Combined Newborn Screening Allows Comprehensive Identification also of Attenuated Phenotypes for Methylmalonic Acidurias and Homocystinuria

Newborn screening (NBS) programs are effective measures of secondary prevention and have been successively extended. We aimed to evaluate NBS for methylmalonic acidurias, propionic acidemia, homocystinuria, remethylation disorders and neonatal vitamin B(12) deficiency, and report on the identification of cofactor-responsive disease variants. This evaluation of the previously established combined multiple-tier NBS algorithm is part of the prospective pilot study “NGS2025” from August 2016 to September 2022. In 548,707 newborns, the combined algorithm was applied and led to positive NBS results in 458 of them. Overall, 166 newborns (prevalence 1: 3305) were confirmed (positive predictive value: 0.36); specifically, methylmalonic acidurias (N = 5), propionic acidemia (N = 4), remethylation disorders (N = 4), cystathionine beta-synthase (CBS) deficiency (N = 1) and neonatal vitamin B(12) deficiency (N = 153). The majority of the identified newborns were asymptomatic at the time of the first NBS report (total: 161/166, inherited metabolic diseases: 9/14, vitamin B(12) deficiency: 153/153). Three individuals were cofactor-responsive (methylmalonic acidurias: 2, CBS deficiency: 1), and could be treated by vitamin B(12), vitamin B(6) respectively, only. In conclusion, the combined NBS algorithm is technically feasible, allows the identification of attenuated and severe disease courses and can be considered to be evaluated for inclusion in national NBS panels.