Clinical, pathological and genetic examination revealed an as yet uncharacterized
juvenile-onset neuroaxonal dystrophy (
NAD) in Spanish water dogs. Affected dogs presented with various neurological deficits including gait abnormalities and behavioral deficits. Histopathology demonstrated spheroid formation accentuated in the grey matter of the cerebral hemispheres, the cerebellum, the brain stem and in the sensory pathways of the spinal cord.
Iron accumulation was absent. Ultrastructurally spheroids contained predominantly closely packed vesicles with a double-layered membrane, which were characterized as autophagosomes using immunohistochemistry. The family history of the four affected dogs suggested an autosomal recessive inheritance. SNP genotyping showed a single genomic region of extended homozygosity of 4.5 Mb in the four cases on CFA 8. Linkage analysis revealed a maximal parametric LOD score of 2.5 at this region. By whole genome re-sequencing of one affected dog, a perfectly associated, single, non-synonymous coding variant in the canine tectonin beta-propeller repeat-containing
protein 2 (TECPR2) gene affecting a highly conserved region was detected (c.4009C>T or p.R1337W). This canine
NAD form displays etiologic parallels to an inherited TECPR2 associated type of human hereditary
spastic paraparesis (HSP). In contrast to the canine
NAD, the spinal cord lesions in most types of human HSP involve the sensory and the motor pathways. Furthermore, the canine
NAD form reveals similarities to cases of human
NAD defined by widespread spheroid formation without
iron accumulation in the basal ganglia. Thus TECPR2 should also be considered as candidate gene for human
NAD. Immunohistochemistry and the ultrastructural findings further support the assumption, that TECPR2 regulates autophagosome accumulation in the autophagic pathways. Consequently, this report provides the first genetic characterization of juvenile canine
NAD, describes the histopathological features associated with the TECPR2 mutation and provides evidence to emphasize the association between failure of autophagy and neurodegeneration.