Abstract
BackgroundThe 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.ResultsForty-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.ConclusionsMost 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.
Highlights
The urea cycle is the final common pathway for the excretion of waste nitrogen as well as arginine synthesis [1]
Synopsis This is the first case series of urea cycle deficiency patients from Argentina diagnosed at a single center, describing a high prevalence of neonatal onset, and confirming high recurrence of common worldwide mutations plus some private mutations first described in our cohort
Urea cycle disorders (UCDs) are inborn errors of ammonia detoxification/arginine synthesis caused by mutations in one of five core enzymes, one activating enzyme, or one of two mitochondrial antiporters
Summary
The urea cycle is the final common pathway for the excretion of waste nitrogen as well as arginine synthesis [1]. Two transporters are involved in the cycle, the ornithine/citrulline antiporter (ORNT1), associated with the hyperornithinemia-hyperammonemiahomocitrullinuria (HHH) syndrome (MIM #238970), and Silvera-Ruiz et al Orphanet Journal of Rare Diseases (2019) 14:203 the glutamate/aspartate antiporter (CITRIN), whose deficiency gives rise to citrullinemia type 2 (MIM #605814 and #603471). All these deficiencies are inherited in an autosomal recessive manner, except for OTCD which has X-linked recessive inheritance, and in some cases arises from spontaneous mutations in germ cells. The incidence, prevalence, and molecular epidemiology of urea cycle disorders (UCDs) in Argentina remain underexplored.
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