OMIA:001592-9615 : Episodic falling in Canis lupus familiaris (dog)
Categories: Nervous system phene
Possibly relevant human trait(s) and/or gene(s) (MIM number): 600347 (gene)
Links to MONDO diseases: No links.
Mendelian trait/disorder: yes
Mode of inheritance: Autosomal recessive
Considered a defect: yes
Key variant known: yes
Year key variant first reported: 2012
Species-specific name: also called: episodic falling syndrome, episodic hypertonicity, hyperekplexia, muscle hypertonicity, paroxysmal exercise-induced dystonia, dyskinesia
Species-specific symbol: EFS
Mapping: By conducting a GWAS on 5 affected, one obligate carrier and 9 control Cavalier King Charles spaniels, each of which had been genotyped with the Affymetrix Canine SNP Array version 2 (yielding 58,873 informative SNPs for analysis), Gill et al. (2012) mapped this disorder to a 3.48Mb region on chromosome CFA7.
By conducting a GWAS on 31 affected and 38 control Cavalier King Charles Spaniels, each genotyped with the Illumina Canine HD SNP chip (yielding 91,427 SNPs for analysis), Forman et al. (2012) highlighted the same region on chromosome CFA7 as had been reported by Gill et al. (2012).
Molecular basis: By sequencing the most likely positional candidate gene in the candidate region they had identified (see Mapping section), Gill et al. (2012) reported that this disorder in Cavalier King Charles Spaniels is due to a 15.7kb deletion in the BCAN gene, which encodes brain-specific extracellular matrix proteoglycan brevican. By sequencing 5 affected dogs within their candidate region (see Mapping section), Forman et al. (2012) reported the same mutation.
Clinical features: Episodic falling syndrome (EFS) in Cavalier King Charles Spaniels is characterised by episodes of ascending hypertonicity affecting the thoracic and pelvic limbs (Gill et al., 2012). Onset of the disease is between 14 weeks and 4 years of age, with varying frequency and severity (Gill et al., 2012). During an episode the dog is ultimately immobilised in a distinctive “deer-stalking” or “praying” position (Gill et al., 2012) and usually recovery of limb function takes 10 minutes (Wright et al., 1987). These episodes can be triggered by exercise, stress, apprehension, or excitement (Herrtage & Palmer, 1983). During exercise, the dogs fall while maintaining consciousness and without cyanosis (Gill et al., 2012). Facial muscle stiffening, stumbling, “bunny-hopping” gait, arching of the back or vocalisation may also be observed (Gill et al., 2012). Dogs present completely normal neurologically between the episodes (Herrtage and Palmer, 1983; Gill et al., 2012). [IT thanks DVM students Kiva Waugh and Samantha Su Yuen Lim, who provided the basis of this contribution in April 2022]
Gill et al., 2012 report that "brevican has an essential role in the formation of perineuronal nets governing synapse stability and nerve conduction velocity". Mutations in this gene could therefore explain the observed EFS phenotype. EFS muscle usually appears normal under light microscopy, allowing exclusion of many congenital myopathies (Wright et al., 1987; Gill et al., 2012). Electron microscopy revealed dilation of the sarcoplasmic reticulum with finely granular material (Wright et al., 1987). Some dogs appeared to have completely normal mitochondria. However, in other dogs, there was selective damage such that some swollen mitochondria were interspersed between normal ones. The authors also noted proliferation of tubular structures as the predominant feature in some dogs. Gill et al. (2012) observed only swollen sarcoplasmic reticulum in muscle samples under electron microscopy, and considered this as a secondary change due to muscle overstimulation, further suggesting a CNS basis of the pathology. [IT thanks DVM students Kiva Waugh and Samantha Su Yuen Lim, who provided the basis of this contribution in April 2022]
EFS muscle usually appears normal under light microscopy, allowing exclusion of many congenital myopathies (Wright et al., 1987; Gill et al., 2012). Electron microscopy revealed dilation of the sarcoplasmic reticulum with finely granular material (Wright et al., 1987). Some dogs appeared to have completely normal mitochondria. However, in other dogs, there was selective damage such that some swollen mitochondria were interspersed between normal ones. The authors also noted proliferation of tubular structures as the predominant feature in some dogs. Gill et al. (2012) observed only swollen sarcoplasmic reticulum in muscle samples under electron microscopy, and considered this as a secondary change due to muscle overstimulation, further suggesting a CNS basis of the pathology. [IT thanks DVM students Kiva Waugh and Samantha Su Yuen Lim, who provided the basis of this contribution in April 2022]
Genetic testing: As explained on the web site of the Animal Health Trust (http://www.aht.org.uk/genetics_curleycoat.html), a DNA test for this disorder in Cavalier King Charles Spaniels was discovered by geneticists at the Trust in early 2011, and is available from the Trust. Their discovery was reported by Forman et al. (2012). As described under "Molecular basis", another research group independently discovered and published a causal mutation in 2012.
Cavalier King Charles Spaniel.
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|BCAN||brevican||Canis lupus familiaris||7||NC_051811.1 (41193313..41176717)||BCAN||Homologene, Ensembl , NCBI gene|
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WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.
Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.
|OMIA Variant ID||Breed(s)||Variant Phenotype||Gene||Allele||Type of Variant||Source of Genetic Variant||Reference Sequence||Chr.||g. or m.||c. or n.||p.||Verbal Description||EVA ID||Inferred EVA rsID||Year Published||PubMed ID(s)||Acknowledgements|
|635||Cavalier King Charles Spaniel||Episodic falling||BCAN||deletion, gross (>20)||Naturally occurring variant||CanFam3.1||7||g.41325010_41340731delinsAAGGCC||c.-13991_466+85delinsGGCCTT||XM_005622698.1; a 15.7kb deletion in the BCAN gene removing the first 3 exons||2012||21821125|
Cite this entry
Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
|2022||Santifort, K.M., Mandigers, P.J.J. :|
|Dystonia in veterinary neurology. J Vet Intern Med 36:1872-1881, 2022. Pubmed reference: 36086931 . DOI: 10.1111/jvim.16532.|
|2019||Lewis, T.W., Mellersh, C.S. :|
|Changes in mutation frequency of eight Mendelian inherited disorders in eight pedigree dog populations following introduction of a commercial DNA test. PLoS One 14:e0209864, 2019. Pubmed reference: 30650096 . DOI: 10.1371/journal.pone.0209864.|
|2014||Urkasemsin, G., Olby, N.J. :|
|Canine paroxysmal movement disorders. Vet Clin North Am Small Anim Pract 44:1091-102, 2014. Pubmed reference: 25441627 . DOI: 10.1016/j.cvsm.2014.07.006.|
|2012||Forman, O.P., Penderis, J., Hartley, C., Hayward, L.J., Ricketts, S.L., Mellersh, C.S. :|
|Parallel mapping and simultaneous sequencing reveals deletions in BCAN and FAM83H associated with discrete inherited disorders in a domestic dog breed. PLoS Genet 8:e1002462, 2012. Pubmed reference: 22253609 . DOI: 10.1371/journal.pgen.1002462.|
|Gill, J.L., Tsai, K.L., Krey, C., Noorai, R.E., Vanbellinghen, J.F., Garosi, L.S., Shelton, G.D., Clark, L.A., Harvey, R.J. :|
|A canine BCAN microdeletion associated with episodic falling syndrome. Neurobiol Dis 45:130-6, 2012. Pubmed reference: 21821125 . DOI: 10.1016/j.nbd.2011.07.014.|
|2005||Rusbridge, C. :|
|Neurological diseases of the Cavalier King Charles spaniel. J Small Anim Pract 46:265-72, 2005. Pubmed reference: 15971896 . DOI: 10.1111/j.1748-5827.2005.tb00319.x.|
|1987||Wright, J.A., Smyth, J.B., Brownlie, S.E., Robins, M. :|
|A myopathy associated with muscle hypertonicity in the Cavalier King Charles Spaniel. J Comp Pathol 97:559-65, 1987. Pubmed reference: 3680644 . DOI: 10.1016/0021-9975(87)90006-5.|
|1986||Wright, J.A., Brownlie, S.E., Smyth, J.B., Jones, D.G., Wotton, P. :|
|Muscle hypertonicity in the cavalier King Charles spaniel--myopathic features. Vet Rec 118:511-2, 1986. Pubmed reference: 3716135 . DOI: 10.1136/vr.118.18.511.|
|1983||Herrtage, M.E., Palmer, A.C. :|
|Episodic falling in the cavalier King Charles spaniel. Vet Rec 112:458-9, 1983. Pubmed reference: 6868317 . DOI: 10.1136/vr.112.19.458.|
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