Categories: Nervous system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 606352 (gene) , 205100 (trait) , 606353 (trait) , 607225 (trait)

Single-gene trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2025

Species-specific name: Murrurundi disease, and Mudgee ataxia

History: Segmental axonopathy has been present for more than 80 years in Merrino sheep and was first reported by Hartley & Loomis (1981).

Molecular basis: Eager et al. (2025): "Whole genome sequencing and genotyping of affected and unaffected Merino sheep identified a novel homozygous frameshift variant in the ALS2 gene [NC_056055.1:g.204020069-204020070del, XM_012142668.4:c.4138-4139del, omia.variant:1828] that segregated with disease. RNA sequencing of cerebellar peduncle tissue confirmed the nonsense consequence on the ALS2 transcript."

Clinical features: Eager et al. (2025): "Affected sheep have progressive hindlimb weakness, knuckling of fetlocks, ataxia and paresis [Hartley & Loomis, 1981; Harper et al., 1986; Jolly et al., 2006], and either die of misadventure or are euthanised [Hartley & Loomis, 1981; Harper et al., 1986; Jolly et al., 2006; Windsor, 2006]. Segmental axonopathy is a recessive, late-onset disease that manifests first clinical signs between 1 to 5 years of age and progresses slowly to severe disease [Windsor, 2006]."

Pathology: Eager et al. (2025) summarises pathological findings. Affected animals show no gross lesions of the nervous system at post mortem. "Histologically, segmental axonopathy is characterized by large pale eosinophilic foamy swellings in the white matter of the central and peripheral nervous systems [Hartley & Loomis, 1981; Harper et al., 1986; Jolly et al., 2006]. Although they may be found throughout the central nervous system, they have a particular predilection for the dorsal rootlets of some sensory nerves, the dorsal funiculus where these enter the cord, in the fasiculus gracilis, the trigeminal nerve root, the dorsal spinocerebellar tract and the superficial transverse tracts of the pons where they extend into the middle cerebellar peduncles. Wallerian degeneration and intra-myelinic oedema also occur in white matter and nuclei, along with peripheral nerve Wallerian degeneration and Schwann nuclei proliferation. Electron microscopy showed that the axonal swellings consisted mainly of membrane bound vesicles derived from in-pouching of myelin [Jolly et al., 2006; Windsor, 2006]."

Breed: Merino (Sheep) (VBO_0001508).
Breeds in which the phene or likely causal variants have been documented. If a likely causal variant has been documented, see variant-specific breed information in the variant table. (Breed information may be incomplete).

Associated gene: