ABSTRACT
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.
Subject(s)
Urea Cycle Disorders, Inborn/epidemiology , Urea Cycle Disorders, Inborn/genetics , Urea Cycle Disorders, Inborn/pathology , Argentina/epidemiology , Argininosuccinic Aciduria/epidemiology , Argininosuccinic Aciduria/genetics , Argininosuccinic Aciduria/pathology , Child , Child, Preschool , Citrullinemia/epidemiology , Citrullinemia/genetics , Citrullinemia/pathology , Female , Humans , Hyperammonemia/epidemiology , Hyperammonemia/genetics , Hyperammonemia/pathology , Infant , Infant, Newborn , Male , Mutation/genetics , Ornithine Carbamoyltransferase Deficiency Disease/epidemiology , Ornithine Carbamoyltransferase Deficiency Disease/genetics , Ornithine Carbamoyltransferase Deficiency Disease/pathologyABSTRACT
Adult-onset type II citrullinemia, characterized by a liver-specific argininosuccinate synthetase deficiency, is caused by a deficiency of citrin that is encoded by the SLC25A13 gene. Three patients with infantile cholestatic jaundice were found to have mutations of the SLC25A13 gene. Adult-onset type II citrullinemia may be associated with infantile cholestatic disease.
Subject(s)
Cholestasis/complications , Citrullinemia/complications , Jaundice, Neonatal/complications , Biopsy , Citrullinemia/pathology , Female , Humans , Infant, Newborn , Liver/pathology , Molecular Sequence DataABSTRACT
We describe 2 patients with adult-onset type II citrullinemia who developed transient hypoproteinemia and jaundice in early infancy. Liver histology showed a marked fatty change and fibrosis. After the patients had lived without symptoms to the ages of 5 and 16 years, respectively, the diagnosis was made by genetic analysis.