Skip to main content
SpringerLink
Log in

Future Developments in the Laboratory Diagnosis of OXPHOS Disorders

  • Chapter
Book cover Oxidative Phosphorylation in Health and Disease

Part of the book series: Medical Intelligence Unit ((MIUN))

  • 685 Accesses

Abstract

Laboratory diagnosis of OXPHOS disorders has evolved substantially since mitochondrial DNA mutations were first shown to cause human disease in 1988. Traditional approaches such as skeletal muscle OXPHOS enzyme analysis and histochemistry remain among the most important diagnostic tools. However, molecular diagnosis of mitochondrial DNA mutations and, more recently, nuclear gene mutations are responsible for an increasing number of diagnoses. This trend will continue over the next two decades with new genomic approaches such as mutation chips eventually likely to become front-line diagnostic tools. In order to completely replace traditional approaches though, much work needs to be done identifying novel OXPHOS disease-causing genes and distinguishing pathogenic mutations in such genes from polymorphisms. In the interim, a number of other approaches will improve the ease and certainty of OXPHOS diagnosis. These are likely to include increased use of spectroscopic and other methods for assessing in vivo OXPHOS function, use of minimally invasive tissue biopsies, improved assays of OXPHOS function using immunocapture antibodies or fluorescent probes, and methods for assessing expression of OXPHOS genes and proteins using antibody chips, proteomics and cDNA microarrays. All these methods will require extensive validation studies to distinguish primary OXPHOS defects from other disease states and development of improved algorithms for defining how much evidence is needed for a definite diagnosis of OXPHOS disease.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

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

    Article  CAS  Google Scholar 

  2. Taivassalo T, Jensen TD, Kennaway N et al. The spectrum of exercise tolerance in mitochondrial myopathies: a study of 40 patients. Brain 2003; 126:413–23.

    Article  PubMed  Google Scholar 

  3. Takahashi S, Oki J, Miyamoto A et al. Proton magnetic resonance spectroscopy to study the metabolic changes in the brain of a patient with Leigh syndrome. Brain Dev 1999; 21:200–4.

    Article  PubMed  CAS  Google Scholar 

  4. Dubeau F, De Stefano N, Zifkin BG et al. Oxidative phosphorylation defect in the brains of carriers of the tRNAleu(UUR) A3243G mutation in a MELAS pedigree. Ann Neurol 2000; 47:179–85.

    Article  PubMed  CAS  Google Scholar 

  5. Argov Z, Lofberg M, Arnold DL. Insights into muscle diseases gained by phosphorus magnetic resonance spectroscopy. Muscle Nerve 2000; 23:1316–34.

    Article  PubMed  CAS  Google Scholar 

  6. Chen JT, Taivassalo T, Argov Z et al. Modeling in vivo recovery of intracellular pH in muscle to provide a novel index of proton handling: application to the diagnosis of mitochondrial myopathy. Magn Reson Med 2001; 46:870–8.

    Article  PubMed  CAS  Google Scholar 

  7. Bank W, Chance B. Diagnosis of defects in oxidative muscle metabolism by non-invasive tissue oximetry. Mol Cell Biochem 1997; 174:7–10.

    Article  PubMed  CAS  Google Scholar 

  8. Roef MJ, Reijngoud DJ, Jeneson JA et al. Resting oxygen consumption and in vivo ADP are increased in myopathy due to complex I deficiency. Neurology 2002; 58:1088–93.

    PubMed  CAS  Google Scholar 

  9. Roef MJ, Kalhan SC, Reijngoud DJ et al. Lactate disposal via gluconeogenesis is increased during exercise in patients with mitochondrial myopathy due to complex I deficiency. Pediatr Res 2002; 51:592–7.

    PubMed  Google Scholar 

  10. Shoffher JM. Maternal inheritance and the evaluation of oxidative phosphorylation diseases. Lancet 1996; 348:1283–8.

    Article  Google Scholar 

  11. Lamont PJ, Surtees R, Woodward CE et al. Clinical and laboratory findings in referrals for mitochondrial DNA analysis. Arch Dis Child 1998; 79:22–7.

    Article  PubMed  CAS  Google Scholar 

  12. Thorburn DR. Practical problems in detecting abnormal mitochondrial functions and genomes. Human Reprod 2000; 15(Suppl.2):57–67.

    Google Scholar 

  13. Rahman S, Poulton J, Marchington D et al. Decrease of 3243 A->G mtDNA Mutation from Blood in MELAS Syndrome: A Longitudinal Study. Am J Hum Genet 2000; 68:238–240.

    Article  PubMed  Google Scholar 

  14. Andreu AL, Hanna MG, Reichmann H et al. Exercise intolerance due to mutations in the cytochrome b gene of mitochondrial DNA. N Engl J Med 1999; 341:1037–44.

    Article  PubMed  CAS  Google Scholar 

  15. Schwartz M, Vissing J. Paternal inheritance of mitochondrial DNA. N Engl J Med 2002; 347:576–80.

    Article  PubMed  Google Scholar 

  16. Sancho S, Mongini T, Tanji K et al. Analysis of dystrophin expression after activation of myogenesis in amniocytes, chorionic-villus cells, and fibroblasts. A new method for diagnosing Duchenne’s muscular dystrophy. N Engl J Med 1993; 329:915–20.

    Article  PubMed  CAS  Google Scholar 

  17. Roest PA, Bakker E, Fallaux FJ et al. New possibilities for prenatal diagnosis of muscular dystrophies: forced myogenesis with an adenoviral MyoD-vector. Lancet 1999; 353:727–8.

    Article  PubMed  CAS  Google Scholar 

  18. Aggeler RJ, Coons J, Taylor SW et al. A functionally-active human F1F0 ATPase can be purified by immunocapture from heart tissue and fibroblast cell lines: Subunit structure and activity studies. J Biol Chem 2002; 277:33906–12.

    Article  PubMed  CAS  Google Scholar 

  19. Kirby DM, Crawford M, Cleary MA et al. Respiratory chain complex I deficiency. An underdiagnosed energy generation disorder. Neurology 1999; 52:1255–1264.

    PubMed  CAS  Google Scholar 

  20. Murray J, Zhang B, Taylor SW et al. The subunit composition of the human NADH dehydrogenase obtained by rapid one-step immunopurification. J Biol Chem 2003; 278:13619–22.

    Article  PubMed  CAS  Google Scholar 

  21. Lib M, Rodriguez-Mari A, Marusich MF et al. Immunocapture and microplate-based activity measurement of mammalian pyruvate dehydrogenase complex. Anal Biochem 2003; 314:121–7.

    Article  PubMed  CAS  Google Scholar 

  22. Bentlage H, de Coo R, ter Laak H et al. Human diseases with defects in oxidative phosphorylation. 1. Decreased amounts of assembled oxidative phosphorylation complexes in mitochondrial encephalomyopathies. Eur J Biochem 1995; 227:909–15.

    Article  PubMed  CAS  Google Scholar 

  23. Van Coster R, Smet J, George E et al. Blue native polyacrylamide gel electrophoresis: a powerful tool in diagnosis of oxidative phosphorylation defects. Pediatr Res 2001; 50:658–65.

    PubMed  Google Scholar 

  24. Nijtmans LG, Henderson NS, Holt IJ. Blue Native electrophoresis to study mitochondrial and other protein complexes. Methods 2002; 26:327–34.

    Article  PubMed  CAS  Google Scholar 

  25. Kirby DM, Boneh A, Chow CW et al. Low mutant load of mitochondrial DNA G13513A mutation can cause Leigh Disease. Ann Neurol 2003; 54(4):473–8.

    Article  PubMed  CAS  Google Scholar 

  26. Sperl W, Skladal D, Gnaiger E et al. High resolution respirometry of permeabilized skeletal muscle fibers in the diagnosis of neuromuscular disorders. Mol Cell Biochem 1997; 174:71–8.

    Article  PubMed  CAS  Google Scholar 

  27. Kuznetsov AV, Strobl D, Ruttmann E et al. Evaluation of mitochondrial respiratory function in small biopsies of liver. Anal Biochem 2002; 305:186–94.

    Article  PubMed  CAS  Google Scholar 

  28. Williams AJ, Coakley JC, Christodoulou J. Flow cytometric evaluation of defects of the mitochondrial respiratory chain. J Child Neurol 1999; 14:518–23.

    PubMed  CAS  Google Scholar 

  29. Setterfield K, Williams AJ, Donald J et al. Flow cytometry in the study of mitochondrial respiratory chain disorders. Mitochondrion 2002; 1:437–445.

    Article  PubMed  CAS  Google Scholar 

  30. Lopez MF, Melov S. Applied proteomics: mitochondrial proteins and effect on function. Circ Res 2002; 90:380–9.

    Article  PubMed  CAS  Google Scholar 

  31. Rabilloud T, Strub JM, Carte N et al. Comparative proteomics as a new tool for exploring human mitochondrial tRNA disorders. Biochemistry 2002; 41:144–50.

    Article  PubMed  CAS  Google Scholar 

  32. Brookes PS, Pinner A, Ramachandran A et al. High throughput two-dimensional blue-native electrophoresis: A tool for functional proteomics of mitochondria and signaling complexes. Proteomics 2002; 2:969–77.

    Article  PubMed  CAS  Google Scholar 

  33. Hanson BJ, Schulenberg B, Patton WF et al. A novel subfractionation approach for mitochondrial proteins: a three-dimensional mitochondrial proteome map. Electrophoresis 2001; 22:950–9.

    Article  PubMed  CAS  Google Scholar 

  34. Lopez MF, Kristal BS, Chernokalskaya E et al. High-throughput profiling of the mitochondrial proteome using affinity fractionation and automation. Electrophoresis 2000; 21:3427–40.

    Article  PubMed  CAS  Google Scholar 

  35. Taylor SW, Fahy E, Zhang B et al. Characterization of the human heart mitochondrial proteome. Nat Biotechnol 2003; 21:281–6.

    Article  PubMed  CAS  Google Scholar 

  36. Ogasahara S, Engel AG, Frens D et al. Muscle coenzyme Q deficiency in familial mitochondrial encephalomyopathy. Proc Natl Acad Sci USA 1989; 86:2379–2382.

    Article  PubMed  CAS  Google Scholar 

  37. Musumeci O, Naini A, Slonim AE et al. Familial cerebellar ataxia with muscle coenzyme Q10 deficiency. Neurology 2001; 56:849–55.

    PubMed  CAS  Google Scholar 

  38. Lamperti C, Naini A, Hirano M et al. Cerebellar ataxia and coenzyme Q10 deficiency. Neurology 2003; 60:1206–8.

    PubMed  CAS  Google Scholar 

  39. Bione S, Dadamo P, Maestrini E et al. A novel X-linked gene, G4.5. is responsible for Barth syndrome. Nat Genet 1996; 12:385–389.

    Article  PubMed  CAS  Google Scholar 

  40. Vreken P, Valianpour F, Nijtmans LG et al. Defective remodeling of cardiolipin and phosphatidylglycerol in Barth syndrome. Biochem Biophys Res Commun 2000; 279:378–82.

    Article  PubMed  CAS  Google Scholar 

  41. Schlame M, Towbin JA, Heerdt PM et al. Deficiency of tetralinoleoyl-cardiolipin in Barth syndrome. Ann Neurol 2002; 51:634–7.

    Article  PubMed  CAS  Google Scholar 

  42. Jaksch M, Gerbitz KD, Kilger C. Screening for mitochondrial DNA (mtDNA) point mutations using nonradioactive single strand conformation polymorphism (SSCP) analysis. Clin Biochem 1995; 28:503–9.

    Article  PubMed  CAS  Google Scholar 

  43. Michikawa Y, Hofhaus G, Lerman LS et al. Comprehensive, rapid and sensitive detection of sequence variants of human mitochondrial tRNA genes. Nucleic Acids Res 1997; 25:2455–63.

    Article  PubMed  CAS  Google Scholar 

  44. van Den Bosch BJ, de Coo RF, Scholte HR et al. Mutation analysis of the entire mitochondrial genome using denaturing high performance liquid chromatography. Nucleic Acids Res 2000; 28:E89.

    Article  Google Scholar 

  45. Larsen LA, Christiansen M, Vuust J et al. Recent developments in high-throughput mutation screening. Pharmacogenomics 2001; 2:387–99.

    Article  PubMed  CAS  Google Scholar 

  46. Chee M, Yang R, Hubbell E et al. Accessing genetic information with high-density DNA arrays. Science 1996; 274:610–4.

    Article  PubMed  CAS  Google Scholar 

  47. He L, Chinnery PF, Durham SE et al. Detection and quantification of mitochondrial DNA deletions in individual cells by real-time PCR. Nucleic Acids Res 2002; 30:E68.

    Article  PubMed  Google Scholar 

  48. von Wurmb-Schwark N, Higuchi R, Fenech AP et al. Quantification of human mitochondrial DNA in a real time PCR. Forensic Sci Int 2002; 126:34–9.

    Article  Google Scholar 

  49. Shoubridge EA. Nuclear genetic defects of oxidative phosphorylation. Hum Mol Genet 2001;10:2277–84.

    Article  PubMed  CAS  Google Scholar 

  50. 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  PubMed  CAS  Google Scholar 

  51. Benit P, Chretien D, Kadhom N et al. Large-scale deletion and point mutations of the nuclear NDUFV1 and NDUFS1 genes in mitochondrial complex I deficiency. Am J Hum Genet 2001; 68:1344–52.

    Article  PubMed  CAS  Google Scholar 

  52. Kirby DM, Kahler SG, Freckmann ML et al. Leigh disease caused by the mitochondrial DNA G14459A mutation in two unrelated families. Ann Neurol 2000; 48:102–104.

    Article  PubMed  CAS  Google Scholar 

  53. 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(1):58–64.

    Article  PubMed  CAS  Google Scholar 

  54. Pequignot MO, Dey R, Zeviani M et al. Mutations in the SURF1 gene associated with Leigh syndrome and cytochrome C oxidase deficiency. Hum Mutat 2001; 17:374–81.

    Article  PubMed  CAS  Google Scholar 

  55. 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.

    PubMed  CAS  Google Scholar 

  56. Mootha VK, Lepage P, Miller K et al. Identification of a gene causing human cytochrome c oxidase deficiency by integrative genomics. Proc Natl Acad Sci USA 2003; 100:605–610.

    Article  PubMed  CAS  Google Scholar 

  57. Fortina P, Surrey S, Kricka LJ. Molecular diagnostics: hurdles for clinical implementation. Trends Mol Med 2002; 8:264–6.

    Article  PubMed  Google Scholar 

  58. Van Der Westhuizen FH, Van Den Heuvel LP, Smeets R et al. Human mitochondrial complex I deficiency: investigating transcriptional responses by microarray. Neuropediatrics 2003; 34:14–22.

    Article  PubMed  Google Scholar 

  59. Procaccio VF, Golik PZ, Kerstann KW et al. Alterations in gene expression in Leigh’s patients with Complex I defects detected using the Mitochip microarray. Mitochondrion 2001; 1:S77.

    Google Scholar 

  60. Sreekumar R, Unnikrishnan J, Fu A et al. Impact of high-fat diet and antioxidant supplement on mitochondrial functions and gene transcripts in rat muscle. Am J Physiol Endocrinol Metab 2002; 282:E1055–61.

    PubMed  CAS  Google Scholar 

  61. Sreekumar R, Unnikrishnan J, Fu A et al. Effects of caloric restriction on mitochondrial function and gene transcripts in rat muscle. Am J Physiol Endocrinol Metab 2002; 283:E38–43.

    PubMed  CAS  Google Scholar 

  62. Thorburn DR, Dahl HHM. Mitochondrial disorders: genetics, counseling, prenatal diagnosis and reproductive options. Am J Med Genet (Semin Med Genet) 2001; 106:102–114.

    Article  CAS  Google Scholar 

  63. Robinson BH. Prenatal diagnosis of disorders of energy metabolism. Semin Neurol 2001; 21(3):269–73.

    Article  PubMed  CAS  Google Scholar 

  64. Poulton J, Marchington DR. Segregation of mitochondrial DNA (mtDNA) in human oocytes and in animal models of mtDNA disease: Clinical implications. Reproduction 2002; 123:751–5.

    Article  PubMed  CAS  Google Scholar 

  65. Faivre L, Cormier-Daire V, Chretien D et al. Determination of enzyme activities for prenatal diagnosis of respiratory chain deficiency. Prenat Diagn 2000; 20:732–7.

    Article  PubMed  CAS  Google Scholar 

  66. Niers LE, Smeitink JA, Trijbels JM et al. Prenatal diagnosis of NADH:ubiquinone oxidoreductase deficiency. Prenat Diagn 2001; 21:871–80.

    Article  PubMed  CAS  Google Scholar 

  67. Schuelke M, Detjen A, van den Heuvel L et al. New nuclear encoded mitochondrial mutation illustrates pitfalls in prenatal diagnosis by biochemical methods. Clin Chem 2002; 48:772–5.

    PubMed  CAS  Google Scholar 

  68. Amiel J, Gigarel N, Benacki A et al. Prenatal diagnosis of respiratory chain deficiency by direct mutation screening. Prenat Diagn 2001; 21:602–4.

    Article  PubMed  CAS  Google Scholar 

  69. Consortium. ESHRE Preimplantation Genetic Diagnosis Consortium: data collection III (May 2001). Hum Reprod 2002; 17:233–46.

    Article  Google Scholar 

  70. Poulton J, Turnbull DM. 74th ENMC international workshop: mitochondrial diseases 19–20 november 1999, Naarden, the Netherlands. Neuromuscul Disord 2000; 10:460–2.

    Article  PubMed  CAS  Google Scholar 

  71. White SL, Shanske S, McGill JJ et al. Mitochondrial DNA mutations at nudeotide 8993 show a lack of tissue-or age-related variation. J Inherit Metab Dis 1999; 22:899–914.

    Article  PubMed  CAS  Google Scholar 

  72. Letellier T, Durrieu G, Malgat M et al. Statistical analysis of mitochondrial pathologies in childhood: identification of deficiencies using principal component analysis. Lab Invest 2000; 80:1019–30.

    PubMed  CAS  Google Scholar 

  73. Bernier FP, Boneh A, Dennett X et al. Diagnostic Criteria for Respiratory Chain Disorders in Adults and Children. Neurology 2002; 59:1406–1411.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  Google Scholar 

  75. Schagger H, Pfeiffer K. Supercomplexes in the respiratory chains of yeast and mammalian mitochondria. EMBO J 2000; 19:1777–83.

    Article  PubMed  CAS  Google Scholar 

  76. Woollacott AJ, Simpson PB. High throughput fluorescence assays for the measurement of mitochondrial activity in intact human neuroblastoma cells. J Biomol Screen 2001; 6:413–20.

    Article  PubMed  CAS  Google Scholar 

  77. Poot M, Pierce RH. Analysis of mitochondria by flow cytometry. Methods Cell Biol 2001; 64:117–28.

    PubMed  CAS  Google Scholar 

  78. Pham NA, Robinson BH, Hedley DW. Simultaneous detection of mitochondrial respiratory chain activity and reactive oxygen in digitonin-permeabilized cells using flow cytometry. Cytometry 2000; 41:245–51.

    Article  PubMed  CAS  Google Scholar 

  79. Pitkanen S, Robinson BH. Mitochondrial complex I deficiency leads to increased production of superoxide radicals and induction of superoxide dismutase. J Clin Invest 1996; 98:345–351.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Murdoch Childrens Research Institute and Genetic Health Services Royal Children’s Hospital Department of Paediatrics, University of Melbourne, Melbourne, Australia

    David R. Thorburn

Authors
  1. David R. Thorburn
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

Copyright information

© 2004 Eurekah.com and Kluwer Academic / Plenum Publishers

About this chapter

Cite this chapter

Thorburn, D.R. (2004). Future Developments in the Laboratory Diagnosis of OXPHOS Disorders. In: Oxidative Phosphorylation in Health and Disease. Medical Intelligence Unit. Springer, Boston, MA. https://doi.org/10.1007/0-387-26992-4_12

Download citation

  • DOI: https://doi.org/10.1007/0-387-26992-4_12

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-0-306-48232-8

  • Online ISBN: 978-0-387-26992-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation