Variations in IBD (ACAD8) in Children with Elevated C4-Carnitine Detected by Tandem Mass Spectrometry Newborn Screening
2006; Springer Nature; Volume: 60; Issue: 3 Linguagem: Inglês
10.1203/01.pdr.0000233085.72522.04
ISSN1530-0447
AutoresChristina B. Pedersen, Claus Bischoff, Ernst Christensen, Henrik Toft Simonsen, Allan M. Lund, Sarah P. Young, Dwight D. Koeberl, David S. Millington, Charles R. Roe, Diane S. Roe, Ronald J. A. Wanders, Jos P.N. Ruiter, Laura Davis Keppen, Quinn Stein, Inga Knudsen, Niels Gregersen, Brage Storstein Andresen,
Tópico(s)Mitochondrial Function and Pathology
ResumoThe 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. Molecular genetic analysis revealed seven new rare variations in the IBD gene (c.348C>A, c.400G>T, c.409G>A, c.455T>C, c.958G>A, c.1000C>T and c.1154G>A). Furthermore, sequence analysis of the short-chain acyl-CoA dehydrogenase (SCAD) gene revealed heterozygosity for the prevalent c.625G>A susceptibility variation in all newborns and in the first reported IBD patient. Functional studies in isolated mitochondria demonstrated that the IBD variations present in the Danish newborn (c.409G>A and c.958G>A) together with a previously published IBD variation (c.905G>A) disturbed protein folding and reduced the levels of correctly folded IBD tetramers. Accordingly, low/no IBD residual enzyme activity was detectable when the variant IBD proteins were overexpressed in Chang cells.
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