Urea cycle disorders and indications for liver transplantation.

Urea cycle disorders (UCD) are inborn errors of metabolism caused by deficiency of enzymes required to convert nitrogen from ammonia into urea. Current paradigms of treatment focus on dietary manipulations, ammonia scavenger drugs, and liver transplantation. The aim of this study was to describe the characteristics and indication of liver transplantation in UCD in a tertiary hospital. We performed a retrospective study of children with UCD seen in the period 2000-2021. Data was collected on clinical onset, hyperammonemia severity, evolution and liver transplantation. There were 33 patients in the study period, whose diagnosis were: ornithine transcarbamylase (OTC, n = 20, 10 females), argininosuccinate synthetase (ASS, n = 6), carbamylphosphate synthetase 1 (CPS1, n = 4), argininosuccinate lyase (ASL, n = 2) and N-acetylglutamate synthetase (NAGS, n = 1) deficiency. Thirty one were detected because of clinical symptoms (45% with neonatal onset). The other 2 were diagnosed being presymptomatic, by neonatal/family screening. Neonatal forms (n = 14) were more severe, all of them presented during the first week of life as severe hyperammonemia (mean peak 1,152 µmol/L). Seven patients died (6 at debut) and all survivors received transplantation. There was no mortality among the late forms. Of the 27 patients who did not die in the neonatal period, 16 (59%) received liver transplantationwith 100% survival, normal protein tolerance and usual need of citrulline supplementation. The transplant's metabolic success was accompanied by neurologic sequelae in 69%, but there was no progression of brain damage. Decision of continuous medical treatment in 11 patients appeared to be related with preserved neurodevelopment and fewer metabolic crises.

Value of genetic analysis for confirming inborn errors of metabolism detected through the Spanish neonatal screening program.

The present work describes the value of genetic analysis as a confirmatory measure following the detection of suspected inborn errors of metabolism in the Spanish newborn mass spectrometry screening program. One hundred and forty-one consecutive DNA samples were analyzed by next-generation sequencing using a customized exome sequencing panel. When required, the Illumina extended clinical exome panel was used, as was Sanger sequencing or transcriptional profiling. Biochemical tests were used to confirm the results of the genetic analysis. Using the customized panel, the metabolic disease suspected in 83 newborns (59%) was confirmed. In three further cases, two monoallelic variants were detected for two genes involved in the same biochemical pathway. In the remainder, either a single variant or no variant was identified. Given the persistent absence of biochemical alterations, carrier status was assigned in 39 cases. False positives were recorded for 11. In five cases in which the biochemical pattern was persistently altered, further genetic analysis allowed the detection of two variants affecting the function of BCAT2, ACSF3, and DNAJC12, as well as a second, deep intronic variant in ETFDH or PTS. The present results suggest that genetic analysis using extended next-generation sequencing panels can be used as a confirmatory test for suspected inborn errors of metabolism detected in newborn screening programs. Biochemical tests can be very helpful when a diagnosis is unclear. In summary, simultaneous genomic and metabolomic analyses can increase the number of inborn errors of metabolism that can be confirmed following suggestive newborn screening results.