Categories: Nervous system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 600347 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2012

Cross-species summary: Renamed from 'Episodic falling' to 'Episodic falling, BCAN-related' [11/06/2024]

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]

Pathology: 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]

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.

Breed: Cavalier King Charles Spaniel (Dog) (VBO_0200309).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: