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Review of the Discovery of the Basis for a Seasonal Pasture Myopathy/Atypical Myopathy
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The amino acid hypoglycin A is present in the seeds of box elder and sycamore maple trees. When pastured horses ingest seeds in the fall and early spring they develop a highly fatal form of rhabdomyolysis. A definitive diagnosis is made by measurement of serum acylcarnitines, which accumulate because the toxin blocks muscle lipid metabolism. Author’s address: Department of VPM, University of Minnesota, 1365 Gortner Avenue, St. Paul, MN 55108; e-mail: valbe001@ umn.edu.
1. Introduction
Seasonal pasture myopathy,1,2 atypical myopathy,3,4 and atypical myoglobinuria5 are terms used to describe an often-fatal form of rhabdomyolysis that develops in unexercised horses kept on pastures. Although initial clinical signs resemble colic, the apparent discomfort, trembling, tachycardia, short stiff stride, periods of recumbency, tachypnea, and myoglobinuria actually arise from severe degeneration of postural and respiratory muscles.5–7 The first reports date back to 1939 in Wales8 and 1959 in Southern Ontario.9 Although described for 75 years, the cause of this disorder has remained a mystery until very recently. The purpose of this review is to highlight the sentinel findings that led to the discovery of the toxin associated with cases of seasonal pasture myopathy in European and North American horses.
2. Epidemiology
Vital epidemiological information on a large number of cases of pasture myopathy arose from the Atypical Myopathy Alert Group (http://www.myopathieatypique.fr/en/amag-2/). Many hundreds of cases were documented in Denmark, France, Germany, Ireland, United Kingdom, Latvia, Luxembourg, Spain, Switzerland, The Netherlands, Austria, Czech Republic, Italy, Norway, and Sweden.7,10-12 Fewer carefully researched cases were documented in North America.1,2,13 It became apparent that the number of outbreaks of pasture myopathy varied from year to year, were preceded by stormy weather, and occurred in pastures with trees in or around them that also contained dead leaves, dead wood and wet areas. The clustering of cases to specific pastures where horses were housed for at least 12 h a day, the seasonal occurrence in fall or the subsequent spring, the cessation of cases from December to January, and the lack of gender or breed predilection suggested a toxin was present in pastures on a seasonal basis. The wide variety of plants that could be implicated in causing pasture myopathy made the search for potential toxins confounding. Potential etiologic agents initially under investigation included white snakeroot,1 clostridium toxins in soil,14,15 toxins in dead leaves,10,12 and the tar spot fungus growing on the leaves of Acer pseudoplatanus,16 the European sycamore maple. Studies from 1988 in the United Kingdom5 and 2010 in the Netherlands16 had identified the sycamore maple as a consistent presence on affected pastures. Information on the mechanism by which the toxin produced rhabdomyolysis was an important missing piece of the puzzle.
3. Pathophysiology
Serum biochemistry profiles of horses with pasture myopathy provided little direction for toxin investigation. Profiles revealed marked elevations in serum creatine kinase (CK) and aspartate transaminase and a moderate elevation in gamma-glutamyl transferase activities. Electrolyte derangements (high potassium and phosphorus, low sodium, chloride, and calcium), hyperglycemia, and lactic acidosis were often present.1,7,13,17,18 Similarly, hematoxylin and eosin stains of formalin fixed muscle merely confirmed severe myodegeneration of postural and respiratory muscles and inconsistent degeneration of cardiac muscle.4,5 Advances were made, however, when special stains were applied to muscle tissues and a lipid storage disorder was identified in postural and respiratory muscles of horses with pasture myopathy in both North America and Europe.1,3
A critical piece of the puzzle was contributed by Westerman et al. in 2008 that both narrowed the list of potential toxins causing pasture myopathy and led to a specific means to diagnose the condition.19 An acquired defect in the enzyme multiple acyl-coA dehydrogenase (MAD) that represents the first step of ß-oxidation of short and medium chain fatty acids as well as branched chain amino acids was found in muscle cells from Dutch horses with pasture myopathy. A diagnosis of MAD deficiency could readily be established by measuring the backlog of byproducts of lipid (acylcarnitines) and amino acid metabolism (glycine conjugates) in the bloodstream or urine. The specific diagnostic indicators of MAD were high short (C2-C5) and medium chain (C6-C10) acylcarnitines, variably high long chain (C14-C18) acylcarnitines, and marked elevations in urine ethylmalonic and methylsuccinic acids and glycine conjugates ([iso]valeryl-,butyryl-, and hexanoylglylcine).19 Serum and urine samples from horses in North America with pasture myopathy were later found to also have a deficiency of MAD.13 Thus, it seemed that the underlying mechanism for pasture myopathy was the same in Europe and North America.
4. The Toxin
Combining epidemiologic and pathophysiologic information, the responsible toxin would have to be seasonally associated with trees and capable of blocking MAD in muscle cells. In 2012, we determined that seeds from one particular tree in the midwestern U.S., Acer negundo (box elder, Manitoba maple) (Fig. 1A), were present in the fall on all inspected pastures where horses had succumbed to pasture myopathy.2 The seeds of this tree (Fig. 1B) remain on the trees in the fall and are distributed onto the ground by high winds prior to an outbreak.2 The topographical distribution of Acer negundo matched previous cases of pasture myopathy diagnosed in North America. A key connector was the fact that another tree within the same Sapinidae family, the Jamaican Ackee tree, produced a fruit that when unripe contained a nonproteogenic amino acid hypoglycin A, capable of causing an acquired deficiency of MAD when ingested by humans.20 Subsequent studies found hypoglycin A in seeds from box elder trees growing in pastures where outbreaks of pasture myopathy had occurred.2 In addition, the conjugated toxic metabolite of hypoglycin A, methylenecyclopropyl acetic acid (MCPA)-carnitine, was found in the bloodstream and urine of horses with pasture myopathy in the midwestern U.S.2 Thus, hypoglycin A appeared to cause pasture myopathy in North America.
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