  80. Sarnat HB, Marín-García J. Pathology of mitochondrial encephalomyopathies. Can J Neurol Sci 2005; 32:152.
  81. Barron MJ, Chinnery PF, Howel D, et al. Cytochrome c oxidase deficient muscle fibres: substantial variation in their proportions within skeletal muscles from patients with mitochondrial myopathy. Neuromuscul Disord 2005; 15:768.
  82. Debray FG, Lambert M, Mitchell GA. Disorders of mitochondrial function. Curr Opin Pediatr 2008; 20:471.
  83. James AM, Wei YH, Pang CY, Murphy MP. Altered mitochondrial function in fibroblasts containing MELAS or MERRF mitochondrial DNA mutations. Biochem J 1996; 318 ( Pt 2):401.
  84. Tucker EJ, Compton AG, Thorburn DR. Recent advances in the genetics of mitochondrial encephalopathies. Curr Neurol Neurosci Rep 2010; 10:277.