Very long-chain acyl-CoA dehydrogenase deficiency: clinical and genetic features of the cases identified during expanded neonatal screening in the Russian Federation in 2023–2024

Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a rare autosomal recessive disorder of long-chain fatty acid betaoxidation, resulting from mutations in the ACADVL gene. The disease exhibits a heterogeneous phenotypic spectrum, ranging from asymptomatic cases to severe neonatal forms, and is associated with a high risk of a lethal outcome in the absence of treatment. As of January 1, 2023, VLCADD has been included in the expanded neonatal screening program in the Russian Federation. 1,231,401 newborns born in the Russian Federation between January and December 2023, and 1,199,015 newborns born between January and December 2024 were screened during the expanded neonatal screening program. Primary neonatal screening (24-48 h of life) conducted in regional centers of the Russian Federation identified 4342 newborns with elevated levels of tetradecenoylcarnitine (C14:1) in their blood, categorizing these patients as being at risk for VLCADD. Confirmatory diagnostics at the Research Center for Medical Genetics involved remeasuring acylcarnitine concentrations in the blood using tandem mass spectrometry (MS/MS), as well as a molecular genetic analysis of the coding region of the ACADVL gene (NM_000018.4). During the confirmatory biochemical diagnostics, an increase in blood C14:1 level was detected in 35 patients. VLCADD was confirmed at the molecular genetic level in 22 patients. The cumulative incidence of VLCADD in the Russian Federation was estimated to be 1 in 110,473 live births (95% CI: 1:1:72,123 — 175,963). This article presents the clinical, biochemical and molecular genetic characteristics of 22 patients diagnosed with VLCADD during the first two years of expanded neonatal screening in the Russian Federation.

1. Lin Y., Lin C., Lin B., et al. Newborn screening for fatty acid oxidation disorders in a southern Chinese population. Heliyon. 2024;10(1).

2. Hesse J., Braun C., Behringer S., et al. The diagnostic challenge in very−long chain acyl−CoA dehydrogenase deficiency (VLCADD). Journal of inherited metabolic disease. 2018;41(6):1169-1178.

3. Ruoppolo M., Malvagia S., Boenzi S., et al. Expanded newborn screening in Italy using tandem mass spectrometry: two years of national experience. International Journal of Neonatal Screening. 2022;8(3):47.

4. Remec Z.I., Groselj U., Drole Torkar A., et al. Very long-chain acylCoA dehydrogenase deficiency: High incidence of detected patients with expanded newborn screening program. Frontiers in Genetics. 2021;12:648493.

5. Sharma S., McKenzie M. The Pathogenesis of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency. Biomolecules. 2025;15(3):416.

6. Soyuz pediatrov Rossii. Klinicheskiye rekomendatsii: Defitsit atsilKoA degidrogenazy zhirnykh kislot s ochen’ dlinnoy uglerodnoy tsep’yu u detey [Union of Pediatricians of Russia. Clinical guidelines: Very-long-chain fatty acid acyl-CoA dehydrogenase deficiency in children]. 2016. (In Russ.)

7. Kang S. Very Long Chain Acyl-coenzyme A Dehydrogenase Deficiency: A Review of Pathophysiology, Clinical Manifestations, Diagnosis, and Treatment. Journal of The Korean Society of Inherited Metabolic disease. 2022;22(1):21-27.

8. Bertrand C., Largillière C., Zabot M.T., et al. Very long chain acylCoA dehydrogenase deficiency: identification of a new inborn error of mitochondrial fatty acid oxidation in fibroblasts. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease. 1993;1180(3):327-329.

9. Loeber J.G., Platis D., Zetterström R.H., et al. Neonatal screening in Europe revisited: an ISNS perspective on the current state and developments since 2010. International journal of neonatal screening. 2021;7(1):15.

10. Mitchell B., Scott-Schwoerer J., Kuhl A., et al. A Review of Newborn Screening for VLCADD: The Wisconsin Experience. International Journal of Neonatal Screening. 2025;11(2):23.

11. Ryzhkova O.P., Kardymon O.L., Prohorchuk E.B., et al. Rukovodstvo po interpretatsii dannykh posledovatel’nosti DNK cheloveka, poluchennykh metodami massovogo parallel’nogo sekvenirovaniya (MPS) (redaktsiya 2018, versiya 2) [Guidelines for the interpretation of massive parallel sequencing variants (update 2018, v2)]. Meditsinskaya genetika [Medical Genetics]. 2019;18(2):3- 23. (In Russ.)

12. Neonatal’nyy skrining: natsional’noye rukovodstvo. Pod red. S.I.Kutseva [Neonatal screening: national guidelines. Edited by S.I. Kutsev]. Moscow: GEOTAR-Media, 2023. 360 p. (In Russ.)

13. Burrage L.C., Miller M.J., Wong L.J., et al. Elevations of C14: 1 and C14: 2 plasma acylcarnitines in fasted children: a diagnostic dilemma. The Journal of pediatrics. 2016;169:208-213.

14. Diekman E., de Sain-van der Velden M., Waterham H., et al. The newborn screening paradox: sensitivity vs. overdiagnosis in VLCAD deficiency. Springer Berlin Heidelberg. 2016;101-106.

15. Nikolaeva E.A., Shulyakova I.V., Tsygankova P.G. et al. Simptomaticheskaya epilepsiya kak proyavleniye defitsita atsil-KoA degidrogenazy zhirnykh kislot s ochen’ dlinnoy uglerodnoy tsep’yu [Symptomatic epilepsy as a manifestation of very long chain acylCoA dehydrogenase deficiency]. Rossiyskiy vestnik perinatologii i pediatrii [Russian Bulletin of Perinatology and Pediatrics]. 2008;53(3):87-91. (In Russ.)

16. Spiekerkoetter U., Haussmann U., Mueller M., et al. Tandem mass spectrometry screening for very long-chain acyl-CoA dehydrogenase deficiency: the value of second-tier enzyme testing. The Journal of pediatrics. 2010;157(4):668-673.

17. Olsson D., Barbaro M., Haglind C., et al. Very long‐chain acyl‐CoA dehydrogenase deficiency in a Swedish cohort: Clinical symptoms, newborn screening, enzyme activity, and genetics. JIMD reports. 2022;63(2),181-190.

18. Alhumaidi S.S., Algaeed F.A., Aladhadh M.F., et al. Very long-chain acyl-CoA dehydrogenase deficiency revisited: a retrospective genotype–phenotype analysis in a Saudi tertiary center. Frontiers in Genetics. 2025;16:1584817.

19. Obaid A., Nashabat M., Alfadhel M., et al. Clinical, biochemical, and molecular features in 37 Saudi patients with very long chain acyl CoA dehydrogenase deficiency. JIMD Reports. 2018;40:47-53.