Very-Long-Chain Acyl-CoA Dehydrogenase

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Ute Spiekerkoetter - One of the best experts on this subject based on the ideXlab platform.

  • The fate of medium-chain fatty acids in very long-chain acyl‑CoA Dehydrogenase deficiency (VLCADD): A matter of sex?
    Biochimica et biophysica acta. Molecular and cell biology of lipids, 2019
    Co-Authors: Zeinab Wehbe, Ute Spiekerkoetter, Khaled Alatibi, Julia Jellusova, Sara Tucci
    Abstract:

    Abstract Medium-chain-triglycerides (MCT) are widely applied in the treatment of long-chain fatty acid oxidation disorders (lcFAOD). Long-term treatment with MCT led to a sexually dimorphic response in the mouse model of Very-Long-Chain-Acyl-CoA-Dehydrogenase-deficiency (VLCAD−/−) with the subsequent development of a metabolic syndrome in female mice. In order to evaluate the molecular mechanisms responsible for this sex specific response we performed a comprehensive metabolic phenotyping, SILAC-based quantitative proteomics and characterized the involved signaling pathways by western blot analysis and gene expression. WT and VLCAD−/− mice showed strong sex-dependent differences in basal metabolism and expression of proteins involved in the distinct metabolic pathways, even more prominent after treatment with octanoate. The investigation of molecular mechanisms responsible for the sexual dimorphisms delineated the selective activation of the ERK/mTORc1 signaling pathway leading to an increased biosynthesis and elongation of fatty acids in VLCAD−/− females. In contrast, octanoate induced the activation of ERK/PPARγ pathway and the subsequent upregulation of peroxisomal β‑oxidation in males. We here provide first evidence that sex has to be considered as important variable in disease phenotype. These findings may have implications on treatment strategies in the different sexes.

  • The diagnostic challenge in very-long chain Acyl-CoA Dehydrogenase deficiency (VLCADD).
    Journal of Inherited Metabolic Disease, 2018
    Co-Authors: Julia Hesse, Ute Spiekerkoetter, Carina Braun, Sidney Behringer, Uta Matysiak, Sara Tucci
    Abstract:

    Very long-chain Acyl-CoA Dehydrogenase deficiency (VLCADD) is the most common defect of mitochondrial β-oxidation of long-chain fatty acids. However, the unambiguous diagnosis of true VLCADD patients may be challenging, and a high rate of false positive individuals identified by newborn screening undergo confirmation diagnostics. In this study, we show the outcome of enzyme testing in lymphocytes as a confirmatory tool in newborns identified by screening, and the correlation with molecular sequencing of the ACADVL gene. From April 2013 to March 2017, in 403 individuals with characteristic acylcarnitine profiles indicative of VLCADD, palmitoyl-CoA oxidation was measured followed by molecular genetic analysis in most of the patients with residual activity (RA) 50%, one-third of the individuals (125/403) displayed a RA of 30–50% and 69/403 individuals showed a residual activity of 0–30%. Sequencing of the ACADVL gene revealed that all individuals with activities below 24% were true VLCADD patients, individuals with residual activities between 24 and 27% carried either one or two mutations. Twenty new mutations could be identified and functionally classified based on their effect on enzyme function. Finally, we observed an up-regulation of MCAD-activity in many patients. However, this did not correlate with the degree of VLCAD RA. Although the likely clinical phenotype cannot be fully foreseen by genetic and functional tests as it depends on many factors, our data demonstrate the strength of this functional enzyme test in lymphocytes as a quick and reliable method for confirmation diagnostics of VLCADD.

  • Mitochondrial fatty acid biosynthesis and muscle fiber plasticity in very long-chain Acyl-CoA Dehydrogenase-deficient mice.
    FEBS letters, 2018
    Co-Authors: Sara Tucci, Nadja Mingirulli, Zeinab Wehbe, Verónica I. Dumit, Janbernd Kirschner, Ute Spiekerkoetter
    Abstract:

    The white skeletal muscle of very long-chain Acyl-CoA-Dehydrogenase-deficient (VLCAD-/- ) mice undergoes metabolic modification to compensate for defective β-oxidation in a progressive and time-dependent manner by upregulating glucose oxidation. This metabolic regulation seems to be accompanied by morphologic adaptation of muscle fibers toward the glycolytic fiber type II with the concomitant upregulation of mitochondrial fatty acid biosynthesis (mFASII) and lipoic acid biosynthesis. Dietary supplementation of VLCAD-/- mice with different medium-chain triglycerides over 1 year revealed that odd-chain species has no effect on muscle fiber switch, whereas even-chain species inhibit progressive metabolic adaptation. Our study shows that muscle may undergo adaptive mechanisms that are modulated by dietary supplementation. We describe for the first time a concomitant change of mFASII in this muscular adaptation process.

  • Triheptanoin: long-term effects in the very long-chain Acyl-CoA Dehydrogenase-deficient mouse.
    Journal of lipid research, 2016
    Co-Authors: Sara Tucci, Sidney Behringer, Ulrich Floegel, Frauke Beermann, Ute Spiekerkoetter
    Abstract:

    A rather new approach in the treatment of long-chain fatty acid oxidation disorders is represented by triheptanoin, a triglyceride with three medium-odd-chain heptanoic acids (C7), due to its anaplerotic potential. We here investigate the effects of a 1-year triheptanoin-based diet on the clinical phenotype of very long-chain-Acyl-CoA-Dehydrogenase-deficient (VLCAD-/-) mice. The cardiac function was assessed in VLCAD-/- mice by in vivo MRI. Metabolic adaptations were identified by the expression of genes regulating energy metabolism and anaplerotic processes using real-time PCR, and the results were correlated with the measurement of the glycolytic enzymes pyruvate Dehydrogenase and pyruvate kinase. Finally, the intrahepatic lipid accumulation and oxidative stress in response to the long-term triheptanoin diet were assessed. Triheptanoin was not able to prevent the development of systolic dysfunction in VLCAD-/- mice despite an upregulation of cardiac glucose oxidation. Strikingly, the anaplerotic effects of triheptanoin were restricted to the liver. Despite this, the hepatic lipic content was increased upon triheptanoin supplementation. Our data demonstrate that the concept of anaplerosis does not apply to all tissues equally.

  • Renal response to short- and long-term exercise in Very-Long-Chain Acyl-CoA Dehydrogenase-deficient (VLCAD^−/−) mice
    Molecular and Cellular Pediatrics, 2014
    Co-Authors: Sara Tucci, Diran Herebian, Antonia Krogmann, Ute Spiekerkoetter
    Abstract:

    Background Deficiency of very long-chain Acyl-CoA Dehydrogenase (VLCAD) is the most common disorder of mitochondrial β-oxidation of long-chain fatty acids. In order to maintain glucose homeostasis, the kidney and liver as the main gluconeogenic organs play an important role under conditions of impaired fatty acid oxidation. However, little is known about how a defective fatty acid oxidation machinery affects renal metabolism and function as well as renal energy supply especially during catabolic situations. Methods In this study, we analyzed VLCAD^−/− mice under different metabolic conditions such as after moderate (1 h) and intensive long-term (1 h twice per day over 2 weeks) physical exercise and after 24 h of fasting. We measured the oxidation rate of palmitoyl-CoA (C16-CoA) as well as the expression of genes involved in lipogenesis and renal failure. Oxidative stress was assessed by the function of antioxidant enzymes. Moreover, we quantified the content of glycogen and long-chain acylcarnitines in the kidney. Results We observed a significant depletion in renal glycogen with a concomitant reduction in long-chain acylcarnitines, suggesting a substrate switch for energy production and an optimal compensation of impaired fatty acid oxidation in the kidney. In fact, the mutants did not show any signs of oxidative stress or renal failure under catabolic conditions. Conclusions Our data demonstrate that despite Acadvl ablation, the kidney of VLCAD^−/− mice fully compensates for impaired fatty acid oxidation by enhanced glycogen utilization and preserves renal energy metabolism and function.

Arnold W. Strauss - One of the best experts on this subject based on the ideXlab platform.

  • A Delphi clinical practice protocol for the management of very long chain Acyl-CoA Dehydrogenase deficiency
    Molecular genetics and metabolism, 2009
    Co-Authors: Georgianne L. Arnold, Arnold W. Strauss, Can Ficicioglu, Johan L.k. Van Hove, Debra Freedenberg, Nicola Longo, Barbara K. Burton, Cheryl Garganta, Stephen D. Cederbaum, Cary O. Harding
    Abstract:

    Introduction: Very long chain Acyl-CoA Dehydrogenase (VLCAD) deficiency is a disorder of oxidation of long chain fat, and can present as cardiomyopathy or fasting intolerance in the first months to years of life, or as myopathy in later childhood to adulthood. Expanded newborn screening has identified a relatively high incidence of this disorder (1:31,500), but there is a dearth of evidence-based outcomes data to guide the development of clinical practice protocols. This consensus protocol is intended to assist clinicians in the diagnosis and management of screen-positive newborns for VLCAD deficiency until evidencebased guidelines are available. Method: The Oxford Centre for Evidence-based Medicine system was used to grade the literature review and create recommendations graded from A (evidence level of randomized clinical trials) to D (expert opinion). Delphi was used as the consensus tool. A panel of 14 experts (including clinicians, diagnostic laboratory directors and researchers) completed three rounds of survey questions and had a face-to-face meeting. Result: Panelists reviewed the initial evaluation of the screenpositive infant, diagnostic testing and management of diagnosed patients. Grade C and D consensus recommendations were made in each of these three areas. The panel did not reach consensus on all issues, particularly in the dietary management of asymptomatic infants diagnosed by newborn screening.

  • Polymorphic ventricular tachycardia and abnormal Ca2+ handling in Very-Long-Chain Acyl-CoA Dehydrogenase null mice.
    American journal of physiology. Heart and circulatory physiology, 2007
    Co-Authors: Andreas A. Werdich, Franz J. Baudenbacher, Igor Dzhura, Loice H. Jeyakumar, J. Kannankeril, Sidney Fleischer, Alison W. Legrone, Dejan Milatovic, Michael Aschner, Arnold W. Strauss
    Abstract:

    Patients with mutations in the mitochondrial Very-Long-Chain Acyl-CoA Dehydrogenase (VLCAD) gene are at risk for cardiomyopathy, myocardial dysfunction, ventricular tachycardia (VT), and sudden car...

  • Pitfalls of neonatal screening for Very-Long-Chain Acyl-CoA Dehydrogenase deficiency using tandem mass spectrometry.
    The Journal of pediatrics, 2006
    Co-Authors: Ina Schymik, Martina Mueller, Ertan Mayatepek, Arnold W. Strauss, Michaela Liebig, Udo Wendel, Ronald J.a. Wanders, Ute Spiekerkoetter
    Abstract:

    Neonatal screening programs for Very-Long-Chain Acyl-CoA Dehydrogenase deficiency (VLCADD) have recently been implemented. We report 2 newborns with elevated C14:1-carnitine levels on day 3 of life and normal levels on days 5 to 7. Enzyme and molecular analyses confirmed VLCADD in the first patient and heterozygosity in the second patient. We conclude that the diagnosis of VLCADD can be missed by acylcarnitine analysis during anabolic conditions. An increased C14:1-carnitine level can also occur in heterozygous individuals. Elevated C14:1-carnitine level on neonatal screening warrants further diagnostic workup even if a repeat sample demonstrates normal acylcarnitine levels.

  • Abnormal mitochondrial bioenergetics and heart rate dysfunction in mice lacking Very-Long-Chain Acyl-CoA Dehydrogenase
    American journal of physiology. Heart and circulatory physiology, 2005
    Co-Authors: Vernat Exil, Harold F. Sims, Carla D. Gardner, Jeffrey N. Rottman, Beatrijs Bartelds, Zaza Khuchua, Rekha Sindhal, Arnold W. Strauss
    Abstract:

    Mitochondrial Very-Long-Chain Acyl-CoA Dehydrogenase (VLCAD) deficiency is associated with severe hypoglycemia, cardiac dysfunction, and sudden death in neonates and children. Sudden death is commo...

  • Changes in blood carnitine and acylcarnitine profiles of very long-chain Acyl-CoA Dehydrogenase-deficient mice subjected to stress.
    European journal of clinical investigation, 2004
    Co-Authors: Ute Spiekerkoetter, Ertan Mayatepek, Vernat Exil, R. J. A. Wanders, Udo Wendel, Frits A. Wijburg, Marinus Duran, C. Tokunaga, Arnold W. Strauss
    Abstract:

    Background  In humans with deficiency of the very long-chain Acyl-CoA Dehydrogenase (VLCAD), C14–C18 acylcarnitines accumulate. In this paper we have used the VLCAD knockout mouse as a model to study changes in blood carnitine and acylcarnitine profiles under stress. Design  VLCAD knockout mice exhibit stress-induced hypoglycaemia and skeletal myopathy; symptoms resembling human VLCADD. To study the extent of biochemical derangement in response to different stressors, we determined blood carnitine and acylcarnitine profiles after exercise on a treadmill, fasting, or exposure to cold. Results  Even in a nonstressed, well-fed state, knockout mice presented twofold higher C14–C18 acylcarnitines and a lower free carnitine of 72% as compared to wild-type littermates. After 1 h of intense exercise, the C14–C18 acylcarnitines in blood significantly increased, but free carnitine remained unchanged. After 8 h of fasting at 4 °C, the long-chain acylcarnitines were elevated 5-fold in knockout mice in comparison with concentrations in unstressed wild-type mice (P 

Sara Tucci - One of the best experts on this subject based on the ideXlab platform.

  • The fate of medium-chain fatty acids in very long-chain acyl‑CoA Dehydrogenase deficiency (VLCADD): A matter of sex?
    Biochimica et biophysica acta. Molecular and cell biology of lipids, 2019
    Co-Authors: Zeinab Wehbe, Ute Spiekerkoetter, Khaled Alatibi, Julia Jellusova, Sara Tucci
    Abstract:

    Abstract Medium-chain-triglycerides (MCT) are widely applied in the treatment of long-chain fatty acid oxidation disorders (lcFAOD). Long-term treatment with MCT led to a sexually dimorphic response in the mouse model of Very-Long-Chain-Acyl-CoA-Dehydrogenase-deficiency (VLCAD−/−) with the subsequent development of a metabolic syndrome in female mice. In order to evaluate the molecular mechanisms responsible for this sex specific response we performed a comprehensive metabolic phenotyping, SILAC-based quantitative proteomics and characterized the involved signaling pathways by western blot analysis and gene expression. WT and VLCAD−/− mice showed strong sex-dependent differences in basal metabolism and expression of proteins involved in the distinct metabolic pathways, even more prominent after treatment with octanoate. The investigation of molecular mechanisms responsible for the sexual dimorphisms delineated the selective activation of the ERK/mTORc1 signaling pathway leading to an increased biosynthesis and elongation of fatty acids in VLCAD−/− females. In contrast, octanoate induced the activation of ERK/PPARγ pathway and the subsequent upregulation of peroxisomal β‑oxidation in males. We here provide first evidence that sex has to be considered as important variable in disease phenotype. These findings may have implications on treatment strategies in the different sexes.

  • The diagnostic challenge in very-long chain Acyl-CoA Dehydrogenase deficiency (VLCADD).
    Journal of Inherited Metabolic Disease, 2018
    Co-Authors: Julia Hesse, Ute Spiekerkoetter, Carina Braun, Sidney Behringer, Uta Matysiak, Sara Tucci
    Abstract:

    Very long-chain Acyl-CoA Dehydrogenase deficiency (VLCADD) is the most common defect of mitochondrial β-oxidation of long-chain fatty acids. However, the unambiguous diagnosis of true VLCADD patients may be challenging, and a high rate of false positive individuals identified by newborn screening undergo confirmation diagnostics. In this study, we show the outcome of enzyme testing in lymphocytes as a confirmatory tool in newborns identified by screening, and the correlation with molecular sequencing of the ACADVL gene. From April 2013 to March 2017, in 403 individuals with characteristic acylcarnitine profiles indicative of VLCADD, palmitoyl-CoA oxidation was measured followed by molecular genetic analysis in most of the patients with residual activity (RA) 50%, one-third of the individuals (125/403) displayed a RA of 30–50% and 69/403 individuals showed a residual activity of 0–30%. Sequencing of the ACADVL gene revealed that all individuals with activities below 24% were true VLCADD patients, individuals with residual activities between 24 and 27% carried either one or two mutations. Twenty new mutations could be identified and functionally classified based on their effect on enzyme function. Finally, we observed an up-regulation of MCAD-activity in many patients. However, this did not correlate with the degree of VLCAD RA. Although the likely clinical phenotype cannot be fully foreseen by genetic and functional tests as it depends on many factors, our data demonstrate the strength of this functional enzyme test in lymphocytes as a quick and reliable method for confirmation diagnostics of VLCADD.

  • Mitochondrial fatty acid biosynthesis and muscle fiber plasticity in very long-chain Acyl-CoA Dehydrogenase-deficient mice.
    FEBS letters, 2018
    Co-Authors: Sara Tucci, Nadja Mingirulli, Zeinab Wehbe, Verónica I. Dumit, Janbernd Kirschner, Ute Spiekerkoetter
    Abstract:

    The white skeletal muscle of very long-chain Acyl-CoA-Dehydrogenase-deficient (VLCAD-/- ) mice undergoes metabolic modification to compensate for defective β-oxidation in a progressive and time-dependent manner by upregulating glucose oxidation. This metabolic regulation seems to be accompanied by morphologic adaptation of muscle fibers toward the glycolytic fiber type II with the concomitant upregulation of mitochondrial fatty acid biosynthesis (mFASII) and lipoic acid biosynthesis. Dietary supplementation of VLCAD-/- mice with different medium-chain triglycerides over 1 year revealed that odd-chain species has no effect on muscle fiber switch, whereas even-chain species inhibit progressive metabolic adaptation. Our study shows that muscle may undergo adaptive mechanisms that are modulated by dietary supplementation. We describe for the first time a concomitant change of mFASII in this muscular adaptation process.

  • Triheptanoin: long-term effects in the very long-chain Acyl-CoA Dehydrogenase-deficient mouse.
    Journal of lipid research, 2016
    Co-Authors: Sara Tucci, Sidney Behringer, Ulrich Floegel, Frauke Beermann, Ute Spiekerkoetter
    Abstract:

    A rather new approach in the treatment of long-chain fatty acid oxidation disorders is represented by triheptanoin, a triglyceride with three medium-odd-chain heptanoic acids (C7), due to its anaplerotic potential. We here investigate the effects of a 1-year triheptanoin-based diet on the clinical phenotype of very long-chain-Acyl-CoA-Dehydrogenase-deficient (VLCAD-/-) mice. The cardiac function was assessed in VLCAD-/- mice by in vivo MRI. Metabolic adaptations were identified by the expression of genes regulating energy metabolism and anaplerotic processes using real-time PCR, and the results were correlated with the measurement of the glycolytic enzymes pyruvate Dehydrogenase and pyruvate kinase. Finally, the intrahepatic lipid accumulation and oxidative stress in response to the long-term triheptanoin diet were assessed. Triheptanoin was not able to prevent the development of systolic dysfunction in VLCAD-/- mice despite an upregulation of cardiac glucose oxidation. Strikingly, the anaplerotic effects of triheptanoin were restricted to the liver. Despite this, the hepatic lipic content was increased upon triheptanoin supplementation. Our data demonstrate that the concept of anaplerosis does not apply to all tissues equally.

  • Renal response to short- and long-term exercise in Very-Long-Chain Acyl-CoA Dehydrogenase-deficient (VLCAD^−/−) mice
    Molecular and Cellular Pediatrics, 2014
    Co-Authors: Sara Tucci, Diran Herebian, Antonia Krogmann, Ute Spiekerkoetter
    Abstract:

    Background Deficiency of very long-chain Acyl-CoA Dehydrogenase (VLCAD) is the most common disorder of mitochondrial β-oxidation of long-chain fatty acids. In order to maintain glucose homeostasis, the kidney and liver as the main gluconeogenic organs play an important role under conditions of impaired fatty acid oxidation. However, little is known about how a defective fatty acid oxidation machinery affects renal metabolism and function as well as renal energy supply especially during catabolic situations. Methods In this study, we analyzed VLCAD^−/− mice under different metabolic conditions such as after moderate (1 h) and intensive long-term (1 h twice per day over 2 weeks) physical exercise and after 24 h of fasting. We measured the oxidation rate of palmitoyl-CoA (C16-CoA) as well as the expression of genes involved in lipogenesis and renal failure. Oxidative stress was assessed by the function of antioxidant enzymes. Moreover, we quantified the content of glycogen and long-chain acylcarnitines in the kidney. Results We observed a significant depletion in renal glycogen with a concomitant reduction in long-chain acylcarnitines, suggesting a substrate switch for energy production and an optimal compensation of impaired fatty acid oxidation in the kidney. In fact, the mutants did not show any signs of oxidative stress or renal failure under catabolic conditions. Conclusions Our data demonstrate that despite Acadvl ablation, the kidney of VLCAD^−/− mice fully compensates for impaired fatty acid oxidation by enhanced glycogen utilization and preserves renal energy metabolism and function.

Seiji Yamaguchi - One of the best experts on this subject based on the ideXlab platform.

  • Two siblings with very long-chain Acyl-CoA Dehydrogenase (VLCAD) deficiency suffered from rhabdomyolysis after l-carnitine supplementation
    Molecular genetics and metabolism reports, 2018
    Co-Authors: Kenji Watanabe, Kenji Yamada, Koji Sameshima, Seiji Yamaguchi
    Abstract:

    Abstract Introduction Very long-chain Acyl-CoA Dehydrogenase (VLCAD) deficiency is an autosomal recessive mitochondrial fatty acid oxidation disorder and presents as hypoketotic hypoglycemia or rhabdomyolysis during childhood. l -Carnitine supplementation for patients with VLCAD deficiency is controversial. Herein, we describe two siblings with VLCAD deficiency who experienced more frequent episodes of rhabdomyolysis after l -carnitine supplementation. Case presentation Case 1 involved a 6-year-old boy who was diagnosed with VLCAD deficiency after repeated episodes of hypoketotic hypoglycemia at 3 years of age. He developed rhabdomyolysis more frequently after starting l -carnitine supplementation. Case 2 involved an 8-year-old boy, the elder brother of case 1, who was also diagnosed with VLCAD deficiency by sibling screening at the age of 5 years. He first developed rhabdomyolysis during a common cold after treatment with l -carnitine. Both patients had fewer rhabdomyolysis episodes after the cessation of l -carnitine supplementation. Conclusion Our cases suggest that l -carnitine supplementation can increase rhabdomyolysis attacks in patients with VLCAD deficiency.

  • Novel Mutation of Early, Perinatal-Onset, Myopathic-Type Very-Long-Chain Acyl-CoA Dehydrogenase Deficiency
    Pediatric neurology, 2009
    Co-Authors: Seigo Korematsu, Yujiro Kosugi, Toshihide Kumamoto, Seiji Yamaguchi, Tatsuro Izumi
    Abstract:

    A male neonate demonstrated fetal distress, neonatal asphyxia, and transient hyper-creatine kinase-emia (8400IU/L), followed by repeated episodes of rhabdomyolysis 1-2 times/year during infancy and early childhood. At age 6 years, decreased levels of total and free carnitine in serum, and mild fiber size variation and increased fatty droplets in muscle, were confirmed. Both blood and serum fatty-acid analysis demonstrated elevated 5-tetradecenoate levels, and the Acyl-CoA Dehydrogenase activity of the palmitoyl-CoA/octanoyl-CoA ratio decreased in skin fibroblasts. The sequenced clone analysis of a complimentary DNA fragment revealed a compound heterozygote mutation of exon 9 (A790G) and exon 10 (997 ins T), which is a novel mutation of a myopathic-type Very-Long-Chain Acyl-CoA Dehydrogenase deficiency. The patient has reached age 13 years. By treatment with an avoidance of fasting, feeding with a high-carbohydrate and low-fat diet, and intravenous drip infusion soon after every onset of rhabdomyolysis, his physical and mental development has stayed within the normal range. Patients with a perinatal onset of myopathic-type Very-Long-Chain Acyl-CoA Dehydrogenase deficiency have not yet been reported. His novel mutation might be related to his clinical characterization.

  • A two-year-old infant with a myopathic form of Very-Long-Chain Acyl-CoA Dehydrogenase deficiency
    No to hattatsu = Brain and development, 2003
    Co-Authors: Yasushi Ito, Seiji Yamaguchi, Kazutoshi Nakano, Keiko Shishikura, Haruko Suzuki, Norihisa Iida, Nobutaka Sasaki, Masahiko Kimura, Yuki Hasegawa, Makiko Osawa
    Abstract:

    A two-year-three-month old girl was hospitalized for detailed examination following repeated hyper-creatine kinasemia and cervical muscle cramps induced by pyrexia and persistent hypertonicity of the cervical muscles. Physical examination showed mild hypotonia but no muscle weakness. Induction of symptoms by continuous cervical muscular exercise and the appearance of dicarboxylic aciduria during the fasting test indicated a disorder of fatty acid oxidation. Free fatty acid and acyl carnitine analyses using dried blood spots, and Acyl-CoA Dehydrogenase activity assays using cultured skin fibroblasts established a diagnosis of Very-Long-Chain Acyl-CoA Dehydrogenase (VLCAD) deficiency. Currently VLCAD deficiency has been divided into three phenotypes; a severe childhood form, a milder childhood form, and an adult form. However, we suggest that the severe and milder childhood forms would be better described as a systemic form, and the adult form and our infant case as a myopathic form. An early onset of the myopathic form within the first year of life, as well as its diagnosis in early infancy, has never been described in the literature.

  • A case of Very-Long-Chain Acyl-CoA Dehydrogenase deficiency with adolescent onset being diagnosed by immunostain of biopsy muscle
    Rinsho shinkeigaku = Clinical neurology, 2003
    Co-Authors: Naohiro Sakata, Yuki Hasegawa, Motoharu Kawai, Mitsunori Morimatsu, Yuuko Oohashi, Ichizou Nishino, Seiji Yamaguchi
    Abstract:

    We report a case of myopathic form of Very-Long-Chain Acyl-CoA Dehydrogenase (VLCAD) deficiency with adolescent onset which presented with recurrent rhabdomyolysis and was diagnosed by immunostain of biopsy muscle. She was an 18-year-old woman who showed recurrent episodes of rhabdomyolysis after exercise since the age of 15. The diagnosis was made by the immunostain using anti-VLCAD antibody and the measurement of Acyl-CoA Dehydrogenase activity for the biopsy muscle. Her elder sister had also showed recurrent episodes of rhabdomyolysis at least two times. The analysis of genomic DNA on blood samples of the patient and her sister was performed and the same mutations were identified. Hence, these sister were revealed to have VLCAD deficiency. We should keep in mind this disorder for those presenting with recurrent rhabdomyolysis. In addition, as far as we know, this is the first report that a correct diagnosis was obtained by immunostain. Immunostain is probably a useful diagnostic procedure to identify an uncommon myopathy.

  • Identification and characterization of temperature-sensitive mild mutations in three Japanese patients with nonsevere forms of Very-Long-Chain Acyl-CoA Dehydrogenase deficiency.
    Molecular genetics and metabolism, 2002
    Co-Authors: Yuichi Takusa, Wataru Abo, Toshiyuki Fukao, Naomi Kondo, Masahiko Kimura, Atsushi Uchiyama, Yoshio Tsuboi, Shinichi Hirose, Hideki Fujioka, Seiji Yamaguchi
    Abstract:

    Abstract Very-Long-Chain Acyl-CoA Dehydrogenase (VLCAD) deficiency is clinically classified into severe, intermediate, and myopathic forms. We identified mutations in three unrelated Japanese patients with VLCAD deficiency: two with the myopathic form and one with the intermediate form, all compound heterozygotes of K264E/M437V, A416T/1798delA, and P89S/IVS16-3delAA, respectively. We characterized four missense mutations, K264E, M437V, A416T, and P89S, by transisent expression analysis, using SV40-transformed fibroblasts derived from a VLCAD-null patient, as recipient cells. In transient expression of the wild-type VLCAD cDNA, VLCAD activity at 30°C was higher than at 37°C. Moreover, this temperature-sensitive character is more evident in all the mutant proteins tested than in wild type. Based on characterization of the five missense mutations identified in four Japanese patients, including data on one patient with the myopathic form previously reported, patients with the nonsevere forms (intermediate or myopathic forms) have missense mutations with residual activities in at least one allele. Expression analysis at 30°C may be more useful for evaluating these missense mutations, compared with that at 37°C.

Christine Vianey-saban - One of the best experts on this subject based on the ideXlab platform.

  • Oxidation of unsaturated fatty acids by human fibroblasts with Very-Long-Chain Acyl-CoA Dehydrogenase deficiency: aspects of substrate specificity and correlation with clinical phenotype
    Clinica Chimica Acta, 2001
    Co-Authors: Diane S. Roe, Christine Vianey-saban, Marie Thérèse Zabot, Shailja Sharma, Charles R. Roe
    Abstract:

    The degradation of unsaturated fatty acids was examined in fibroblasts from 16 patients with Very-Long-Chain Acyl-CoA Dehydrogenase (VLCAD) deficiency. Analysis of acylcarnitine intermediates following incubation of intact human cells with these compounds revealed that the milder clinical phenotypes could be distinguished from the severe cardiomyopathic phenotype. These findings may reflect more effective contributions of alternate pathways in the milder forms of the disease. Incubation of VLCAD-deficient cells with cis-9 or trans-9 unsaturated fatty acids indicate that VLCAD is largely responsible for the 2,3-dehydrogenation of cis-5 or trans-5 intermediates in fibroblasts. The first two cycles of β-oxidation with oleic and linoleic acids occur in the absence of VLCAD activity suggesting the presence of an additional Acyl-CoA Dehydrogenase or alternate pathway for the oxidation of these unsaturated fatty acids. These observations have clinical relevance for determining diagnosis, prognosis and strategies for dietary treatment of these patients.

  • A severe genotype with favourable outcome in very long chain Acyl-CoA Dehydrogenase deficiency
    Archives of disease in childhood, 2001
    Co-Authors: E H Touma, M S Rashed, Christine Vianey-saban, A Sakr, P. Divry, N. Gregersen, Brage S. Andresen
    Abstract:

    A patient with very long chain Acyl-CoA Dehydrogenase (VLCAD) deficiency is reported. He had a severe neonatal presentation and cardiomyopathy. He was found to be homozygous for a severe mutation with no residual enzyme activity. Tandem mass spectrometry on dried blood spots revealed increased long chain acylcarnitines. VLCAD enzyme activity was severely decreased to 2% of control levels. Dietary management consisted of skimmed milk supplemented with medium chain triglycerides and L-carnitine. Outcome was good and there was no acute recurrence.

  • DNA-based prenatal diagnosis for Very-Long-Chain Acyl-CoA Dehydrogenase deficiency.
    Journal of inherited metabolic disease, 1999
    Co-Authors: Brage S. Andresen, Christine Vianey-saban, R. J. A. Wanders, Simon E. Olpin, E. A. Kvittingen, Persephone Augoustides-savvopoulou, D. Lindhout, Dicky J. J. Halley, Lodewijk Ijlst, Lisbeth Dahl Schroeder
    Abstract:

    Very-Long-Chain Acyl-CoA Dehydrogenase (VLCAD) (EC 1.3.99.13) deficiency (McKusick 201475) is a clinically heterogeneous disease of mitochondrial fatty acid oxidation, which often has a rather severe outcome. Although the disease was only discovered recently, and fewer than 40 families have been reported in the literature, there have already been reports of seven prenatal diagnoses performed in six unrelated families (Nada et al 1996; Vianey-Saban et al 1998), clearly illustrating that prenatal diagnosis is warranted. So far, prenatal diagnosis in VLCAD deficiency has been carried out by traditional enzyme assays (Vianey-Saban et al 1998) or by the in vitro probe assay performed on cultured cells (Nada et al 1996). We have recently established a fast and reliable method for PCR amplification and direct sequencing of the entire VLCAD coding region from genomic DNA and used this method to identify 58 different disease-causing mutations in 55 unrelated families (Andresen et al 1996a,b, 1999), thereby enabling DNA-based prenatal diagnosis.

  • Clear Correlation of Genotype with Disease Phenotype in Very–Long-Chain Acyl-CoA Dehydrogenase Deficiency
    American journal of human genetics, 1999
    Co-Authors: Brage S. Andresen, Christine Vianey-saban, Simon E. Olpin, Lodewijk Ijlst, Ronald J.a. Wanders, Hans R. Scholte, Ben J. H. M. Poorthuis, Andrew A. M. Morris, Morteza Pourfarzam, Kim Bartlett
    Abstract:

    Summary Very–long-chain Acyl-CoA Dehydrogenase (VLCAD) catalyzes the initial rate-limiting step in mitochondrial fatty acid β-oxidation. VLCAD deficiency is clinically heterogenous, with three major phenotypes: a severe childhood form, with early onset, high mortality, and high incidence of cardiomyopathy; a milder childhood form, with later onset, usually with hypoketotic hypoglycemia as the main presenting feature, low mortality, and rare cardiomyopathy; and an adult form, with isolated skeletal muscle involvement, rhabdomyolysis, and myoglobinuria, usually triggered by exercise or fasting. To examine whether these different phenotypes are due to differences in the VLCAD genotype, we investigated 58 different mutations in 55 unrelated patients representing all known clinical phenotypes and correlated the mutation type with the clinical phenotype. Our results show a clear relationship between the nature of the mutation and the severity of disease. Patients with the severe childhood phenotype have mutations that result in no residual enzyme activity, whereas patients with the milder childhood and adult phenotypes have mutations that may result in residual enzyme activity. This clear genotype-phenotype relationship is in sharp contrast to what has been observed in medium-chain Acyl-CoA Dehydrogenase deficiency, in which no correlation between genotype and phenotype can be established.

  • Very Long Chain Acyl-CoA Dehydrogenase Deficiency: Successful Treatment of Acute Cardiomyopathy
    Biochemical and molecular medicine, 1996
    Co-Authors: Mary Carole Brown-harrison, Christine Vianey-saban, Mohamed A. Nada, Howard Sprecher, John Farquhar, Angela C. Gilladoga, Charles R. Roe
    Abstract:

    Very-Long-Chain Acyl-CoA Dehydrogenase (VLCAD) deficiency is a severe defect of mitochondrial fatty acid oxidation characterized by hypertrophic cardiomyopathy, pericardial effusion, steatosis, and hypoglycemia, often resulting in death by 4-5 months of age. The onset of cardiomyopathy and pericardial effusion is insidious and sudden, necessitating early diagnosis and intervention to prevent death. A family affected with this defect is described in which dietary therapy with medium-chain triglycerides (MCT) was associated with rapid reversal of these severe clinical symptoms. Diagnosis by acylcarnitine analysis in the neonatal period can provide the opportunity for early clinical intervention. Prenatal diagnosis from amniocytes by enzymology or in vitro analysis of the fat oxidation pathway with deuterated fatty acid precursors has also been successful and permits intervention at birth. Of 10 affected children, 7 untreated cases died within the first several months while the remaining 3 cases survived when treated with medium-chain triglycerides as the major source of dietary fat.