The frequency of short-chain acyl-CoA dehydrogenase gene variants in the US population and correlation with the C4-acylcarnitine concentration in newborn blood spots

Nagan, Narasimhan; Kruckeberg, Kent E.; Tauscher, Angela L.; Bailey, Karen S.; Rinaldo, Piero; Matern, Dietrich

doi:10.1016/s1096-7192(03)00034-9

Cited by 60 publications

(54 citation statements)

References 15 publications

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“…Ascertainment of variant SCAD by MS/MS newborn screening will depend on the value of the normal cutoff (upper limit of the normal range) used by the newborn screening laboratory, which varies from state to state. However, the C 4 -carnitine levels in newborn screening may be low enough to preclude detection of those infants with variant SCAD, given the current cutoff value for C 4 -carnitine in Minnesota (24) and in North Carolina. In North Carolina, we have not detected any infant with variant SCAD by newborn screening using a cutoff value of the mean ϩ 4 SDs.…”

Section: Discussionmentioning

confidence: 99%

Rare Disorders of Metabolism with Elevated Butyryl- and Isobutyryl-Carnitine Detected by Tandem Mass Spectrometry Newborn Screening

et al. 2003

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Section: Discussionmentioning

confidence: 99%

Rare Disorders of Metabolism with Elevated Butyryl- and Isobutyryl-Carnitine Detected by Tandem Mass Spectrometry Newborn Screening

et al. 2003

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“…The two common SCAD gene variants 625G Ǟ A (Gly185Ser) and 511C Ǟ T (Arg147Trp) are polymorphic in the Western European population and encode proteins with decreased catalytic activity and/or thermostability (Gregersen et al, 1998;Corydon et al, 2001). van Maldegem and coworkers (2006) calculated that a birth prevalence of at least 1:50,000 in the Netherlands occurs for SCADD, indicating that SCADD is far more common than previously assumed (Nagan et al, 2003).…”

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Biochemical Correction of Short-Chain Acyl-Coenzyme A Dehydrogenase Deficiency After Portal Vein Injection of rAAV8-SCAD

et al. 2008

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Recombinant adeno-associated viral vectors pseudotyped with serotype 5 and 8 capsids (AAV5 and AAV8) have been shown to be efficient gene transfer reagents for the liver. We have produced AAV5 and AAV8 vectors that express mouse short-chain acyl-CoA dehydrogenase (mSCAD) cDNA under the transcriptional control of the cytomegalovirus-chicken ␤-actin hybrid promoter. We hypothesized that these vectors would produce sufficient hepatocyte transduction (after administration via the portal vein) and thus sufficient SCAD enzyme to correct the phenotype observed in the SCAD-deficient (BALB/cByJ) mouse, which includes elevated blood butyrylcarnitine and hepatic steatosis. Ten weeks after portal vein injection into 8-week-old mice, AAV8-treated livers contained acyl-CoA dehydrogenase activity (14.3 mU/mg) toward butyryl-CoA, compared with 7.6 mU/mg in mice that received phosphate-buffered saline. Immunohistochemistry showed expression of mSCAD within rAAV8-mSCAD-transduced hepatocytes, as seen by light microscopy. A significant reduction of circulating butyrylcarnitine was seen in AAV5-mSCAD-and AAV8-mSCAD-injected mice. Magnetic resonance spectroscopy of fasted mice demonstrated a significant reduction in relative lipid content within the livers of AAV8-mSCAD-treated mice. These results demonstrate biochemical correction of SCAD deficiency after AAV8-mediated SCAD gene delivery. 579

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“…1 The c.625GϾA variant of the SCAD gene is frequent in the European population and is considered to confer increased susceptibility to clinical SCAD deficiency in combination with other genetic or non-genetic factors (20). Although, previous reports have indicated that newborn blood spots from c.625GϾA heterozygotes may not have significantly higher C 4 -carnitine concentrations than c.625G homozygotes (21,22), in vitro probe analysis of newborn B and patient E suggests that c.625GϾA heterozygosity may contribute to an elevation of C 4 -carnitine in cultured fibroblasts as reported in (23). However, more cases should be investigated to clarify if there is an association between IBD deficiency and the SCAD c.625GϾA variation.…”

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Variations in IBD (ACAD8) in Children with Elevated C4-Carnitine Detected by Tandem Mass Spectrometry Newborn Screening

et al. 2006

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ABSTRACT:The isobutyryl-CoA dehydrogenase (IBD) enzyme is involved in the degradation of valine. IBD deficiency was first reported in 1998 and subsequent genetic investigations identified acyl-CoA dehydrogenase (ACAD) 8, now IBD, as the gene responsible for IBD deficiency. Only three individuals homozygous or compound heterozygous for variations in the IBD gene have been reported. We present IBD deficiency in an additional four newborns with elevated C 4 -carnitine identified by tandem mass spectrometry (MS/MS) screening in Denmark and the United States. Three showed urinary excretions of isobutyryl-glycine, and in vitro probe analysis of fibroblasts from two newborns indicated enzymatic IBD defect. T he acyl-CoA dehydrogenases (ACAD) (EC 1.3.99) are a family of nuclear-encoded mitochondrial enzymes involved in the metabolism of fatty acids and branched chain amino acids (1-3). Inherited deficiencies of the ACADs are important causes of metabolic disorders. During the catabolism of valine and isoleucine, the branched side chains are converted into isobutyryl-CoA and 2-methylbutyryl-CoA, respectively. These dehydrogenations were initially suggested to be carried out by one enzyme, the short branched chain acyl-CoA dehydrogenase (SBCAD) (2,4). However, identification of the ACAD8 gene, which encodes isobutyryl-CoA dehydrogenase (IBD), and subsequent functional analysis, demonstrated that IBD is responsible for the conversion of isobutyryl-CoA to methacrylyl-CoA in the valine metabolism (5,6). The first patient with IBD deficiency was reported in 1998 (7) and genetic analysis revealed homozygosity for the IBD c.905GϾA (Ala302Gln) variation (3). Tandem mass spectrometry (MS/MS) based newborn screening is established in several countries world wide, and allows early detection and intervention of a wide range of metabolic disorders (8). With the addition of IBD deficiency to the list of metabolic disorders, the number of metabolites that must be traceable to identify specific inborn errors of metabolism has increased. Acyl-carnitine profiles representing elevated C 4 -carnitine may either indicate IBD deficiency or short-chain acyl-CoA dehydrogenase (SCAD) deficiency, as the routine MS/MS analysis does not allow discrimination between the C 4 -metabolites, isobutyryl-carnitine and butyryl-carnitine, which accumulate in these enzyme defects (7,9). SCAD (EC 1.3.99.2) is a mitochondrial fatty acid oxidation enzyme involved in the dehydrogenation of butyryl-CoA into crotonylCoA. To discriminate between SCAD deficiency and IBD deficiency, the MS/MS analysis of newborns with elevated C 4 -carnitine requires further evaluation for follow-up. Gas Received January 11, 2006; accepted April 13, 2006

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The frequency of short-chain acyl-CoA dehydrogenase gene variants in the US population and correlation with the C4-acylcarnitine concentration in newborn blood spots

Cited by 60 publications

References 15 publications

Rare Disorders of Metabolism with Elevated Butyryl- and Isobutyryl-Carnitine Detected by Tandem Mass Spectrometry Newborn Screening

Rare Disorders of Metabolism with Elevated Butyryl- and Isobutyryl-Carnitine Detected by Tandem Mass Spectrometry Newborn Screening

Biochemical Correction of Short-Chain Acyl-Coenzyme A Dehydrogenase Deficiency After Portal Vein Injection of rAAV8-SCAD

Variations in IBD (ACAD8) in Children with Elevated C4-Carnitine Detected by Tandem Mass Spectrometry Newborn Screening

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