Mild citrullinemia in Caucasians is an allelic variant of argininosuccinate synthetase deficiency (citrullinemia type 1)

Citrullinemia is caused by either deficiency of argininosuccinate synthetase (ASS, citrullinemia type 1) or a defect of the SLC25A13 gene encoding a mitochondrial aspartate–glutamate transporter (citrullinemia type II). Citrullinemia type 1—referred to as classical citrullinemia— is characterized by largely elevated concentrations of citrulline, manifesting with acute hyperammonemic crises predominantly early in life and occurs panethnically. Citrullinemia type II is a rare multisystem-disorder nearly exclusively observed in the Japanese population and characterized by less pronounced elevations of plasma citrulline and mainly a late onset of clinical symptoms. Here, we investigated 21 citrullinemic patients (mean peak plasma citrulline 1023 (mu)mol/l, range 152–3360), all of whom remained asymptomatic during the observation period (6–156 months). These patients were referred to as mild citrullinemia due to less striking peak citrulline concentrations or absent clinical symptoms. Extended newborn screening using tandem mass spectrometry detected 15/21 patients, 4/21 patients were identified by investigation of siblings, 2/21 during metabolic work-up of unspecific neurological symptoms. We characterized the genetic defects in all affected families and found all patients affected by citrullinemia type 1 due to mutations of the ASS gene. We identified 15 different mutations, 14/15 missense and 1/15 nonsense, 6/15 were novel mutations. This is the first genetic study in a series of patients with hitherto asymptomatic citrullinemia. According to the mutations found in this study, mild citrullinemia seems to be primarily related to the human ASS gene, at least in patients of caucasian origin.