A canine orthologue of the human GFAP c.716G>A (p.Arg239His) variant causes Alexander disease in a Labrador retriever

Abstract

Alexander disease (AxD) is a fatal neurodegenerative disorder of astrocyte dysfunction in man, for which already a number of causal variants are described, mostly de novo dominant missense variants in the glial fibrillary acidic protein (GFAP). A similar disorder was already phenotypically described in animals but without the identification of causal variants. We diagnosed a Labrador retriever with a juvenile form of AxD based on clinical (tetraparesis with spastic front limbs mimicking 'swimming puppy syndrome') and pathological (the detection of GFAP containing Rosenthal fibers in astrocytes) features. In order to identify a causal variant, the coding sequences of the four detected GFAP transcript variants (orthologues from human transcript variants α, γ, δ/ε and κ) were sequenced. From the five detected variants, a heterozygous c

TSEN54 missense variant in Standard Schnauzers with leukodystrophy

“…The progressive clinical course, the lesions visible in MRI and loss of myelin in the cerebrum seen light microscopically point towards a demyelinating leukodystrophy rather than to a hypomyelinating disease. Although there are many different types of leukodystrophy described in dogs [6][7][8][9][10][11][12][13][14][15], the distribution and also the histopathological appearance of the lesions described in the TSEN54 mutant dogs were different compared to previously described cases of canine leukodystrophy.…”

“…1-4), five unaffected littermates (no. 13,14,[19][20][21] and the four unaffected parents (no. 15-18) of these two litters.…”

“…In veterinary medicine, leukodystrophies were described in many different dog breeds, such as leukomyeloencephalopathy in Rottweiler [6][7][8] and Leonberger dogs [9], globoid cell leukodystrophy or Krabbe's disease in West Highland White Terriers [10,11] and Australian Kelpies [12], cavitating leukodystrophy in Dalmatians [13], fibrinoid leukodystrophy or Alexander's disease in a Labrador Retriever [14] and necrotizing myelopathy in Afghan hounds [15]. In some of these diseases an autosomal recessive mode of inheritance was described [11][12][13].…”

“…In some of these diseases an autosomal recessive mode of inheritance was described [11][12][13]. Causative genetic variants have been identified in GFAP (Labrador Retriever, [14]), NAPELD (Leonberger Dogs, [9]), and VPS11 (Rottweiler dogs, [8]). The present study aimed to characterize clinical and pathological features of a new leukodystrophy in Standard Schnauzer puppies and to identify its underlying genetic cause.…”

Long-term survival of a dog with Alexander disease

“…The characteristic pathological feature of AxD is the presence of abnormal astrocytes that contain glial fibrillary acidic protein (GFAP) aggregates, termed Rosenthal fibers, distributed around the vessels in the white matter as well as subpial and subependymal areas [ 10 , 20 ]. In total, 13 dogs have been clinically and histopathologically diagnosed with AxD [ 1 , 5 , 8 , 9 , 14 , 18 , 21 , 22 , 23 ]. Because of the poor prognosis, the owners of dogs with AxD tend to elect euthanasia.…”