Background The incidence, prevalence, and molecular epidemiology of urea cycle disorders (UCDs) in Argentina remain underexplored. The present study is the first to thoroughly assess the clinical and molecular profiles of UCD patients examined at a single reference center in Argentina. Results Forty-nine UCD cases were collected. About half (26/49, 53%) manifested neonatally with classical presentation and had a high mortality (25/26, 96%). Ornithine transcarbamylase deficiency (OTCD) was the most common UCD (26 patients). Argininosuccinate synthetase deficiency (ASSD) was detected in 19 cases, while argininosuccinate lyase deficiency (ASLD) was diagnosed in 4 cases. Molecular genetic analysis revealed 8 private OTC mutations and two large deletion/duplication events in the OTC gene. Most mutations in the ASS1 and ASL genes were recurrent missense changes, and four alterations were novel. The clinical outcome of our UCD cohort was poor, with an overall mortality of 57% (28/49 cases), and a 28% (6/21) disability rate among the survivors. Conclusions Most patients in our case series showed severe neonatal onset, with high morbidity/mortality. We detected in total 19 mutations, most of them recurrent and of high frequency worldwide. Noteworthy, we highlight the presence of a geographic cluster with high prevalence of a point mutation in the ASS1 gene. This study suggests that these disorders may be more frequent than commonly assumed, and stresses the need for increased awareness amongst health professionals and greater availability of diagnostic tools for accurate identification, early diagnosis, and timely treatment. Electronic supplementary material The online version of this article (10.1186/s13023-019-1177-3) contains supplementary material, which is available to authorized users.

X-linked ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle disorder. Hemizygous males with complete deficiency manifest neonatal acute hyperammonemia, while those with partial deficiency have a late presentation. The symptomatology of heterozygotes depends on the inactivation pattern of X chromosome. Hyperammonemic episodes can cause neurological damage and are potentially fatal. Here, we match clinical, biochemical, and molecular findings with bioinformatics analyses to report genotype-phenotype correlations in 14 Argentine patients with OTCD from 11 unrelated families: 4 hemizygotes with neonatal onset (complete OTC gene deletion, 533C > T, c.540þ1G > A, c.697delG); 4 hemizygotes with late onset (c.216þ1G > A, c.386G > A, c.622G > A, c.829C > T); and 6 symptomatic heterozygotes (complete OTC gene deletion, c.533C > T, c.452T > G, c.540þ1G > A, dupE1-9/delE10). Three of these mutations were previously unreported: c.540þ1G > A, c.697delG, and dup1-9/del10. Our data highlight the relevance of combining molecular and bioinformatics analyses for accurate diagnosis and outcome prediction in suspected patients with OTCD and the importance of carrier testing for effective genetic counseling.

No abstract

Classical citrullinemia type I (CTLN1) is an autosomal recessive disorder encoded by the ASS1 gene, which codes for argininosuccinate synthetase (ASS), the rate-limiting enzyme in the urea cycle. Previously, we identified the mutation p.G390R in patients with CTLN1 in the San Luis Province of Argentina. Here, we report the results of p.G390R analysis in a larger number of probands, relatives of involved families and additionally, a population study to identify carriers. Altogether, we analyzed 420 alleles, belonging to 12 probands, 26 relatives, and 172 healthy volunteers. All the probands were homozygous for the mutation, and 21 of 26 relatives were carriers. The occurrence of the disease in descendants of couples at risk was 57% showing a preferential transmission of the mutant allele compared to the normal allele. The carrier frequency in the general San Luis Province population was 4.1%, suggesting the incidence of CTLN1 to be 1:2,427, which is approximately 20 times higher than for the general population. This work suggests that there should be an increased awareness of preconceptual screening of CTNL1 among individuals/couples who are at risk in the San Luis Province in order to better inform them of their reproductive options.Cascade/family and population molecular screening for carrier identification were performed in an Argentinean province with high incidence of CTLN1, a first step to preconceptional screening.