Abstract
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.
Highlights
Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD, OMIM 201475) is the second most common disorder of inborn errors of fatty acid metabolism; its incidence varies between 1:30,000 and 1:400,000 live births, with some outliers such as Saudi Arabia with reported incidence of 1:3200 and Taiwan with 1:1,400,000
Fats that are not properly broken down can build-up and damage tissues in the heart, liver, and skeletal muscles, which can cause the other clinical features observed in people with VLCADD [Leslie et al, 1993; Very Long Chain Acyl CoA Dehydrogenase Deficiency (VLCADD) - NORD (National Organization for Rare Disorders)]
This study aimed to describe five patients with VLCADD diagnosed through the pilot and expanded newborn screening (NBS) program in Slovenia
Summary
Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD, OMIM 201475) is the second most common disorder of inborn errors of fatty acid metabolism; its incidence varies between 1:30,000 and 1:400,000 live births, with some outliers such as Saudi Arabia with reported incidence of 1:3200 and Taiwan with 1:1,400,000. VLCADD is caused by pathogenic variants in the ACADVL gene and is inherited in an autosomal recessive manner, resulting in deficient enzyme in the mitochondrial βoxidation of long-chain fatty acids. In VLCADD long-chain fatty acids with chain lengths of 14– 20 carbons are not metabolized, which can lead to metabolic crises due to inadequate energy supply. This lack of energy may result in symptoms such as lethargy and hypoglycemia. Fats that are not properly broken down can build-up and damage tissues in the heart, liver, and skeletal muscles, which can cause the other clinical features observed in people with VLCADD [Leslie et al, 1993; Very Long Chain Acyl CoA Dehydrogenase Deficiency (VLCADD) - NORD (National Organization for Rare Disorders)]
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