OMIA 001208-9615 : Alexander disease in Canis lupus familiaris

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 203450 (trait) , 137780 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Dominant

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2016

Species-specific name: Fibrinoid leukodystrophy

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: Bernese Mountain dog, Chihuahua, French Bulldog, Labrador Retriever, Miniature Poodle, Scottish Terrier, Toy Poodle.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
GFAP glial fibrillary acidic protein Canis lupus familiaris 9 NC_051813.1 (19243310..19252910) GFAP Homologene, Ensembl, NCBI gene

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.

Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.

OMIA Variant ID Breed(s) Variant Phenotype Gene Allele Type of Variant Source of Genetic Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Inferred EVA rsID Year Published PubMed ID(s) Acknowledgements
114 Labrador Retriever Alexander disease GFAP missense Naturally occurring variant CanFam3.1 9 g.18572769G>A c.719G>A p.(R240H) rs850986067 rs850986067 2016 26486469 Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool

References


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
2020 Kobatake, Y., Nishimura, N., Sakai, H., Iwana, S., Yamato, O., Nishii, N., Kamishina, H. :
Long-term survival of a dog with Alexander disease. J Vet Med Sci 82:1704-1707, 2020. Pubmed reference: 33055453. DOI: 10.1292/jvms.20-0133.
2016 Van Brantegem, L., Van Poucke, M., Martlé, V., Ducatelle, R., Van Ham, L., Peelman, L. :
A Labrador Retriever diagnosed with Alexander’s disease and the identification of the causal GFAP mutation. J Comp Pathol 154:88, 2016. DOI: doi.org/10.1016/j.jcpa.2015.10.072.
Van Poucke, M., Martlé, V., Van Brantegem, L., Ducatelle, R., Van Ham, L., Bhatti, S., Peelman, L.J. :
A canine orthologue of the human GFAP c.716G>A (p.Arg239His) variant causes Alexander disease in a Labrador retriever. Eur J Hum Genet 24:852-6, 2016. Pubmed reference: 26486469. DOI: 10.1038/ejhg.2015.223.
2015 Wrzosek, M., Giza, E., Płonek, M., Podgórski, P., Vandevelde, M. :
Alexander disease in a dog: case presentation of electrodiagnostic, magnetic resonance imaging and histopathologic findings with review of literature. BMC Vet Res 11:115, 2015. Pubmed reference: 25985984. DOI: 10.1186/s12917-015-0393-x.
2010 Gruber, A., Pakozdy, A., Leschnik, M., Mai, S., Weissenböck, H. :
Morbus Alexander – 4 Fälle bei Hunden in Österreich. Wien. Tierärztl. Mschr. 97:298, 2010.
Ito, T., Uchida, K., Nakamura, M., Nakashima, K., Suzuki, K., Nakayama, H. :
Fibrinoid leukodystrophy (Alexander's disease-like disorder) in a young adult French bulldog. J Vet Med Sci 72:1387-90, 2010. Pubmed reference: 20526046. DOI: 10.1292/jvms.10-0085.
2006 Alemañ, N., Marcaccini, A., Espino, L., Bermúdez, R., Nieto, J.M., López-Peña, M. :
Rosenthal fiber encephalopathy in a dog resembling Alexander disease in humans. Vet Pathol 43:1025-8, 2006. Pubmed reference: 17099166. DOI: 10.1354/vp.43-6-1025.
1996 Weissenböck, H., Obermaier, G., Dahme, E. :
Alexander's disease in a Bernese mountain dog. Acta Neuropathol 91:200-204, 1996. Pubmed reference: 8787155. DOI: 10.1007/s004010050414.
1991 Richardson, J.A., Tang, K., Burns, D.K. :
Myeloencephalopathy with Rosenthal fiber formation in a miniature poodle. Vet Pathol 28:536-8, 1991. Pubmed reference: 1771743. DOI: 10.1177/030098589102800612.
1986 Cox, NR., Kwapien, RP., Sorjonen, DC., Braund, KG. :
Myeloencephalopathy resembling Alexander's disease in a Scottish terrier dog. Acta Neuropathol 71:163-6, 1986. Pubmed reference: 3776469. DOI: 10.1007/BF00687980.

Edit History


  • Created by Frank Nicholas on 06 Sep 2005
  • Changed by Frank Nicholas on 19 May 2017
  • Changed by Imke Tammen2 on 06 Aug 2021
  • Changed by Imke Tammen2 on 03 Jun 2022