Rare Disorders of Metabolism with Elevated Butyryl- and Isobutyryl-Carnitine Detected by Tandem Mass Spectrometry Newborn Screening

Koeberl, Dwight D.; Young, Sarah P.; Gregersen, Niels; Vockley, Jerry; Smith, Wendy E.; Benjamin, Daniel K.; An, Yan; Weavil, S. D.; Chaing, Shu; Bali, Deeksha; McDonald, Marie; Kishnani, Priya S.; Yt, Chen; Millington, David S.

doi:10.1203/01.pdr.0000074972.36356.89

Cited by 80 publications

(58 citation statements)

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“…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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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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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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“…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.…”

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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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“…Till date, 25 patients have been identified and 50 reported worldwide based upon reduced or absent SCAD activity in vitro [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]. Genotype-phenotype correlations have been inconsistent [8,18].…”

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A Rare Case of Short-Chain Acyl-COA Dehydrogenase Deficiency: The Apparent Rarity of the Disorder Results in Under Diagnosis

Reddy

Sujatha

2011

Ind J Clin Biochem

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Short-chain acyl-CoA dehydrogenase (ACAD) deficiency is an extremely rare inherited mitochondrial disorder of fat metabolism. This belongs to a group of diseases known as fatty acid oxidation disorders. Screening programmes have provided evidence that all the fatty acid oxidation disorders combined are among the most common inborn errors of metabolism. Mitochondrial beta oxidation of fatty acids is an essential energy producing pathway. It is a particularly important pathway during prolonged periods of starvation and during periods of reduced caloric intake due to gastrointestinal illness or increased energy expenditure during febrile illness. The most common presentation is an acute episode of life threatening coma and hypoglycemia induced by a period of fasting due to defective hepatic ketogenesis. Here, the case of a 4 month old female patient who had seizures since the third day of her birth and persistent hypoglycemia is described. She was born to parents of second degree consanguinity after 10 years of infertility treatment. There was history of delayed cry after birth. Metabolic screening for TSH, galactosemia, 17-OHP, G6PD, cystic fibrosis, biotinidase were normal. Tandem mass spectrometric (TMS) screening for blood amino acids, organic acids, fatty acids showed elevated butyryl carnitine (C4) as 3.40 lmol/L (normal \2.00 lmol/L), hexanoyl carnitine (C6) as 0.92 lmol/L (normal \0.72 lmol/L), C4/C3 as 2.93 lmol/L (normal \1.18 lmol/L). The child was started immediately on carnitor syrup (carnitine) 1/2 ml twice daily. Limitation of fasting stress and dietary fat was advised. Baby responded well by gaining weight and seizures were controlled. Until now, less than 25 patients have been reported worldwide. The limited number of patients diagnosed until now is due to the rarity of the disorder resulting in under diagnosis.

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Rare Disorders of Metabolism with Elevated Butyryl- and Isobutyryl-Carnitine Detected by Tandem Mass Spectrometry Newborn Screening

Cited by 80 publications

References 20 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

A Rare Case of Short-Chain Acyl-COA Dehydrogenase Deficiency: The Apparent Rarity of the Disorder Results in Under Diagnosis

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