Biochemical and molecular characteristics among infants with abnormal newborn screen for very-long-chain acyl-CoA dehydrogenase deficiency: A single center experience

Jariya Upadia; Grace Noh; John J Lefante; Hans C Andersson

doi:10.1016/j.ymgmr.2023.101002

Biochemical and molecular characteristics among infants with abnormal newborn screen for very-long-chain acyl-CoA dehydrogenase deficiency: A single center experience

Mol Genet Metab Rep. 2023 Aug 25:37:101002. doi: 10.1016/j.ymgmr.2023.101002. eCollection 2023 Dec.

Authors

Jariya Upadia^{1

2}, Grace Noh^{1

2}, John J Lefante³, Hans C Andersson^{1

2}

Affiliations

¹ Hayward Genetics Center, Tulane University School of Medicine, New Orleans, LA, United States of America.
² Department of Pediatrics, Tulane University School of Medicine, New Orleans, LA, United States of America.
³ Department of Biostatistics and Data Science, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, United States of America.

Abstract

Objective: To define the biochemical and molecular characteristics and diagnostic outcomes of a large US cohort of VLCAD deficiency positive cases as detected by newborn screening (NBS) with MS:MS. This relatively common disorder of fatty acid oxidation is screened for in every state in America and often results in extensive testing of multiple samples to arrive at a diagnostic conclusion.

Materials and methods: We compared NBS dried blood spot (DBS) acylcarnitine profile (ACP) C14, C14:1, C14:2, C14:1/C12:1 ratio and plasma C14, C14:1, C14:2, C14:1/C12:1, C14:1/C16 and C14:1/C2 ratios among true positive and false positive cases. Results of VLCAD enzyme analysis, molecular testing and fibroblast fatty acid oxidation probe assay were analyzed.

Results: The presence of compound heterozygous or homozygous pathogenic variants, along with elevations of C14, C14:1 and C14:1/C12:1 ratio, identified 19 VLCAD deficiency cases. All were asymptomatic at most recent follow-up visits. The C14:1/C12:1 ratio in NBS-DBS ACP and plasma acylcarnitine profiles at follow-up (follow-up plasma ACP), is the most useful marker to differentiate between true and false positive cases. Among all cases with molecular analysis data available, approximately 56.7% had a single pathogenic mutation. Lymphocyte enzyme analysis (n = 61) was uninformative in 23% of cases studied.

Conclusion: VLCAD deficiency NBS by MS:MS is highly effective at identifying asymptomatic affected infants. Our cohort showed that elevation of C14:1/C12:1, in both NBS DBS and plasma ACP, was informative in discriminating affected from unaffected individuals and contributes to improve the accuracy of confirmatory testing of infants with presumptive positive for VLCAD deficiency.

Keywords: Acylcarnitine; Newborn screening; Very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency.