Categories: Nervous system phene

Possibly relevant human trait(s) and/or gene(s) (MIM number): 611753 (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: 2022

Species-specific description: Cerebellar abiotropy has been first described in Australian kelpies by Thomas and Robertson in 1989. Wade et al. (2022) "identified two distinct clinical and pathological features of CA in Australian working kelpies. These were associated with two separate genomic regions ... An early-onset CA form is observable within a few weeks of birth and in some cases is seen within days of birth. This form affects dogs that are homozygous for a risk marker on CFA20 [see 'OMIA 000175-9615 : Cerebellar abiotrophy in Canis lupus familiaris']. A second region of association, identified on CFA9, is associated with a later-onset form of CA [described in this OMIA entry] that is not usually diagnosed until the dogs are 4–6 months or older."

Mapping: Wade et al. (2022): “Investigation of clinical and pathological features [in Australian working kelpie dogs] indicated two closely related diseases with differences in age of onset. … A genome-wide association study on 45 CA affected and 290 normal healthy Kelpies identified two significantly associated loci, one on CFA9 and a second on CFA20. [See 'OMIA 000175-9615 : Cerebellar abiotrophy in Canis lupus familiaris' for information on the early onset (clinical signs before ten weeks of age) disease associated with the the risk haplotype on CFA20] ... Genome-wide significant association identified a second significant region of association CFA9:32,419,297–35,242,435 (UU GSD1.0)."

Molecular basis: Wade et al. (2022): "one dog exhibiting symptoms of CA, its dam, and a sib without symptoms at the time of observation ... were subjected to whole-genome sequencing (WGS) on the Illumina HiSeq 2500 platform ... . A further five whole genome sequences from unrelated healthy AWK were obtained by collaboration ... . ... The most associated array marker: BICF2G630835610 CFA9:32,949,504G>A, (pgenome 5.13 × 10−8) segregated in perfect LD with a missense variant in the fifth exon of VMP1 NM_030938p.P160Q."

Genetic engineering: Unknown
Have human generated variants been created, e.g. through genetic engineering and gene editing

Clinical features: Clinical presentation in the two forms of CA in Australian Kelpies mainly differ in regard to onset of clinical signs. The form with later onset of disease at 4-6 month of age is associated with the VMP1 variant (Wade et al., 2022). Clinical signs include ataxia, wide-based stance, head tremors/intention tremor, dysmetria/incoordination, hypermetria/high-stepping gate, decreased limb proprioception (particularly hind limbs), and/or body tremors when excited. The condition is non-painful and does not affect the dog’s normal mentation or alertness. More severe forms can include fitting/grand mal seizures when overheated or excited. The condition may present mildly with only occasional periods of incoordination and no progression to more severe forms. Commonly, it will present with signs that become more obvious or progress as the animal ages (Thomas and Robertson, 1989; Shearman et al., 2008; Shearman et al., 2011; Pan et al., 2017; Wade et al., 2022). IT thanks DVM student Beatrice Humphries, who provided the basis of this contribution in May 2023.

Pathology: Wade et al. (2022) "Histopathology shows that affected animals regardless of age of onset exhibit granule cell loss, regional Purkinje cell loss and activated astrocytes. However, the histopathological features are distinct between animals affected with the early-onset disease associated with homozygosity at CFA20 and those affected with the later-onset disease that were homozygous at CFA9. The early-onset group (CFA20) demonstrate abnormality of foliar development in the cerebellar cortex, and a relatively reduced molecular layer (ML). Dogs that were homozygous for the CFA9 locus had normal foliar development, later disorder onset, and demonstrated axonal spheroids in their white matter tracts."

Breed: Working Kelpie (Dog) (VBO_0201434).
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below

Associated gene: