Atypical myopathy Flashcards
1
Q
Discuss the pathogenesis of atypical myopathy
A
- hypoglycin A is the toxin involved which is present in the seeds of Box Elder (Acer negundo) in North America and sycamore maple (Acer pseudoplatanus) trees in Europe
- hypoglycin is metabolised by transamination and oxidative carboxylation in the liver to form the toxic metabolite, methylenecyclopropylacetic acid (MCPA)
- Magnesium, pyridoxal phosphate, thiamine and co-enzyme A are all co-factors in the metabolism of hypoglycin to MCPA
- MCPA can be detected in the serum of affected horses
- underlying biochemical defect of AM is acquired multiple acyl-CoA dehydrogenase deficiency (MADD). These enzymes are crucial for the oxidation of fatty acids and the generation of energy within type 1 muscle fibres. Consequently, increased concentrations of blood acylcarnitines and urinary organic acids ensue.
- excessive myofibre lipid storage and fatty acids
conjugated with carnitine and glycine accumulate in serum and urine - MCPA is a specific inhibitor of multiple acyl-CoA dehydrogenases
- The disease is characterised by a lipid storage disorder of the b-oxidation dependent skeletal muscle fibres finally leading to death
- MCPA is conjugated to form ester with carnitine and glycine (latter excreted more readily) and excreted in urine
- development of multiple acyl-CoA dehydrogenase deficiency (MADD) blocks several steps in mitochondrial lipid metabolism and causes an accumulation of specific acylcarnitines in plasma
and urinary excretion of organic acids, glycine conjugates and metabolites derived from the accumulated acyl-CoA ester intermediates
2
Q
What are some possible reasons for the variable expression of clinical disease between individuals on the same pasture?
A
- may result from differences doses of toxin ingested - ie. this supports a dose-dependent effect of hypoglycin intoxication
- large variation in hypoglycin content of seeds from the same tree esp. in Acer pseudoplatanus (Sycamore)
- different amounts of seeds, sprouts and leaves ingested by different horses
- variation in bioavailability
- other dietary factors may limit toxin absorption and protect against disease. Providing supplementary food has been identified as a protective factor against AM
- finding of high concentration of serum hypoglyin A in an apparently normal horse (Baise EVJ 2016) suggest there may be additional factors that are required to either induce clinical disease or may protect an animal from it, following absorption of the toxin
- differences in the rate of hypoglycin metabolism to the active MCPA - this may explain greater difference in concentration of hypoglycin metabolites between cases and co-grazers compared to unmetabolised hypoglycin concentration
- Magnesium, pyridoxal phosphate, thiamine and co-enzyme A are all co-factors in the metabolism of hypoglycin to MCPA - availability of these compounds may modify the rate and extent of hypoglycin metabolism and hence an individual’s susceptibility to disease.
- sensitivity of the individual horse - unknown if there is an intrinsic or acquired resistance to the toxic metabolite in horses that remain healthy despite exposure to hypoglycin.
- some individuals may be able to adapt to the toxin but mechanisms of possible detoxification are unknown
- some horses may have more sensitive feed intake behaviour
- some horses may have a learned aversion over time
- some horses may have particular effective metabolic strategies for detoxification
3
Q
Are there any environmental factors which may play a role in development of disease?
A
- environmental stressors, such as temperature fluctuations or pollutants, may act to modify the structure or concentration of hypoglycin in the seeds and leaves of the Sycamore trees, increasing toxicity
- toxicity of seeds and seedlings may vary according to seasons
- availability of seeds, leaves, and sprouts largely is determined by the season and weather, with changes in wind and temperature loosening the attachment of leaves and seeds.
- inclement weather or high winds have been reported to precede clinical signs of AM
- strong winds can disperse leaves and seeds over a long distance, perhaps depositing them in pastures that do not contain Acer trees ie. Acer trees are not always found in paddock or pastures grazed by horses with AM
- seeds not consumed by horses in the Autumn could sprout in the Spring
- tree stress or abiotic stress may increase conc of hypoglycin A in seeds
4
Q
Why can’t results regarding hypoglycin concentrations in plant extracts be compared between studies?
A
- the methodologies used to measure hypoglycin often differ considerably
- the solvent used (eg. milliQ water vs methanol)
- extraction time
5
Q
What are the characteristic clinical signs of atypical myopathy?
A
- nonexercise induced rhabdomyolysis of grazing horses affecting mostly respiratory and postural muscles
- weakness
- stiffness
- sweating
- trembling
- recumbency leading to death
- other nonspecific clinical signs may include colic (mild colic at beginning), myoglobinuria
- after the development of recumbency and respiratory difficulties, more than 75% of all cases die or are subjected to euthanasia
6
Q
In which countries has atypical myopathy been diagnosed?
A
- Europe
- USA
- New Zealand
7
Q
What pathologic and histologic findings are associated with a diagnosis of atypical myopathy?
A
- affected muscles may have pale and dark red areas. Other unaffected skeletal muscles have no macroscopic changes
- fragments of maple tree seeds may be identified within the stomach
- high urine amino acid concentrations
- histology: severe, acute rhabdomyolysis with minimal neutrophilic accumulation and lipid storage myopathy
- Sudan III stain reveals extensive, finely dispersed, intracellular lipid droplets in affected skeletal muscles, thus confirming a lipid-accumulation myopathy
8
Q
Describe the laboratory diagnosis of atypical myopathy
A
- detection of conjugated MCPA, the toxic metabolite of hypoglycin in urine (MCPA glycine and MCPA carnitine) and serum (MCPA carnitine)
- When concentrations of HGA and MCPA-esters have been measured concurrently in blood and urine, both media gave the same information regarding the clinical status
- blood samples easier to collect than urine so may just focus on blood samples ie. use blood samples to determine HGA and MCPA-carnitine concentrations and also establish acylcarnitine profile in serum which enables us to confirm dx of AM
- also increased acyl carnitine and acyl glycine concentrations in serum
- presence of both HGA and MCPA-conjugates in body fluids seems to indicate the clinical status of AM.
- increased plasma CK activity (>10,000-100,000 IU/L)
9
Q
What are the main differential diagnoses in cases of atypical myopathy?
A
- vitamin E/selenium deficiency
- metabolic problems including, Clostrium sordelli and Clostridium perfringens toxins and tremetone
10
Q
List the risk factors for the development of AM
A
- full-time pasture access
- no food supplementation
- changing weather conditions
- presence of maple leaves
- can affect any breed and any age but tends to affect younger horses
11
Q
Which maple species are associated with the development of AM?
A
- maple trees belonging to the genus Acer are extensively present worldwide
- there are >100 species of Acer
- Acer negundo (box elder tree) and Acer pseudoplatanus (sycamore maple) have been associated with AM
- concentration of hypoglycin A in samples of Acer pseudoplatanus significantly different between pastures used by healthy horses and AM horses
- other common maple species in Netherlands are Acer campestre (hedge maple) and Acer platanoides (Norway maple) - do not contain detectable hypoglycin A concentrations
- most common maple in Netherlands is Acer pseudoplatanus - leaves, sprouts and seeds contain measurable concentrations of hypoglycin A
- concentrations in seeds is highly variable among trees on the same or different farms
12
Q
Are there differences in toxicity between leaves, seeds or sprouts of Acer species?
A
- per kilogram, sprouts are most dangerous to horses, followed by seeds, with leaves being potentially least harmful
13
Q
At what time of year are cases of AM more commonly diagnosed?
A
- more cases of AM in the Autumn than in Spring
- sprouts are more common in Spring and seeds are more common in Autumn —–> it would appear that horses eat more seeds than sprouts either because more seeds are available or because they prefer
seeds to sprouts. - whether horses eat seeds or sprouts is to a large extent determined by the availability of other feedstuff
—–> Spring pasture contains more and better grass than Autumn pasture, and thus horses may have less reason to eat other feedstuff
14
Q
What are important considerations for prevention of AM?
A
- The finding that the concentration of hypoglycin A is
high in sprouts suggests that horse owners should be
alert to the presence of Acer sprouts in pastures - mow areas of pasture with Maple sprouts and remove the mown material.
- some Acer species contain hypoglycin A and others do not. Unfortunately, the amount of hypoglycin A in seeds is so variable that a reliable prediction of the occurrence of AM cannot be made for individual farms
- therefore not worthwhile to measure hypoglycin con-
centrations in individual seed samples in order to
predict AM risk. - prevent horses from eating seeds, sprouts, leaves, or any combination of these from Acer pseudoplatanus
– move horse to safer pasture
– decrease size of the pasture (away from the trees)
– blow away seeds and leaves
– mow and remove sprouts - Adequate roughage supplementation in sparse pastures during the high-risk season also may prevent AM.
15
Q
Can serum concentration of hypoglycin alone be used to diagnose AM?
A
- Determination of HGA concentration in body fluid in
horses exposed to seeds and seedlings of Acer
pseudoplatanus may be useful to confirm ingestion of this toxic precursor - In some European regions where A. pseudoplatanus is ubiquitous, exposure to HGA is very difficult to control as the configuration of maple samaras favours seed dispersal far away from the mother tree —> It is likely that all horses grazing nearby sycamore maples have, to varying degrees, HGA circulating in their blood
- not all horses with confirmed HGA in their blood will demonstrate clinical signs of AM
- HGA was present in body fluids of healthy cograzing horses whereas MCPA-conjugates were not detectable, in contrast to the AM horse.
—-> Therefore, increasing concentrations of MCPA-conjugates are supposed to be linked with the
onset of AM and both parameters seem to indicate the
clinical stage of disease. - presence of both HGA and MCPA-conjugates in body fluids seems to indicate the clinical status of AM.
- detection of HGA in body fluids of cograzing horses might be a promising step in preventing the disease ie. detect horses consuming toxic seeds with elevated risk of becoming diseased
