Atypical myopathy associated with box elder in Europe

IF 0.8 4区 农林科学 Q3 VETERINARY SCIENCES
E. J. Knowles, R. J. Piercy
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The severe myopathy results from the ingestion of the seeds or seedlings of European sycamore (<i>Acer pseudoplatanus</i>) in Europe and the box elder (<i>Acer negundo</i>) in the USA (Valberg et al., <span>2013</span>; Westermann et al., <span>2008</span>). The seeds, seedlings, and leaves of these trees contain the protoxin HGA, and to a lesser extent its analogue methylenecyclopropylglycine (MCPrG; Bochnia et al., <span>2019</span>). These protoxins are metabolised to the active toxins methylenecyclopropylacetyl-CoA (MCPA-CoA) and MCPrG-CoA, respectively, at tissue-specific rates and primarily in skeletal muscle (Sander et al., <span>2023</span>). The toxic effects mainly occur in the highly-oxidative ‘slow-twitch’ type I muscle fibres such as the postural muscles, masseters, diaphragm and cardiac muscle (Cassart et al., <span>2007</span>). The primary toxin, MCPA-CoA inhibits acyl-CoA dehydrogenase enzymes involved in the beta-oxidation of fatty acids and catabolism of branched-chain amino acids resulting in failure of mitochondrial energy generation and subsequently muscle cell death (Westermann et al., <span>2008</span>). Inhibition of Acyl-CoA dehydrogenase enzymes causes an accumulation of their acyl-CoA substrates and the carnitine and glycine conjugates of those substrates in serum and urine, a characteristic metabolic profile known as multiple acyl-CoA dehydrogenase deficiency (MADD) (Westermann et al., <span>2008</span>). The accumulation of acylcarnitines together with the protoxins (HGA and MCPrG) and the carnitine conjugates of the toxins (MCPA-carnitine and MCPF-carnitine) can be detected in serum by liquid-chromatography-mass-spectometry (LCMS) (Bochnia et al., <span>2019</span>; González-Medina et al., <span>2021</span>; Valberg et al., <span>2013</span>).</p><p>In many cases a diagnosis of atypical myopathy can be made relatively confidently based on the characteristic clinical signs, serum biochemical changes, the seasonal occurrence and, in Europe, the presence of sycamore (<i>Acer psuedoplatanus</i>) seeds or seedlings on the pasture (Dunkel et al., <span>2018</span>; González-Medina et al., <span>2017</span>). Detection of serum HGA or MCPA-carnitine by LCMS may be useful to confirm the diagnosis and may be particularly useful to identify sub-clinically affected cases, or those with less-severe or unusual presentations or when a toxic (tree) source cannot readily be identified.</p><p>HGA or MCPA-carnitine has been detected in the serum of horses co-grazing with affected cases (Baise et al., <span>2016</span>; Bochnia et al., <span>2018</span>; Renaud et al., <span>2024</span>). Whilst these co-grazing horses were apparently healthy it is unknown whether clinical signs would have been apparent if they had undertaken higher levels of exercise or if they could have been precipitated by a greater negative energy balance, requiring a greater reliance on metabolism of stored fats. It is therefore plausible that HGA could affect the exercise performance of a much greater number of horses than those with overt clinical signs.</p><p>Identification of serum HGA or MCPA-carnitine can also be useful in cases such as the case described by Jahn et al. (<span>2025</span>) in which box elder but not sycamore trees were present on the pasture. Whilst the presence of box elder had been reported on one European pasture grazed by an AM-affected horse previously, sycamore was also present on that pasture (Votion et al., <span>2014</span>) and to the author's knowledge, confirmed box elder related atypical myopathy has not been reported previously in Europe.</p><p>Many clinicians in Europe will not be familiar with the box elder tree as an alternative source of HGA, However, given that the box elder has been identified as a major invasive species in forests in the European Union (Campagnaro et al., <span>2018</span>), it is likely to be responsible for further cases of atypical myopathy in Europe in future. Clinicians should also be aware of the potential for many other trees of the <i>Acer</i> family that are grown in gardens or as ornamental trees to contain HGA. HGA has been identified in the sugar maple (<i>Acer saccharum</i>), Japanese maple (<i>Acer palmatum</i>), trident maple (<i>Acer buergerianum</i>), paperbark maple (<i>Acer griseum</i>), Himalayan maple (<i>Acer oblongum</i>), mountain maple (<i>Acer spicatum</i>), big leaf maple (<i>Acer macrophyllum</i>), full moon maple (<i>Acer</i> japonicum), lime-leafed maple (<i>Acer distylum</i>) and Siebold's maple (<i>Acer sieboldianum</i>; Fowden &amp; Pratt, <span>1973</span>; Novotná et al., <span>2023</span>). Given the potential for the winged samaras of these species to spread widely in windy conditions, it is plausible that cases of atypical myopathy could occur if these species are grown in gardens adjoining paddocks.</p><p>Acylcarnitine profiling combined with HGA/MCPA-carnitine assays may also be clinically useful to identify unusual cases of atypical myopathy, other pasture toxicities and inborn errors of metabolism. For example, a rare case of atypical myopathy was diagnosed using these methods in a newborn foal in which the mare had suffered from atypical myopathy during pregnancy (Karlíková et al., <span>2018</span>). In another case, severe clinical signs in a newborn foal resulted from suspected concurrent atypical myopathy with inborn metabolic disease (Sander et al., <span>2021</span>). Finally, acylcarnitine profiling was also successfully used to identify an inborn form of MADD without HGA toxicity in a Paint foal (Pinn et al., <span>2018</span>).</p><p>Recently, acylcarnitine profiling was also used to identify cases of marsh mallow (<i>Malva parviflora</i>) toxicity in which it is proposed that malvalic and/or sterculic acid inhibit very-long-chain acyl-CoA dehydrogenase, thus slowing the beta-oxidation of very-long-chain fatty acids (Bauquier et al., <span>2017</span>). Acylcarnitine profiles have also revealed suspected disorders of fatty acid metabolism without the detection of HGA MCPA-carnitine in serum samples submitted to the authors' laboratory (unpublished data) and it is likely that as yet unidentified pasture-associated toxicities occur in the UK and Europe.</p><p>In conclusion, the interesting case report by Jahn et al. (<span>2025</span>) is an important reminder to clinicians in Europe of the potential for <i>Acer</i> species other than sycamore to cause atypical myopathy. Acylcarnitine profiles and detection of HGA/ MCPA-carnitine by LCMS can be a useful diagnostic aid in myopathy cases.</p><p><b>E. J. Knowles:</b> Writing – original draft. <b>R. J. Piercy:</b> Writing – review and editing.</p><p>There are no funders for this submission.</p><p>No conflicts of interest have been declared.</p><p>Not applicable to this clinical commentary.</p>","PeriodicalId":11786,"journal":{"name":"Equine Veterinary Education","volume":"37 5","pages":"231-233"},"PeriodicalIF":0.8000,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/eve.14117","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Equine Veterinary Education","FirstCategoryId":"97","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/eve.14117","RegionNum":4,"RegionCategory":"农林科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"VETERINARY SCIENCES","Score":null,"Total":0}
引用次数: 0

Abstract

The case report by Jahn et al. (2025) describes a case of atypical myopathy in Europe caused by ingestion of the protoxin hypoglycin A (HGA) from box elder seedlings. This is an important report. It reminds clinicians in Europe that trees other than The European sycamore (Acer pseudoplatanus) may contain HGA and that there is a potential for other unfamiliar plant species to cause pasture-associated toxicities.

After many years of research, the pathogenesis of atypical myopathy, also known as seasonal pasture myopathy, is now well understood. The severe myopathy results from the ingestion of the seeds or seedlings of European sycamore (Acer pseudoplatanus) in Europe and the box elder (Acer negundo) in the USA (Valberg et al., 2013; Westermann et al., 2008). The seeds, seedlings, and leaves of these trees contain the protoxin HGA, and to a lesser extent its analogue methylenecyclopropylglycine (MCPrG; Bochnia et al., 2019). These protoxins are metabolised to the active toxins methylenecyclopropylacetyl-CoA (MCPA-CoA) and MCPrG-CoA, respectively, at tissue-specific rates and primarily in skeletal muscle (Sander et al., 2023). The toxic effects mainly occur in the highly-oxidative ‘slow-twitch’ type I muscle fibres such as the postural muscles, masseters, diaphragm and cardiac muscle (Cassart et al., 2007). The primary toxin, MCPA-CoA inhibits acyl-CoA dehydrogenase enzymes involved in the beta-oxidation of fatty acids and catabolism of branched-chain amino acids resulting in failure of mitochondrial energy generation and subsequently muscle cell death (Westermann et al., 2008). Inhibition of Acyl-CoA dehydrogenase enzymes causes an accumulation of their acyl-CoA substrates and the carnitine and glycine conjugates of those substrates in serum and urine, a characteristic metabolic profile known as multiple acyl-CoA dehydrogenase deficiency (MADD) (Westermann et al., 2008). The accumulation of acylcarnitines together with the protoxins (HGA and MCPrG) and the carnitine conjugates of the toxins (MCPA-carnitine and MCPF-carnitine) can be detected in serum by liquid-chromatography-mass-spectometry (LCMS) (Bochnia et al., 2019; González-Medina et al., 2021; Valberg et al., 2013).

In many cases a diagnosis of atypical myopathy can be made relatively confidently based on the characteristic clinical signs, serum biochemical changes, the seasonal occurrence and, in Europe, the presence of sycamore (Acer psuedoplatanus) seeds or seedlings on the pasture (Dunkel et al., 2018; González-Medina et al., 2017). Detection of serum HGA or MCPA-carnitine by LCMS may be useful to confirm the diagnosis and may be particularly useful to identify sub-clinically affected cases, or those with less-severe or unusual presentations or when a toxic (tree) source cannot readily be identified.

HGA or MCPA-carnitine has been detected in the serum of horses co-grazing with affected cases (Baise et al., 2016; Bochnia et al., 2018; Renaud et al., 2024). Whilst these co-grazing horses were apparently healthy it is unknown whether clinical signs would have been apparent if they had undertaken higher levels of exercise or if they could have been precipitated by a greater negative energy balance, requiring a greater reliance on metabolism of stored fats. It is therefore plausible that HGA could affect the exercise performance of a much greater number of horses than those with overt clinical signs.

Identification of serum HGA or MCPA-carnitine can also be useful in cases such as the case described by Jahn et al. (2025) in which box elder but not sycamore trees were present on the pasture. Whilst the presence of box elder had been reported on one European pasture grazed by an AM-affected horse previously, sycamore was also present on that pasture (Votion et al., 2014) and to the author's knowledge, confirmed box elder related atypical myopathy has not been reported previously in Europe.

Many clinicians in Europe will not be familiar with the box elder tree as an alternative source of HGA, However, given that the box elder has been identified as a major invasive species in forests in the European Union (Campagnaro et al., 2018), it is likely to be responsible for further cases of atypical myopathy in Europe in future. Clinicians should also be aware of the potential for many other trees of the Acer family that are grown in gardens or as ornamental trees to contain HGA. HGA has been identified in the sugar maple (Acer saccharum), Japanese maple (Acer palmatum), trident maple (Acer buergerianum), paperbark maple (Acer griseum), Himalayan maple (Acer oblongum), mountain maple (Acer spicatum), big leaf maple (Acer macrophyllum), full moon maple (Acer japonicum), lime-leafed maple (Acer distylum) and Siebold's maple (Acer sieboldianum; Fowden & Pratt, 1973; Novotná et al., 2023). Given the potential for the winged samaras of these species to spread widely in windy conditions, it is plausible that cases of atypical myopathy could occur if these species are grown in gardens adjoining paddocks.

Acylcarnitine profiling combined with HGA/MCPA-carnitine assays may also be clinically useful to identify unusual cases of atypical myopathy, other pasture toxicities and inborn errors of metabolism. For example, a rare case of atypical myopathy was diagnosed using these methods in a newborn foal in which the mare had suffered from atypical myopathy during pregnancy (Karlíková et al., 2018). In another case, severe clinical signs in a newborn foal resulted from suspected concurrent atypical myopathy with inborn metabolic disease (Sander et al., 2021). Finally, acylcarnitine profiling was also successfully used to identify an inborn form of MADD without HGA toxicity in a Paint foal (Pinn et al., 2018).

Recently, acylcarnitine profiling was also used to identify cases of marsh mallow (Malva parviflora) toxicity in which it is proposed that malvalic and/or sterculic acid inhibit very-long-chain acyl-CoA dehydrogenase, thus slowing the beta-oxidation of very-long-chain fatty acids (Bauquier et al., 2017). Acylcarnitine profiles have also revealed suspected disorders of fatty acid metabolism without the detection of HGA MCPA-carnitine in serum samples submitted to the authors' laboratory (unpublished data) and it is likely that as yet unidentified pasture-associated toxicities occur in the UK and Europe.

In conclusion, the interesting case report by Jahn et al. (2025) is an important reminder to clinicians in Europe of the potential for Acer species other than sycamore to cause atypical myopathy. Acylcarnitine profiles and detection of HGA/ MCPA-carnitine by LCMS can be a useful diagnostic aid in myopathy cases.

E. J. Knowles: Writing – original draft. R. J. Piercy: Writing – review and editing.

There are no funders for this submission.

No conflicts of interest have been declared.

Not applicable to this clinical commentary.

非典型肌病与欧洲的箱形老人有关
Jahn等人(2025)的病例报告描述了欧洲一例因从箱形接骨木苗中摄取原素低糖素a (HGA)而引起的非典型肌病。这是一份重要的报告。它提醒欧洲的临床医生,欧洲梧桐树(Acer pseudoplatanus)以外的树木可能含有HGA,其他不熟悉的植物物种也有可能引起牧场相关的毒性。经过多年的研究,非典型肌病的发病机制,也被称为季节性牧场肌病,现在已经很好地理解了。严重的肌病是由于在欧洲摄入了欧洲梧桐树(Acer pseudoplatanus)的种子或幼苗,在美国摄入了木盒接骨木(Acer negundo) (Valberg et al., 2013;Westermann et al., 2008)。这些树木的种子、幼苗和叶子含有原毒素HGA,在较小程度上含有其类似物亚甲基环丙基甘氨酸(MCPrG);Bochnia et al., 2019)。这些原毒素分别以组织特异性速率和主要在骨骼肌中代谢为活性毒素亚甲基环丙基乙酰辅酶a (MCPA-CoA)和MCPrG-CoA (Sander等,2023)。毒性作用主要发生在高度氧化的“慢抽搐”I型肌纤维中,如体位肌、咬肌、膈肌和心肌(Cassart et al., 2007)。主要毒素MCPA-CoA抑制酰基辅酶a脱氢酶,这些酶参与脂肪酸的β -氧化和支链氨基酸的分解代谢,导致线粒体能量产生失败,随后导致肌肉细胞死亡(Westermann等人,2008)。抑制酰基辅酶a脱氢酶会导致其酰基辅酶a底物以及这些底物的肉碱和甘氨酸偶联物在血清和尿液中的积累,这是一种称为多重酰基辅酶a脱氢酶缺乏症(MADD)的特征代谢谱(Westermann等人,2008)。通过液相色谱-质谱(LCMS)可以检测血清中酰基肉毒碱与原毒素(HGA和MCPrG)以及毒素的肉毒碱偶联物(mcpa -肉毒碱和mcpf -肉毒碱)的积累(Bochnia等人,2019;González-Medina等,2021;Valberg et al., 2013)。在许多情况下,非典型肌病的诊断可以相对自信地基于特征性临床体征、血清生化变化、季节发生,以及在欧洲,在牧场上存在梧桐(Acer pseudodoplatanus)种子或幼苗(Dunkel等人,2018;González-Medina等人,2017)。LCMS检测血清HGA或mcpa -肉碱可能有助于确认诊断,尤其适用于鉴别亚临床感染病例,或那些不太严重或不寻常的症状,或当有毒(树)源不能轻易确定。在与感染病例共食的马的血清中检测到HGA或mcpa -肉碱(Baise et al., 2016;Bochnia et al., 2018;Renaud et al., 2024)。虽然这些共同放牧的马显然是健康的,但尚不清楚临床症状是否会明显,如果它们进行了更高水平的运动,或者如果它们可能是由更大的负能量平衡引起的,需要更多地依赖于储存脂肪的代谢。因此,与那些有明显临床症状的马相比,HGA对运动表现的影响要大得多,这是合理的。血清HGA或mcpa -肉碱的鉴定在诸如Jahn等人(2025)所描述的牧场上有木接骨木而没有梧桐树的情况下也很有用。虽然此前曾有报道称,在一匹am病马放牧的一个欧洲牧场上发现了箱形接骨木,但该牧场上也发现了梧桐树(Votion et al., 2014),据作者所知,欧洲此前未报道过与箱形接骨木相关的非典型肌病。欧洲的许多临床医生并不熟悉箱形接骨木树作为HGA的替代来源,然而,鉴于箱形接骨木已被确定为欧盟森林中的主要入侵物种(Campagnaro等人,2018),它很可能是未来欧洲更多非典型肌病病例的原因。临床医生也应该意识到在花园中种植或作为观赏树木的槭科许多其他树木含有HGA的潜力。在糖枫(Acer saccharum)、日本枫(Acer palmatum)、三叉戟枫(Acer buergerianum)、树皮枫(Acer griseum)、喜马拉雅枫(Acer oblongum)、山枫(Acer spicatum)、大叶枫(Acer macrophyllum)、满月枫(Acer japonicum)、酸叶枫(Acer distylum)和西博尔德枫(Acer sieboldianum)中已鉴定出HGA;Fowden,普拉特,1973;novotn<e:1>等人,2023)。
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来源期刊
Equine Veterinary Education
Equine Veterinary Education 农林科学-兽医学
CiteScore
2.40
自引率
22.20%
发文量
132
审稿时长
18-36 weeks
期刊介绍: Equine Veterinary Education (EVE) is the official journal of post-graduate education of both the British Equine Veterinary Association (BEVA) and the American Association of Equine Practitioners (AAEP). Equine Veterinary Education is a monthly, peer-reviewed, subscription-based journal, integrating clinical research papers, review articles and case reports from international sources, covering all aspects of medicine and surgery relating to equids. These papers facilitate the dissemination and implementation of new ideas and techniques relating to clinical veterinary practice, with the ultimate aim of promoting best practice. New developments are placed in perspective, encompassing new concepts and peer commentary. The target audience is veterinarians primarily engaged in the practise of equine medicine and surgery. The educational value of a submitted article is one of the most important criteria that are assessed when deciding whether to accept it for publication. Articles do not necessarily need to contain original or novel information but we welcome submission of this material. The educational value of an article may relate to articles published with it (e.g. a Case Report may not have direct educational value but an associated Clinical Commentary or Review Article published alongside it will enhance the educational value).
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