Detection of beta-ureidopropionase deficiency with HPLC-electrospray tandem mass spectrometry and confirmation of the defect at the enzyme level.
The pyrimidine bases uracil and thymine are degraded via the consecutive action of three enzymes to beta-alanine and beta-aminoisobutyric acid, respectively. To date, a number of patients have been described with a deficiency of dihydropyrimidine dehydrogenase and dihydropyrimidinase, the first two enzymes of the pyrimidine degradation pathway. In this study, we demonstrate that the first patient presenting with N-carbamyl-beta-amino aciduria, due to a deficiency of beta-ureidopropionase, was easily diagnosed at the metabolite level using HPLC-tandem mass spectrometry. Urinary analysis showed strongly elevated levels of N-carbamyl-beta-alanine and N-carbamyl-beta-aminoisobutyric acid, with normal or moderately increased levels of the pyrimidine bases and the dihydropyrimidines, respectively. The deficiency of beta-ureidopropionase was confirmed by measuring all three enzymes of the pyrimidine degradation pathway. No activity of beta-ureidopropionase could be detected in a liver biopsy of the patient, while a normal activity of dihydropyrimidine dehydrogenase and dihydropyrimidinase was present. Thus, HPLC-tandem mass specrometry proved to be a powerful tool for the initial diagnosis of patients with deficiency of beta-ureidopropionase.
Van Kuilenburg
A B
AB
Academic Medical Center, University of Amsterdam, Emma Children's Hospital and Department of Clinical Chemistry, The Netherlands. a.b.vanKuilenburg@amc.uva.nl
Van Lenthe
H
H
Assmann
B
B
Göhlich-Ratmann
G
G
Hoffmann
G F
GF
Bräutigam
C
C
Wevers
R A
RA
Van Gennip
A H
AH
D000581:Amidohydrolases / Q000032:analysis / Q000172:deficiency*; D000621:Aminoisobutyric Acids / Q000032:analysis; D002851:Chromatography, High Pressure Liquid; D042943:Dihydrouracil Dehydrogenase (NADP); D005260:Female; D006801:Humans; D007223:Infant; D008099:Liver / Q000201:enzymology*; D013058:Mass Spectrometry; D010088:Oxidoreductases / Q000032:analysis; D011743:Pyrimidines / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization
D000621:Aminoisobutyric Acids; D011743:Pyrimidines; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D000581:Amidohydrolases; C021590:beta-ureidopropionase; C020047:dihydropyrimidinase; C030986:pyrimidine; C033435:3-aminoisobutyric acid