Clinicaland Mutation Analyses Of 11 Cases With Late-onset Ornithine Transcarbamylase Deficiency

Objective:To improve the ability of identification and diagnosis of late-onset ornithine transcarbamylase deficiency(OTCD)by summarizing the clinical and mutations characteristics of 11 cases,predict the changes of three-dimensional structure of protein and the effect of mutation on protein function.Methods:The clinical characteristics,process of diagnosis and treatment,gene analysis of 11 patients with OTCD treated in Children’s Hospital of Chongqing Medical University from Jan.2013 to Dec.2018 were studied and summarized.We analyze the residues of missensemutant sites together with nearby residues and homology modeling methods.Results: 11 children(6 boys and 5 girls)first visited the emergency department at the age from 6 months to 13 years and 3 months due to conscious disturbance,vomiting mental and behavior disorder,and convulsions.Significantly elevated blood ammonia,liver dysfunction,decreased blood citrulline,and elevated urine orotic acid and uracil were found by laboratory tests.10 different mutations in their OTC gene wereidentified from these 11 patients.3 mutations,c.865A>T、c.78-2A>G、c.893G>T were novel mutations.There are five amino acids translated from the 7 missense mutations showed polarity changes,and 3 amino acids showed changes in the surrounding hydrogen bonds.We found significantly changes of the 3D structure of the protein in 2 missense mutation compared with wild protein.After hemofiltration and other active symptomatic treatment,9 patients were improved,while the other 2 patients who discontinued treatment died soon.Conclusion:OTCD is mainly manifested as central nervous system dysfunction and liver injury caused by hyperammoniaemia,and the peak concentration of blood ammonia is closely related to the prognosis of patients’ neurological function.Children with unexplained vomiting,disturbance of consciousness and dysfunction of liver should be highly alert to the diagnosis of OTCD.Early treatment can improve the prognosis.Changes in the polarity of amino acids and the surrounding hydrogen bonds may affect the binding of enzymes to substrates and the stability of enzymes,thus damaging the urea cycle and causing the accumulation of ammonia.Mutations located at the active site have severe clinical symptoms and poor prognosis in the acute stage,and missense mutations occurring in the SMG loop are prone to change in protein structure and affect protein function.