title: NMR-based urinalysis for rapid diagnosis of β-ureidopropionase deficiency in a patient with Dravet syndrome.
abstract: BACKGROUND
  Beta-ureidopropionase deficiency is a rare inborn error of metabolism (IEM) affecting pyrimidine metabolism. To-date, about 30 genetically confirmed cases had been reported. The clinical phenotypes of this condition are variable; some patients were asymptomatic while some may present with developmental delay or autistic features. In severe cases, patients may present with profound neurological deficit including hypotonia, seizures and mental retardation. Using NMR-based urinalysis, this condition can be rapidly diagnosed within 15 min.
  
  
  METHODS
  An 11-month-old Chinese boy had dual molecular diagnoses, β-ureidopropionase deficiency and Dravet syndrome. He presented with intractable and recurrent convulsions, global developmental delay and microcephaly. Urine organic acid analysis using GC-MS and NMR-based urinalysis showed excessive amount of β-ureidopropionic acid and β-ureidoisobutyric acid, the two disease-specific markers for β-ureidopropionase deficiency. Genetic analysis confirmed homozygous known disease-causing mutation UPB1 NM_016327.2: c.977G>A; NP_057411.1:p.R326Q. In addition, genetic analysis for Dravet syndrome showed the presence of heterozygous disease-causing mutation SCN1A NM_001165963.1:c.4494delC; NP_001159435.1:p.F1499Lfs*2.
  
  
  CONCLUSIONS
  The differentiation between Dravet syndrome and β-ureidopropionase deficiency is clinically challenging since both conditions share overlapping clinical features. The detection of urine β-ureidoisobutyric and β-ureidopropionic acids using NMR or GC-MS is helpful in laboratory diagnosis of β-ureidopropionase deficiency. The disease-causing mutation, c.977G>A of β-ureidopropionase deficiency, is highly prevalent in Chinese population (allele frequency=1.7%); β-ureidopropionase deficiency screening test should be performed for any patients with unexplained neurological deficit, developmental delay or autism.
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, China. Electronic address: ching-wanlam@pathology.hku.hk.
authors.forename: Ching-Wan
authors.initials: CW
authors.lastname: Lam
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, China.
authors.forename: Chun-Yiu
authors.initials: CY
authors.lastname: Law
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, China.
authors.forename: Ka-Fei
authors.initials: KF
authors.lastname: Leung
authors.affiliation: Department of Pathology, Princess Margaret Hospital, Hong Kong, China.
authors.forename: Chi-Kong
authors.initials: CK
authors.lastname: Lai
authors.affiliation: Department of Pathology, Princess Margaret Hospital, Hong Kong, China.
authors.forename: Sammy
authors.initials: S
authors.lastname: Pak-lam Chen
authors.affiliation: Department of Paediatrics and Adolescent Medicine, Princess Margaret Hospital, Hong Kong, China.
authors.forename: Bosco
authors.initials: B
authors.lastname: Chan
authors.affiliation: Department of Paediatrics and Adolescent Medicine, Princess Margaret Hospital, Hong Kong, China.
authors.forename: Kwok-Yin
authors.initials: KY
authors.lastname: Chan
authors.affiliation: Department of Pathology, Princess Margaret Hospital, Hong Kong, China.
authors.forename: Yuet-ping
authors.initials: YP
authors.lastname: Yuen
authors.affiliation: Department of Pathology, Princess Margaret Hospital, Hong Kong, China.
authors.forename: Chloe Miu
authors.initials: CM
authors.lastname: Mak
authors.affiliation: Department of Pathology, Princess Margaret Hospital, Hong Kong, China.
authors.forename: Albert
authors.initials: A
authors.lastname: Yan-wo Chan
mesh_terms: D000015:Abnormalities, Multiple / Q000652:urine*; D000581:Amidohydrolases / Q000172:deficiency* / Q000235:genetics / Q000652:urine; D001927:Brain Diseases / Q000652:urine*; D004831:Epilepsies, Myoclonic / Q000150:complications / Q000235:genetics* / Q000652:urine*; D008401:Gas Chromatography-Mass Spectrometry / Q000379:methods; D006720:Homozygote; D006801:Humans; D007223:Infant; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008297:Male; D009069:Movement Disorders / Q000652:urine*; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics; D011686:Purine-Pyrimidine Metabolism, Inborn Errors / Q000652:urine*; D014508:Urea / Q000031:analogs & derivatives / Q000652:urine; D016482:Urinalysis / Q000379:methods*; D015091:beta-Alanine / Q000031:analogs & derivatives / Q000652:urine
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; C568242:SCN1A protein, human; D015091:beta-Alanine; C066926:beta-ureidoisobutyric acid; C035122:N-carbamoyl-beta-alanine; D014508:Urea; D000581:Amidohydrolases; C021590:beta-ureidopropionase
keywords: Dravet syndrome; Dual molecular diagnoses; NMR spectroscopy; β-Ureidopropionase deficiency