Categories: Nervous system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 612780 (trait) , 602208 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0013005: EAST syndrome

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2014

Species-specific name: Spinocerebellar ataxia with myokymia, seizures or both (SAMS); spongy degeneration with cerebellar ataxia 1 (SDCA1)

Species-specific description: Ataxia is characterized by uncoordinated movements and represents a relatively non-specific clinical sign. This entry describes ataxia forms that are caused by genetic variants in the KCNJ10 gene. A phenotypically closely related ataxia in Russell group terriers is caused by a variant in the CAPN1 gene. A phenotypically closely related ataxia in Belgian Shepherds is caused by a variant in the ATP1B2 gene. Other phenotypically related ataxias in dogs may also be caused by variants in the GRM1, ITPR1, RAB24, SEL1L, SNX14, and SPTBN2 genes. There are currently 2 different KCNJ10 pathogenic variants known in dogs (p.Ile209Met in various Terrier breeds and p.Leu329Pro in Belgian Shephers). These canine disorders represent models for SeSAME/EAST syndrome in humans (see MIM link above).

Mapping: Mauri et al. (2017) investigated six litters of Malinois dogs with ataxic puppies by linkage analysis. This analysis revealed heterogeneity in the material. Four of the six litters had overlapping linkage signals. The authors additionally performed a homozygosity mapping analysis, for which they used six affected puppies from the four families and one additional unrelated case. The combined linkage and homozygosity analysis resulted in a ~1.4 Mb critical interval on chromosome 38 (chr38:21,060,597-22,475,242; CanFam 3.1 assembly).

Molecular basis: By whole-genome sequencing a single SAMS affected Russell group terrier (RGT) dog, and comparing that sequence with whole-genome sequence from 81 canid reference genomes, Gilliam et al. (2014) identified 23 missense variants that were homozygous in the affected dog. Of the two variants that occurred in comparative candidate genes, one (KCNJ10:c.627C>G; p.Ile209Met) was shown by subsequent sequencing and genotyping of other dogs to be causal for this subtype of ataxia, namely "spinocerebellar ataxia with myokymia, seizures, or both (SAMS)". Rohdin et al (2015) confirmed these findings and noted that the KCNJ10:c.627C>G (p.Ile209Met) variant also segregates in Smooth-Haired Fox Terriers and related breeds. Gast et al. (2016) confirmed that the KCNJ10 c.627C>G (p.Ile209Met) variant accounts for most (but not all) cases in another cohort of Parson Russell Terriers and in Jack Russell Terriers. A likely causal variant in Malinois dogs with spongy degeneration with cerebellar ataxia 1 (SDCA1), namely a missense mutation in KCNJ10: c.986T>C; p.Leu329Pro, was reported by a Belgian/UK team (Stee et al., 2016; Van Poucke et al., 2017, accepted for publication 29 September 2016). The phenotype in SDCA1 affected Malinois dogs is slightly different from the phenotype in the terriers with SAMS. Mauri et al. (2017; accepted for publication 16 December 2016) reported the same likely causal mutation in this breed.

Clinical features: Spinocerebellar ataxia with myokymia, seizures, or both (SAMS): "The median age at onset of cerebellar ataxia in 12 dogs was 3 months (range, 2–6 months)" (Gilliam et al. 2014). Ten out of twelve SAMS-affected dogs of the Russell terrier group showed muscle twitches (myokymia). The median age at onset for myokymia was 6 months (range, 3–8 months). Some SAMS dogs developed seizures. (Gilliam et al. 2014). Spongy degeneration with cerebellar ataxia 1 (SDCA1): This phenotype occurs in Malinois dogs and has an earlier age of onset than SAMS. Kleiter et al. (2011) investigated 5 closely related litters with presumed SDCA1 (the KCNJ10:p.Leu329Pro variant was confirmed in only one of the litters, Mauri et al. 2017). Malinois puppies with SDCA1 developed a severe ataxia at 4-7 weeks of age. Affected dogs showed shivering and were unable to start walking without falling. The severe condition resulted in euthanasia at 5-13 weeks of age (Kleiter et al. 2011). Van Poucke et al. (2017) reported another detailed clinical analysis of 3 SDCA1 affected Malinois dogs. One of the dogs was still alive at 1 year of age despite severely debilitating non-ambulatory ataxia. Van Poucke et al. noted ataxia, myokymia and neuromyotonia as well as auditory changes in SDCA1 affected dogs.

Pathology: Macroscopically the central nervous system (CNS) and peripheral nervous system (PNS) of dogs carrying the KCNJ10 variants are normal. Based on histopathology, there is apparently some phenotypical variation depending on the breed and report. In Parson Russell Terriers and in Jack Russell Terriers the KCNJ10 c.627C>G (p.Ile209Met) variant is associated with bilateral-symmetrical axonal degeneration in the ventral and lateral funiculi of the spinal cord (Gilliam et al. 2014). Van Poucke et al. (2017) describe a similar axonal degeneration in the ventral funiculi and in the brainstem and cerebellum of Malinois dogs with the KCNJ10: c.986T>C (p.Leu329Pro) variant in association with myelin vacuolisation and additionally axonal changes in the PNS. In comparison, in the descriptions by Kleiter et al. (2011) and Mauri et al. (2017) the neuropathology of affected Malinois dogs is dominated by vacuolisation (spongy degeneration) targeting the cerebellar nuclei, granule cell layer and cerebellar white matter. This vacuolisation is accompanied by axonal degeneration in the brain and spinal cord, which is mainly characterized by the presence of axonal swellings.

Breeds: Belgian Shepherd Dog (Dog) (VBO_0200144), Belgian Shepherd Dog, Malinois (Dog) (VBO_0200147), Dachshund (Dog) (VBO_0200406), Jack Russell Terrier (Dog) (VBO_0200724), Parson Russell Terrier (Dog) (VBO_0200987), Russell Terrier (Dog) (VBO_0201145), Smooth Fox Terrier (Dog) (VBO_0201258).
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: