Carbamoylphosphate synthetase 1 (CPS1) deficiency: clinical, biochemical, and molecular characterization in Malaysian patients

• Published in: European journal of pediatrics Vol. 175; no. 3; pp. 339 - 346
• Main Authors: Ali, Ernie Zuraida, Khalid, Mohd Khairul Nizam Mohd, Yunus, Zabedah Md, Yakob, Yusnita, Chin, Chen Bee, Latif, Kartikasalwah Abd, Hock, Ngu Lock
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.03.2016; Springer Nature B.V
• Subjects: Adenosine; Amino acids; Ammonia; Ammonia - blood; Asian Continental Ancestry Group - genetics; Carbamoyl-Phosphate Synthase (Ammonia) - genetics; Carbamoyl-Phosphate Synthase I Deficiency Disease - diagnosis; Carbamoyl-Phosphate Synthase I Deficiency Disease - genetics; Computer Simulation; E coli; Enzymes; Female; Genetic Testing - methods; Humans; Hyperammonemia - blood; Hyperammonemia - etiology; Hyperammonemia - genetics; Infant, Newborn; Magnetic Resonance Imaging; Malaysia; Male; Medical research; Medicine; Medicine & Public Health; Metabolism; Mutation; Original Article; Pediatrics; Polymorphism; Proteins; Kuala Lumpur Malaysia; Malaysia; Carbamoyl phosphate synthetase 1; Mutation; gene; CPS1 deficiency; Hyperammonemia; CPS1 gene
• ISSN: 0340-6199; 1432-1076
• DOI: 10.1007/s00431-015-2644-z

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. Conclusion : 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. What is Known: • Our patients showed typical clinical and biochemical features of patients with CPS1 deficiency. The spectrum of CPS1 gene mutations in our patients was highly diverse. Majority of the mutations were missense changes followed by nonsense mutations. What is New: • This is the first report on the spectrum of CPS1 variants in Malaysian patient with CPS1 deficiency. This study identified five new mutations including a recurrent missense mutation p.Ile1254Phe, which could be a common and unique to our population.