Newborn screening in Emilia-Romagna (Italy) for cystathionine beta-synthase deficiency: never give up.

Andrea Pession ¹ Egidio Candela ¹ Federico Baronio ¹ Michele Zagariello ² Valeria Di Natale ¹ Rita Ortolano ¹ Francesca Righetti ⁴ Valentina Assirelli ¹ Giacomo Biasucci ³ Alessandra Cassio ¹

¹Pediatric Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy
²Specialty School of Pediatrics, Alma Mater Studiorum, University of Bologna, Italy
³The Pediatric Unit, Maternal and Child Department, Guglielmo da Saliceto Hospital, Italy
⁴Centro Laboratoristico Regionale di Riferimento Screening Neonatale e Malattie Endocrino-Metaboliche, UO Pediatria IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy

BACKGROUND: Cysthiatonine beta-synthase deficiency (CBSD) is an autosomal recessive rare disorder that leads to an increase of homocysteine (Hcy). Early diagnosis and treatment impact on patients’ natural history. Therapy aims to lower promptly and maintain Hcy concentrations below 100 μmol/L.

Methods: We have retrospectively analyzed data from the expanded newborn screening (ENS) of Emilia-Romagna (Italy), since the region included this pathology in the ENS (March 2011). All patients were identified by detecting elevated Methionine (Met) with a positive second-tier test (2TT) for hyperhomocysteinemia at the Dried Blood Spot. The diagnostic confirmation was made by analyzing the mutations of the CBS gene.

Results: In Emilia Romagna (Italy) only four cases of CBSD have been diagnosed (incidence 1: 97.000 live births, all in the last two years (the implementation of the 2TT with Hcy started from the year 2020 in our center). Three patients had been recalled for high Met values (respectively 102 micromol/L, 79 micromol/L and 63 micromol/L; cut-off <45 micromol/l) while a third patient with borderline values of 45.02 micromol/l. A trial of high-dose pyridoxine (100 mg/day) was performed in all patients for 14 days (three patients were partial responder, one non-responder). Because of persistence of the Met values above 50 micromol/L, we started a diet therapy after a complete Met washout in everyone. The current therapy is the same for all (vitamin B12, folic acid, betaine) while maintaining a different dietary restriction of Met. Patients are, at present, asymptomatic.

Discussion: We cannot evaluate the specific benefits of CBSD newborn screening on our patients yet, however the insertion of Met and Hcy as 2TT in ENS programs seems to be a fundamental tool for a preclinical diagnosis.