myopathies Flashcards
breeds predisposed to PSSM1/2
PSSM1: Quarter, Morgan, Draft, Paint, Apalooza
PSSM2: Arabian, Morgan, Throurough, some Quarter
mutation associated with PSSM1 + breeds + preval
GYS1
autosomal dominant
European breeds derived from the Belgian draft (90%),
North American Belgians and
Percherons (36% and 54%)
quarter horses: 6% to 10%
American paint and Appaloosa: 6% to 8%
low prevalence in some warmblood breeds
The prevalence of GYS1 mutation is very low to nonexistent in light horse breeds such as Arabians, Standardbreds, and thoroughbreds
CK in PSSM1/2
PSSM1: always abnormal
PSSM2: normal to moderately increased (except in Quarter: elevated)
Breed spredisposed to myofib myopathy
Arabian
Warmblood
Breeds with maligant hyperthermia
Quarter
Paint
Breed with recurent exercional rhabdo
Throughbreed
Standartbreed
Arabian
Quarter
muscle selection for biopsy
exertional/nonexertional myopathies, the gluteal or semimembranosus muscles (MYHM, a gluteal muscle biopsy is optimal)
horses with generalized weakness and muscle atrophy: sacrocaudalis dorsalis medialis muscle ( high proportion of oxidative type 1 fibers that are most frequently affected in equine motor neuron disease or vitamin E responsive myopathy)
stain + indications
Modified Gomori trichrome stain
mitochondrial abnormalities, inclusion bodies, and myelin integrity in nerve branches
stain + indication
Periodic acid–Schiff (PAS) stain glycogen and polysaccharid
stain + indications
Amylase-PAS is used to identify abnormal polysaccharides
stain + indication
Nicotinamide adenine dinucleotide tetrazolium reductase
(NADH-TR) is used to assess mitochondria and endoplasmic reticulum.
stain + indication
Oil-red-O is used to
identify the amount and distribution of lipid.
stain + indication
Myosin adenosine triphosphatase (ATPase)
stain at pH 4.6 is used to identify contractile fiber types, type 1, 2A, and 2X.
immuno histo for
C. Immunohistochemical stain for desmin
D. Immunohistochemical stain for mitochondrial succinate dehydrogenase demonstrating darker staining oxidative fibers and lighter staining low oxidative fibers.
systematic approch for muscle biopsy
assessment of muscle fiber sizes
fiber shapes
degeneration
inflammation
regeneration
presence of vacuoles, inclusions
staining for glycogen, lipid, desmin,
mitochondrial morphology
diff acute/chronic myodegeneration
Acute myodegeneration: pale, vacuolated fibers
Chronic myodegeneration: macrophage infiltration of
degenerating fibers.
myogenic vs neurogenic atrophy
Myogenic atrophy: anguloid atrophied fibers that have concavity on one or more sides
Neurogenic atrophy: angular atrophied fibers that are compressed into angular shapes
genetic mutation causing fasciculation
normal CK: HYPP
increase CK: Quarter MH, others PSSM1
mutation causing acute muscle atrophy
MYH1
Quarter, increased CK
mutation causing non-exercional rhabdomyolisis
MYH1, GBE foals
increased CK, Quarter and related
mutation causing exercional rhabdomyolisis
PSSM1
Quarter and related: PSSM1, RYR1
mutation associated with hyperkaliemic periodic paralysis, heritability
+ breeds
SCN4A (voltage-gated skeletal muscle sodium channel) codominant
Quarter, American paint, Appaloosas
1.5% of the quarter horse breed and 4.5% of the American paint horse breed are affected
halter horse performance group, where 56% of horses possess the HYPP mutation
Heavily muscled phenotype
Clinical signs of HYPP
normal CK
Twitching or delayed relaxation of muscles, prolapse of the third eyelid Sweating and muscle fasciculations commonly occur in the flanks, neck, and shoulders.
+/- tachycardic and tachypneic, lateral recumbency, paralysis of upper respiratory muscles
Episodes usually last for 15 to 60 minutes.
no apparent abnormalities between episodes
paraclinics abnomalies in HYPP
During episodes of muscle fasciculations, most horses have hyperkalemia (6–9 mEq/L), hemoconcentration, and mild hyponatremia with normal acid-base balance.
Serum potassium concentration returns to normal quickly after the cessation of clinical signs. Some affected horses have normal serum potassium concentrations during minor episodes of muscle fasciculations.
Electromyographic examination of asymptomatic HYPP horses between episodes reveals abnormal fibrillation potentials, complex repetitive discharges, with occasional myotonic potentials and trains of doublets.
Endoscopic findings include pharyngeal collapse and edema, laryngopalatal dislocation, and laryngeal paralysis.
diff heterozyg/homozyg HYPP
N/H horses from asymptomatic to daily episodic muscle fasciculations and weakness
Respiratory distress can occur in N/H and H/H
Foals homozygous for HYPP usually show clinical signs of disease in the first few days of life that include dysphagia, respiratory stridor, periodic obstruction of the upper respiratory tract
Adults that are H/H usually have more frequent and severe episodes of HYPP compared with N/H horses and more severe signs of upper airway obstruction during an episode.Homozygous affected horses also have a high-pitched whinny even between episodes.
precipitator episod HYPP
Feeds high in potassium, starving, anesthesia, heavy sedation, trailer rides (caleche), and stress
Exercise does not seem to induce clinical signs
pathophysiology of HYPP
Sodium channels are normally briefly activated to allow transient sodium entry into muscle cells during the initial phase of the muscle action potential.
mutation results in a failure of a subpopulation of sodium channels to inactivate when serum potassium concentrations are increased.
Failure of inactivation results in membrane depolarization, which manifests as muscle fasciculations and can eventually lead to depolarization block manifesting as muscular
paresis or paralysis.
treatemnt of HYPP
feeding grain or corn syrup to stimulate insulin-mediated movement of potassium into cells and by initiating light exercise.
administration of epinephrine, calcium gluconate (increase in extracellular calcium concentration increases the muscle-membrane threshold potential, which attenuates membrane hyperexcitability)
IV dextrose alone or combined with sodium bicarbonate
With severe dyspnea caused by laryngeal or pharyngeal obstruction, a tracheostomy can be necessary
managment: Restricting dietary potassium = between 0.6% and 1.1% total potassium concentration and meals
containing less than 33 g of potassium. Maj source pot is forage. Pasture grazing need not be restricted because the gradual consumption of grasses, which have a high water content, prevents a spike in blood potassium concentrations. Regular exercise and frequent turnout are beneficial.
In cases where dietary management is insufficient to control episodes of HYPP, Acetazolamide or hydrochlorothiazide
mutation/breed for glycogen branching enz deficiency
GBE1, autosomal recessive
quarter horse (10% carrier) and paint horse (5% carrier)
highest prevalence is seen in Western pleasure horses at 26% followed by cutting (14%) and working cow horses (10%)
clinical signs with GBED
Most foals homozygous for GBED seem to be aborted or stillborn based on the high prevalence of heterozygosity for GBED (4% were Gb/Gb, with most being aborted within the second trimester)
If foals survive to term, they usually appear weak and hypothermic at birth but, with support to nurse, can appear normal for the first weeks of life
Early in life, affected foals usually have a slightly dull mentation and flexural limb deformities that
are corrected by bandaging or tetracycline administration
Within weeks, GBED progresses to involve difficulty rising or respiratory failure or sudden death following hypoglycemic seizures or cardiac arrest. Regardless of the degree of intensive care provided, all affected foals studied to date have died or been euthanized by 18 weeks of age.
leukopenia and moderate increases in CK, aspartate transaminase, and gamma glutamyl transferase activities.
pathophysiology of GBED
The GBE provides an energy-dense structure through adding branching alpha-1,6 glycosidic linkages to the glycogen polymer
The production of straight chains of glycogen without branch points drastically decreases the number of nonreducing ends within the glycogen molecule, thereby limiting the rates of both synthesis and degradation.
Glucose-dependent tissues such as skeletal myocytes, cardiac myocytes, and cardiac Purkinje fibers are subject to catastrophic energy deficits
histopathylogic findings in GBED
in skeletal muscle, Purkinje fibers, or cardiac myocytes
basophilic globules and eosinophilic crystalline inclusions in hematoxylin and eosin stains and deeply magenta inclusions in periodic acid–Schiff (PAS) stains
lack of normal PAS staining for the presence of glycogen and the accumulation of abnormal PAS-positive amylase resistant inclusions
In contrast with polysaccharide storage myopathy (PSSM), cardiac and skeletal muscle tissues from GBED foals have little background staining for glycogen
prognosis for GBED
invariably fatal by 18 weeks of age. H
clinical signs in PSSM1
1-14 years
Acute clinical signs include tucking up of the abdomen, stretching out, fasciculations in the flank, muscle stiffness, sweating, reluctance to move forward, pawing, rolling, and overt firm muscle contractures.
The hindquarters are frequently most affected
Signs of pain usually begin after 15 minutes of exercise and can last for more than 2h. y 10% temporary recumbency.
+/- Severe coliclike pain and myoglobinuric renal failure
Acute episodes are usually associated with markedly increased serum CK activity of greater than 35,000 U/L and myoglobinuria.
Although abnormal polysaccharide can be present in cardiac myocytes in P/P horses, there seems to be no clinical evidence of cardiac disease.
clinical signs of PSSM1 in draft horses/light breed
DRAFT HORSES
many asymptomatic
Clinical signs occur most often in horses fed high-grain diets, exercised irregularly, with little turnout, or horses that undergo general anesthesia.
homozygotes: progressive weakness and muscle loss resulting in difficulty rising in horses with normal CK.
LIGHT BREED
a lack of energy when under saddle, reluctance to move forward, stopping and stretching out. fasciculations or pain on palpation of lumbar muscles. CK are often increased in unmanaged horses, even when horses are rested, or increase from normal values by 2-fold or more after 15 minutes of light exercise.
Pathophysiology of PSSM1
The dominant gain-of-function mutation in the GYS1 gene encoding glycogen synthase results in greater than 1.8-fold higher glycogen concentrations in skeletal muscle and accumulation of amylase-resistant polysaccharide in a small percentage of fast-twitch muscle fibers.
same relative activation of branching enzyme. less highly branched polysaccharide that becomes resistant to amylase digestion.
high serum CK activity following 15 minutes of light aerobic exercise is associated with a deficit in energy metabolism (measured as high myofiber inosine monophosphate concentrations). myophosphorylase is inactive when glycogen synthase is active, resulting in minimal glycogen metabolism. Alternatively or in concert, dysregulation of glycogen concentrations could prevent nutrient switches (AMP kinase) to fully activate enzymes such as pyruvate dehydrogenase during exercise, limiting adequate acetyl coenzyme A (CoA) for oxidative metabolism. unable to generate enough acetyl CoA from either carbohydrate or fat metabolism to fuel muscle contraction.
muscle biopsy in PSSM1
false-negative if biopsy samples are small or if horses are less than 2 years of age
numerous subsarcolemmal vacuoles and dense, crystalline PAS–positive, amylase-resistant inclusions in fast-twitch fibers
acute treatment of PSSM1
acepromazine, xylazine, or, in more painful horses, detomidine combined with butorphanol
in hydrated horses, nonsteroidal antiinflammatory drugs such as ketoprofen,phenylbutazone, or flunixin meglumine
methocarbamol: variable results
CRI detomidine, lidocaine, butor for severe cases
Dantrolene repeated in intervals of 4 to 6 hours in severe rhabdomyolysis because it decreases the release of calcium from the sarcoplasmic reticulum, which provokes muscle contractures and necrosis. Caution is advised when
administering dantrolene to horses with concomitant PSSM1 and HYPP because it can increase serum potassium concentrations and precipitate an episode of HYPP.
small padock
chronic managment of PSSM1
Prolonged rest should be avoided because serum CK activity and clinical signs of PSSM1 are more severe in horses without access to turnout.
2 weeks allowed for dietary adaptations before commencing exercise, program gradually introduced and consistently performed, regulating both the duration and the intensity of exercise, and minimizing days without some form of exercise.
common to have subclinical increases in CK activity when exercise is reintroduced, and a return to normal levels often requires 4 to 6 weeks of gradual exercise.
fed hay with less than 12% nonstructural carbohydrate (NSC) forage 2% body weight
at least 13% of daily digestible energy as fat.
limit grain
Long-chain fats (in corn oil and rice bran) decrease postexercise serum CK activity in horses with PSSM1, whereas odd-chain fat (C7) is detrimental. Vitamin E should be fed to horses receiving high-oil diets because of the potential additional oxidant stress of fats.
grazing muzzle may be needed to reduce sugar intake
fasting for 6 hours before exercise to increase plasma free fatty acids.
prognosis of PSSM1
wide variety of presentations from asymptomatic to debilitating. With adherence to both diet and exercise recommendations, at least 70% of horses show notable improvement in clinical signs and many return to acceptable levels of performance.
Homozygous P/P horses have more severe clinical signs, as do horses with both the GYS1 and RYR1 mutations.
mutation, breeds for malignant hyperthermia
RYR1: skeletal muscle calcium release channel (ryanodine receptor)
autosomal dominant
Homozygosity seems to be lethal
quarter and paint, prevalence <1%
Halter and pleasure horse lines have the highest prevalence.
clinical sign of RYR1
Rhabdomyolysis may be induced by exercise and anesthesia
increased body temperature during episodes
comparison PSSM1 mutated and PSSM1/RYR mut
RYR1, GYS1 mutation–positive horses have more severe episodes of exertional rhabdomyolysis, higher serum CK activity after exercise, and a poorer response to the diet and exercise regimes recommended for PSSM1
During anesthesia, clinical signs of hyperthermia, hypercapnea, and acidosis. hemoconcentration, hyperkalemia, hypercalcemia, hyperphosphatemia, hyperglycemia, and increased creatinine level.
pathophysiology of maligant hyperthermia
decreases the activation and increases the deactivation threshold of the ryanodine receptor (calcium release channel). remains open, causing a drastic efflux of calcium from the sarcoplasmic reticulum and inducing a persistent muscle contracture. The process of reuptake of myoplasmic calcium into the sarcoplasmic reticulum consumes large amounts of oxygen and ATP and generates carbon dioxide and excessive heat. Myofibers are damaged by the depletion of ATP and possibly the high temperatures.
muscle biopsy in maligant hyperthermia
samples often lack any histopathologic changes.
can contain mild myopathic changes, including increased variation in fiber sizes, centrally located nuclei, fiber necrosis, glycogen depletion, and ringbinden fibers.
treatment malignant hyperthermia
Dantrolene binds to RYR1 and inhibits calcium release. (before anesth)
external application of alcohol, fans, chilled IV fluids with sodium bicarbonate, and mechanical ventilation. However, once a fulminant episode is underway under anesthesia, it is difficult to prevent cardiac arrest.
mutation associated with immune-mediated myositis and nonexertional rhabdomyolysis
+ breeds
MYH1 myosin heavy chain 1 gene
autosomal codominant with variable penetrance.
present in the fastest contracting muscle fibers, type 2X
quarter horses (7%) , paint horses, Appaloosas
highest MYH1 mutation prevalence was found in reining (24%), working cow (17%), and halter (16%) horse stallions
clinical signs with MYH1 mut
Nonexertional Rhabdomyolysis: muscle pain, stiffness, and potentially recumbency, frequently affecting young horses. some cases, horses have a concurrent Streptococcus equi equi infection. Myoglobinuria is common with high serum CK. 35% subsequently develop acute muscle atrophy typical of immune-mediated myositis.
Immune-Mediated Myositis: in horses <8 y or > 17 y, rapid symmetric atrophy of lumbar and gluteal muscles. semimembranosus and semitendinosus muscles are relatively unaffected. Muscle mass usually recovers gradually over months. Horses homozygous for MYHM (My/My) have more severe and recurrent atrophy (80 vs 20%) that does not always fully recovery.
neutrophilia and increased fibrinogen level
During acute phase CK and AST increased
Fever 44%
Recurrence of clinical signs is common (50% of cases) and more often seen in homozygous.
Systemic Calcinosis: in association with clinical signs of immune mediated myositis. early indicator : ventral edema. malaise, mild fever, stiffness, muscle atrophy, and diverse organ failure (respiratory distress, colic, laminitis).
mild leukocytosis, hyperfibrinogenemia, and hyperphosphatemia, with a product of total Ca level multiplied by P level > 65 mg/dL
trigering factors for immune mediated polymyositis
reported in 39% of cases
being recently exposed to infectious diseases such as S equi equi or Streptococcus zooepidemicus; influenza virus, equine herpes virus 1 and 4, Corynebacterium pseudotuberculosis (Fig. 3), and Anaplasma phagocytophilum a respiratory virus; or vaccination with influenza, equine herpes virus, or S equi equi. within few weeks
pathophysiology of MYH1 mut
Nonexertional Rhabdomyolysis: affect the activity of the myosin ATPase enzyme of type 2X muscle fibers. role for abnormal actin/myosin interaction is postulated
Immune-Mediated Myositis: activated by release of the mutant form of myosin heavy chain from myofibers following muscle damage (trauma, vaccination). MYH1 mutation is also postulated to lead to conformational changes in myosin that activate Toll-like receptors and autoimmunity. shared epitopes between bacteria such as the M protein of Streptococcus sp and myosin.
Systemic Calcinosis: cytokines , such as TNF-alpha and IL6, -> activation of the receptor activator of nuclear factor kappa B ligand (RANKL) -> enhanced bone resorption. hyperphosphatemia induce dystrophic calcification through passive calcium phosphate deposition, an active process promoting the conversion of smooth muscle cells to osteogenic cell types, directly increasing PTH secretion and transcription, and interference with renal production of 1,25-dihydroxyvitamin D levels.
muscle biopsy in MYH1 mutation
Muscle biopsy samples with nonexertional rhabdomyolysis are often normal, 30% show marked glycogen depletion, and less than 18% of muscle samples contain lymphocytic infiltrates
immune-mediated myositis: gluteal and epaxial muscles of horses have lymphocytic infiltrates in myofibers and surrounding small blood vessels without glycogen depletion
combination of sarcolemmal MHC I and II expression and lymphocytic infiltration. more CD4+ than CD8+ T lymphocytes.
systemic calcinosis: multinucleated giant cells and dystrophic calcification of muscle fibers
managment/prognose of MYH1 mut
Nonexertional Rhabdomyolysis: Acute management same than PSSM. Dantrolene until serum CK activity has declined significantly
Immune-Mediated Myositis: Antiinflammatory doses of corticosteroids for approximately 1 month combined with antibiotics if infection is present
Horses with nonexertional rhabdomyolysis and immune-mediated myositis can make a full recovery. Muscle mass regenerates over weeks to months. However, the MYH1 mutation results in recurrent episodes in almost 50% of horses. Horses homozygous My/My are more likely to have frequent episodes and more severe episodes with less return of normal muscle mass
Horses with systemic signs of calcinosis have a grave prognosis.
prevention MYH1
Minimizing exposure to infectious agents, using intranasal vaccines or intramuscular vaccines that cause the least muscle irritation, spreading out vaccines at 1-month intervals, and avoiding immunostimulants are advised. Strangles vaccination is contraindicated in My/N and My/My horses.
highest prevalence of horses with multiple genetic mutations
halter horse performance group of quarter horses
Other myopathies with a potential inherited basis
PSSM2, myotonic dystrophy, lipid storage myopathy, centronuclear myopathy, myofibrillar myopathy, and
recurrent exertional rhabdomyolysis.
histo diff inflam myopathy/myodegeneration
inflam lymphocytes
myodegen macrophagesFMT
mutations associated with MYH1
Double loci with MYH1 include those causing MH, GBED, and HYPP
triple loci include those causing MH and GBED.
immune mediated myositis and Anaplasma
A phagocytophilum, which infects and replicates in leukocytes
Ixodes ricinus
vasculitis
fever, lethargy, anorexia, icterus, and limb edema
neurologic and muscle disease was seen in 41% and 18% of the cases.
anemia, leukopenia with neutropenia and lymphopenia, thrombocytopenia, and hyperbilirubinemia. Elevated CK
Hyperfibrinogenemia is more
commonly seen in horses with neurologic and muscle disease
Muscle manifestations in horses with anaplasmosis should prompt the clinician to test for the MYH1 mutation in QH and related breeds.
highly responsive to tetracyclines with signs improving or resolving within hours to days
causes of systemic calcinosis
- enzootic calcinosis due to the ingestion of toxic plants with calcinogenic effects: Solanaceae (eg, Solanum glaucophyllum and Cestrum diurnum) and Gramineae (eg, Trisetum flavescens), contain vitamin D-like or active metabolites of vitamin D3
- tumoral calcinosis
- systemic calcinosis with a suspected underlying immune-mediated process
+ Chronic renal failure, secondary hyperparathyroidism, vitamin D intoxication
treatment of systemic calcinosis
oral aluminum hydroxide and IV sodium thiosulfate, glucocorticoids
causes of seasonal pasture myopathy/atypical myopathy
Boxelder maple (Acer negundo, ash-leaved maple, box elder) and sycamore maple (A pseudoplatanus)
Ingestion of the seeds or seedlings in fall or spring
toxine: hypoglycine A
pathophysiology of atypical myopathy
hypoglycine A is metabolized in the mitochondrial matrix in a enzymatic process of transamination
and oxidative carboxylation, similar to other BCAAs.
The resulting toxic metabolite methylenecyclopropylacetyl-CoA (MCPA-CoA) inhibits multiple flavin adenine dinucleotide (FAD)–dependent mitochondrial acyl-coenzyme A dehydrogenases that
catalyze the first step of fatty acid ß-oxidation and are involved in amino acid catabolism.
Methylenecyclopropylglycine (MCPG), a homolog of MCPA present in lower
concentrations than HGA in both maple species, may contribute to the pathogenesis
through in vivo formation of the toxic metabolite methylenecyclopropylformyl-CoA.
The latter is a potent inhibitor of enoyl-CoA hydratases, the catalysts of the second
step of fatty acid ß-oxidation
Inhibited mitochondrial ß-oxidation leads to cellular energy depletion and accumulation of fatty acids with resulting acute myonecrosis and lipid storage myopathy.
which muscle type is preferentially affected by atypical myopathy
affects highly oxidative (type 1) myofibers, abundant in postural and respiratory muscles, and cardiac myocytes
depend highly on fatty acids as an energy source
clinical signs, mortality rate of atypical myopathy
acute muscular weakness, stiffness, muscle tremors,
prolonged recumbency, myoglobinuria, depression, congested mucous membranes, sweating and tachycardia.
colic, cardiac arrhythmias, dyspnea, dysphagia, esophageal obstruction, bladder distention, and
dysuria
Mortality rates from 70% to 90% in the first 2 to 3 days
Diagnosis of Seasonal Pasture Myopathy/Atypical Myopathy
markedly elevated CK
increased cardiac troponin 1
hyperglycemia and hypocalcemia
elevated serum acyclcarnitine and urine organic acids
hypoglycin A or MCPA in serum, urine or muscle
toxic cause of nonexertional rhabdomyolysis and cardiac myonecrosis
White snakeroot
toxine : tremetone
diff homozyg/heterozyg for MYH1 mut
1. amotrophy
2. recurence
3. stiffness
4. recovery
5. reported vacc or resp/gi disease in 3 months
6. vaccination/pathogens reported to cause inflam myositis
7. horses archiving 100% expected perf
7. treatment for increased CK
8. frequent abnomalie at NF
- more frqt (80 vs 17%) atrophy than heteroz, more rapid
- 50% homoz
- stifness 40% homoz vs 18% heterozyg, normal 17%
- fewer homoz vs heteroz
- 50% heteroz 20% homoz
- vacc: Strangles, influeza, herpesvirus, patho: S. equi, C. pseudotuberculosis, Anaplasma phago, herpes virus, influenza
- heteroz=homoz
- dantrolene
- leucocytosis
prognostic facteur immune med myositis
fever, other illness decreased survival
diff warmblood/quarter in NAD/ DM
Warmblood behavioural change, pigment retinoathy, lower vit E
Quarter inonstant menace resp, abnormal mentation, more increased serum pNfH
pNfH more valuable in which horses for diagnosis NAD/DM
low sensitivity
Quarter and horses <5y more likely to have increase
highly specif serum > 1 ng/mL
CSF > 3ng/mL can indic CVCM/NAD
can only be interpreted if infect/trauma ae excluded
metabolic changes in horses affected by NAD/EDM
Quarter: increased metab rate of alpha tocopherol, increased exp cytochrome P450 CYP4F2 (vitE metab in liver)
increased lipid peroxidation in SC
downregul glutamate recept, cholest biosynthetisis pathway (liver X recept upregul) -> exessive oxysterol
vit E role
neutralize hydroxul radicals and lipid peroxidation products
protecting cells from damage caused by oxidative stress
