Abstract
ABSTRACT
Dual inherited defects affecting urea cycle function are exceptionally rare. We report the first case, to our knowledge, of the coexistence of argininosuccinic aciduria (ASA) and citrin deficiency (CD). A girl born to consanguineous Tunisian parents presented at 6 months of age with recurrent seizures, vomiting, developmental delay, and severe hyperammonemic encephalopathy. Laboratory investigations revealed hyperammonemia, respiratory alkalosis, transaminitis, dyslipidemia, hyperglutaminemia, and mild hypercitrullinemia. Brain imaging showed delayed myelination and basal ganglia abnormalities. Management involved arginine supplementation, ammonia scavengers, protein restriction and antiepileptic drugs. The patient died at 33 months of age from severe hyperammonemia and lactic acidosis. Next‐generation sequencing identified two homozygous variants affecting distinct urea cycle–related genes:
The known pathogenic ASL
variant c.1153C>T p.(Arg385Cys), responsible for ASA, and a previously unreported likely pathogenic
SLC25A13
variant, c.1474C>T, p.(Arg492Trp), consistent with CD. Segregation analysis confirmed biallelic inheritance of both variants. This unique association illustrates how multilocus pathogenic variation can generate an atypical phenotype. From a pathophysiological perspective, CD may aggravate urea cycle dysfunction by reducing cytosolic aspartate availability and ASS1 activity, while ASL deficiency blocks the downstream conversion of argininosuccinate, resulting in a profound impairment of ureagenesis. This dual defect creates diagnostic and therapeutic challenges, highlighting the importance of integrating comprehensive biochemical investigations with molecular testing to enable accurate diagnosis and personalized metabolic management.