Comprehensive analysis of pyrimidine metabolism in 450 children with unspecific neurological symptoms using high–pressure liquid chromatography–electrospray ionization tandem mass spectrometry

Abstract

To evaluate the significance of inborn metabolic disorders of the pyrimidine degradation pathway, 450 children with unspecific neurological symptoms were comprehensively studied; 200 healthy children were recruited as controls. Uracil and thymine as well as their degradation products in urine were determined with an improved method based on reversed-phase HPLC coupled with electrospray ionization tandem mass spectrometry and detection by multiple-reaction monitoring using stable-isotope-labelled reference compounds as internal standards. From the results of the control group we established age-related reference ranges of all pyrimidine degradation products. In the patient group, two children with dihydropyrimidine dehydrogenase (DPYD) deficiency were identified; one of these was homozygous for the exon 14-skipping mutation of the DPYD gene. In addition, two patients with high uracil, dihydrouracil and beta-ureidopropionate were found to have ornithine transcarbamylase deficiency. In the urine of 9 patients, beta-alanine was markedly elevated owing to treatment with vigabatrin, an irreversible inhibitor of GABA transaminase, which interferes with beta-alanine breakdown. Four patients had exclusively high levels of beta-aminoisobutyrate (beta-AIB) due to a low activity of the D-beta-AIB-pyruvate aminotransferase, probably without clinical significance. In conclusion, quantitative investigation of pyrimidine metabolites in children with unexplained neurological symptoms, particularly epileptic seizures with or without psychomotor retardation, can be recommended as a helpful tool for diagnosis in clinical practice. Sensitive methods and age-related reference ranges enable the detection of partial enzyme deficiencies.

Alanine-glyoxylate aminotransferase 2 (AGXT2) Polymorphisms Have Considerable Impact on Methylarginine and β-aminoisobutyrate Metabolism in Healthy Volunteers

“…The isotope labeled BAIB standard ([ 2 H 6 ]-BAIB) was a kind gift of Dr. Ute Hofmann (Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany) [17]. The isotope labeled SDMA ([ 2 H 6 ]-SDMA) was obtained from Toronto Research Chemicals Inc. (Toronto, Canada).…”

Clinical Pharmacogenetics Implementation Consortium Guidelines for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing

“…Patients homozygous for inactivating variants of the DPYD gene have DPD deficiency, a disease that shows large phenotypic variability, ranging from no symptoms to severe convulsive disorders with motor and mental retardation. 28,29 Other considerations…”

Neurotrophic keratitis in a patient with dihydroxypyrimidine dehydrogenase deficiency

“…This may explain the reduced corneal sensation and the development of neurotrophic keratitis in this child. Various manifestations associated with DHPD deficiency have been described, but most children present with microcephaly, epilepsy and abnormal EEG profile, however, many may be asymptomatic 4. Ocular manifestations such as microphthalmia, choroidal coloboma and nystagmus have also been reported 2…”