The diagnostic challenge of mild citrulline elevation at newborn screening.

Barbara Siri, Giorgia Olivieri, Antonio Angeloni, Sara Cairoli, Claudia Carducci, Giovanna Cotugno, Silvia Di Michele, Teresa Giovanniello, Giancarlo La Marca, Francesca Romana Lepri, Antonio Novelli, Claudia Rossi, Michela Semeraro, Carlo Dionisi-Vici

Journal: Molecular genetics and metabolism 2022;135(4):327-332

PMID: 35279366

Full Text on Elsevier Science View on PubMed

Abstract

Citrulline is a target analyte measured at expanded newborn screening (NBS) and its elevation represents a biomarker for distal urea cycle disorders and citrin deficiency. Altered ratios of citrulline with other urea cycle-related amino acids are helpful for the differential diagnosis. However, the use of cut-off values in screening programmes has raised the issue about the interpretation of mild elevation of citrulline levels detected at NBS, below the usual range observed in the "classical/severe" forms of distal urea cycle disorders and in citrin deficiency. Herein, we report ten subjects with positive NBS for a mild elevation of citrulline (<100 μmol/L), in whom molecular investigations revealed carriers status for argininosuccinate synthase deficiency, a milder form of argininosuccinate lyase deficiency and two other diseases, lysinuric protein intolerance and dihydrolipoamide dehydrogenase deficiency, not primarily affecting the urea cycle. To guide the diagnostic process, we have designed an algorithm for mild citrulline elevation (<100 μmol/L) at NBS, which expands the list of disorders to be included in the differential diagnosis.

Address: Division of Metabolism, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy; Department of Paediatrics, Città della Salute e della Scienza, OIRM, Univerisity of Turin, Italy. Electronic address: [email protected].; Division of Metabolism, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.; Department of Experimental Medicine, Sapienza University of Rome and Newborn Screening Center, Clinical Pathology Unit, University Hospital Policlinico Umberto I, Rome, Italy.; Division of Metabolism and Metabolic Diseases Research Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.; Department of Pediatrics, "Spirito Santo" Hospital, Pescara, Italy.; Department of Experimental and Clinical Biomedical Sciences, University of Florence and Newborn Screening, Clinical Chemistry and Pharmacology Lab, Meyer Children's University Hospital, Florence, Italy.; Translational Cytogenomics Research Unit, Laboratory of Medical Genetics, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.; Center for Advanced Studies and Technology (CAST), Department of Psychological, Health and Territorial Sciences, "G. d'Annunzio", University of Chieti-Pescara, Chieti, Italy.

DOI: 10.1016/j.ymgme.2022.02.008