Episodic Falling Syndrome (Muscle Hypertonicity): Cavaliers Collapse Suddenly After Exercise
- Symptoms
- Diagnosis
- DNA Testing
- Treatment
- Breeders' Responsibilities
- Current Research
- Related Links
- Veterinary Resources
Episodic falling syndrome (EFS) is a unique genetic disorder in the cavalier King Charles spaniel. It has been recognized in the breed since the 1960s. No other breed is known to suffer from it.
EFS is a non-progressive disorder that tends to improve with therapy, and the life spans of affected dogs do not appear to be shortened by the disease.
Veterinarians may refer to it as hyperexplexia or muscle hypertonicity (and medically known as "paroxysmal exercise-induced dystonia or dyskinesia"). However, recent research (November 2010, July 2011, and January 2012) has established that EFS is not a muscular condition, but is due to a single recessive gene associated with brain function, a mutation of the BCAN gene. As a result, affected puppies are more likely to be found in cases of line breeding or inbreeding on carrier bloodlines.
Until 2010, EFS appeared to be a life-long condition of the cavaliers affected by it. However, research that year found that milder cases of EFS are more of a common condition in the CKCS, which tend to stabilize by age one year. EFS rarely is life-threatening. A July 2011 UK/US study found that, "carriers are extremely common (12.9%)." In a May 2012 report of DNA testing of 2,811 cavaliers, only 3.7% were affected with EFS, but another 21.52% were carriers of the EFS gene, which is nearly double the percentage predicted in the July 2011 study.
Some researchers have suggested that EFS in cavaliers may be associated with another disorder unique to the breed, called "idiopathic asymptomatic thrombocytopenia", an abnormally low number of blood platelets. Drs. Jens Häggström and Clarence Kvart of Sweden have noted in a 1997 article that thromboembolic events in the cerebral circulation of blood may be involved in EFS. See Blood Platelets for more information.
UK's Animal Health Trust offers a DNA swab test to detect the mutations causing episodic falling syndrome in the CKCS. UK's LABOKLIN also offers a detection test, as a result of the UK/US July 2011 study.
Symptoms
Symptoms of EFS vary, but they all are attributed to the dog’s muscles being unable to relax. Typical signs include the cavalier engaged in exercise or being excited or stressed, and then suddenly develop a rigid gait in the rear limbs, extending and retracting in an exaggerated, stiff manner, like that of a hopping rabbit. The dog’s back may be arched, and the dog often yelps. One or more limbs may also protract excessively. The dog may lose its footing while running. It usually loses all coordination and collapses on its side or on its face. When the cavalier collapses, it may hold its forelegs over its head. In some instances, the cavalier’s symptoms follow a “deer-stalking” behavior, with its head held close to the ground and its rear high in the air, as if stalking game. In the most severe cases, the dog may hold its head so low that its hind quarters somersault over its head. The affected cavalier may exhibit these symptoms only when excited or stressed, but in some cases, the behaviors have not been stress-induced. The dog may also overheat during an episode, possibly due to an inability to pant.
See videoed examples of EFS episodes on
YouTube here.The cavalier does not lose consciousness during the episodes, and mentally, it remains normal. Technically, the collapse is not a seizure, although it may be appear as one. The CKCS appears to know what is happening to it, and sees clearly, but loses control of its body. Afterwards, in most instances the dog recovers relatively quickly; it stands up and acts as if nothing unusual had occurred. However, if the cavalier exercises again immediately after recovery, it may induce another episode.
Also, some severely affected cavaliers have been known to lapse into repeated, lengthy episodes of the syndrome, and may even suffer permanent neurological injuries and not be able to recover from the attacks. At least a few CKCSs are known to have been euthanized to avoid continued suffering from the disorder.
It is to be distinguished from presyncope, another disorder to which cavalier King Charles spaniels are predisposed, which has some of the same symptoms. Syncope in cavaliers is associated with late stages of mitral valve disease. For more information on syncope and presyncope in CKCSs, see Mitral Valve Disease and Syncope.
Diagnosis
Episodic falling syndrome is the result of a single recessive gene mutation associated with neurological function. Until 2010, EFS had been believed to be a type of metabolic muscle disorder. The ages of cavaliers studied with EFS have varied from two months to four years. Both male and female CKCSs are affected.
The dogs are neurologically normal between episodes. Electromyographic evaluation detects the muscles at rest and engaged in no abnormal spontaneous activity. There is no evidence of heart or respiratory problems during the episode or the collapse. Blood tests, spinal fluid analysis, muscle biopsies, and magnetic resonance imaging (MRI) of the brain have not proved to be helpful in diagnosing the syndrome. Diagnosis, therefore, has been based solely upon the symptoms of the episode.
Since some of the symptoms of EFS are similar to other disorders, such as liver shunt, an epileptic seizure, or syringomyelia, the examining veterinarian may mis-diagnose the episodes and unnecessarily screen the dog for those other maladies. The primary differences between EFS and other disorders are that they usually are induced by exercise, excitement, stress, or apprehension; the EFS-affected dog remains conscious during the episodes; and the dog rarely will experience any continuing pain or discomfort.
Therefore, video recordings of the dog’s EFS episodes are helpful to the veterinarian in diagnosing the disorder. If a video device is not available, the owner should write a precise report of the Cavalier’s behaviors during the episode, to avoid mis-diagnosis, needless testing, and treatment with drugs which may inadvertently aggravate the condition.
In a brief July 2009 article, UK researchers Dr. Richard J Piercy and Gemma Walmsley disclosed that they had identified a genetic form of muscular dystrophy in the cavalier, with symptoms (weakness and exercise intolerance) similar to some of those of EFS. However, these other symptoms of this muscular dystrophy may clearly distinguish it from EFS: muscle atrophy, difficulty swallowing, and an enlarged tongue. Also, the researchers have found that only males are affected by this form of muscular dystrophy, and the females are only carriers of the mutation.
DNA Testing
In 2011, two UK research groups (see below) independently developed DNA swab tests for detecting a recessive gene associated with brain function, the BCAN gene, which, when mutated, is the cause of episodic falling disorder in the CKCS. EFS is inherited as a autosomal recessive trait. If a DNA-tested cavalier is found to not have the mutated BCAN gene, then it is "clear" of EFS. If the dog is found to have two of the mutated gene, then it is "affected" and has EFS, whether it shows symptoms or not. If the dog is found to have only one of the mutated gene, then it is not affected but is "a carrier".
The knowledge of whether a cavalier is clear, affected, or a carrier of EFS is important to the responsible breeder who wants to avoid passing EFS to future generations in her bloodline of cavaliers. See Breeders' Responsibilities below for additional information about how to use the results of DNA testing to choose breeding partners.
4Animal Health Trust: The UK's Animal Health Trust offers a DNA swab test for the gene mutations causing EFS, through the AHT’s online DNA testing webshop. The test was developed by Dr. Jacques Penderis (at the University of Glasgow) and a research team at the Animal Health Trust. The DNA test is available world-wide.
4LABOKLIN: Researchers led by Dr. Robert Harvey of the London School of Pharmacy, Dr. Leigh Anne Clark (Clemson) and Dr. Diane Shelton (Univ. Cal. at San Diego) (email gshelton@ucsd.edu) have identified the underlying genetic defect causing EFS in cavaliers. They found:
"Consistent with the unique clinical observed in affected dogs, we discovered that a homozygous microdeletion affecting BCAN is associated with EFS in CKCS dogs, confirming that this disorder is inherited in an autosomal recessive manner. This mutation was not detected in control DNA samples from 54 other dog breeds, confirming the unique nature of this genomic rearrangement. ... Wider testing of a larger population of CKCS dogs without a history of EFS from the USA revealed that carriers are extremely common (12.9%). The development of molecular genetic tests for the EFS microdeletion will allow the implementation of directed breeding programs aimed at minimizing the number of animals with EFS and enable confirmatory diagnosis and pharmacotherapy of affected dogs."
See report here for details. LABOKLIN's website for ordering the test kit is here.
The Animal Health Trust reported that, as of May 15, 2012: 2,811 cavaliers had been DNA-tested for episodic falling syndrome, of which 104 (3.7%) were "affected" with two of the mutated EFS gene; 605 (21.52%) were "carriers" with only one of the mutated gene; and the rest, 2,102 (74.78%), were clear of the defective gene.
Treatment
During
and after an episode, consider trying to comfort the dog by holding it gently.
Do not force the dog's legs to assume any position. Keep the dog as cool as
possible, and allow it to rest as much as it wishes after the episode.
Until recently, no medications appeared to remedy the condition, and there was no known effective treatment. Affected dogs have not been found to respond to anticholinesterases. Phenobarbital (Solfoton), a barbiturate, frequently is prescribed.
Some temporary improvement has been observed following treatment with a benzodiazepine drug called diazepam (Valium). In a study concluded in 2003, a group of affected cavaliers was treated with another benzodiazepine drug, clonazepam (Klonopin, Rivotril), which is a drug used to treat humans for hereditary hyperexplexia or hyperekplexia ("startle disease"). Both diazepam and clonazepam enhance GABA neurotransmission. However, clonazepam is more potent than diazepam in equivalent doses, and clonazepam has more anti-convulsant effects. In the 2003 study, with clonazepam treatment (at 0.5 mg/kg tid), the episodes decreased in frequency from between 25 and 30 per week to as few as one every two to three months. After two years of treatment with clonazepam, dogs in the study were described as clinically normal. It has been reported that CKCSs tend to be less responsive to diazepam than other breeds, but that cavaliers can markedly improve with clonazepam.
Dr. Jacques Penderis
(at right)
(formerly a senior research neurologist at the Animal Health Trust in the UK and
now at the University of Glasgow) has found that although some cavaliers
initially respond well to treatment with clonazepam or diazepam, the dogs tend
to develop tolerance to the drugs after a while and the beneficial effect wears
off. Dr. Penderis states that the current treatment options for CKCSs with
episodic falling syndrome are extremely limited.
In cases that do not respond to clonazepam and where the episodes are not particularly severe or frequent, it may be best to accept the collapse episodes and try to identify and avoid events or stressors that may trigger the episodes. In severe cases, treatment can be tried with acetazolamide (Diamox), which is a carbonic anhydrase inhibitor which has shown some efficacy in autosomal dominant hyperkalemic periodic paralysis. Use of acetazolamide must only be done under careful veterinary supervision, and a number of dogs do not appear to tolerate the drug very well.
For more advice on treatment please contact Dr. Penderis. He may be contacted at Clinical Neurology / Neurosurgery Service, Faculty of Veterinary Medicine, University of Glasgow, Bearsden Road, Glasgow G61 1QH, Tel: +(44) 0141 330 5738 (office), Email: jacques.penderis@glasgow.ac.uk
Vitamin E and tryptophan reportedly may decrease the frequency and severity of episodes.
Periodic chiropractic treatments may be able to minimize an affected dog's symptoms of EFS.
Breeders' Responsibilities
UK's Animal Health Trust offers a DNA swab test to detect the mutations causing episodic falling syndrome in the CKCS. UK's LABOKLIN also offers a detection test, as a result of the UK/US July 2011 study. See Current Research for more information about these DNA testing programs.
-- breeding decisions using DNA results
• If two clear cavaliers are mated, all offspring likewise should be clear of EFS.
• If a clear cavalier is mated to a carrier, the odds are that half of the puppies in the resulting litter will be clear and half will be carriers.
• If two carriers are mated, the odds are that half of the litter will be carriers, a quarter will be affected, and a quarter will be clear.
• If a carrier and an affected are mated, half of the litter should be affected and half should be carriers.
• If two affecteds are mated, all puppies in the litter should be affected.
Obviously, it would be preferable to mate only clear cavaliers to each other. But if a cavalier breeder finds that one of her breeding stock is a carrier, she should mate that dog only to a clear cavalier. Then, once the litter is produced, the breeder should DNA-test the puppies to identify the half that are clear and half that are carriers, and remove the carriers from the breeding program.*
* Read the UK Animal Health Trust's article on "Should We Breed Carriers?" by Dr. Cathryn Mellersh here.
Two carriers should not be mated to each other, and, of course, no affecteds should be mated at all.
If a breeder DNA-tests her breeding stock for the mutated gene causing EFS and then follows the above breeding protocol, she could eliminate all EFS-carriers from her bloodline within two generations.
Current Research
4May 2012: UK's Animal Health Trust reports interim results of DNA testing. The Animal Health Trust reported that, as of May 15, 2012: 2,811 cavaliers have been DNA-tested for episodic falling syndrome, of which 104 (3.7%) have been found to be "affected" with two of the mutated EFS gene; 605 (21.52%) are "carriers" with only one of the mutated gene; and the rest, 2,102 (74.78%), are clear of the defective gene.
4January 2012: UK researchers identify mutated gene causing episodic falling syndrome (EFS) in the cavalier. Drs. Oliver P. Forman, Jacques Penderis, Claudia Hartley, Louisa J. Hayward, Sally L. Ricketts, and Cathryn S. Mellersh of the Animal Health Trust and University of Glasgow have identified a mutation of the BCAN gene was associated with EFS in the CKCS. See report below. They confirmed an identical finding by Drs. Jennifer L. Gill, Kate L. Tsai, Christa Krey, Rooksana E. Noorai, Jean-François Vanbellinghen, Laurent S. Garosi, G. Diane Shelton, Leigh Anne Clark, and Robert J. Harvey, in another January 2012 study.
4July 2011: UK's LABOKLIN offers genetic test for Episodic Falling Syndrome. Researchers led by Dr. Robert Harvey of the London School of Pharmacy, Dr. Leigh Anne Clark (Clemson) and Dr. Diane Shelton (Univ.Cal. at San Diego) have identified the underlying genetic defect causing EFS in cavaliers. They found:
"Consistent with the unique clinical observed in affected dogs, we discovered that a homozygous microdeletion affecting BCAN is associated with EFS in CKCS dogs, confirming that this disorder is inherited in an autosomal recessive manner. This mutation was not detected in control DNA samples from 54 other dog breeds, confirming the unique nature of this genomic rearrangement. ... Wider testing of a larger population of CKCS dogs without a history of EFS from the USA revealed that carriers are extremely common (12.9%). The development of molecular genetic tests for the EFS microdeletion will allow the implementation of directed breeding programs aimed at minimizing the number of animals with EFS and enable confirmatory diagnosis and pharmacotherapy of affected dogs."
See January 2012 report here for details. LABOKLIN's website for ordering the test kit is here.
4April 2011: UK's Animal Health Trust begins offering a DNA test for EFS. Starting on April 18, the Animal Health Trust will offer to cavalier breeders a DNA swab test to detect the mutations causing episodic falling syndrome in their cavalier breeding stock. Go to AHT’s online DNA testing webshop for more details. The DNA test is available world-wide. Read more here.
4February 2011: Dr. Penderis reports discovery of single gene causing EFS. Dr. Jacques Penderis reported at the 2011 Veterinary Ireland Conference and in an interview with Irish journalist Karlin Lillington that his reasearch team has identified a single recessive gene mutation causing EFS. He said that a genetic test for the gene should be released in the spring of 2011, probably in April.
4November 2010: DNA Region for Episodic Falling Syndrome Has Been Found. Animal Health Trust veterinary geneticist Dr. Tom Lewis announced at the UK Cavalier Club's "Cavalier Health Day" on November 20 that the DNA region for the episodic falling syndrome in cavaliers has been located. The AHT is continuing its research to identify the precise mutations of gene(s) causing EFS. The Trust's future plan is to offer a DNA test for the mutations to cavalier breeders.
4April 2009: Dr. Penderis is conducting research to try to establish the pattern of inheritance of episodic falling in the cavalier. He is collecting pedigrees from affected dogs for pedigree analysis, particularly where the disease status of related dogs (e.g. parents and litter mates) are known.
He reports that funding is now in place to perform a genome scan in the cavalier to try and identify the genetic region of interest responsible for episodic falling. Funding is still required for the fine sequencing to follow the genome scan. Anyone interested in contributing to these projects should contact Dr. Cathryn Mellersh at the Animal Health Trust, email: Cathryn.Mellersh@ aht.org.uk
For this study Dr. Penderis is very interested in collecting blood samples or cheek swabs for DNA extraction from affected dogs, and normal related dogs. Dr. Penderis requires blood samples from known affected dogs and from as many normal related dogs as possible (particularly litter mates, parents, grandparents and offspring). The study's goal is to develop a genetic test to allow identification of the affected dogs and asymptomatic carriers, so that the disease may be totally eradicated from all tested breeding lines. Dr. Penderis may be contacted at Clinical Neurology / Neurosurgery Service, Faculty of Veterinary Medicine, University of Glasgow, Bearsden Road, Glasgow G61 1QH, Tel: +(44) 0141 330 5738 (office), Email: j.penderis@vet.gla.ac.uk
4October 2007: Dr. Penderis reported that he has teamed up with Dr. Cathryn Mellersh of the Animal Health Trust and a graduate student, Oliver Forman, to conduct a study of four canine neurological conditions, including episodic falling in the CKCS. Also, Professor Robert Harvey, of The School of Pharmacy in London. has proposed some "interesting candidate genes" for the cavaliers they we will be jointly studying.
These candidate gene studies are in need of financial underwriting. Dr. Penderis estimates that it will cost £2,000 +/- for the candidate gene work, and there will be the sequencing costs to follow that, in excess of £6,000. Anyone interested in contributing to these projects should contact Dr. Cathryn Mellersh at the Animal Health Trust, email: Cathryn.Mellersh@aht.org.uk
Related Links
Questions for Breeders
Blood Platelets
Syncope
An excellent website to learn more about Cavaliers with episodic falling
syndrome is
Cavalier Episodic Falling
Veterinary Resources
Episodic falling in the Cavalier King Charles spaniel. Herrtage ME, Palmer AC. Veterinary Record 1983;112:458-459.
Muscle hypertonicity in the cavalier King Charles spaniel - myopathic features. Wright JA, Brownlie SE, Smyth JBA et al. Veterinary Record 1986;118:511-512.
A myopathy associated with muscle hypertonicity in the Cavalier King Charles Spaniel. Wright JA, Smyth JBA, Brownlie S, Robins M. J Com Path 1987;97:559-565. Quote: "Clinical signs of electrically silent muscle hypertonicity are described in five Cavalier King Charles dogs. Biopsies of the biceps femoris and triceps muscles, when examined with the electron miscroscope, revealed evidence of sarcotubular and mitochondrial abnormalities. These included enlargement of the sarcoplasmic reticulum, hydropic degeneration of mitochondria, tubular proliferations in the vicinity of the triads and vacuolar invagination of mitochondria. The exact nature of these findings is not clear and it is suggested that utilization of tracer techniques would help to explain them."
Low cerebrospianl fluid concentration of free gamma-aminobutyric acid in startle disease. Dubowitz LM, Bouza H, Hird MF, Jackson J. Lancet 1992;340:80-81.
Mutations in the alpha 1 subunit of the inhibitory glycine receptor cause the dominant neurologic disorder, hyperekplexia. Shiang R, Ryan S, Ya-Zhen Z et al. Nature Genetics 1993;5:351-358.
Update on Mitral Valve Disease. Jens Häggström and Clarence Kvart. Proc. 15th ACVIM Forum; 1997. Quote: "An interesting observation that may be of comparative interest is that Cavalier King Charles Spaniels have been shown to have a high prevalence (30%) of thrombocytopenia and macrothrombocytosis. Humans with MVP [mitral valve prolapse] tend to have shortened platelet survival times and thromboembolic episodes primarily in the retinal and cerebral circulation. Thromboembolic events in the retinal ore cerebral circulation may be involved in the disturbances described in the breed as 'episodic falling' and 'fly catching'."
Control of Canine Genetic Diseases. Padgett, G.A., Howell Book House1998, pp. 198-199, 234.
Hypertonicity in Cavalier King Charles Spaniels. Shelton GD, Comparative Neuromuscular Lab, June 2001.
Muscular dystrophies and other inherited myopathies. Shelton GD, Engvall E,Vet Clin North Am Small Anim Pract 2002; 32:103-124.
Hypertonicity in Cavalier King Charles Spaniels. Garosi LS, Platt SR, Shelton GD, J Vet Intern Med 2002; 16:330.
Clinical Neurology in Small Animals - Localization, Diagnosis and Treatment. K.G. Braund, International Veterinary Information Service, Ithaca, New York, USA; Paroxysmal Disorders (6-Feb-2003). Quote: "Episodic falling or hypertonicity is a well-recognized paroxysmal disorder in Cavalier King Charles Spaniels in the UK, and has been seen in the United States and Australia." www.ivis.org/special_books/Braund/braund29/ivis.pdf
Breed Predispositions to Disease in Dogs & Cats. Alex Gough, Alison Thomas. 2004; Blackwell Publ. 44-45.
Neurological diseases of the Cavalier King Charles spaniel. Rusbridge, C. J Small Animal Practice, 30 June 2005, 46(6): 265-272.
A Practical Guide to Canine and Feline Neurology. Curtis W. Dewey. John Wiley & Sons; 2008; 4-6, 482-483. Quotes: "Breed-associated neurologic abnormalities of dogs and cats. ... Cavalier King Charles Spaniels ... Episodic muscle hypertonicity ("falling cavaliers" -- probable dyskinesia" pg. 4-6. ""An age range ... has been reported of ... 14 weeks to 4 years for Cavalier King Charles Spaniels. ... Crossing of the thoracic limbs over the top of the head has been described in collapsing Cavalier King Charles Spaniels. ... Cavalier King Charles Spaniels tend to be less responsive to diaaepam than other breeds with the condition, but they can markedly improve with clonazepam treatment. Tolerance to clonzepam may develop in the long term. Other therapies reported to decrease frequency and severity of episodes include vitamin E and tryptophan. This is a nonprogressive disorder that tends to improve with therapy. Life spans of affected dogs do not appear to be shortened by the disease." pp. 482-483.
A canine DNM1 mutation is highly associated with the syndrome of exercise-induced collapse. Patterson EE, Minor KM, Tchernatynskaia AV, Taylor SM, Shelton GD, Ekenstedt KJ, Mickelson JR. Nat Genet 2008; 40:1235-1239.
Muscular dystrophy in Cavalier King Charles spaniels. Piercy, Richard. J. and Walmsley, Gemma. Vet Rec. 2009 165 (2), p. 62. Quote: "We have recently identified the genetic cause of a form of muscular dystrophy in CKCS. The causative mutation is in the dystrophin gene and the X-linked disease is associated with weakness, muscle atrophy and exercise intolerance, detectable from a few months of age. Prominent signs in affected dogs are dysphagia [the symptom of difficulty in swallowing] and macroglossia (enlarged tongue)[tongue enlargement that leads to functional and cosmetic problems]. Serum creatine kinase is usually markedly elevated. Male dogs with the mutation [are] clinically affected and female dogs with the mutation are silent carriers. We are also keen to hear from veterinary surgeons who believe they may have seen an affected dog in their practice, in order to estimate the prevalence of this disease and limit its spread by genetic testing." Contact Dr. Piercy at the Royal Veterinary College's Comparative Neuromuscular Diseases Laboratory at rpiercy@rvc.ac.uk
Breed Predispositions to Disease in Dogs & Cats (2d Ed.). Alex Gough, Alison Thomas. 2010; Wiley-Blackwell Publ. 52.
New DNA tests for Cavalier King Charles spaniels. Vet Rec 2011 168(14):370. "NEW DNA tests to detect the mutations causing congenital keratoconjunctivitis sicca and ichthyosiform dermatosis (dry eye and curly coat syndrome) and episodic falling in Cavalier King Charles spaniels will be available from the Animal Health Trust (AHT) later this month. Episodic falling is a neurological condition induced by exercise, excitement or frustration. The dog's muscle tone increases and the animal is unable to relax its muscles, becomes rigid and falls over. Dry eye and curly coat syndrome results in an affected dog producing no tears, so its eyes become sore. The skin becomes flaky and dry, particularly around the feet, which can make standing and walking difficult and painful. The syndrome appears to be unique to Cavalier King Charles spaniels and most dogs diagnosed with it are euthanased. Researchers at the Kennel Club Genetics Centre at the AHT have now identified the mutations responsible for the two conditions. This has allowed the development of the new DNA tests, which will be available from the AHT from April 18. Cathryn Mellersh, head of canine genetics at the AHT, said: To date there has been no long-term effective treatment for either dry eye and curly coat syndrome or episodic falling so the development of the DNA tests is an important breakthrough for breeders and owners of Cavalier King Charles spaniels. As with all inherited disease, it's important that breeders are armed with the facts and that they still continue to use carrier dogs in their breeding programmes. Breeding a carrier with a non-carrier will not produce affected puppies; however, breeding just clear dogs with other clear dogs could reduce the gene pool within the breed and this could lead to other health problems in the future."
A canine BCAN microdeletion associated with Episodic Falling Syndrome. Jennifer L. Gill, Kate L. Tsai, Christa Krey, Rooksana E. Noorai, Jean-François Vanbellinghen, Laurent S. Garosi, G. Diane Shelton, Leigh Anne Clark, and Robert J. Harvey. Neurobiology of Disease. Jan 2012;45(1):130-136. Quote: "Episodic falling syndrome (EFS) is a canine paroxysmal hypertonicity disorder found in Cavalier King Charles spaniels. Episodes are triggered by exercise, stress or excitement and characterized by progressive hypertonicity throughout the thoracic and pelvic limbs, resulting in a characteristic 'deer-stalking' position and/or collapse. We used a genome-wide association strategy to map the EFS locus to a 3.48 Mb critical interval on canine chromosome 7. By prioritizing candidate genes on the basis of biological plausibility, we found that a 15.7 kb deletion in BCAN, encoding the brain-specific extracellular matrix proteoglycan brevican, is associated with EFS. This represents a compelling causal mutation for EFS, since brevican has an essential role in the formation of perineuronal nets governing synapse stability and nerve conduction velocity. ... Consistent with the unique clinical signs observed in affected dogs, we discovered that a homozygous microdeletion affecting BCAN is associated with EFS in CKCS dogs, confirming that this disorder is inherited in an autosomal recessive manner. This mutation was not detected in control DNA samples from 54 other dog breeds, confirming the unique nature of this genomic rearrangement. ... Certainly, since EFS appears to result from a central nervous system rather than a muscle defect, the associated sarcoplasmic reticulum pathology is likely to be a secondary manifestation of muscle overstimulation. ... Mapping of the deletion breakpoint enabled the development of Multiplex PCR and Multiplex Ligation-dependent Probe Amplification (MLPA) genotyping tests that can accurately distinguish normal, carrier and affected animals. Wider testing of a larger population of CKCS dogs without a history of EFS from the USA revealed that carriers are extremely common (12.9%). The development of molecular genetic tests for the EFS microdeletion will allow the implementation of directed breeding programs aimed at minimizing the number of animals with EFS and enable confirmatory diagnosis and pharmacotherapy of affected dogs."
Parallel Mapping and Simultaneous Sequencing Reveals Deletions in BCAN and FAM83H Associated with Discrete Inherited Disorders in a Domestic Dog Breed. Oliver P. Forman, Jacques Penderis, Claudia Hartley, Louisa J. Hayward, Sally L. Ricketts, and Cathryn S. Mellersh. PLoS Genet. 2012 January; 8(1): e1002462. Quote: "The domestic dog (Canis familiaris) segregates more naturally-occurring diseases and phenotypic variation than any other species and has become established as an unparalled model with which to study the genetics of inherited traits. We used a genome-wide association study (GWAS) and targeted resequencing of DNA from just five dogs to simultaneously map and identify mutations for two distinct inherited disorders that both affect a single breed, the Cavalier King Charles Spaniel. We investigated episodic falling (EF), a paroxysmal exertion-induced dyskinesia, alongside the phenotypically distinct condition congenital keratoconjunctivitis sicca and ichthyosiform dermatosis (CKCSID), commonly known as dry eye curly coat syndrome. EF is characterised by episodes of exercise-induced muscular hypertonicity and abnormal posturing, usually occurring after exercise or periods of excitement. CKCSID is a congenital disorder that manifests as a rough coat present at birth, with keratoconjunctivitis sicca apparent on eyelid opening at 10–14 days, followed by hyperkeratinisation of footpads and distortion of nails that develops over the next few months. We undertook a GWAS with 31 EF cases, 23 CKCSID cases, and a common set of 38 controls and identified statistically associated signals for EF and CKCSID on chromosome 7 (Praw 1.9×10−14; Pgenome=1.0×10−5) and chromosome 13 (Praw 1.2×10−17; Pgenome=1.0×10−5), respectively. We resequenced both the EF and CKCSID disease-associated regions in just five dogs and identified a 15,724 bp deletion spanning three exons of BCAN associated with EF and a single base-pair exonic deletion in FAM83H associated with CKCSID. Neither BCAN or FAM83H have been associated with equivalent disease phenotypes in any other species, thus demonstrating the ability to use the domestic dog to study the genetic basis of more than one disease simultaneously in a single breed and to identify multiple novel candidate genes in parallel."
