Citrullinemia type I (CTLN1) is a rare autosomal recessive disorder of the urea cycle caused by a deficiency in the argininosuccinate synthetase (ASS1) enzyme due to mutations in the ASS1 gene. Only a few Chinese patients with CTLN1 have been reported, and ASS1 gene mutations have been identified sporadically in China.
A Chinese family with one member affected with mild CTLN1 was enrolled. Targeted exome sequencing was performed on the proband, and Sanger sequencing was used to validate the detected mutation. We also reviewed the genetic and clinical characteristics of CTLN1 in Chinese patients that have been published to date. Newborn screening showed remarkably increased concentrations of citrulline with elevated ratios of citrulline/arginine and citrulline/phenylalanine, and the patient presented with a speech delay at age three. The urinary organic acid profiles were normal. A novel homozygous splicing variant c.773 + 4A > C in the ASS1 gene was identified in the proband, and it was predicted to affect splicing by in silico analysis. To date, only nine Chinese patients with CTLN1 have been reported, with a total of 15 ASS1 mutations identified and no high frequency or hot spot mutations found; the mutation spectrum of Chinese patients with CTLN1 was heterogeneous.
We described a mild Chinese CTLN1 case with a novel homozygous splicing variant c.773 + 4A > C and reviewed previous genotypes and phenotypes in Chinese patients with CTLN1. Thus, our findings contribute to understanding the molecular genetic background and clinical phenotype of CTLN1 in this population.

BACKGROUND: For urea cycle disorders (UCD), proportions and mortality of early onset (EO) patients, as well as outcome at one year of life show large variability. We aimed to integrate available evidence to create benchmarks for new diagnostic and therapeutic strategies.
METHODS: Medline search for reports published between 1978 and Dec 22, 2014 was completed by hand search. Random effects meta-analysis was done for four UCDs, deficiency of carbamylphosphate synthetase 1 (CPS1D), male/female ornithine transcarbamylase (OTCDm/f), argininosuccinate synthetase (ASSD) and lyase (ASLD). Effects of publication year and geographic area were analysed by meta-regression.
RESULTS: Twenty-four publications report onset time (n = 1542 patients), survival of EO (n = 665 patients) and outcome at one year of life (n = 172 patients). Proportions for EO manifestation (95% confidence interval) were: CPS1D = 0.75 (0.61;0.88); OTCDm = 0.52 (0.39;0.65); OTCDf = 0.07 (0.03;0.11); ASSD = 0.65 (0.57;0.73); ASLD = 0.60 (0.44;0.77); for surviving EO patients: CPS1D = 0.64 (0.50;0.79); OTCDm = 0.40 (0.16;0.64); OTCDf = 0.57 (0.29;0.85); ASSD = 0.67 (0.48;0.86); ASLD = 0.81 (0.68;0.94); and for normal outcome at one year for survivors: CPS1D = 0.20 (0.07;0.38); OTCDm = 0.15 (0.00;0.39); OTCDf no data; ASSD = 0.36 (0.13;0.60); ASLD = 0.36 (0.17;0.58). Between study variation was large. Year of publication had no effect. Studies from Europe showed lower survival rates than those from Japan or USA.
CONCLUSIONS: UCDs, except for OTCDf, have high risks of EO disease manifestation and, except for ASLD, of neonatal death. No improvement of survival was observed over more than three decades. Geographic variation remains to be explained. This comprehensive description of the natural history of EO UCDs should be considered by scientists, clinicians, health policy makers and guideline developers.

Prenatal diagnosis of citrullinaemia has been accomplished by three different methods to date: (1) enzyme assay of cultured fetal cells; (2) quantification of citrulline in amniotic fluid supernatant; and (3) incorporation of [14C]citrulline into protein by cultured fetal cells. Our laboratory has used these methods to perform prenatal diagnosis for 28 fetuses over a 10-year period. More recently, DNA polymorphisms were used for prenatal diagnosis by linkage analysis. Of the 28 fetuses studied, 23 were predicted to be unaffected, four were predicted to be affected, and results were conflicting in one case where [14C]citrulline incorporation erroneously indicated an affected fetus but linkage analysis correctly predicted an unaffected fetus. Because of low levels of enzyme activity in heterozygotes and in certain amniotic fluid cell types, biochemical diagnosis of citrullinaemia is complicated by the risk of false affected results, although [14C]citrulline incorporation is relatively reliable. When informative, linkage analysis is the preferable method for cases with a 25 per cent risk. The risk of false affected results makes prenatal diagnosis for cases with less than 25 per cent risk of questionable value.