Incidence, disease onset and short-term outcome in urea cycle disorders –cross-border surveillance in Germany, Austria and Switzerland

Abstract

BackgroundUrea cycle disorders (UCDs) are a group of rare inherited metabolic disorders. Affected individuals often present with hyperammonemic encephalopathy (HE) and have an increased risk of severe neurologic disease and early death. The study aims to provide epidemiologic data and to describe the disease manifestation and short-term outcome.MethodCross-border surveillance of newly diagnosed patients with UCDs - below 16 years of age - was performed from July 2012 to June 2015 in Germany and Austria and from January 2012 to December 2015 in Switzerland. Inquiries were sent monthly to all Pediatric Departments in Germany and Switzerland, and quarterly to the Austrian Metabolic Group. In addition, data were collected via a second source (metabolic laboratories) in all three countries.ResultsBetween July 2012 and June 2015, fifty patients (Germany: 39, Austria: 7, Switzerland: 4) with newly diagnosed UCDs were reported and later confirmed resulting in an estimated cumulative incidence of 1 in 51,946 live births. At diagnosis, thirty-nine patients were symptomatic and 11 asymptomatic [10 identified by newborn screening (NBS), 1 by high-risk-family screening (HRF)]. The majority of symptomatic patients (30 of 39 patients) developed HE with (n = 25) or without coma (n = 5), 28 of them with neonatal onset. Despite emergency treatment 15 of 30 patients with HE already died during the newborn period. Noteworthy, 10 of 11 patients diagnosed by NBS or HRF remained asymptomatic. Comparison with the European registry and network for intoxication type metabolic diseases (E-IMD) demonstrated that cross-national surveillance identified a higher number of clinically severe UCD patients characterized by earlier onset of symptoms, higher peak ammonium concentrations in plasma and higher mortality.ConclusionCross-border surveillance is a powerful tool to identify patients with UCDs demonstrating that (1) the cumulative incidence of UCDs is lower than originally suggested, (2) the mortality rate is still high in patients with neonatal onset of symptoms, and (3) onset type and peak plasma ammonium concentration predict mortality.

Impact of Diagnosis and Therapy on Cognitive Function in Urea Cycle Disorders

“…Except for selected UCDs such as ASL-D, showing progressive neurological and hepatic disease, 18 this is unexpected and not consistent with previous studies. 1,3,4,12 This is substantiated by a study demonstrating that cumulative exposures to disease-specific neurotoxic biomarkers (ie, plasma ammonium, L-glutamine, L-citrulline, and L-arginine) appear to be sensitive predictors of global neuropsychological outcome in ASS1-D, ASL-D, and ARG1-D. 18 Recently, ASS1, the deficient enzyme in individuals with ASS1-D, has been identified as an RNA-binding protein and as such could potentially interfere with RNA metabolism. 2,8,9 However, ascertainment bias does not seem to fully explain the observed discrepancy in outcomes, and alternative pathomechanisms are also to be considered.…”

“…1 Individuals with UCDs are often affected by morbidity due to neurocognitive deficits and reduced life expectancy. 1 Individuals with UCDs are often affected by morbidity due to neurocognitive deficits and reduced life expectancy.…”

Disease-causing mutations in the promoter and enhancer of the ornithine transcarbamylase gene

“…Males with hypomorphic OTC alleles that retain residual enzyme activity, or female heterozygotes with skewed lyonization (Caldovic, Abdikarim, Narain, Tuchman, & Morizono, ; McCullough et al., ) typically present symptomatically after the first week of life (Caldovic et al., ; Numata et al., ). The true prevalence of OTCD is unknown, but it has been estimated to be between one in 14,000 and one in 76,000 (Balasubramaniam et al., ; Brusilow & Maestri, ; Dionisi‐Vici et al., ; Nettesheim et al., ; Summar et al., ). In 85%–90% of patients with the biochemical phenotype of OTCD, a mutation can be identified through commercially available sequencing or deletion/duplication testing.…”

Two novel CPS1 mutations in a case of carbamoyl phosphate synthetase 1 deficiency causing hyperammonemia and leukodystrophy

“…The time of onset presents as either in neonates or in a more insidious late‐onset. The morbidity of CPS1D is estimated 1:50 000‐1:300 000 in worldwide, of which 1:800 000 in Japan and 1:50 000‐1:100 000 in European population . To our knowledge, the frequency of CPS1D has not been observed in Chinese cohorts and only three Chinese patients with CPS1D were reported …”

“…The morbidity of CPS1D is estimated 1:50 000-1:300 000 in worldwide, of which 1:800 000 in Japan and 1:50 000-1:100 000 in European population. 1,[3][4][5][6] To our knowledge, the frequency of CPS1D has not been observed in Chinese cohorts and only three Chinese patients with CPS1D were reported. 1,3 The pathogenic gene of CPS1D is CPS1 (CPS1; NC_000002.12), which encodes carbamoyl phosphate synthetase 1 (CPS1).…”