A new chemical diagnostic method for inborn errors of metabolism by mass spectrometry-rapid, practical, and simultaneous urinary metabolites analysis

Mass Spectrom Rev. 1996;15(1):43-57. doi: 10.1002/(SICI)1098-2787(1996)15:1<43::AID-MAS3>3.0.CO;2-B.


In most developed countries, neonatal mass screening programs for the early diagnosis of inborn errors of metabolism (IEM) have been implemented and have been found to be effective for the prevention or significant reduction of clinical symptoms such as mental retardation. These programs rely primarily on simple bacterial inhibition assays (the "Guthrie tests"). We developed a new method for screening IEM using GC/MS, which enables accurate chemical diagnoses through urinary analyses with a simple practical procedure. The urine sample preparation for GC/MS takes one hour for one sample or three hours for a batch of 30 samples (will be fully automated shortly), and the following GC/MS measurement is completed within 15 min per sample. This method allows the simultaneous analyses of amino acids, organic acids, sugars, sugar alcohols, sugar acids, and nucleic acid bases. Therefore, a large number of metabolic disorders can be simultaneously tested by this chemical diagnostic procedure. This method is quite comprehensive and different from conventional GC/MS organic acidemia screening procedures, which are not well-suited to detect metabolic disorders except organic acidurias. Sample preparation includes urease treatment, deproteinization, and derivatization. The method has also been applied to neonate urine specimens that are absorbed into filter paper. The air-dried samples were mailed to the analytical laboratory and eluted with water. The eluate (0.1 mL) was incubated with urease, followed by deproteinization with alcohol, evaporation to dryness of the supernatant, and trimethylsilylation; the samples were applied to GC/MS. A pilot study of the application of this diagnostic procedure to the neonatal mass screening of 22 disorders was started in Japan on February 1, 1995 in cooperation with four medical institutes. This program is supported by the Japanese Society for Biomedical Mass Spectrometry and the Japanese Mass Screening Society. The initial twenty-two target metabolic diseases are: methylmalonic acidemia; propionic acidemia; isovaleric acidemia; maple syrup urine disease; β-ketothiolase deficiency; galactosemia; phenylketonuria; hyperphenylalaninemia; homocystinuria; alkaptonuria; multiple carboxylase deficiency; nonketotic hyperglycinemia; lysinuria; cystinuria; tyrosinemia; glutaric aciduria type I; β-hydroxy-β-methylglutaric acidemia; β-methylcrotonylglycinuria; α-aminoadipic-α-ketoadipic aciduria; ornitine transcarbamylase deficiency (four urea cycle disorders can be screened); glutaric aciduria type II; and neuroblastoma. Neuroblastoma is not an IEM, and is examined at ca. 6 months of age. The twenty-two target diseases will be reconsidered during the pilot study. An accurate chemical diagnosis and hence early treatment of not only organic acidemias but also amino acidemias, and sugar-, polyol-, and nucleic acid base-accumulating metabolic disorders can be made at a very early stage of life. This procedure is also applicable to metabolic profiling of other body fluids that are potentially informative for the study and characterization of a wide range of inherited and acquired metabolic disorders. © 1997 John Wiley & Sons, Inc.

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