Categories: Nervous system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 610876 (gene) , 616756 (trait)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2022

Inheritance: Pedigree analysis of eight affected dogs from 5 litters suggested an autosomal recessive mode of inheritance (Bellamy et al., 2022)

Molecular basis: Bellamy et al. (2022): "Whole genome sequencing ... detected only four closely linked private variants at CFA12 ... . All four variants were located within HACE1 ... .Two of the variants were located in the 5’-region ... and the other two ... were located ...in exon 11 (ENSCAFT00000072236.1). [One variant] ... was an already annotated synonymous variant ... [and the likely causal variant] was a 1 bp deletion ... leading to a frameshift creating 33 new amino acids and a premature stop codon in exon 12."

Clinical features: Bellamy et al. (2022): "Owners reported an abnormal gait, especially in the pelvic limbs, of the affected dogs from around 4 weeks of age. The puppies were said to be unsteady, easily slipping on the floor with the pelvic limbs, occasionally falling over. In addition, they all had a hanging tail instead of the curled tail normal for this spitz breed. ... On neurological examination, the body posture was kyphotic with a broad-based pelvic limb stance. The gait was moderately ataxic with hypermetric tendencies, most prominent in the pelvic limbs."

Pathology: Bellamy et al. (2022): "No macroscopical abnormalities were observed .... In the cerebellum of all the examined cases, homogenous eosinophilic axonal swellings were present multifocally in the cerebellar granule cell layer ... . These structures stained positively for neurofilament by immunohistochemistry and immunofluorescence and were consistent with spheroids in the Purkinje cell axons (torpedoes) ... . Occasionally, the torpedoes were shrunken and surrounded by a vacuolated space. In the brain stem, vacuoles were found in a moderate number disseminated and multifocally, both in the white matter tracts and in neuronal nuclei close to neurons."

Breed: Norwegian Elkhound (Dog) (VBO_0200955).
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: