Clinical and Genetic Analysis of 8 Children With Ornithine Transcarbamylase Deficiency: Two Novel Mutations.

Background and objectives: Cases and studies of neurologic symptoms in children caused by genetic metabolic diseases have been widely reported. Ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle disorder, which is due to mutations in the OTC gene located on chromosome Xp21.1. In this study, we analyzed the clinical and genetic characteristics of 8 Chinese children diagnosed with OTCD.

Methods: A total of 8 patients (5 male and 3 female) were diagnosed with OTCD by biochemical and molecular analysis between 2015 and 2023. Clinical manifestations, biochemical features, and OTC gene sequencing analysis were reviewed retrospectively. The effect of c.664-1G>C on OTC mRNA synthesis was confirmed by a minigene splicing assay.

Results: All children were late-onset patients, with a median onset age of 3.6 years (range 1.8-17 years). Neurologic symptoms caused by hyperammonemia include vomiting, coma, dyssomnia, and seizures. The peak plasma ammonia levels ranged from 149 to 4,490 μmol/L, and alanine transaminase levels ranged from 20 to 1316 U/L. Four of them had received CRRT, and only 1 patient was admitted for liver transplantation. By December 2023, 4 patients had survived and 4 were deceased. Blood amino acids or urinary organic acids were detected in 7 cases. All patients underwent whole-exome sequencing, and 2 novel mutations were revealed (P1, c.617dupT and P2, c.664-1G>C). The alteration (c.664-1G>C) leads to the deletion of a 54-bp sequence in the exon 7 of the OTC gene (NM_000531.6: c.664_717del).

Discussion: Two novel pathogenic variants in the OTC gene were confirmed in 8 Chinese children by biochemical findings and genetic analysis. These findings will provide a better understanding of the diagnosis and treatment of pediatric patients with OTCD.