Categories: Nervous system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 203450 (trait) , 137780 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0008752: Alexander disease

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal dominant

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2016

Species-specific name: Fibrinoid leukodystrophy, fibrinoid encephalomyelopathy

Molecular basis: Van Poucke et al. (2016): "c.719G>A nucleotide substitution resulting in a p.Arg240His substitution was considered to be causal, because it is orthologous to the heterozygous de novo dominant c.716G>A (p.Arg239His) hotspot variant in man, proven to cause a severe phenotype. In addition, the variant was not found in 50 unrelated healthy Labrador retrievers."

Clinical features: Alexander disease is a progressive fatal neurodegenerative disease. The observed cases have been found in younger dogs, usually <12 months of age (Wrzosek et al., 2015). Early signs may begin as incoordination, a head tilt, knuckling on limbs, issues with balance, nystagmus and an aversion to touch (Wrzosek et al., 2015). As the disease progresses clinical features are ataxia and paresis in the hindlimbs (Kobatake et al., 2020) and in later stages tetraparesis (Van Poucke et al., 2016). Some patients may experience spastic front limbs along with vestibular signs (e.g., head tilt, strabismus) and myoclonic jerks of the head and cervical regions (Van Poucke et al., 2016). Generalised muscle atrophy, stiffness, regurgitation, increasing difficulty in swallowing and changes in vocalisation can be observed (Van Poucke et al., 2016; Kobatake et al., 2020). [IT thanks DVM students Bri Pepper and Carmen Tu for contributions to this entry in April 2022]

Pathology: Blood examinations reveal no remarkable changes for both complete blood counts and serum biochemistry (Wrzosek et al., 2015, Kobatake et al., 2020). Gross pathological changes are not always obvious in all cases (Wrzosek et al., 2015; Van Poucke et al., 2016), but can include diffuse atrophy of brain and spinal cord (Kobatake et al., 2020), discoloured foci in the brain and spinal cord (Ito et al., 2010) and lateral ventricle enlargement (Alemañ et al., 2006; Weissenböck et al., 1996). Histopathological examination reveals eosinophilic round, club-shaped or elongated deposits that are consistent with Rosenthal fibers (eosinophilic corkscrew bundles), occurring in the astrocytes throughout the central nervous system (Weissenböck et al., 1996; Alemañ et al., 2006; Van Poucke et al., 2016). The Rosenthal fibers are immunopositive for glial fibrillary acidic protein (GFAP). The astrocytes also present with large nuclei, prominent nucleoli, and a glassy eosinophilic cytoplasm (Wrzosek et al., 2015; Van Poucke et al., 2016) and are often distributed around blood vessels in the white matter, beneath the pia matter and subependymal areas (Alemañ et al., 2006; Van Poucke et al., 2016). Demyelination in the brain may or may not be present (Alemañ et al., 2006). [IT thanks DVM students Bri Pepper and Carmen Tu for contributions to this entry in April 2022]

Breeds: Beagle (Dog) (VBO_0200131), Bernese Mountain Dog (Dog) (VBO_0200161), Chihuahua (Dog) (VBO_0200338), French Bulldog (Dog) (VBO_0201455), Labrador Retriever (Dog) (VBO_0200800), Poodle, Miniature (Dog) (VBO_0201051), Poodle, Toy (Dog) (VBO_0201061), Scottish Terrier (Dog) (VBO_0201198).
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: