Severe Inhibition of Long-Chain Acyl-CoA Enoylhydratase (EC 4.2.1.74) in a Newborn Foal Suffering From Atypical Myopathy.
Abstract: In horses, congenital defects of energy production from long-chain fatty acids have not been described so far. In contrast, inhibition of fatty acid degradation caused by the toxins hypoglycin A and methylenecyclopropylglycine from various maple species are observed frequently. These non-proteinogenic aminoacids are passed on placentally to fetuses or with collostrum or milk to newborn foals. Nevertheless, newborn foals become very rarely symptomatic. Vertical transmission apparently is not sufficient to induce clinical disease without a particular genetic constellation being present. One of these rare cases was investigated here using samples from a mare and her foal. Intoxication by hypoglycin A and methylenecyclopropylglycine is also of interest to human pathology, because these toxins have caused fatal poisonings after consumption of certain fruits many times, especially in children. Maple toxins, their metabolites and some short-chain acyl compounds were quantified by ultrahigh-pressure liquid chromatography/tandem mass spectrometry. An comprehensive spectrum of long-chain acylcarnitines was prepared using electrospray ionization tandem mass spectrometry. Organic acids and acylglycines were determined by gas chromatography mass spectrometry. For evaluation, results of other horses poisoned by maple material as well as unaffected control animals were used. In the serum of the foal, hypoglycin A was detected at a low concentration only. Toxin metabolites reached <3.5% of the mean of a comparison group of horses suffering from atypical myopathy. The spectrum of acylcarnitines indicated enzyme inhibition in short-chain and medium-chain regions typical of acer poisoning, but the measured concentrations did not exceed those previously found in clinically healthy animals after maple consumption. The values were not sufficient to explain the clinical symptoms. In contrast, a remarkably strong enrichment of tetradecenoylcarnitine and hexadecenoylcarnitine was observed. This proves a blockade of the long-chain enoyl-CoA hydratase (EC 4.2.1.74). Vertical transfer of maple toxins to a newborn foal is sufficient for induction of clinical disease only if there is an additional specific reactivity to the active toxins. This was found here in an inhibition of long-chain enoyl-CoA hydratase. Isolated dysfunction of this enzyme has not yet been reported in any species. Further studies are necessary to prove a specific genetic defect.
Copyright © 2021 Sander, Terhardt and Janzen.
Publication Date: 2021-10-26 PubMed ID: 34765670PubMed Central: PMC8576321DOI: 10.3389/fvets.2021.765623Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- Journal Article
Summary
This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.
The research investigates a rare case of a newborn horse experiencing severe energy production defects from long-chain fatty acids, which is linked to inherited toxins from certain maple species. These toxins interfere with fatty acid degradation, but the symptoms are seldom visible in newborns without a specific genetic makeup. However, this study confirms that the presence of these toxins can trigger clinical disease in the presence of particular reactivity to them.
Research Objectives and Methods
- The study aimed to investigate an unusual case of a newborn horse, the offspring of a mare, which was displaying clinical symptoms typically associated with toxins from maple trees.
- The toxins in question were hypoglycin A and methylenecyclopropylglycine – non-proteinogenic amino acids found in various species of maple. These toxins can pass from the mare to the foal, either through the placenta or via colostrum or milk.
- The research involved quantifying the presence of maple toxins, their metabolites, and other short-chain acyl compounds. This was achieved using ultrahigh-pressure liquid chromatography/tandem mass spectrometry.
- Other methods employed for data collection included electrospray ionization tandem mass spectrometry (to prepare a spectrum of long-chain acylcarnitines), as well as gas chromatography mass spectrometry to measure organic acids and acylglycines.
- The results were evaluated alongside data from other horses poisoned by maple material, as well as unaffected control animals.
Key Findings
- Hypoglycin A was present in the serum of the foal but at a low concentration. Metabolites of the toxin were meaningfully below the average levels found in a comparison group of horses suffering from atypical myopathy – an uncommon muscular condition.
- The acylcarnitines spectrum signified enzyme inhibitions typically seen in cases of acer (maple) poisoning. However, the measured concentrations did not exceed those previously found in healthy animals after maple consumption, suggesting they were not behind the clinical symptoms.
- On the contrary, significant enrichment of tetradecenoylcarnitine and hexadecenoylcarnitine was observed, confirming a blockade of the long-chain enoyl-CoA hydratase (EC 4.2.1.74).
- This suggests that vertical transfer of maple toxins to a newborn horse can instigate clinical disease only if there’s an additional specific reactivity to the toxins.
- The phenomenon of isolated dysfunction of this enzyme has not been reported in any species, bringing into consideration the existence of a unique genetic defect. However, this needs to be confirmed through further investigation.
Cite This Article
APA
Sander J, Terhardt M, Janzen N.
(2021).
Severe Inhibition of Long-Chain Acyl-CoA Enoylhydratase (EC 4.2.1.74) in a Newborn Foal Suffering From Atypical Myopathy.
Front Vet Sci, 8, 765623.
https://doi.org/10.3389/fvets.2021.765623 Publication
Researcher Affiliations
- Screening-Labor Hannover, Hanover, Germany.
- Hanover Medical School, Hanover, Germany.
- Screening-Labor Hannover, Hanover, Germany.
- Screening-Labor Hannover, Hanover, Germany.
- Hanover Medical School, Hanover, Germany.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
This article includes 24 references
- Votion DM, François AC, Kruse C, Renaud B, Farinelle A, Bouquieaux MC. Answers to the frequently asked questions regarding horse feeding and management practices to reduce the risk of atypical myopathy. Animals (2020) 10:365.
- Kean EA. Selective inhibition of acyl-CoA dehydrogenases by a metabolite of hypoglycin. Biochim Biophys Acta (1976) 422:8–14.
- Li D, Agnihotri G, Dakoji S, Zhou HQ, Liu HW. The toxicity of methylenecyclopropylglycine: studies of the inhibitory effects of (methylenecyclopropyl)formyl-CoA on enzymes involved in fatty acid metabolism and the molecular basis of its inactivation of enoyl-CoA hydratases. J Am Chem Soc (1999) 121:9034–42.
- Westermann CM, de Sain-van der Velden MG, van der Kolk JH, Berger R, Wijnberg ID, Koeman JP. Equine biochemical multiple acyl-CoA dehydrogenase deficiency (MADD) as a cause of rhabdomyolysis. Mol Genet Metab (2007) 91:362–9.
- Karlíková R, Široká J, Mech M, Friedecký D, Janečková H, Mádrová L. Newborn foal with atypical myopathy. J Vet Intern Med (2018) 32:1768–72.
- Sander J, Terhardt M, Janzen N. Detection of maple toxins in mare's milk. J Vet Intern Med (2020) 35:606–9.
- Renaud B, François AC, Boemer F, Kruse C, Stern D, Piot A. Grazing mares on pasture with sycamore maples: a potential threat to suckling foals and food safety through milk contamination. Animals (2021) 11:87.
- González-Medina S, Bevin W, AlzolaDomingo R, Chang Y-M, Piercy RJ. Hypoglycin A absorption in sheep without concurrent clinical or biochemical evidence of disease. J Vet Intern Med (2021) 35:1170–6.
- Sander J, Terhardt M, Sander S, Aboling S, Janzen N. A new method for quantifying causative and diagnostic markers of methylenecyclopropylglycine poisoning. Toxicol Rep (2019) 6:803–8.
- Sander J, Terhardt M, Sander S, Janzen N. Quantification of methylenecyclopropyl compounds and acyl conjugates by UPLC-MS/MS in the study of the biochemical effects of the ingestion of canned ackee (Blighia sapida) and lychee (Litchi chinensis). J Agric Food Chem (2017) 65:2603–8.
- Sander J, Cavalleri JM, Terhardt M, Bochnia M, Zeyner A, Zuraw A. Rapid diagnosis of hypoglycin A intoxication in atypical myopathy of horses. J Vet Diagn Invest (2016) 28:98–104.
- Sander J, Terhardt M, Sander S, Janzen N. Quantification of hypoglycin A as butyl ester. J Chromatogr B Analyt Technol Biomed Life Sci (2016) 1029-1030:169–73.
- Chace DH, DiPerna JC, Naylor EW. Laboratory integration and utilization of tandem mass spectrometry in neonatal screening: a model for clinical mass spectrometry in the next millennium. Acta Paediatr Suppl (1999) 88:45–7.
- Rashed MS, Rahbeeni Z, Ozand PT. Application of electrospray tandem mass spectrometry to neonatal screening. Semin Perinatol (1999) 23:183–93.
- Sander J, Terhardt M, Sander S, Janzen N. Use of a standard newborn screening test for the rapid diagnosis of inhibited ß-Oxidation in atypical myopathy in horses. J Equine Vet Sci (2018) 67:71–4.
- Hoffmann G, Aramaki S, Blum-Hoffmann E, Nyhan WL, Sweetman L. Quantitative analysis for organic acids in biological samples: batch isolation followed by gas chromatographic-mass spectrometric analysis. Clin Chem (1989) 35:587–95.
- Bochnia M, Ziegler J, Sander J, Uhlig A, Schaefer S, Vollstedt S. Hypoglycin A content in blood and urine discriminates horses with atypical myopathy from clinically normal horses grazing on the same pasture. PLoS One (2015) 10:e0136785.
- Korman SH, Andresen BS, Zeharia A, Gutman A, Boneh A, Pitt JJ. 2-ethylhydracrylic aciduria in short/branched-chain acyl-CoA dehydrogenase deficiency: application to diagnosis and implications for the R-pathway of isoleucine oxidation. Clin Chem (2005) 51:610–7.
- Sass JO, Ensenauer R, Röschinger RW, Reich H, Steuerwald U, Schirrmacher O. 2-Methylbutyryl-coenzyme A dehydrogenase deficiency: functional and molecular studies on a defect in isoleucine catabolism. Mol Genet Metab (2007) 93:30–5.
- Baise E, Habyarimana JA, Amory H, Boemer F, Douny C, Gustin P. Samaras and seedlings of Acer pseudoplatanus are potential sources of hypoglycin A intoxication in atypical myopathy without necessarily inducing clinical signs. Equine Vet J (2016) 48:414–7.
- Boutron A, Acquaviva C, Vianey-Saban C. Comprehensive cDNA study and quantitative analysis of mutant HADHA and HADHB transcripts in a French cohort of 52 patients with mitochondrial trifunctional protein deficiency. Mol Genet Metab (2011) 103:341–8.
- Sander J, Sander S, Steuerwald U, Janzen N, Peter M, Wanders RJA. Neonatal screening for defects of the mitochondrial trifunctional protein. Mol Genet Metab (2005) 85:108–14.
- Van Calcar SC, Sowa M, Rohr F, Beazer J, Setlock T, Weihe TU. Nutrition management guideline for very-long chain acyl-CoA dehydrogenase deficiency (VLCAD): an evidence- and consensus-based approach. Mol Genet Metab (2020) 131:23–37.
- Lepori V Mühlhause F, Sewell AC, Jagannathan V, Janzen N, Rosati M. Nonsense variant in the ACADVL gene in german hunting terriers with exercise induced metabolic myopathy. G3 (Bethesda) (2018) 8:1545–54.
Citations
This article has been cited 0 times.Use Nutrition Calculator
Check if your horse's diet meets their nutrition requirements with our easy-to-use tool Check your horse's diet with our easy-to-use tool
Talk to a Nutritionist
Discuss your horse's feeding plan with our experts over a free phone consultation Discuss your horse's diet over a phone consultation
Submit Diet Evaluation
Get a customized feeding plan for your horse formulated by our equine nutritionists Get a custom feeding plan formulated by our nutritionists
