title: Carbamoylphosphate synthetase 1 (CPS1) deficiency: clinical, biochemical, and molecular characterization in Malaysian patients.
abstract: Carbamoyl phosphate synthetase 1 (CPS1) deficiency is a rare autosomal recessive disorder of ureagenesis presenting as life-threatening hyperammonemia. In this study, we present the main clinical features and biochemical and molecular data of six Malaysian patients with CPS1 deficiency. All the patients have neonatal-onset symptoms, initially diagnosed as infections before hyperammonemia was recognized. They have typical biochemical findings of hyperglutaminemia, hypocitrullinemia, and low to normal urinary excretion of orotate. One neonate succumbed to the first hyperammonemic decompensation. Five neonatal survivors received long-term treatment consisting of dietary protein restriction and ammonia-scavenging drugs. They have delayed neurocognitive development of varying severity. Genetic analysis revealed eight mutations in CPS1 gene, five of which were not previously reported. Five mutations were missense changes while another three were predicted to create premature stop codons. In silico analyses showed that these new mutations affected different CPS1 enzyme domains and were predicted to interrupt interactions at enzyme active sites, disturb local enzyme conformation, and destabilize assembly of intact enzyme complex.
  
  
  CONCLUSIONS
  All mutations are private except one mutation; p.Ile1254Phe was found in three unrelated families. Identification of a recurrent p.Ile1254Phe mutation suggests the presence of a common and unique mutation in our population. Our study also expands the mutational spectrum of the CPS1 gene.
authors.affiliation: Molecular Diagnostics and Protein Unit, Specialised Diagnostics Centre, Institute for Medical Research, Jalan Pahang, 50588, Kuala Lumpur, Malaysia. erniez1980@gmail.com.
authors.forename: Ernie Zuraida
authors.initials: EZ
authors.lastname: Ali
authors.affiliation: Molecular Diagnostics and Protein Unit, Specialised Diagnostics Centre, Institute for Medical Research, Jalan Pahang, 50588, Kuala Lumpur, Malaysia. mknizam@imr.gov.my.
authors.forename: Mohd Khairul Nizam Mohd
authors.initials: MK
authors.lastname: Khalid
authors.affiliation: Biochemistry Unit, Specialised Diagnostics Centre, Institute for Medical Research, Jalan Pahang, 50588, Kuala Lumpur, Malaysia. zabedah@imr.gov.my.
authors.forename: Zabedah Md
authors.initials: ZM
authors.lastname: Yunus
authors.affiliation: Molecular Diagnostics and Protein Unit, Specialised Diagnostics Centre, Institute for Medical Research, Jalan Pahang, 50588, Kuala Lumpur, Malaysia. yusnita@imr.gov.my.
authors.forename: Yusnita
authors.initials: Y
authors.lastname: Yakob
authors.affiliation: Medical Genetics Department, Kuala Lumpur Hospital, Jalan Pahang, 50588, Kuala Lumpur, Malaysia. beechinmy@yahoo.com.
authors.forename: Chen Bee
authors.initials: CB
authors.lastname: Chin
authors.affiliation: Department of Diagnostic Imaging, Kuala Lumpur Hospital, Jalan Pahang, 50588, Kuala Lumpur, Malaysia. kartiks04@yahoo.com.
authors.forename: Kartikasalwah
authors.initials: K
authors.lastname: Abd Latif
authors.affiliation: Medical Genetics Department, Kuala Lumpur Hospital, Jalan Pahang, 50588, Kuala Lumpur, Malaysia. ngulh@hotmail.com.
authors.forename: Ngu Lock
authors.initials: NL
authors.lastname: Hock
mesh_terms: D000641:Ammonia / Q000097:blood*; D044466:Asian People / Q000235:genetics; D002222:Carbamoyl-Phosphate Synthase (Ammonia) / Q000235:genetics*; D020165:Carbamoyl-Phosphate Synthase I Deficiency Disease / Q000175:diagnosis* / Q000235:genetics; D003198:Computer Simulation; D005260:Female; D005820:Genetic Testing / Q000379:methods; D006801:Humans; D022124:Hyperammonemia / Q000097:blood / Q000209:etiology* / Q000235:genetics; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging; D008296:Malaysia; D008297:Male; D009154:Mutation
chemical_list: D000641:Ammonia; D002222:Carbamoyl-Phosphate Synthase (Ammonia)
keywords: CPS1 deficiency; CPS1 gene; Carbamoyl phosphate synthetase 1; Hyperammonemia; Mutation