Variations in IBD (ACAD8) in children with elevated C4-carnitine detected by tandem mass spectrometry newborn screening

Christina B Pedersen, Claus Bischoff, Ernst Christensen, Henrik 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 D Keppen, Quinn Stein, Inga Knudsen, Niels Gregersen, Brage S Andresen

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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.

OriginalsprogEngelsk
TidsskriftPediatric Research
Vol/bind60
Udgave nummer3
Sider (fra-til)315-20
Antal sider6
ISSN0031-3998
DOI
StatusUdgivet - sep. 2006

Fingeraftryk

Tandem Mass Spectrometry
Newborn Infant
2-methylacyl-CoA dehydrogenase
Valine
Enzymes
Denmark
Glycine
Sequence Analysis
Fibroblasts

Citer dette

Pedersen, Christina B ; Bischoff, Claus ; Christensen, Ernst ; Simonsen, Henrik ; Lund, Allan M ; Young, Sarah P ; Koeberl, Dwight D ; Millington, David S ; Roe, Charles R ; Roe, Diane S ; Wanders, Ronald J A ; Ruiter, Jos P N ; Keppen, Laura D ; Stein, Quinn ; Knudsen, Inga ; Gregersen, Niels ; Andresen, Brage S. / Variations in IBD (ACAD8) in children with elevated C4-carnitine detected by tandem mass spectrometry newborn screening. I: Pediatric Research. 2006 ; Bind 60, Nr. 3. s. 315-20.
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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.",
keywords = "Acyl-CoA Dehydrogenases, Carnitine, Female, Genetic Variation, Humans, Infant, Newborn, Male, Mass Spectrometry, Neonatal Screening, Point Mutation, Protein Folding, Protein Structure, Quaternary",
author = "Pedersen, {Christina B} and Claus Bischoff and Ernst Christensen and Henrik Simonsen and Lund, {Allan M} and Young, {Sarah P} and Koeberl, {Dwight D} and Millington, {David S} and Roe, {Charles R} and Roe, {Diane S} and Wanders, {Ronald J A} and Ruiter, {Jos P N} and Keppen, {Laura D} and Quinn Stein and Inga Knudsen and Niels Gregersen and Andresen, {Brage S}",
year = "2006",
month = "9",
doi = "10.1203/01.pdr.0000233085.72522.04",
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pages = "315--20",
journal = "Pediatric Research",
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Pedersen, CB, Bischoff, C, Christensen, E, Simonsen, H, Lund, AM, Young, SP, Koeberl, DD, Millington, DS, Roe, CR, Roe, DS, Wanders, RJA, Ruiter, JPN, Keppen, LD, Stein, Q, Knudsen, I, Gregersen, N & Andresen, BS 2006, 'Variations in IBD (ACAD8) in children with elevated C4-carnitine detected by tandem mass spectrometry newborn screening', Pediatric Research, bind 60, nr. 3, s. 315-20. https://doi.org/10.1203/01.pdr.0000233085.72522.04

Variations in IBD (ACAD8) in children with elevated C4-carnitine detected by tandem mass spectrometry newborn screening. / Pedersen, Christina B; Bischoff, Claus; Christensen, Ernst; Simonsen, Henrik; Lund, Allan M; Young, Sarah P; Koeberl, Dwight D; Millington, David S; Roe, Charles R; Roe, Diane S; Wanders, Ronald J A; Ruiter, Jos P N; Keppen, Laura D; Stein, Quinn; Knudsen, Inga; Gregersen, Niels; Andresen, Brage S.

I: Pediatric Research, Bind 60, Nr. 3, 09.2006, s. 315-20.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Variations in IBD (ACAD8) in children with elevated C4-carnitine detected by tandem mass spectrometry newborn screening

AU - Pedersen, Christina B

AU - Bischoff, Claus

AU - Christensen, Ernst

AU - Simonsen, Henrik

AU - Lund, Allan M

AU - Young, Sarah P

AU - Koeberl, Dwight D

AU - Millington, David S

AU - Roe, Charles R

AU - Roe, Diane S

AU - Wanders, Ronald J A

AU - Ruiter, Jos P N

AU - Keppen, Laura D

AU - Stein, Quinn

AU - Knudsen, Inga

AU - Gregersen, Niels

AU - Andresen, Brage S

PY - 2006/9

Y1 - 2006/9

N2 - 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.

AB - 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.

KW - Acyl-CoA Dehydrogenases

KW - Carnitine

KW - Female

KW - Genetic Variation

KW - Humans

KW - Infant, Newborn

KW - Male

KW - Mass Spectrometry

KW - Neonatal Screening

KW - Point Mutation

KW - Protein Folding

KW - Protein Structure, Quaternary

U2 - 10.1203/01.pdr.0000233085.72522.04

DO - 10.1203/01.pdr.0000233085.72522.04

M3 - Journal article

C2 - 16857760

VL - 60

SP - 315

EP - 320

JO - Pediatric Research

JF - Pediatric Research

SN - 0031-3998

IS - 3

ER -