Acquired multiple Acyl-CoA dehydrogenase deficiency in 10 horses with atypical myopathy

Westermann, C.M.; Dorland, L.; Votion, Dominique; Velden, Monique G.M. de Sain–van der; Wijnberg, Inge D.; Wanders, R. J. A.; Spliet, Wim G.M.; Testerink, N.; Berger, Ruud; Ruiter, J. P. N.; Kolk, Johannes H. van der

doi:10.1016/j.nmd.2008.02.007

Cited by 80 publications

(136 citation statements)

References 15 publications

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“…Previous studies 11,14,15 reported increased levels of most of the up to 35 carnitines tested in plasma or serum. With the serum samples available in our laboratory, we received similar results by parent ion scans of m/z 85 fragments in a spectrum of 32 carnitines (not shown).…”

Section: Discussionmentioning

confidence: 89%

“…Analyzing urine or plasma samples for acyl glycines, including MCPA glycine, should therefore also be a way to prove HGA intoxication. Previous studies 11,12,15 described qualitatively positive results for butyryl, isovaleryl, and hexanoyl glycines in the urine of poisoned horses. One study 10 extracted glycine conjugates by liquid partition chromatography and transferred them, as in a previous study, 15 to trimethylsilyl derivatives.…”

Section: Introductionmentioning

confidence: 92%

“…Analysis was done by GC-MS. These authors 15 were also able to quantify MCPA glycine in this way, and found 0.79-3.97 mmol/mol creatinine in 6 of 7 poisoned horses. MCPA glycine was not detected in 1 poisoned horse and 5 normal horses.…”

Section: Introductionmentioning

confidence: 93%

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Rapid diagnosis of hypoglycin A intoxication in atypical myopathy of horses

et al. 2016

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Abstract. Hypoglycin A (2-amino-3-(2-methylidenecyclopropyl)propanoic acid) is the plant toxin shown to cause atypical myopathy in horses. It is converted in vivo to methylenecyclopropyl acetic acid, which is transformed to a coenzyme A ester that subsequently blocks beta oxidation of fatty acids. Methylenecyclopropyl acetic acid is also conjugated with carnitine and glycine. Acute atypical myopathy may be diagnosed by quantifying the conjugates of methylenecyclopropyl acetic acid plus a selection of acyl conjugates in urine and serum. We describe a new mass spectrometric method for sample volumes of <0.5 mL. Samples were extracted with methanol containing 5 different internal standards. Extracts were analyzed by ultra-highperformance liquid chromatography-tandem mass spectrometry focusing on 11 metabolites. The total preparation time for a series of 20 samples was 100 min. Instrument run time was 14 min per sample. For the quantification of carnitine and glycine conjugates of methylenecyclopropyl acetic acid in urine, the coefficients of variation for intraday quantification were 2.9% and 3.0%, respectively. The respective values for interday were 9.3% and 8.0%. Methylenecyclopropyl acetyl carnitine was detected as high as 1.18 µmol/L in serum (median: 0.46 µmol/L) and 1.98 mmol/mol creatinine in urine (median: 0.79 mmol/ mol creatinine) of diseased horses, while the glycine derivative accumulated up to 1.97 mmol/mol creatinine in urine but was undetectable in most serum samples. In serum samples from horses with atypical myopathy, the intraday coefficients of variation for C4-C8 carnitines and glycines were ≤4.5%. Measured concentrations exceeded those in healthy horses by ~10 to 1,400 times.

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Section: Discussionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 92%

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Rapid diagnosis of hypoglycin A intoxication in atypical myopathy of horses

et al. 2016

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“…This acquired equine MADD is associated with a substantial elevation of C2-, C3-, C4-, C5-, C6-, C8-, C8:1-, C10:1-and C10:2-carnitine concentrations in plasma in the majority of cases (Westermann et al 2008a). As single carnitine supplementation increases the utilization of C5-and C8-carnitne in healthy horses, it is a plausible idea to use it in horses affected with MADD and other potential fatty acid oxidation disorders (Wijnberg et al 2008).…”

Section: Acylcarnitinesmentioning

confidence: 98%

Acylcarnitine ester utilization by the hindlimb of warmblood horses at rest and following low intensity exercise and carnitine supplementation

Peters¹,

Smiet²,

Velden³

et al. 2015

Veterinary Quarterly

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Background: Acylcarnitines play an important role in fuel metabolism in skeletal muscle. Objective: To assess acylcarnitine ester utilization by the hindlimb of horses at rest and following low intensity exercise and carnitine supplementation. Animals and methods: Acylcarnitine ester uptake by the hindlimb was investigated using the arteriovenous difference technique. Blood from six warmblood mares (mean age 12 § 3 (SD) years and weighing 538 § 39 kg) was collected simultaneously from the transverse facial artery and from the caudal vena cava. Food was withheld for 12 hours prior to exercise. Exercise comprised a standardized treadmill protocol consisting of 5 minutes of walk, 20 minutes of trot and thereafter another 5 minutes of walk. At the end of the first exercise day, three horses were given carnitine supplementation (100 mg/kg bodyweight), whereas the other horses received saline. The next day the exercise was repeated and blood samples collected similarly. Free carnitine and acylcarnitines were analyzed as their butyl ester derivatives in heparinized plasma by electrospray tandem mass spectrometry. Statistical analysis was performed using a general linear mixed model. Results: C3-carnitine, C6-carnitine and C14:1-carnitine showed the largest average extraction by the hindlimb at rest and C3-carnitine, C5:1-carnitine and C16-carnitine immediately after low-intensity exercise. Carnitine supplementation significantly increased free carnitine, C5-carnitine and C8-carnitine extraction. Conclusion: Carnitine supplementation altered the extraction of acylcarnitines by the hindlimb in horses exercising at low intensity. Clinical importance: Findings might aid in optimizing performance and myopathy prevention of the equine athlete.

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“…In animals, outbreaks of fatal MADD have been recorded in horses with atypical myopathy in particular weather conditions (Finno et al 2006;Cassart et al 2007;Westermann et al 2008;van der Kolk et al 2010;Valberg et al 2012). In these cases, an exogenous factor was predicted to cause MADD, and a genetic mutation of ETF and ETFDH has never been recognized.…”

Section: Introductionmentioning

confidence: 99%

Multiple Acyl-CoA Dehydrogenation Deficiency (Glutaric Aciduria Type II) with a Novel Mutation of Electron Transfer Flavoprotein-Dehydrogenase in a Cat

et al. 2013

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Multiple acyl-CoA dehydrogenation deficiency (MADD; also known as glutaric aciduria type II) is a human autosomal recessive disease classified as one of the mitochondrial fatty-acid oxidation disorders. MADD is caused by a defect in the electron transfer flavoprotein (ETF) or ETF dehydrogenase (ETFDH) molecule, but as yet, inherited MADD has not been reported in animals. Here we present the first report of MADD in a cat. The affected animal presented with symptoms characteristic of MADD including hypoglycemia, hyperammonemia, vomiting, diagnostic organic aciduria, and accumulation of medium-and long-chain fatty acids in plasma. Treatment with riboflavin and L-carnitine ameliorated the symptoms. To detect the gene mutation responsible for MADD in this case, we determined the complete cDNA sequences of feline ETFa, ETFb, and ETFDH. Finally, we identified the feline patient-specific mutation, c.692T>G (p.F231C) in ETFDH. The affected animal only carries mutant alleles of ETFDH. p.F231 in feline ETFDH is completely conserved in eukaryotes, and is located on the apical surface of ETFDH, receiving electrons from ETF. This study thus identified the mutation strongly suspected to have been the cause of MADD in this cat.

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Acquired multiple Acyl-CoA dehydrogenase deficiency in 10 horses with atypical myopathy

Cited by 80 publications

References 15 publications

Rapid diagnosis of hypoglycin A intoxication in atypical myopathy of horses

Rapid diagnosis of hypoglycin A intoxication in atypical myopathy of horses

Acylcarnitine ester utilization by the hindlimb of warmblood horses at rest and following low intensity exercise and carnitine supplementation

Multiple Acyl-CoA Dehydrogenation Deficiency (Glutaric Aciduria Type II) with a Novel Mutation of Electron Transfer Flavoprotein-Dehydrogenase in a Cat

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