MYOPATHIC FORM OF VERY-LONG CHAIN ACYL-COA DEHYDROGENASE (VLCAD) DEFICIENCY DIAGNOSED BY BIOCHEMICAL AND GENETIC ANALYSIS FROM DRIED BLOOD SPOT. IDENTIFICATION OF TWO NOVEL MUTATIONS

Abstract Analysis of the acylcarnitines’ (ACs) is the mainstay for screening for fatty acid oxidation disorders (FAOD). Data about the ACs profile in the dried blood spot samples of healthy newborns in Serbia are not at disposal. Therefore, we determined the ACs levels and established the cut-offs. Between August 2018 and August 2019 a total of 1771 samples had been analysed. Cut-offs, established using a non-parametric approach, were verified in comparison with the worldwide target ranges and the data for several Caucasian populations. The majority of ACs had comparable distribution in Serbian and the worldwide population. In case of discrepancy, the individual alterations had a frequency of less than 10%. Seventeen out of 25 established cut-offs were in the worldwide target range. Reliability of the cut-offs positioning out of the target ranges is not jeopardized, since alterations are negligible or similar findings were reported for other Caucasian populations. The established and verified set of cut-offs can be used in the future screening for carnitine uptake/transport defect, medium- chain acyl-CoA dehydrogenase deficiency, very long-chain acyl-CoA dehydrogenase deficiency, long-chain L-3 hydroxyacyl- CoA dehydrogenase deficiency, trifunctional protein deficiency, carnitine palmitoyltransferase deficiency Ia and II, as well as carnitine: acylcarnitine translocase deficiency.

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Very long-chain acyl CoA dehydrogenase (VLCAD) deficiency

Atlas of Metabolic Diseases Second edition ◽

10.1201/b13565-49 ◽

2005 ◽

pp. 279-283

Keyword(s):

Chain Acyl ◽

Vlcad Deficiency ◽

Long Chain

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Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States

Molecular Genetics and Metabolism ◽

10.1016/j.ymgme.2015.08.011 ◽

2015 ◽

Vol 116 (3) ◽

pp. 139-145 ◽

Cited By ~ 31

Author(s):

Marcus J. Miller ◽

Lindsay C. Burrage ◽

James B. Gibson ◽

Meghan E. Strenk ◽

Edward J. Lose ◽

...

Keyword(s):

United States ◽

The United States ◽

Newborn Screen ◽

Chain Acyl ◽

Vlcad Deficiency ◽

Long Chain

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Very Long-Chain Acyl-CoA Dehydrogenase Deficiency: High Incidence of Detected Patients With Expanded Newborn Screening Program

Frontiers in Genetics ◽

10.3389/fgene.2021.648493 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ziga I. Remec ◽

Urh Groselj ◽

Ana Drole Torkar ◽

Mojca Zerjav Tansek ◽

Vanja Cuk ◽

...

Keyword(s):

Enzyme Activity ◽

Pilot Study ◽

Genetic Analysis ◽

Newborn Screening ◽

Dehydrogenase Deficiency ◽

Screening Program ◽

Dried Blood Spots ◽

Expanded Newborn Screening ◽

Chain Acyl ◽

Long Chain

Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a rare autosomal recessive disorder of fatty acid metabolism with a variable presentation. The aim of this study was to describe five patients with VLCADD diagnosed through the pilot study and expanded newborn screening (NBS) program that started in 2018 in Slovenia. Four patients were diagnosed through the expanded NBS program with tandem mass spectrometry; one patient was previously diagnosed in a pilot study preceding the NBS implementation. Confirmatory testing consisted of acylcarnitines analysis in dried blood spots, organic acids profiling in urine, genetic analysis of ACADVL gene, and enzyme activity determination in lymphocytes or fibroblasts. Four newborns with specific elevation of acylcarnitines diagnostic for VLCADD and disease-specific acylcarnitines ratios (C14:1, C14, C14:2, C14:1/C2, C14:1/C16) were confirmed with genetic testing: all were compound heterozygotes, two of them had one previously unreported ACDVL gene variant each (NM_000018.3) c.1538C > G; (NP_000009) p.(Ala513Gly) and c.661A > G; p.(Ser221Gly), respectively. In addition, one patient diagnosed in the pilot study also had a specific elevation of acylcarnitines. Subsequent ACDVL genetic analysis confirmed compound heterozygosity. In agreement with the diagnosis, enzyme activity was reduced in five patients tested. In seven other newborns with positive screening results, only single allele variants were found in the ACDVL gene, so the diagnosis was not confirmed. Among these, two variants were novel, c.416T > C and c.1046C > A, respectively (p.Leu139Pro and p.Ala349Glu). In the first 2 years of the expanded NBS program in Slovenia altogether 30,000 newborns were screened. We diagnosed four cases of VLCADD. The estimated VLCADD incidence was 1:7,500 which was much higher than that of the medium-chain acyl-CoA dehydrogenase deficiency (MCADD) cases in the same period. Our study also provided one of the first descriptions of ACADVL variants in Central-Southeastern Europe and reported on 4 novel variants.

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