Dynamin-1 Associated Exercise-Induced Collapse

Affected dogs can tolerate mild to moderate exercise, but 5 to 20 minutes of strenuous exercise with extreme excitement induces weakness and then collapse. Severely affected dogs may collapse whenever they are exercised to this extent - other dogs only exhibit collapse sporadically.

The first thing noted is usually a rocking or forced gait. The rear limbs then become weak and unable to support weight. Many affected dogs will continue to run while dragging their back legs. Some of the dogs appear to be uncoordinated, especially in the rear limbs, with a wide-based, long, loose stride rather than the short, stiff strides typically associated with muscle weakness. In some dogs the rear limb collapse progresses to forelimb weakness and occasionally to a total inability to move. Muscles are relatively flaccid during collapse, although when restrained in lateral recumbency some dogs exhibit increased extensor tone in the forelimbs. Manipulation and palpation of the muscles, joints, and spine during or after an episode does not seem to cause discomfort.

Some dogs appear to have a loss of balance and may fall over, particularly as they recover from complete collapse. Most collapsed dogs are totally conscious and alert, still trying to run and retrieve during an episode but as many as 25% of affected dogs have had at least one episode where the owner reports that they appear stunned or disoriented during the episode.

It is common for the symptoms to worsen for 3 to 5 minutes even after exercise has been terminated. 

NOTE: A few affected dogs have died during exercise or while resting immediately after an episode of exercise-induced collapse, so an affected dog's exercise should ALWAYS be stopped at the first hint of incoordination or wobbliness.

Veterinary Evaluation of Affected Dogs

Nervous system, cardiovascular and musculoskeletal examinations are unremarkable at rest in dogs with EIC as is routine blood analysis at rest and during an episode of collapse. These dogs do not experience heart rhythm abnormalities, low blood sugar, electrolyte disturbances or respiratory difficulty that could explain their collapse. Body temperature is remarkably elevated during collapse (average 107.1F [41.7C], many up to 108F [42.2C]), but this magnitude of body temperature elevation has been found in normal exercise-tolerant Labradors as well. Affected dogs hyperventilate and experience dramatic alterations in their blood carbon dioxide concentration (decreased) and their blood pH (increased) but these changes are also observed in the normal exercising dogs. Affected dogs always completely lose their patellar reflexes during collapse and for a short period of time during recovery - even while they are able to walk relatively normally. Testing for myasthenia gravis (ACh-R ABy) is negative. Thyroid gland function (T4, TSH) and adrenal gland cortisol production (ACTH Stimulation test) are normal. Affected dogs are negative for the genetic mutation known to cause malignant hyperthermia.

Recovery From Collapse

Most dogs recover quickly but the recovery is gradual rather than instantaneous. Dogs are normal within 5 to 25 minutes with no residual weakness or stiffness. Dogs are not painful during the collapse or after recovery. Massage of the muscles or palpation of the joints or spine does not cause discomfort. Affected dogs are not stiff or sore or limping upon recovery.

Body Temperature

Body temperature is normal at rest in dogs with EIC but is almost always dramatically increased at the time of collapse (temperature >41.5 C, >107.6F). We have shown experimentally, however, that clinically normal Labrador Retrievers doing this type of exercise for 10 minutes routinely had similar dramatic elevations in body temperature yet exhibited no signs of weakness, collapse or disorientation. Dogs with EIC will pant hard during the time of collapse, in an attempt to cool off, but this is similar to normal dogs exercised in the same manner. The time it takes for dogs with EIC to return to their resting temperature after exercise is not different from normal Labrador Retrievers. Although temperature may play some role in EIC related collapse, and may even contribute to the death of some affected dogs, inability to properly regulate temperature is not the underlying problem in dogs with EIC.

First identified and described in the Labrador Retriever, the syndrome of exercise intolerance and collapse (EIC) is a common inherited disorder in the breed. Black, yellow and chocolate Labradors of both sexes are affected, with the distribution of colors and sexes closely reflecting the typical distribution in field trials (black males most common). Signs first become apparent in young dogs - usually between 5 months and 3 years of age (average 14 months). In dogs used for field trials, this usually coincides with the age at which they enter heavy training. Littermates and other related dogs are commonly affected but depending on their temperament and lifestyle they may or may not manifest symptoms. Affected dogs exhibiting symptoms of collapse are usually described as being extremely fit, muscular, prime athletic specimens of their breed with an excitable temperament and lots of drive.  Since the identification of the EIC mutation, it has been discovered in several closely, and more distantly, related breeds.

Breeds in which the Dynamin-1 EIC mutation has been identified:

• American Cocker Spaniel
• Bouvier des Flanders
• Boykin Spaniel
• Chesapeake Bay Retriever
• Clumber Spaniel
• Curly-Coated Retriever
• English Cocker Spaniel
• German Wirehaired Pointer
• Labrador Retriever
• Old English Sheepdog
• Pembroke Welsh Corgi
• Vizsla

Complete list of breeds tested and carrier & affected rates at the University of Minnesota 

Different collapse conditions, not caused by the dynamin-1 EIC mutation, are being investigated in the following:

• Australian Cattle Dog
  
• Australian Kelpie
• Australian Shepherd
• Bearded Collie
• Belgian Malinois
• Belgian Tervuren
• Border Collie
• Collie
• Shetland Sheepdog
• Whippet

EIC is the most common reason for exercise/excitement induced collapse in young, apparently healthy Labrador Retrievers.

EIC is common in Labrador Retrievers, and now that we have identified the mutation we can test for the condition. Current data shows that 30% to 40% of Labradors are carriers (with one copy of the mutation) and 3% to 13% of dogs are affected (with 2 copies) and susceptible to collapse. The percentage of affected dogs varies with the populations of dogs being tested, and the reason for testing. The prevalence does not seem to be very different between field trial/hunt test dogs, show dogs and pet dogs. Most (>80%) affected Labradors (E/E: 2 copies of the mutation) experience at least one episode of collapse by the time they are 4 years of age. A few genetically affected (E/E) dogs never exhibit collapse, perhaps because they do not engage in the required strenuous activity with extreme excitement as required to produce collapse. DNA testing is the only way to know for certain whether a dog has EIC.

The research laboratory has tested 100-400 samples from each of the common retriever breeds - they have tested Golden Retrievers, Flat-Coated Retrievers, Chesapeake Bay Retrievers, Nova Scotia Duck Tolling Retrievers and Curly Coated Retrievers. They have also tested numerous dogs from many non-retriever breeds. So far, the mutation has only been found in Labrador Retrievers, Curly Coated Retrievers, Chesapeake Bay Retrievers, Boykin Spaniels, German Wire-haired Pointers, Old English Sheepdog, Cocker Spaniels and Pembroke Welsh Corgis.

Complete list of breeds tested and carrier & affected rates

Ambient Temperature: Actual ambient temperature does not seem to be a critical factor contributing to collapse, but if the temperature is much warmer or the humidity is much higher than what the dog is accustomed to, collapse may be more likely. Excessive panting (hyperventilation) in hot weather may be a contributing factor. Affected dogs are less likely to collapse in cold weather or while swimming, but some dogs have exhibited collapse while breaking ice retrieving waterfowl in frigid temperatures and some dogs have drowned when experiencing EIC -related collapse in the water.

Excitement: Dogs that exhibit the symptoms of EIC are most likely to have intense, excitable personalities, and it is very apparent that their level of excitement plays a role in inducing the collapse. There are some severely affected dogs who, if they are extremely excited, do not even require much exercise to induce the collapse. Dogs with EIC are most likely to collapse when engaging in activities that they find very exciting or stressful. This can include retrieving of live birds, participation in field trials, training drills with electric collar pressure and quartering for upland game.

Type of Exercise: Routine exercise like jogging, hiking, swimming, most waterfowl hunting and even agility or flyball training are not very likely to induce an episode in dogs with EIC. Activities with continuous intense exercise, particularly if accompanied by a high level of excitement or anxiety most commonly cause collapse. Activities commonly implicated include grouse or pheasant hunting, repetitive "happy retrieves", retrieving drills or repetition of difficult marks or blinds where the dog is being repeatedly corrected or is anticipating electric collar correction, and excitedly running alongside an ATV.

Until October of 2008, EIC could only be diagnosed by systematically ruling out all other disorders causing exercise intolerance and collapse and by observing characteristic clinical features, history and laboratory test results in affected dogs. Even today, any Labrador Retriever with exercise intolerance should always have a complete veterinary evaluation to rule-out treatable conditions such as orthopedic disorders, heart failure, anemia, heart rhythm disturbances, respiratory problems, low blood sugar, cauda equina syndrome, myasthenia gravis, hypoadrenocorticism, and muscle disease. Genetic (DNA) testing for EIC can now be performed to confirm a suspected diagnosis of EIC.

Long Term Outlook

Dogs symptomatic for EIC are rarely able to continue training or competition. It seems that if affected dogs are removed from training and not exercised excessively the condition will not progress and they will be fine as pets. They are able to continue to live fairly normal lives if owners limit their intense exercise and excitement. Many dogs will seem to "get better" as they age and slow down their activity and their excitement level.

It is important that owners of dogs with EIC be made aware that the dog's exercise should be stopped at the first hint of incoordination or wobbliness as some affected dogs have died during collapse when their owners allowed or encouraged continuing exercise. Not all of the EIC deaths have occurred in dogs rated as severely affected based on their number of episodes of collapse or the amount of activity required to induce an episode. 

Treatment

The best treatment in most dogs consists of avoiding known trigger activities and activities that involve intensive exercise in conjunction with extreme excitement especially in hot weather. Most dogs that are retired from training/competition or trigger activities like upland hunting live the remainder of their life without any episodes of collapse. Owners/trainers must always keep in mind the importance of ending exercise at the first sign of weakness/wobbliness if it does occur since these dogs are susceptible to collapse and death from EIC.

A few EIC affected male dogs have experienced improvement after neutering - with an improved ability to tolerate intensive exercise without collapse. This improvement may be a result of a decrease in the general excitement level of the dog. 

What To Do If Your EIC Affected Dog Collapses

If a collapsing Labrador Retriever is confirmed to have EIC (i.e. blood test confirms two copies of the EIC mutation), it should be recommended that participation in trigger activities be limited and that the dog be monitored closely so that exercise can be ended at the first sign of weakness/wobbliness. If the dog does collapse, (1) make sure that it has unobstructed breathing so it can hyperventilate to blow off heat, (2) offer water and ice orally, and (3) cool the dog by immersing it in cool water or wetting it down. Enforce rest until the dog is fully recovered.

There have been a number of good veterinary reviews of heat stroke in dogs recently and the syndrome we are seeing with EIC is very different. With heat stroke - induced collapse in dogs you expect to see a very slow or prolonged recovery that can take hours to days, or else progression to death. Laboratory evaluation reveals a dramatic increase in muscle enzymes (CK usually 7-11X normal). Mentation changes that are severe, progressive and persistent (for hours to days) occur in 80% of affected dogs and significant endothelial injury leads to microvascular thrombosis, DIC, thrombocytopenia and bleeding as well as acute renal failure in most patients. In contrast, dogs with EIC collapse without showing laboratory abnormalities and they recover quickly - happy and running around within 5 to 25 minutes. 

Differentiating EIC From Malignant Hyperthermia

We have also learned enough about EIC to say with certainty that it is not the same as malignant hyperthermia (MH). The Minnesota collaborators in the EIC Project (Mickelson et al) have confirmed that in dogs as in other species MH is caused by a mutation in the calcium release channel of the sarcoplasmic reticulum in skeletal muscle – the ryanodine receptor. All of the affected EIC dogs evaluated at the WCVM were genotyped and tested for the known ryanodine receptor mutation and for linkage to other sites on chromosome 1, eliminating this mutated gene as the cause of EIC. Dogs with collapse due to MH typically look very different from our dogs with EIC. Their muscles are rigid (not flaccid/floppy like EIC) and they have increased CK in their serum. Histologically their muscles show rhabdomyolysis (our dogs' muscles are normal). Dogs with MH often hypoventilate due to persistent muscular contraction so they are hypercarbic (whereas dogs with EIC hyperventilate).

Differentiating EIC From a Mitochondrial Myopathy

Although our initial study of dogs with EIC was designed to detect a mitochondrial myopathy (a defect in the oxidative metabolism leading to energy production in muscle), we now know that EIC is not a metabolic myopathy. Most dogs with mitochondrial myopathies have severe exercise intolerance that can be consistently demonstrated with even mild exercise. Most develop extreme lactic acidemia with even mild exercise and an elevated lactate to pyruvate ratio. Many have “ragged red fibers” demonstrated on histopathology which are really just subsarcolemmal mitochondria as well as ultrastructural changes to the mitochondria - none of this is evident in dogs with EIC and it has become apparent that dogs with EIC suffer more from neurologic dysfunction than from muscular weakness.   

Differentiating EIC From Epilepsy

Some Labrador Retrievers that we have evaluated because of collapse episodes do not have EIC but instead have an unusual form of epilepsy. The "collapse" episodes that these dogs experience typically have a very sudden onset and very sudden resolution and are sometimes very brief (less than 2 minutes) - unlike EIC where there seems to be a more gradual progression of weakness, incoordination or collapse and a gradual recovery taking from 5 to 30 minutes. In this unusual form of epilepsy (almost exclusively seen in Labrador Retrievers) the dog maintains consciousness but exhibits a problem with gait, balance, or muscle tone. Excitement and exercise are common triggers for these seizures in affected dogs (perhaps because of hyperventilation), leading to confusion between this seizure disorder and EIC. In some dogs with this form of epilepsy the episodes do not progress further, but other dogs will develop more typical generalized seizures later in life with loss of consciousness, muscle twitches, paddling of the limbs, etc. 

For more information, see Atypical Collapse/Paroxysmal Dyskinesia.

EIC is a hereditary condition, with littermates and other related dogs commonly affected. It is inherited as an autosomal recessive trait. In 2007 the chromosomal locus (site) of the mutation causing EIC was found on chromosome 9, and the genetic mutation responsible for susceptibility to EIC was identified. This is a mutation in the gene for dynamin-1 (DNM1) that causes a change in the amount or function of the dynamin-1 protein in dogs homozygous for the mutation (E/E: affected). The scientific papers state that this mutation is "highly associated with EIC" - the wording required until experimental studies on the actual DNM1 protein function in the brain of dogs with EIC takes place.

Dynamin-1 is a protein expressed only in the brain and spinal cord where it plays a key role in repackaging synaptic vesicles containing neurotransmitters. DNM1 is not required during low level neurological stimulation, but when a heightened stimulus creates a heavy load on release of CNS neurotransmitters (as with intense exercise, a high level of excitement or perhaps increased body temperature) DNM1 is essential for sustained synaptic transmission in the brain and spinal cord. Dogs with 2 copies of the EIC mutation (E/E) are susceptible to collapse in those conditions.

DNA testing for the genetic mutation causing EIC susceptibility can now be performed. This is a reliable test for the actual mutation(not linkage) so results are definitive and accurate - determining with certainty whether a dog has one copy of the mutation (carrier, E/N), 2 copies of the mutation (affected, E/E) or no copies of the mutation (clear, N/N). Instructions for collecting and submitting samples for testing, sample shipping and the necessary forms are available on the website of the Veterinary Diagnostic Laboratory at the University of Minnesota. In addition to testing blood samples submitted by veterinarians from adult dogs or puppies, cheek swabs can now be submitted and litters of newborn puppies can be tested by sending in dewclaws. Frozen stored semen can also be tested from deceased sires.

One way to present the probability that puppies with EIC will be produced from the mating of parents of each of the three possible genotypes is shown above.  Each parent, depending on its genotype, will contribute either the E or the N form of the EIC gene to a puppy.  This in turn will  result  in  that  particular  puppy’s  own  genotype  of  N/N,  E/N,  or  E/E. Each of  the four  squares shown for each of the six possible matings in the Figure represents a 25% chance for producing  a  pup  with  that  genotype. Thus,  the  matings  resulting  in  one,  two  or  four  red  squares  will  on  average  produce  litters  containing  25%,  50%  and  100%  EIC  affected  pups, respectively.

For  example,  breeding  an  E/N  sire  to  an  N/N  dam  can  only  produce  puppies  that  are  E/N or N/N,  and  according  to  our  current  data  that  supports  a  recessive  mode  of  inheritance,  none would  be  susceptible  to  EIC  (2  blue  squares  and  2  purple  squares). On the other hand,  breeding  an  E/N  sire  to  an  E/E  dam  gives  a  50%  chance  that  a  puppy  will  have  EIC,  since  puppies can be either E/N or E/E (2 purple squares and 2 red squares).  All puppies from the mating of two E/E parents will be E/E and thus likely be susceptible to EIC (four red squares).