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Clinical Chemistry 52: 1127-1137, 2006. First published April 13, 2006; 10.1373/clinchem.2005.058842
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(Clinical Chemistry. 2006;52:1127-1137.)
© 2006 American Association for Clinical Chemistry, Inc.

Endocrinology and Metabolism

Comprehensive Detection of Disorders of Purine and Pyrimidine Metabolism by HPLC with Electrospray Ionization Tandem Mass Spectrometry

Susen Hartmann1,a, Jürgen G. Okun1, Christiane Schmidt1, Claus-Dieter Langhans1, Sven F. Garbade1, Peter Burgard1, Dorothea Haas1, Jörn Oliver Sass2, William L. Nyhan3 and Georg F. Hoffmann1

1 Division of Metabolic Diseases, Department of General Pediatrics, University Children’s Hospital Heidelberg, Heidelberg, Germany.
2 Laboratory of Metabolism, Department of General Pediatrics and Adolescent Medicine, University Children’s Hospital Freiburg, Freiburg, Germany.
3 University of California, San Diego, La Jolla, CA.

aAddress correspondence to this author at: Division of Metabolic Diseases, Department of General Pediatrics, University Children’s Hospital Heidelberg, Im Neuenheimer Feld 150, D-69120 Heidelberg, Germany. Fax 49-6221-564069; e-mail Susen.Hartmann{at}med.uni-heidelberg.de.

Background: Clinical presentation and disease severity in disorders of purine and pyrimidine metabolism vary considerably. We present a method that allows comprehensive, sensitive, and specific diagnosis of the entire spectrum of abnormalities in purine and pyrimidine metabolism in 1 analytical run.

Methods: We used reversed-phase HPLC electrospray ionization tandem mass spectrometry to investigate 24 metabolites of purine and pyrimidine metabolism in urine samples from healthy persons and from patients with confirmed diagnoses of inherited metabolic disorders. Urine samples were filtered and diluted to a creatinine concentration of 0.5 mmol/L. Stable-isotope–labeled internal standards were used for quantification. The metabolites were analyzed by multiple-reaction monitoring in positive and negative ionization modes.

Results: Total time of analysis was 20 min. Recovery (n = 8) of a compound after addition of a known concentration was 85%–133%. The mean intraday variation (n = 10) was 12%. The interday variation (n = 7) was ≤17%. Age-related reference intervals were established for each compound. Analysis of patient urine samples revealed major differences in tandem mass spectrometry profiles compared with those of control samples. Twelve deficiencies were reliably detected: hypoxanthine guanine phosphoribosyl transferase, xanthine dehydrogenase, purine nucleoside phosphorylase, adenylosuccinate lyase, uridine monophosphate synthase, adenosine deaminase, adenine phosphoribosyl transferase, molybdenum cofactor, thymidine phosphorylase, dihydropyrimidine dehydrogenase, dihydropyrimidinase, and ß-ureidopropionase.

Conclusion: This method enables reliable detection of 13 defects in purine and pyrimidine metabolism in a single analytical run.




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T. M. Annesley
Methanol-Associated Matrix Effects in Electrospray Ionization Tandem Mass Spectrometry
Clin. Chem., October 1, 2007; 53(10): 1827 - 1834.
[Abstract] [Full Text] [PDF]


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