Categories: Nervous system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 601455 (trait) , 605262 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2010

Species-specific description: The polyneuropathy of juvenile Greyhounds shows clinical similarities to the genetically heterogeneous Charcot-Marie-Tooth disease in humans.

Molecular basis: After genotyping 7 affected Grehounds and 17 normal related Greyhounds with the 50K dog SNP chip, Drögemüller et al. (2010) used homozygosity mapping to identify the candidate 19.5 Mb region on chromosome CFA13. By sequencing the most likely candidate gene in this region, they identified the causative mutation as a 10 bp deletion in exon 15 of the NDRG1 gene (c.1080_1089del10). Bruun et al. (2013) investigated the same disorder in Alaskan Malumutes and reported a novel mutation in the same gene: "The coding sequence of the NDRG1 gene derived from one healthy and one affected Alaskan Malamute revealed a non-synonymous G>T mutation in exon 4 in the affected dog that causes a Gly98Val amino acid substitution." The causative variant in the Alaskan Malamute is c.293G>T.

Clinical features: In Greyhounds, this polyneuropathy becomes evident in juvenile dogs between the ages of three and nine months (Drögemüller et al., 2010). Early clinical features include exercise intolerance (e.g. shaking and collapse after exercise), abnormal gait (e.g. bunny hopping and high stepping), while ataxia, dysphonia and severe muscle atrophy were associated with later clinical features (Drögemüller et al., 2010). Neurological examination may reveal progressive lower motor neuron signs, including progressive ataxia and tetraparesis, delayed proprioceptive paw positioning, distal limb muscle atrophy, hyporeflexia, and inspiratory stridor (high pitched noise during inspiration) (Drögemüller et al., 2010). [IT thanks DVM student Anna Johnston, who provided the basis of this contribution in April 2022.]

Pathology: In Greyhounds, a mild to marked decrease in the density of myelinated nerve fibres can be observed. A proportion of the remaining nerve fibres may show a “marked to severe loss of circularity due to para- and internodal crenation” and “outfolded myelin loops at paranodes” (Drögemüller et al., 2010). In approximately 10% of the large, myelinated fibres a mild to marked hyperplasia of axon-Schwann cell network can be seen (Drögemüller et al., 2010). Signs of chronic denervation may be present, including neurogenic atrophy present within some skeletal muscles, de-myelination of fibres within intramuscular nerve branches, as well as perimysial lipid accumulation (Drögemüller et al., 2010). A study of affected Alaskan Malamutes found that these dogs demonstrated more than a 70% reduction in expression of the NDRG1 protein. This suggests that affected animals produce insufficient NDRG1 protein levels for the maintenance of the myelin of Schwann cells, thus resulting in this progressive degenerative polyneuropathy (Skedsmo et al., 2021). [IT thanks DVM student Anna Johnston, who provided the basis of this contribution in April 2022.]

Prevalence: By genotyping archived samples, Jäderlund et al. (2017) showed that "historical and recent phenotypic polyneuropathy cases were carrying the same NDRG1-mutation [c.293G>T; p.Gly98Val]. The pedigree analysis showed that all affected Alaskan malamute cases with polyneuropathy could be traced back to one common ancestor of North American origin."

Breeds: Alaskan Malamute (Dog) (VBO_0200017), Greyhound (Dog) (VBO_0200638).
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: