title: Infants suspected to have very-long chain acyl-CoA dehydrogenase deficiency from newborn screening.
abstract: Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a fatty acid oxidation disorder with widely varying presentations that has presented a significant challenge to newborn screening (NBS). The Western States Regional Genetics Services Collaborative developed a workgroup to study infants with NBS positive for VLCADD. We performed retrospective analysis of newborns with elevated C14:1-acylcarnitine on NBS in California, Oregon, Washington, and Hawai'i including available confirmatory testing and clinical information. Overall, from 2,802,504 children screened, there were 242 cases screen-positive for VLCADD. There were 34 symptomatic true positive cases, 18 asymptomatic true positives, 112 false positives, 55 heterozygotes, 11 lost to follow-up, and 12 other disorders. One in 11,581 newborns had an abnormal NBS for suspected VLCADD. Comparison of analytes and analyte ratios from the NBS demonstrated statistically significant differences between true positive and false positive groups for C14:1, C14, C14:1/C2, and C14:1/C16. The positive predictive value for all true positive cases was 94%, 54%, and 23% when C14:1 was ≥2.0 μM, ≥1.0 μM, and ≥0.7 μM, respectively. Sequential post-analytical analysis could reduce the referral rate in 25.8% of cases. This study is the largest reported follow-up of infants with NBS screen-positive results for suspected VLCADD and demonstrates the necessity of developing comprehensive and consistent long-term follow-up NBS systems. Application of clinical information revealed differences between symptomatic and asymptomatic children with VLCADD. Comparison of NBS analytes and analyte ratios may be valuable in developing more effective diagnostic algorithms.
authors: Pediatrics, University of Washington, Seattle, WA, USA. Electronic address: lawrence.merritt@seattlechildrens.org.
authors: J Lawrence
authors: JL
authors: Merritt
authors: Environmental and Occupational Health, University of Washington, Seattle, WA, USA.
authors: Sverre
authors: S
authors: Vedal
authors: Pediatrics, Children's Hospital of Orange County, Orange, CA, USA.
authors: Jose E
authors: JE
authors: Abdenur
authors: Genomics Section, Hawai'i Department of Health, Honolulu, HI, USA.
authors: Sylvia M
authors: SM
authors: Au
authors: Pediatrics, University of California San Diego, La Jolla, CA, USA.
authors: Bruce A
authors: BA
authors: Barshop
authors: Genetic Disease Screening Program, California Department of Public Health, Richmond, CA, USA.
authors: Lisa
authors: L
authors: Feuchtbaum
authors: Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA.
authors: Cary O
authors: CO
authors: Harding
authors: Northwest Regional Newborn Screening Program, Oregon State Public Health Laboratory, Hillsboro, OR, USA.
authors: Cheryl
authors: C
authors: Hermerath
authors: Genetic Disease Screening Program, California Department of Public Health, Richmond, CA, USA.
authors: Fred
authors: F
authors: Lorey
authors: Northwest Regional Newborn Screening Program, Oregon State Public Health Laboratory, Hillsboro, OR, USA.
authors: David E
authors: DE
authors: Sesser
authors: Office of Newborn Screening, Washington State Department of Health, Shoreline, WA, USA.
authors: John D
authors: JD
authors: Thompson
authors: Genomics Section, Hawai'i Department of Health, Honolulu, HI, USA.
authors: Arthur
authors: A
authors: Yu
mesh_terms: D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000172:deficiency*; D002331:Carnitine / Q000031:analogs & derivatives / Q000378:metabolism; D000080984:Congenital Bone Marrow Failure Syndromes; D004252:DNA Mutational Analysis; D003710:Demography; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008052:Lipid Metabolism, Inborn Errors / Q000175:diagnosis*; D008297:Male; D028361:Mitochondrial Diseases / Q000175:diagnosis*; D009135:Muscular Diseases / Q000175:diagnosis*; D015997:Neonatal Screening / Q000379:methods*; D010641:Phenotype; D015203:Reproducibility of Results
chemical_list: D005227:Fatty Acids; C116917:acylcarnitine; D044942:Acyl-CoA Dehydrogenase, Long-Chain; D002331:Carnitine
keywords: Clinical outcome research; False positive; Newborn screening; VLCADD; Very-long chain acyl-CoA dehydrogenase deficiency