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Serum metabolomics for the diagnosis and classification of myasthenia gravis

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Abstract

Myasthenia gravis (MG) is a chronic autoimmune neuromuscular disease with few reliable diagnostic measures. Therefore, it is great important to explore novel tools for the diagnosis of MG. In this study, a serum metabolomic approach based on LC–MS in combination with multivariate statistical analyses was used to identify and classify patients with various grades of MG. Serum samples from 42 MG patients and 16 healthy volunteers were analyzed by liquid chromatography Fourier transform mass spectrometry (LC-FTMS). MG patients were clearly distinguished from healthy subjects based on their global serum metabolic profiles by using orthogonal partial least squares (OPLS) analysis. Moreover, different changes in metabolic profiles were observed between early- and late-stages MG patients. Nine biomarkers, including gamma-aminobutyric acid and sphingosine 1-phosphate were identified. In addition, 92.8% sensitivity, 83.3% specificity and 90% accuracy were obtained from the OPLS discriminant analysis (OPLS-DA) class prediction model in detecting MG. The results presented here illustrate that serum metabolomics exhibits great potential in the detecting and grading of MG, and it is potentially applicable as a new diagnostic approach for MG.

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References

  • Alshekhlee, A., Miles, J. D., Katirji, B., Preston, D. C., & Kaminski, H. J. (2009). Incidence and mortality rates of myasthenia gravis and myasthenic crisis in US hospitals. Neurology, 72(18), 1548–1554.

    Article  PubMed  CAS  Google Scholar 

  • Baets, M. H., & Oosterhuis, H. J. G. H. (1993). Myasthenia gravis. Boca Raton, FL: DRD Press.

    Google Scholar 

  • Brindle, J. T., Antti, H., Holmes, E., Tranter, G., Nicholson, J. K., Bethell, H. W., et al. (2002). Rapid and noninvasive diagnosis of the presence and severity of coronary heart disease using 1H-NMR-based metabonomics. Nature Medicine, 8(12), 1439–1444.

    Article  PubMed  CAS  Google Scholar 

  • Cheng, C., Wu, G., Yeung, S. C., Li, R., Bella, A. E., Pang, J., et al. (2009). Serum protein profiles in myasthenia gravis. The Annals of Thoracic Surgery, 88(4), 1118–1123.

    Article  PubMed  Google Scholar 

  • de Kraker, M., Kluin, J., Renken, N., Maat, A. P., & Bogers, A. J. (2005). CT and myasthenia gravis: Correlation between mediastinal imaging and histopathological findings. Interactive Cardiovascular and Thoracic Surgery, 4(3), 267–271.

    Article  PubMed  Google Scholar 

  • Denery, J. R., Nunes, A. A. K., Hixon, M. S., Dickerson, T. J., & Janda, K. D. (2010). Metabolomics-based discovery of diagnostic biomarkers for onchocerciasis. PLoS Neglected Tropical Diseases, 4(10), e834.

    Article  PubMed  Google Scholar 

  • Eng, J. (2007). ROC analysis: web-based calculator for ROC curves. Retrieved June 18, 2011 from http://www.jrocfit.org.

  • Gajdos, P., Chevret, S., & Toyka, K. (2008). Intravenous immunoglobulin for myasthenia gravis. Cochrane Database of Systematic Reviews, Issue 1, Art. No. CD002277. doi:10.1002/14651858.CD002277.pub3.

  • Gika, H. G., Theodoridis, G. A., Wingate, J. E., & Wilson, I. D. (2007). Within-day reproducibility of an HPLC-MS-based method for metabonomic analysis: Application to human urine. Journal of Proteome Research, 6(8), 3291–3303.

    Article  PubMed  CAS  Google Scholar 

  • Godoy, M. M. G., Lopes, E. P. A., Silva, R. O., Hallwass, F., Koury, L. C. A., Moura, I. M., et al. (2010). Hepatitis C virus infection diagnosis using metabonomics. Journal of Viral Hepatitis, 17(12), 854–858.

    Article  PubMed  CAS  Google Scholar 

  • Gu, H., Pan, Z., Xi, B., Asiago, V., Musselman, B., & Raftery, D. (2011). Principal component directed partial least squares analysis for combining nuclear magnetic resonance and mass spectrometry data in metabolomics: Application to the detection of breast cancer. Analytica Chimica Acta, 686(1–2), 57–63.

    Article  PubMed  CAS  Google Scholar 

  • Guy, P. A., Tavazzi, I., Bruce, S. J., Ramadan, Z., & Kochhar, S. (2008). Global metabolic profiling analysis on human urine by UPLC-TOFMS: Issues and method validation in nutritional metabolomics. Journal of Chromatography B Analytical Technologies in the Biomedical and Life Sciences, 871(12), 253–260.

    CAS  Google Scholar 

  • Henneges, C., Bullinger, D., Fux, R., Friese, N., Seeger, H., Neubauer, H., et al. (2009). Prediction of breast cancer by profiling of urinary RNA metabolites using Support Vector Machine-based feature selection. BMC Cancer, 9, 104.

    Article  PubMed  Google Scholar 

  • Juo, C. G., Chiu, D. T., & Shiao, M. S. (2008). Liquid chromatography-mass spectrometry in metabolite profiling. Biofactors, 34(2), 159–169.

    Article  PubMed  CAS  Google Scholar 

  • Kim, K., Aronov, P., Zakharkin, S. O., Anderson, D., Perroud, B., Thompson, I. M., et al. (2009). Urine Metabolomics Analysis for Kidney cancer detection and biomarker discovery. Molecular and Cellular Proteomics, 8(3), 558–570.

    Article  PubMed  CAS  Google Scholar 

  • Kirschenlohr, H. L., Griffin, J. L., Clarke, S. C., Rhydwen, R., Grace, A. A., Schofield, P. M., et al. (2006). Proton NMR analysis of plasma is a weak predictor of coronary artery disease. Nature Medicine, 12(6), 705–710.

    Article  PubMed  CAS  Google Scholar 

  • Li, X., Yang, S., Qiu, Y., Zhao, T., Chen, T., Su, M., et al. (2010). Urinary metabolomics as a potentially novel diagnostic and stratification tool for knee osteoarthritis. Metabolomics, 6(1), 109–118.

    Article  Google Scholar 

  • Llorach, R., Garrido, I., Monagas, M., Urpi-Sarda, M., Tulipani, S., Bartolome, B., et al. (2010). Metabolomics study of human urinary metabolome modifications after intake of almond (Prunus dulcis (Mill.) D.A. Webb) skin polyphenols. Journal of Proteome Research, 9(11), 5859–5867.

    Article  PubMed  CAS  Google Scholar 

  • Lv, Y., Liu, X., Yan, S., Liang, X., Yang, Y., Dai, W., et al. (2010). Metabolomic study of myocardial ischemia and intervention effects of Compound Danshen Tablets in rats using ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry. Journal of Pharmaceutical and Biomedical Analysis, 52(1), 129–135.

    Article  PubMed  CAS  Google Scholar 

  • Nicholson, J. K., & Lindon, J. C. (2008). Systems biology: Metabonomics. Nature, 455(7216), 1054–1056.

    Article  PubMed  CAS  Google Scholar 

  • Nicholson, J. K., Lindon, J. C., & Holmes, E. (1999). ‘Metabonomics’: Understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica, 29(11), 1181–1189.

    Article  PubMed  CAS  Google Scholar 

  • Osserman, K. E., & Genkins, G. (1971). Studies in myasthenia gravis: Review of a twenty-year experience in over 1200 patients. Mount Sinai Journal of Medicine, 38(6), 497–537.

    PubMed  CAS  Google Scholar 

  • Pasikanti, K. K., Esuvaranathan, K., Ho, P. C., Mahendran, R., Kamaraj, R., Wu, Q. H., et al. (2010). Noninvasive urinary metabonomic diagnosis of human bladder cancer. Journal of Proteome Research, 9(6), 2988–2995.

    Article  PubMed  CAS  Google Scholar 

  • Sangster, T., Major, H., Plumb, R., Wilson, A. J., & Wilson, I. D. (2006). A pragmatic and readily implemented quality control strategy for HPLC-MS and GC-MS-based metabonomic analysis. Analyst, 131(10), 1075–1078.

    Article  PubMed  CAS  Google Scholar 

  • Scherer, K., Bedlack, R. S., & Simel, D. L. (2005). Does this patient have myasthenia gravis? Journal of the American Medical Association, 293(15), 1906–1914.

    Article  PubMed  CAS  Google Scholar 

  • Seybold, M. E. (1986). The office Tensilon test for ocular myasthenia gravis. Archives of Neurology, 43(8), 842–843.

    Article  PubMed  CAS  Google Scholar 

  • Slupsky, C. M. (2010). NMR-based analysis of metabolites in urine provides rapid diagnosis and etiology of pneumonia. Biomarkers in medicine, 4(2), 195–197.

    Article  PubMed  Google Scholar 

  • Slupsky, C. M., Rankin, K. N., Fu, H., Chang, D., Rowe, B. H., Charles, P. G. P., et al. (2009). Pneumococcal pneumonia: Potential for diagnosis through a urinary metabolic profile. Journal of Proteome Research, 8(12), 5550–5558.

    Article  PubMed  CAS  Google Scholar 

  • Slupsky, C. M., Steed, H., Wells, T. H., Dabbs, K., Schepansky, A., Capstick, V., et al. (2010). Urine metabolite analysis offers potential early diagnosis of ovarian and breast cancers. Clinical Cancer Research, 16(23), 5835–5841.

    Article  PubMed  CAS  Google Scholar 

  • Spiegel, S., & Milstien, S. (2011). The outs and the ins of sphingosine-1-phosphate in immunity. Nature Reviews Immunology, 11(6), 403–415.

    Article  PubMed  CAS  Google Scholar 

  • Tan, C., Chen, H., & Xia, C. (2009). Early prediction of lung cancer based on the combination of trace element analysis in urine and an Adaboost algorithm. Journal of Pharmaceutical and Biomedical Analysis, 49(3), 746–752.

    Article  PubMed  CAS  Google Scholar 

  • Tiziani, S., Lopes, V., & Günther, U. L. (2009). Early stage diagnosis of oral cancer using 1H NMR-based metabolomics. Neoplasia, 11(3), 269–276.

    PubMed  CAS  Google Scholar 

  • Vincent, A., Palace, J., & Hilton-Jones, D. (2001). Myasthenia gravis. The Lancet, 357(9274), 2122–2128.

    Article  CAS  Google Scholar 

  • Watanabe, M., Maemura, K., Kanbara, K., Tamayama, T., & Hayasaki, H. (2002). GABA and GABA receptors in the central nervous system and other organs. International Review of Cytology, 213, 1–47.

    Article  PubMed  CAS  Google Scholar 

  • Wen, H., Yoo, S. S., Kang, J., Kim, H. G., Park, J. S., Jeong, S., et al. (2010). A new NMR-based metabolomics approach for the diagnosis of biliary tract cancer. Journal of Hepatology, 52(2), 228–233.

    Article  PubMed  CAS  Google Scholar 

  • Xie, G. X., Chen, T. L., Qiu, Y. P., Shi, P., Zheng, X. J, Su, M. M., et al. (2011). Urine metabolite profiling offers potential early diagnosis of oral cancer. Metabolomics. doi:10.1007/s11306-011-0302-7.

  • Yang, J., Xu, G., Hong, Q., Liebich, H., Lutz, K., Schmulling, R., et al. (2004). Discrimination of Type 2 diabetic patients from healthy controls by using metabonomics method based on their serum fatty acid profiles. Journal of Chromatography B Analytical Technologies in the Biomedical and Life Sciences, 813(1–2), 53–58.

    CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by major project of Chinese national programs for fundamental research and development (973 Program) (2005CB523502) and Hong Kong UGC AoE Plant and Agricultural Biotechnology Project AoE-B-07/09.

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Correspondence to Saiming Ngai.

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Yonghai Lu, Chunmei Wang are equal contributors.

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Lu, Y., Wang, C., Chen, Z. et al. Serum metabolomics for the diagnosis and classification of myasthenia gravis. Metabolomics 8, 704–713 (2012). https://doi.org/10.1007/s11306-011-0364-6

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  • DOI: https://doi.org/10.1007/s11306-011-0364-6

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