Urea cycle disorders in Argentine patients: clinical presentation, biochemical and genetic findings

Abstract

Urea cycle defects; Argininosuccinate synthetase deficiency; Hyperammonemia

Defectos del ciclo de la urea; Deficiencia de argininosuccinato sintetasa; Hiperamonemia

Defectes del cicle de la urea; Dèficit d’argininosuccinat sintetasa; Hiperammonèmia

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.

This study was supported by grants from the Secretaría de Ciencia y Tecnología, Universidad Nacional de Córdoba and Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina. Work on urea cycle disorders in Zurich is supported by the Swiss National Science Foundation (grant no SNF 310030_153196 to JH).