Retrospective review of urine organic acids data from patients with citrullinemia type I – Looking for the ‘cyclic derivative of citrulline’

European Research Network for evaluation and improvement of screening, Diagnosis, and treatment of Inherited disorders of Metabolism (ERNDIM) provides proficiency testing to clinical laboratories that offer biochemical testing, including urine organic acids analysis. Following an educational challenge, ERNDIM provided a mass spectrum of the ‘trimethylsilyl derivative of cyclic derivative of citrulline’ to participating laboratories. Though there is knowledge among some in the biochemical genetics' community, that the cyclic derivative of citrulline can be identified in urine of patients with citrullinemia type I, we could not find any published literature regarding this analyte in patient samples, nor were able to obtain any standard material. We did note two publications that proposed chemical structures for the cyclic derivative of citrulline, but neither suggested a clinical utility for this compound and the two proposed structures differed. Here, we used the mass spectrum provided by ERNDIM to retrospectively evaluate existing urine organic acids data from patients affected with conditions associated with elevated levels of plasma citrulline to learn more about this marker in urine and to correlate it with plasma citrulline data in diagnostic and follow-up samples. We document a positive correlation between the concentration of this compound in patient urine and the concentration of citrulline in concurrently collected plasma. We establish that this analyte is a good marker for citrullinemia type I but is not unique to this condition. Finally, we correlate the mass spectrum with the chemical structure originally proposed by Wilson et al. in 1978.