Five cases of β‐ureidopropionase deficiency detected by GC/MS analysis of urine metabolome

Abstract

The clinical presentation of inborn errors of pyrimidine degradation varies considerably from asymptomatic to severe neurological illness. We have reported a method to screen for and make a chemical diagnosis of beta-ureidopropionase deficiency, leading to the discovery of the first asymptomatic case of this disease. In this method, the recovery of beta-ureidopropionate and beta-ureidoisobutyrate, the key biomarkers, was very high,and the adoption of GC/MS and targeted analysis enabled us to simultaneously obtain information related and unrelated to pyrimidine metabolism. The present study reports the results of a large-scale screening of 24,000 newborns using dried urine on filter paper. Identification of a total of four asymptomatic patients among newborns suggests the high incidence (1/6000) of this disease in Japan. While these newborns were asymptomatic, two additional cases detected at the age of 5 years as well as 3 months with this method for high-risk screening had autism and West syndrome, respectively.The key biomarkers and alpha-ureidobutyrate used as an internal standard were found to give not only their di-trimethylsilyl derivatives but also tri-trimethylsilyl derivatives, upon derivatization. The mass spectra and retention times of their tri-trimethylsilyl derivatives and data handling for quantification of the markers are presented.Identification of individuals with defects in pyrimidine metabolism would realize personalized medication in cancer chemotherapy with pyrimidine analogs such as 5-fluorouracil.

Clinical, biochemical and molecular analysis of 13 Japanese patients with β‐ureidopropionase deficiency demonstrates high prevalence of the c.977G > A (p.R326Q) mutation

“…a) indicates same family members (child and mother). b) indicates same family members (two siblings and father)Biochemical data of patient 1, 2, 4, 5, 6 and 7 were previously reported (Kuhara et al 2009)…”

“…She was diagnosed with West syndrome. Biochemical investigation of urine obtained during her first admission revealed significantly increased levels of N-carbamyl-β-alanine and N-carbamyl-β-aminoisobutyric acid (Kuhara et al 2009). The infantile spasms and abnormal EEGs did not respond to zonisamide, therefore adrenocorticotropic hormone (ACTH) therapy was started at three months of age, and subsequently, the seizures disappeared and EEG abnormalities subsided.…”

“…Patients 4–7 were detected through neonatal screening performed from 1996 to 2009 in Kanazawa (Kuhara et al 2009). Since screening, they have been followed regularly by an attending paediatrician.…”

“…In general patients are tested for metabolic disorders if patients presented with developmental delay, hyperammonemia, metabolic acidosis and neurological manifestations such as convulsions, autism and related disorders. Patients 4–7 and 8–13 were from two different areas in Japan, detected in a pilot study screening for inborn errors of metabolism by GC/MS in newborn urine samples, and conducted at Kanazawa Medical University (Kuhara et al 2009) (patients 4–7) and Kurume University (patients 8–13). After informed consent was obtained from their parents, urine and blood samples from all patients were sent to the Laboratory for Genetic Metabolic Diseases in Amsterdam, the Netherlands for further analysis.…”

“…The clinical phenotype of these patients is highly variable, but tends to center around neurological problems (van Kuilenburg et al 2012). However, in Japan, four asymptomatic individuals have been detected through newborn screening by gas chromatography-mass spectrometry (GC/MS), and the prevalence of βUP deficiency in Japan has been estimated to be one in 6000 (Kuhara et al 2009). Thus, the clinical presentation and biochemical and genetic spectrum of patients with βUP deficiency are still largely unknown.…”