Variations in IBD (ACAD8) in children with elevated C4-carnitine detected by tandem mass spectrometry newborn screening.
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.
Pedersen
Christina B
CB
Research Unit for Molecular Medicine, Aarhus University Hospital, Skejby Sygehus, 8200 Aarhus N, Denmark.
Bischoff
Claus
C
Christensen
Ernst
E
Simonsen
Henrik
H
Lund
Allan M
AM
Young
Sarah P
SP
Koeberl
Dwight D
DD
Millington
David S
DS
Roe
Charles R
CR
Roe
Diane S
DS
Wanders
Ronald J A
RJ
Ruiter
Jos P N
JP
Keppen
Laura D
LD
Stein
Quinn
Q
Knudsen
Inga
I
Gregersen
Niels
N
Andresen
Brage S
BS
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
D044944:Acyl-CoA Dehydrogenases; C122081:ACAD8 protein, human; D002331:Carnitine