title: Variations in IBD (ACAD8) in children with elevated C4-carnitine detected by tandem mass spectrometry newborn screening.
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. 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.
authors.affiliation: Research Unit for Molecular Medicine, Aarhus University Hospital, Skejby Sygehus, 8200 Aarhus N, Denmark.
authors.forename: Christina B
authors.initials: CB
authors.lastname: Pedersen
authors.forename: Claus
authors.initials: C
authors.lastname: Bischoff
authors.forename: Ernst
authors.initials: E
authors.lastname: Christensen
authors.forename: Henrik
authors.initials: H
authors.lastname: Simonsen
authors.forename: Allan M
authors.initials: AM
authors.lastname: Lund
authors.forename: Sarah P
authors.initials: SP
authors.lastname: Young
authors.forename: Dwight D
authors.initials: DD
authors.lastname: Koeberl
authors.forename: David S
authors.initials: DS
authors.lastname: Millington
authors.forename: Charles R
authors.initials: CR
authors.lastname: Roe
authors.forename: Diane S
authors.initials: DS
authors.lastname: Roe
authors.forename: Ronald J A
authors.initials: RJ
authors.lastname: Wanders
authors.forename: Jos P N
authors.initials: JP
authors.lastname: Ruiter
authors.forename: Laura D
authors.initials: LD
authors.lastname: Keppen
authors.forename: Quinn
authors.initials: Q
authors.lastname: Stein
authors.forename: Inga
authors.initials: I
authors.lastname: Knudsen
authors.forename: Niels
authors.initials: N
authors.lastname: Gregersen
authors.forename: Brage S
authors.initials: BS
authors.lastname: Andresen
mesh_terms: D044944:Acyl-CoA Dehydrogenases / Q000235:genetics*; D002331:Carnitine / Q000378:metabolism*; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D013058:Mass Spectrometry; D015997:Neonatal Screening; D017354:Point Mutation; D017510:Protein Folding; D020836:Protein Structure, Quaternary / Q000235:genetics
chemical_list: D044944:Acyl-CoA Dehydrogenases; C122081:ACAD8 protein, human; D002331:Carnitine