Abstract
Recent advances in newborn screening (NBS) have improved the diagnosis of inborn errors of metabolism (IEMs); however, many potentially treatable IEMs are not included on NBS panels, nor are they covered in standard, first-line biochemical testing. To examine the utility of untargeted metabolomics as a primary screening tool for IEMs by comparing the diagnostic rate of clinical metabolomics with the recommended traditional metabolic screening approach. This cross-sectional study compares data from 4464 clinical samples received from 1483 unrelated families referred for trio testing of plasma amino acids, plasma acylcarnitine profiling, and urine organic acids (June 2014 to October 2018) and 2000 consecutive plasma samples from 1807 unrelated families (July 2014 to February 2019) received for clinical metabolomic screening at a College of American Pathologists and Clinical Laboratory Improvement Amendments-certified biochemical genetics laboratory. Data analysis was performed from September 2019 to August 2020. Metabolic and molecular tests performed at a genetic testing reference laboratory in the US and available clinical information for each patient were assessed to determine diagnostic rate. The diagnostic rate of traditional metabolic screening compared with clinical metabolomic profiling was assessed in the context of expanded NBS. Of 1483 cases screened by the traditional approach, 912 patients (61.5%) were male and 1465 (98.8%) were pediatric (mean [SD] age, 4.1 [6.0] years; range, 0-65 years). A total of 19 families were identified with IEMs, resulting in a 1.3% diagnostic rate. A total of 14 IEMs were detected, including 3 conditions not included in the Recommended Uniform Screening Panel for NBS. Of the 1807 unrelated families undergoing plasma metabolomic profiling, 1059 patients (58.6%) were male, and 1665 (92.1%) were pediatric (mean [SD] age, 8.1 [10.4] years; range, 0-80 years). Screening identified 128 unique cases with IEMs, giving an overall diagnostic rate of 7.1%. In total, 70 different metabolic conditions were identified, including 49 conditions not presently included on the Recommended Uniform Screening Panel for NBS. These findings suggest that untargeted metabolomics provided a 6-fold higher diagnostic yield compared with the conventional screening approach and identified a broader spectrum of IEMs. Notably, with the expansion of NBS programs, traditional metabolic testing approaches identify few disorders beyond those covered on the NBS. These data support the capability of clinical untargeted metabolomics in screening for IEMs and suggest that broader screening approaches should be considered in the initial evaluation for metabolic disorders.
Highlights
Detection and diagnosis of inborn errors of metabolism (IEMs) are imperative because many conditions are amenable to treatment, and sequelae that develop before therapy is initiated are often irreversible.[1,2,3] Newborn screening (NBS) is the first-tier assessment of IEMs and aims to identify apparently healthy newborns with serious conditions to improve neonatal and lifelong health outcomes
These findings suggest that untargeted metabolomics provided a 6-fold higher diagnostic yield compared with the conventional screening approach and identified a broader spectrum of IEMs
With the exception of L-2/D-2-hydroxyglutaric aciduria, homocystinuria megaloblastic anemia, cblG type, and ethylmalonic encephalopathy, 11 of 14 conditions (78.6%) are included on the Recommended Uniform Screening Panel (RUSP), including 7 conditions covered by the core conditions and 4 disorders covered by RUSP secondary conditions, corresponding to a diagnostic rate of 0.2% for non-RUSP IEMs (3 of 1483 IEMs)
Summary
Detection and diagnosis of inborn errors of metabolism (IEMs) are imperative because many conditions are amenable to treatment, and sequelae that develop before therapy is initiated are often irreversible.[1,2,3] Newborn screening (NBS) is the first-tier assessment of IEMs and aims to identify apparently healthy newborns with serious conditions to improve neonatal and lifelong health outcomes. As a result of advances in tandem mass spectrometry technology, NBS has expanded, and 49 metabolic conditions, including 25 core conditions and 24 secondary conditions, are currently listed on the Recommended Uniform Screening Panel (RUSP) with variations in different states. Laboratory assessments of metabolic disorders may be prolonged because the standard approach involves multiple, and often sequential, targeted biochemical tests.[1,6] Optimal evaluation of patients presenting with nonspecific neurological findings, including intellectual disability, global developmental delays, or autism spectrum disorder, follows recommendations provided by the American Academy of Neurology, the American Academy of Pediatrics, and the National Academy of Clinical Biochemistry, stating that first-line screening for IEMs should be considered in the initial evaluation.[7,8,9] The traditional metabolic screening approach includes a trio of biochemical analyses: plasma amino acids (PAA), plasma acylcarnitine profile (ACP), and urine organic acids (UOA). NBS targets 43 of 49 disorders diagnosable by this trio of tests, and, to our knowledge, no recent studies have assessed the current diagnostic rate for this trio of tests in the era of expanded NBS (eTable 1 in the Supplement)
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