Clinical, biochemical and molecular characterization of newborns with fatty acid beta-oxidation disorders: new variants in the ACADM, ACADVL and SLC22A5 genes

PurposeIn this study, we aimed to describe clinical, laboratory and molecular features of newborns with clinical suspicion for CTD, MCADD and VLCADD. Fatty acid {beta}-oxidation disorders (FAODs) are a heterogenous group of inherited metabolic defects in which the main common features are fasting or stress-induce hypoketotic hypoglycemia, lactic acidemia or hyperammonemia. The implementation of newborn screening (NBS) programs based on acylcarnitine levels in dried blood spots has allowed them to change the natural course of these diseases, facilitating newborns to be referral to reference units shortly after birth to initiate preventive or therapeutical measures to improve health outcomes. However, handling NBS results is challenging and to date, no correlation between NBS acylcarnitine levels and prognosis has been conclusively established. In this context, genetics plays a key role in identifying individuals with FAODs and in correctly characterizing their disease and their risk of medical complications. Methods and resultsThis study included 94 newborns who were admitted between 2016 and 2023. Clinical and biochemical data were collected from hospital records. Variant analysis of 21 genes was performed using a custom targeted next generation sequencing (NGS) panel, and variants were classified according to the American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines recommendations. Molecular diagnostic was confirmed in 16/94 (17%) of newborns, and 17 novel variants were detected in in SLC22A5, ACADM and ACADVL genes. We assessed clinical evolution of patients over time and related their clinical status and evolution to their genotype. ConclusionIn this study, we present a retrospective study of 94 newborns with clinical suspicion of CTD, MCADD and VLCADD, and provide clinical, biochemical and genotypic data. We expand the genotypic spectrum of variants in SLC22A5, ACADM and ACADVL and highlight the role of genetics in identifying, characterizing and estimating the risk of medical complications for newborns and its impact on clinical management.