Isobutyryl‐CoA dehydrogenase deficiency: Isobutyrylglycinuria and <i>ACAD8</i> gene mutations in two infants

Sass, Jörn Oliver; Sander, Stefanie; Zschocke, Johannes

doi:10.1023/b:boli.0000045798.12425.1b

Cited by 30 publications

(34 citation statements)

References 7 publications

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“…5,20 Among the seven known mutations, five are alterations causing missense mutations and two result in the introduction of premature stop codons. 4,5,20 We found five infants who were compound heterozygous for two mutations and three patients in three unrelated families who were homozygous for three different private mutations. Of note, one case (Patient 11, Ta- ble 1) was determined to have only one alteration, 1129GϾA, after complete analysis of the exon and intragenic splice-site sequences of ACAD8.…”

Section: Discussionmentioning

confidence: 93%

“…Nine patients with IBD deficiency have been reported to date. [2][3][4][5] The first patient presented with dilated cardiomyopathy, anemia, and carnitine deficiency. 2 An elevated C 4 -acylcarnitine was noted in a plasma acylcarnitine profile, but a subsequent urine organic acid analysis was normal.…”

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confidence: 99%

“…For six patients, clinical information is available. Two patients have remained asymptomatic for more than 1 year without treatment 4,5 ; one patient was noted to have muscle hypotonia and mild developmental delay at 8 months of age 4 ; two patients were treated for speech delays at 5 years and 2 years of age, respectively 5 , but have normal growth and development; and one patient was incidentally noted at 1 year of age to have mild branch peripheral pulmonary stenosis, which was detected by echocardiography to rule out a cardiomyopathy. 5 Although these case reports are not conclusive regarding the clinical relevance of IBD deficiency, they support the notion that it is detectable by newborn screening through blood spot acylcarnitine analysis by tandem mass spectrometry.…”

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confidence: 99%

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Development of a newborn screening follow-up algorithm for the diagnosis of isobutyryl-CoA dehydrogenase deficiency

Oglesbee¹,

Majumder

et al. 2007

Genetics in Medicine

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Purpose: Isobutyryl-CoA dehydrogenase deficiency is a defect in valine metabolism and was first reported in a child with cardiomyopathy, anemia, and secondary carnitine deficiency. We identified 13 isobutyryl-CoA dehydrogenasedeficient patients through newborn screening due to an elevation of C 4 -acylcarnitine in dried blood spots. Because C 4 -acylcarnitine represents both isobutyryl-and butyrylcarnitine, elevations are not specific for isobutyryl-CoA dehydrogenase deficiency but are also observed in short-chain acyl-CoA dehydrogenase deficiency. To delineate the correct diagnosis, we have developed a follow-up algorithm for abnormal C 4 -acylcarnitine newborn screening results based on the comparison of biomarkers for both conditions. Methods: Fibroblast cultures were established from infants with C 4 -acylcarnitine elevations, and the analysis of in vitro acylcarnitine profiles provided confirmation of either isobutyryl-CoA dehydrogenase or short-chain acyl-CoA dehydrogenase deficiency. Isobutyryl-CoA dehydrogenase deficiency was further confirmed by molecular genetic analysis of the gene encoding isobutyryl-CoA dehydrogenase (ACAD8). Plasma acylcarnitines, urine acylglycines, organic acids, and urine acylcarnitine results were compared between isobutyryl-CoA dehydrogenase-and short-chain acyl-CoA dehydrogenase-deficient patients. Results: Quantification of C 4 -acylcarnitine in plasma and urine as well as ethylmalonic acid in urine allows the differentiation of isobutyryl-CoA dehydrogenase-deficient from short-chain acyl-CoA dehydrogenase-deficient cases. In nine unrelated patients with isobutyryl-CoA dehydrogenase deficiency, 10 missense mutations were identified in ACAD8. To date, 10 of the 13 isobutyryl-CoA dehydrogenase-deficient patients remain asymptomatic, two were lost to follow-up, and one patient required frequent hospitalizations due to emesis and dehydration but is developing normally at 5 years of age. Conclusion: Although the natural history of isobutyryl-CoA dehydrogenase deficiency must be further defined, we have developed an algorithm for rapid laboratory evaluation of neonates with an isolated elevation of C 4 -acylcarnitine identified through newborn screening. Genet Med 2007:9(2):108-116.

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confidence: 93%

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confidence: 99%

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Development of a newborn screening follow-up algorithm for the diagnosis of isobutyryl-CoA dehydrogenase deficiency

Oglesbee¹,

Majumder

et al. 2007

Genetics in Medicine

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“…These biochemical findings strongly suggested an IBD-related defect rather than SCAD deficiency, and genetic analysis demonstrated variations on both alleles of the IBD gene in all newborns. We identified seven new variations in the IBD gene, thus more than doubling the total number of published IBD variations to 13 (3,11,18). So far, little is known about the prevalence of IBD deficiency, except that it has been detected in very few individuals (Table 1).…”

Section: Discussionmentioning

confidence: 99%

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 first documented patient with IBD deficiency was described by Roe et al (6). Additional patients were subsequently reported by other groups (7)(8)(9)(10). These patients ranged from being asymptomatic, to have muscular hypotonia, mild developmental delay, speech delay, and one with reversable cardiomyopathy.…”

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Alternative Splicing in Acad8 Resulting a Mitochondrial Defect and Progressive Hepatic Steatosis in Mice

et al. 2011

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Using a combination of N-ethyl-N-nitrosoureamediated mutagenesis and metabolomics-guided screening, we identified mice with elevated blood levels of short-chain C4-acylcarnitine and increased urine isobutyryl-glycine. Genome-wide homozygosity screening, followed by fine mapping, located the disease gene to 15-25 Mb of mouse chromosome 9 where a candidate gene, Acad8, encoding mitochondrial isobutyryl-CoA dehydrogenase was located. Genomic DNA sequencing revealed a single-nucleotide mutation at -17 of the first intron of Acad8 in affected mice. cDNA sequencing revealed an intronic 28-bp insertion at the site of the mutation, which caused a frame shift with a premature stop codon. In vitro splicing assay confirmed that the mutation was sufficient to activate an upstream, aberrant 3Ј splice site. There was a reduction in the expression of Acad8 at both the mRNA and protein levels. The mutant mice grew normally but demonstrated cold intolerance at young age with a progressive hepatic steatosis. Homozygous mutant mice hepatocytes had abnormal mitochondria with crystalline inclusions, suggestive of mitochondriopathy. This mouse model of isobutyryl-CoA dehydrogenase deficiency could provide us a better understanding of the possible role of IBD deficiency in mitochondriopathy and fatty liver. (Pediatr Res 70: 31-36, 2011)

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Isobutyryl‐CoA dehydrogenase deficiency: Isobutyrylglycinuria and ACAD8 gene mutations in two infants

Cited by 30 publications

References 7 publications

Development of a newborn screening follow-up algorithm for the diagnosis of isobutyryl-CoA dehydrogenase deficiency

Development of a newborn screening follow-up algorithm for the diagnosis of isobutyryl-CoA dehydrogenase deficiency

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

Alternative Splicing in Acad8 Resulting a Mitochondrial Defect and Progressive Hepatic Steatosis in Mice

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