Alexander Disease

Gene: GFAP

Transmission: Autosomal dominant

For an autosomal dominant genetic disease, an animal must have at least one copy of the mutation in question to be at risk of developing the disease.  Animals with two copies of the mutation generally have more severe symptoms and an earlier onset of the disease than animals with just one copy of the mutation.  One or both of the parents of an animal with the mutation has one or two copies of the mutation.  Animals that have one or two copies of the mutation can pass the mutation on to future generations.

Mutation: (seen in a single Labrador Retriever animal)

Substitution, GFAP gene; c.719 G>A, p.(Arg240His), exon 4, chromosome 9

Medical system: Neurological

Breeds: Beagle, Bernese Mountain Dog, Chihuahua, French Bulldog, Labrador Retriever, Poodle - Miniature (Dwarf), Poodle - Toy, Scottish Terrier

Age of onset of symptoms: From 4 to 6 weeks, or less than one year.

Alexander disease is a neurodegenerative genetic disease involving astrocyte dysfunction within the central nervous system. The disease has been recognized in many species including humans. In dogs, the disease is very rare but it has been diagnosed in a number of breeds by clinical signs and histology.  Based on human studies, the disease is due to a mutation within the GFAP gene, which generates a non-functional Glial fibrillary acidic protein within the astrocytes and results in the destruction of the myeline sheath of the astrocytes.  Protein clusters called Rosenthal fibers are seen on histological sections of brain tissue.  Early clinical symptoms include incoordination and balance problems.  These symptoms progress to include muscle atrophy leading to stiffness, hindlimb paralysis, spastic forelimbs, and eventual tetraplegia. The disease is dominant with early onset and is fatal, such that its incidence depends on natural and spontaneous mutations rather than on heredity passage.

Although Alexander disease has been diagnosed in several breeds of dog by clinical and histological signs, a specific mutation has only been characterized in one Labrador Retriever animal.  A recent review of pathological mutations (Donner et al. 2023) was unable to detect the reported mutation in 16,856 Labrador Retriever samples tested, nor in 81,1628 mixed-breed samples tested. The reported mutation is therefore of more academic interest than of clinical relevance.

References:

OMIA link: [1208-9615]

Donner J, Freyer J, Davison S, et al. (2023) Genetic prevalence and clinical relevance of canine Mendelian disease variants in over one million dogs.  PLoS Genet. 19(2):e1010651. [pubmed/36848397]

Vandenberghe H, Baiker K, Nye G, et al. (2023) Diagnostic features of type II fibrinoid leukodystrophy (Alexander disease) in a juvenile Beagle dog. J Vet Intern Med 37(2):670-675. [pubmed/36799664]

Kobatake Y, Nishimura N, Sakai H, et al. (2020) Long-term survival of a dog with Alexander disease. J Vet Med Sci. 82(11):1704-1707. [pubmed/33055453]

Van Poucke M, Martlé V, Van Brantegem L, et al. (2016) A canine orthologue of the human GFAP c.716G>A (p.Arg239His) variant causes Alexander disease in a Labrador retriever. European Journal of Human Genetics, 24(6), 852–856.  [pubmed/26486469]

Wrzosek M, Giza E, Płonek M, et al. (2015) Alexander disease in a dog: case presentation of electrodiagnostic, magnetic resonance imaging and histopathologic findings with review of literature. BMC Vet Res 11:115.  [pubmed/25985984]

Contributed by: Lyanne St-Amour, Léane Trudel-Chénard, class of 2027, Veterinary Medicine Faculty, University of Montreal.  (Translation: DWS).