Abstract

Objective: Classic galactosemia (CG) was one of the first inherited metabolic disorders included in newborn screening (NBS) programs. However, its long-term benefit has been debated for decades. Robust longitudinal data from large single-center cohorts remain limited. We report a 42-year experience with NBS for hypergalactosemia in a regional reference center in Italy.

Patients and Methods: We retrospectively reviewed outcomes of NBS for hypergalactosemia performed at our Department between January 1982 and December 2024.

Results: Among 1,402,200 screened newborns, 142 were recalled for persistently elevated total galactose concentrations. Subsequent diagnostic evaluation identified 15 patients with CG, 24 with partial galactose-1-phosphate uridyltransferase (GALT) deficiency, 6 with galactokinase (GALK) deficiency, 4 with UDP-galactose 4-epimerase (GALE) deficiency, 3 with galactose mutarotase (GALM) deficiency, 1 with congenital portosystemic shunt (PSS), 1 with congenital hepatic endothelial hemangioendothelioma (HEHE), 1 with GLUT2 deficiency, and 87 with transient neonatal hypergalactosemia. Acute neonatal decompensation occurred in all infants with CG, except three second-born siblings who received pre-symptomatic treatment; one patient died at 10 days of age. Despite early diagnosis and long-term dietary management with persistently normal galactose levels, 71% of surviving patients with CG developed neurological and/or endocrine complications. In one infant with severe GALK deficiency, early diagnosis through NBS enabled prompt identification of nuclear cataract, which fully resolved following initiation of a lactose-restricted diet. All patients with other Leloir pathway deficiencies remained clinically asymptomatic during both the perinatal period and long-term follow-up. NBS for hypergalactosemia also enabled favorable outcomes in patients with GLUT2 deficiency, congenital portosystemic shunts (PSS), and HEHE.

Conclusions: NBS for hypergalactosemia enables early identification of multiple inherited and congenital disorders. Although long-term complications of CG remain largely unpreventable, early diagnosis significantly reduces neonatal morbidity and mortality and provides substantial long-term benefits for other Leloir pathway enzymopathies, supporting the continued inclusion of hypergalactosemia in NBS programs.