Diagnosis and follow-up of four organic acidurias in three regions of central Italy (Emilia-Romagna, Tuscany and Umbria): what has been learnt, what can be improved?

Elena Procopio ² Egidio Candela ¹ Federico Baronio ¹ Marta Daniotti ² Valeria Di Natale ¹ Michele Sacchini ² Rita Ortolano ¹ Francesca Pochiero ² Lorenzo Ferri ³ Catia Cavicchi ³ Amelia Morrone ^3,4 Andrea Pession ¹ Giancarlo La Marca ⁵ Alessandra Cassio ¹

¹Pediatric Unit, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Italy
²Metabolic and Neuromuscular Unit, Meyer Children's Hospital IRCCS, University of Florence, Italy
³Laboratory of Molecular Biology of Neurometabolic Diseases, Neuroscience Department, Meyer Children's Hospital IRCCS, Italy
⁴Department of NEUROFARBA, University of Florence, Italy
⁵Newborn Screening, Clinical Chemistry and Pharmacology Lab, Meyer Children's Hospital IRCCS, Italy

Background: Organic acidurias (OA) are inherited metabolic disorders characterised by the accumulation of carboxylic acids which can be detected by expanded newborn screening (ENS).

Methods: This retrospective cohort study investigated four frequent OA, namely methylmalonic aciduria (MMA), isovaleric aciduria (IVA), propionic aciduria (PA) and glutaric aciduria (GA1), comparing patients from the Metabolic Unit in Florence (born in Tuscany and Umbria) with patients from the Unit in Bologna (born in Emilia-Romagna) from January 2011 to July 2022. We focused on the timing of clinical onset and the appearance of complications during follow-up.

Results: Twnety-three patients (10 MMA, 5 PA, 5 IVA, 3 GA1) were diagnosed in Florence and seven patients (2 MMA, 2 IVA, 3 GA1) in Bologna. Seven patients (4/4 MMA mut0, 1/5 PA, 2/7 IVA) presented with acute metabolic decompensation (AMD) 24 hours to 5 days after birth before the ENS results became available. Two patients died: one with IVA on the 7th day of life due to cardiocirculatory arrest during AMD, and one with PA at 26 months because of hypokinetic dilated cardiomyopathy. During follow-up, the most frequent complications were neurological with cardiac complications, which have the greatest impact on prognosis, only observed in patients with PA. Except for one case, dialysis was avoided in patients with hyperammonemia, probably because since 2007, carglumic acid/N-carbamylglutamate has been used to manage AMD. All patients investigated for familiarity were positive for biochemical markers at birth. For GA1, 2/6 patients had classic brain abnormalities in the prenatal period. Neurological involvement was the only clinical element constantly present in all GA1 cases.

Discussion: This study confirms the usefulness of ENS in diagnosing OA. Early diagnosis is especially important for severe phenotypes and collecting dried blood spots (DBS) for ENS in the first 24 hours of life might avoid AMD, thereby reducing morbidity.