Diagnosis and monitoring of inborn errors of metabolism using urease-pretreatment of urine, isotope dilution, and gas chromatography–mass spectrometry

To diagnose inborn errors of metabolism, it would be desirable to simultaneously analyze and quantify organic acids, purines, pyrimidines, amino acids, sugars, polyols, and other compounds using a single-step fractionation; unfortunately, no such method currently exists. The present article will be concerned primarily with a practical yet comprehensive diagnostic procedure of inborn errors of metabolism (IEM). This procedure involves the use of urine or eluates from urine on filter paper, stable isotope dilution, and gas chromatography–mass spectrometry (GC–MS). This procedure not only offers reliable and quantitative evidence for diagnosing, understanding and monitoring the diseases, but also provides evidence for the diagnosis of new kinds of IEM. In this review, the differential diagnosis for hyperammonemia are described; deficiencies of ornithine carbamoyl transferase, argininosuccinate synthase (citrullinemia), argininosuccinate lyase and arginase, lysinuric protein intolerance, hyperammonemia–hyperornithinemia–homocitrullinemia syndrome, and citrullinemia type II. The diagnosis of IEM of purine and pyrimidine such as deficiencies of hypoxanthine–guanine phosphoribosyl transferase, adenine phosphoribosyl transferase, dihydropyrimidine dehydrogenase, dihydropyrimidinase and β-ureidopropionase are described. During the pilot study for newborn screening, we found neonates with diseases at a rate of 1 per 1400 including propionic acidemia, methylmalonic acidemia, orotic aciduria, β-ureidopropionase deficiency, lactic aciduria and neuroblastoma. A rapid and reliable prenatal diagnosis for propionic acidemia is also described.