Urea cycle disorders: clinical and genetic characteristics of the cases identified in the Russian Federation during the expanded neonatal screening

This article presents the clinical and genetic characteristics of 15 cases of urea cycle disorders (UCD) identified in Russia in 2023 during the expanded neonatal screening. Following the primary screening conducted in regional centers, a group of newborns was formed for the confirmatory diagnostics at the Research Centre for Medical Genetics (N=203). The concentrations of amino acids and acylcarnitines in the blood were remeasured using MS/MS, and urinary organic acid concentrations were measured using GC-MS. Molecular genetic analysis of the coding regions of the ASS1, ASL, and ARG1 genes was performed. Citrullinemia type 1 was genetically confirmed in 9 patients, while argininosuccinic aciduria was confirmed in 6 patients. The frequency of UCD was 1:82,093 live newborns. Five newborns diagnosed with citrullinemia type 1 had biallelic mutations in the ASS1 gene, and four patients had mutations in a homozygous state. Three newborns diagnosed with argininosuccinic aciduria had biallelic mutations in the ASL gene, while the other three patients had mutations in a homozygous state. Previously undescribed variants in a heterozygous state were identified: c.682A>G (p.Asn228Asp) in the ASL gene, as well as c.420+3A>G and c.175-2A>G in the ASS1 gene. At the time of examination, symptoms were observed in 13 newborns (87%). The mortality rate during the first months of life (from 5 to 67 days) was high (47%). Blood citrulline concentrations were elevated in all patients both during the primary screening and the retest. Blood citrulline concentrations in patients with citrullinemia type 1 with lethal outcome was statistically significantly higher compared to live newborns with the same diagnosis (p=0.018). In all cases of citrullinemia type 1 with lethal outcome, citrulline concentration was >1000 μmol/L. Thus, blood citrulline concentration can serve as a marker for the severity of citrullinemia type 1.

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