Short-Chain Acyl-CoA Dehydrogenase Deficiency Associated with a Lipid-Storage Myopathy and Secondary Carnitine Deficiency

Turnbull, Douglass M.; Bartlett, K.; Stevens, Dennis L.; Alberti, K. G. M. M.; Gibson, G. Edward; Johnson, Margaret; McCulloch, A. J.; Sherratt, H. S. A.

doi:10.1056/nejm198411083111906

Cited by 134 publications

(43 citation statements)

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“…Lately, sudden infant death syndrome and Reye's-like syndrome have been linked to defects in P-oxidation of fatty acids (5)(6)(7). Other recent studies have demonstrated that a secondary carnitine deficiency associated with the organic acidemia appears involved in the pathogenesis of the episodic events of these disorders (1,4,8). Overall, these diseases appear complex.…”

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“…This mouse model presents important opportunities to investigate the biology of mammalian fatty acid metabolism and the related human diseases. Deficiency of SCAD has been described recently in humans (1)(2)(3)(4). The most severe form of this disorder is characterized by patients with episodes of metabolic acidosis, nonketotic hypoglycemia, and short-chain dicarboxylic aciduria.…”

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Short-Chain Acyl-Coenzyme A Dehydrogenase Deficiency in Mice

et al. 1989

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ABSTRACT. A murine model for short-chain acyl-coenzyme A dehydrogenase (SCAD) deficiency has been identified and characterized in BALBJcByJ mice. These mice have undetectable SCAD activity, severe organic aciduria; excreting ethylmalonic and methylsuccinic acids and Nbutyrylglycine, and develop a fatty liver upon fasting or dietary fat challenge. The mutant mice develop hypoglycemia after an 18-h fast, and have elevated urinary and muscle butyrylcarnitine concentrations. Most of these findings parallel those of human disorders associated with SCAD deficiency and other P-oxidation defects. This mouse model presents important opportunities to investigate the biology of mammalian fatty acid metabolism and the related human diseases. (Pediatr Res 25:38-43, 1989) Abbreviations SCAD, short-chain acyl-CoA dehydrogenase MCAD, medium-chain acyl-CoA dehydrogenase MCT, medium-chain triglycerides Deficiency of SCAD has been described recently in humans (1-4). The most severe form of this disorder is characterized by patients with episodes of metabolic acidosis, nonketotic hypoglycemia, and short-chain dicarboxylic aciduria. The clinical outcomes range from normalcy to unexpected death in homozygotes. Lately, sudden infant death syndrome and Reye's-like syndrome have been linked to defects in P-oxidation of fatty acids (5-7). Other recent studies have demonstrated that a secondary carnitine deficiency associated with the organic acidemia appears involved in the pathogenesis of the episodic events of these disorders (1,4,8). Overall, these diseases appear complex.We have a program to screen mice for inherited metabolic diseases (9) to develop models for investigating the pathogenesis and treatment of these disorders. In the course of screening mutant mice for organic acidurias using gas chromatographymass spectrometry, we discovered a subline of BALB/c mice (BALB/cByJ) that excreted unusually large concentrations of ethylmalonic and methylsuccinic acids and N-butyrylglycine. Butyryl-CoA dehydrogenase activity and electrophoretic mobility are used as a genetic marker for the Bcd-1 locus on mouse 38chromosome 5 (10). Subsequently, we learned that BALB/cByJ mice were found to have no detectable butyryl-CoA dehydrogenase activity by this marker assay (10). The null allele of these mice was designated Bcd-1" and was distinctly different from the normal activity associated with the Bcd-lb allele of BALB/cJ or BALB/cBy mice. To investigate the enzymatic defect and the resulting metabolic consequences, we performed a series of experiments using BALB/c By (Y) mice as controls and the BALB/ c ByJ (J) mutant mice. MATERIALS AND METHODSMice. BALB/cBy and BALB/cByJ mice were purchased from The Jackson Laboratory, (Bar Harbor, ME) and propagated at the Baylor College of Medicine (Houston, TX). All mice were maintained on Wayne rodent food no. 8640 (Wayne Pet Food Division, Continental Grain Co., Chicago, IL) and water ad libitum. Heterozygous mice were produced by crossing a Y female with a J male.Biochemistry. Urinary organic acids were ...

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Short-Chain Acyl-Coenzyme A Dehydrogenase Deficiency in Mice

et al. 1989

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“…Although information on the tissue carnitine concentrations is not complete for all of these disorders, most seem to share the abnormalities seen in MCAD deficiency, namely low plasma concentrations of total carnitine, increased ratio of esterified carnitineltotal carnitine, and low tissue concentrations of total carnitine. Similarly, certain patients with adult onset chronic weakness formerly diagnosed to be primary muscle carnitine deficiency have now been diagnosed to have other defects such as short-chain acyl CoA dehydrogenase deficiency (9,10). A further important and still controversial issue in these cases of secondary carnitine deficiency is the degree to which carnitine therapy is beneficial in either acute or chronic situations (6).…”

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Impaired Skin Fibroblast Carnitine Uptake in Primary Systemic Carnitine Deficiency Manifested by Childhood Carnitine-Responsive Cardiomyopathy

et al. 1990

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ABSTRACT. Evidence is emerging that primary systemic carnitine deficiency, a potentially lethal but eminently treatable inborn error of fatty acid oxidation, involves a cellular defect in the uptake of carnitine. We present four unrelated children with primary carnitine-responsive cardiomyopathy, weakness (with or without hypoketotic hypoglycemic encephalopathy), low serum and/or tissue carnitine concentrations, and severe renal carnitine leak. Dicarboxylic acids were absent in the urine of three children who were tested, and all four had a rapid and dramatic improvement in cardiac function, strength, and somatic growth after carnitine therapy. We studied carnitine uptake in cultured skin fibroblasts from all four children and seven of the eight healthy nonconsanguinous parents.[3H]~-carnitine uptake was evaluated in vitro under linear time kinetics. Substrate concentrations were varied from 0.1 to 1000 wM. Physiologic uptake was determined at carnitine concentrations between 0.1 and 50 wM. Nonspecific uptake was determined at a concentration of 10 mM. The four patients had negligible uptake throughout the physiologic range, implying a marked deficiency in the specific highaffinity, low-concentration, carrier-mediated uptake mechanism. At a concentration of 5 pmol/L, the mean velocity of uptake in the four patients was 2% of control values. Their parents showed intermediate maximal rates of carnitine uptake ranging from 13 to 44% of control V,,, values, but normal Km values, suggesting that the heterozygotes had a reduced number of normal functioning carnitine transporters. The observed reduction in V,,, values for the parents supports an autosomal recessive inheritance pattern and may be a more sensitive indicator of heterozygosity than serum carnitine concentrations. We conclude that carnitine uptake studies in cultured skin fibroblasts are important for diagnosis, screening of siblings and heterozygote parents, understanding pathogenesis, and investigating the molecular basis of this disease. Given the

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“…deficient transport at the level of the plasma membrane (23)(24)(25) or inner mitochondria1 membrane (26). excessive esterification by fatty acids that accumulate due to shortchain (27) or medium-chain (4) acyl-CoA dehydrogenase deficiency, binding by medications such as valproic acid (28) 4 Different rrom "low carnitine" mean at p = 0.036.…”

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Muscle Carnitine Repletion by Long-Term Carnitine Supplementation in Nephropathic Cystinosis

et al. 1993

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ABSTRACT. The renal tubular Fanconi syndrome of children with nephropathic cystinosis causes plasma and musle carnitine depletion. L-Carnitine replacement therapy for up to 18 mo has previously been shown to normalize plasma but not muscle carnitine levels. We treated six cystinosis patients, aged 1 to 4 y, with a mean dosage of 92 mg Lcarnitine/kg/d given every 6 h for an average of 62 mo. Despite fractional excretions of free carnitine ranging from 55 to 108%, plasma-free and total carnitine concentrations were maintained at or above normal levels. At the end of the carnitine replacement period, the six children had muscle-free carnitine values ranging from 16.0 to 28.0 nmol/mg noncollagen protein compared with values of 3.0 to 11.4 for cvstinosis children not s u~~l e m e n t e d with carnitine [normil, 22.7 f 5.0 (SD) nmbi/mg protein]. Total muscle carnitine values were also normalized by L-carnitine replacement. The monthly increase in total body creatinine production, a measure of muscle mass, was higher ( p = 0.036) in children with normal plasma free carnitine concentrations (3.4 f 0.9 mg/d) than in children with low plasma free carnitine (2.3 f 0.7 mg/d). No serious side effects, such as severe diarrhea, were observed. We conclude that oral L-carnitine replacement can normalize muscle carnitine content in children with cystinosis. (Pediatr Res 34: 115-1 19,1993) Carnitine, or 8-hydroxy-trimethylaminobutyric acid, mediates the transport of long-chain fatty acids into the mitochondria1 matrix for subsequent catabolism by @-oxidation to produce energy (1, 2). This process is essential for skeletal muscle (3), which serves as a large reservoir for carnitine (4) but cannot itself synthesize this molecule. Rather, carnitine is synthesized in the liver, kidney, and brain from methionine and lysine (I), and is also supplied by gastrointestinal absorption after the ingestion of meats and milk. Carnitine exists either free or esterified to fatty acids, primarily as acetylcarnitine (1).In normal individuals, free carnitine is filtered by renal glomeruli and is 97% reabsorbed by the kidney tubules (5). Patients with renal Fanconi syndrome, however, fail to reabsorb carnitine (5, 6) along with other small molecules including water, glucose, amino acids, phosphate, calcium, magnesium, sodium, potassium, and bicarbonate. Typically, free carnitine is only 67% reabsorbed in Fanconi syndrome, resulting in low plasma carni-

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Short-Chain Acyl-CoA Dehydrogenase Deficiency Associated with a Lipid-Storage Myopathy and Secondary Carnitine Deficiency

Cited by 134 publications

References 17 publications

Short-Chain Acyl-Coenzyme A Dehydrogenase Deficiency in Mice

Short-Chain Acyl-Coenzyme A Dehydrogenase Deficiency in Mice

Impaired Skin Fibroblast Carnitine Uptake in Primary Systemic Carnitine Deficiency Manifested by Childhood Carnitine-Responsive Cardiomyopathy

Muscle Carnitine Repletion by Long-Term Carnitine Supplementation in Nephropathic Cystinosis

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