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Molecular Diagnostics and Genetics |
1
Neo Gen Screening, 110 Roessler Road, Pittsburgh, PA 15220.
2
California Department of Health Services, Genetic
Disease Branch, 2151 Berkeley Way, Annex 4, Berkeley, CA 94704.
3
Division of Medical Genetics, Department of Pediatrics,
Duke University Medical Center, Research Triangle Park, NC 27709.
a Author for correspondence. Fax 412-341-8926; e-mail dhchace{at}neogenscreening.com.
We compared the screening interpretation of fluorometric analytical results for phenylketonuria (PKU) with tandem mass spectrometry (MS/MS) in filter paper blood spots collected from newborns <24 h of age. In MS/MS, both Phe and Tyr are quantified. Two hundred and eight blood spots collected from infants <24 h of age were retrieved from storage from the California newborn screening program. These samples had been categorized on the basis of fluorometric analysis as initial negative, initial positive for hyperphenylalaninemia with negative determination on recall, or initial positive for hyperphenylalaninemia and confirmed on follow up as PKU or variant hyperphenylalaninemia. The retrieved samples were analyzed in a blinded fashion using MS/MS. Correlation analysis of fluorometry vs MS/MS for Phe concentration was high, with a Pearson correlation coefficient of 0.817. When 180 µmol/L was used as the cutoff Phe concentration for MS/MS and 258 µmol/L was used as the cutoff for fluorometry, all infants with confirmed classical PKU and variant hyperphenylalaninemia were detected. MS/MS analysis reduced the number of false-positive results from 91 to 3. Simultaneous quantification of Phe and Tyr by MS/MS with the use of a cutoff Phe/Tyr molar ratio of 2.5 further reduced the number of false positives to 1. Samples from affected infants showed a discernible trend of increasing Phe concentration and Phe/Tyr molar ratio with age of collection. These results demonstrate the utility of MS/MS in the routine PKU screening of early-discharge newborns. MS/MS reduces the false-positive rate of fluorometric screening almost 100-fold because of the improved accuracy and precision of Phe measurement and simultaneous confirmation with the Phe/Tyr molar ratio. In addition to the detection of PKU, MS/MS can also detect other aminoacidopathies and disorders of fatty acid and organic acid metabolism with lower false-positive rates than other methods currently used in newborn screening programs.
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National Institutes of Health Consensus Developmen National Institutes of Health Consensus Development Conference Statement: Phenylketonuria: Screening and Management, October 16-18, 2000 Pediatrics, October 1, 2001; 108(4): 972 - 982. [Abstract] [Full Text] [PDF]
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D. H. Chace, B. W. Adam, S. J. Smith, J. R. Alexander, S. L. Hillman, and W. H. Hannon Validation of Accuracy-based Amino Acid Reference Materials in Dried-Blood Spots by Tandem Mass Spectrometry for Newborn Screening Assays Clin. Chem., August 1, 1999; 45(8): 1269 - 1277. [Abstract] [Full Text] [PDF]
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H. L. Levy Newborn Screening by Tandem Mass Spectrometry: A New Era Clin. Chem., December 1, 1998; 44(12): 2401 - 2402. [Full Text] [PDF]
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