Urea Cycle defects in Argentina. Rare or undiagnosed diseases? Local experience in its diagnosis and characterization

Abstract

Urea cycle defects (UCD) are inborn errors of ammonia detoxification / arginine synthesis. The severity of the UCD is very variable depending on the specific mutation involved in correlation with the residual enzymatic function. The exact incidence of UCD in Argentina is unknown due to the absence of neonatal screening or national registry. Most patients are detected symptomatically, increasing morbidity / mortality.

The aim is to present the local experience in diagnosis, molecular findings and monitoring of patients with UCD diagnosed at the Hospital de Niños de Córdoba.

According to the inclusion criteria, 600 patients were studied in the period 1998-2019. Biochemical methods included determination of plasma amino acids and urinary orotic acid by HPLC; quantification of plasma ammonia by spectrophotometry. The genetic study consisted of PCR, enzymatic restriction or direct sequencing, SSCP or MLPA.

49 cases of DCU were diagnosed. Ornithine transcarbamylase (OTC) deficiency was the most frequent UCD observed in 26/49 male (hemizygote) and female (symptomatic heterozygous) patients, with OTC gene exclusive mutations. Argininosuccinate synthase (ASS) deficiency was observed in 19 cases, most of them from a delimited population group of CTLN1 with the same mutation. Argininosuccinate lyase (ASL) deficiency was diagnosed in 4 cases that presented frequent "missense" changes worldwide. Patients presented neonatal onset in 53% of cases, observing a critical evolution after a hyperammonemic crisis with a total global mortality of 57% (28/49 cases) and a disability of 28% (6/21) among survivors. The average detection rate in our center is 30% of the expected per year in Argentina.

Most of the patients in our series showed a severe neonatal onset, with high morbi / mortality. The presence of a high prevalence geographic group of a specific mutation in ASS stands out. This work shows our experience in the characterization of the DCU and indicates that these defects are not rare, but that they need tools for their identification, which will lead to improved results through early diagnosis and timely treatment.