Feline Spongy Encephalopathy With a Mutation in the ASPA Gene.

Canavan disease is an autosomal recessive leukodystrophy caused by mutations in the gene encoding aspartoacylase (ASPA), which hydrolyses N-acetylaspartate (NAA) to acetate and aspartate. A similar feline neurodegenerative disease associated with a mutation in the ASPA gene is reported herein. Comprehensive clinical, genetic, and pathological analyses were performed on 4 affected cats. Gait disturbance and head tremors initially appeared at 1 to 19 months of age. These cats eventually exhibited dysstasia and seizures and died at 7 to 53 months of age. Magnetic resonance imaging of the brain revealed diffuse symmetrical intensity change of the cerebral cortex, brainstem, and cerebellum. Gas chromatography-mass spectrometry analysis of urine showed significant excretion of NAA. Genetic analysis of the 4 affected cats identified a missense mutation (c.859G>C) in exon 6 of the ASPA gene, which was not detected in 4 neurologically intact cats examined as controls. Postmortem analysis revealed vacuolar changes predominantly distributed in the gray matter of the cerebrum and brain stem as well as in the cerebellar Purkinje cell layer. Immunohistochemically, these vacuoles were surrounded by neurofilaments and sometimes contained MBP- and Olig2-positive cells. Ultrastructurally, a large number of intracytoplasmic vacuoles containing mitochondria and electron-dense granules were detected in the cerebral cortex. All 4 cats were diagnosed as spongy encephalopathy with a mutation in the ASPA gene, a syndrome analogous to human Canavan disease. The histopathological findings suggest that feline ASPA deficiency induces intracytoplasmic edema in neurons and oligodendrocytes, resulting in spongy degeneration of the central nervous system.

A Missense Variant in KCNJ10 in Belgian Shepherd Dogs Affected by Spongy Degeneration with Cerebellar Ataxia (SDCA1).

Spongy degeneration with cerebellar ataxia (SDCA) is a severe neurodegenerative disease with monogenic autosomal recessive inheritance in Malinois dogs, one of the four varieties of the Belgian Shepherd breed. We performed a genetic investigation in six families and seven isolated cases of Malinois dogs with signs of cerebellar dysfunction. Linkage analysis revealed an unexpected genetic heterogeneity within the studied cases. The affected dogs from four families and one isolated case shared a ∼1.4 Mb common homozygous haplotype segment on chromosome 38. Whole genome sequence analysis of three affected and 140 control dogs revealed a missense variant in the KCNJ10 gene encoding a potassium channel (c.986T>C; p.Leu329Pro). Pathogenic variants in KCNJ10 were reported previously in humans, mice, and dogs with neurological phenotypes. Therefore, we consider KCNJ10:c.986T>C the most likely candidate causative variant for one subtype of SDCA in Malinois dogs, which we propose to term spongy degeneration with cerebellar ataxia 1 (SDCA1). However, our study also comprised samples from 12 Malinois dogs with cerebellar dysfunction which were not homozygous for this variant, suggesting a different genetic basis in these dogs. A retrospective detailed clinical and histopathological analysis revealed subtle neuropathological differences with respect to SDCA1-affected dogs. Thus, our study highlights the genetic and phenotypic complexity underlying cerebellar dysfunction in Malinois dogs and provides the basis for a genetic test to eradicate one specific neurodegenerative disease from the breeding population. These dogs represent an animal model for the human EAST syndrome.

Shetland Sheepdog leukodystrophy.

Three litters of Shetland Sheepdog pups born to the same bitch and 2 different sires were studied because of uncontrollable seizures or progressive neurologic dysfunction. Four pups from the 1st litter, 1 from the 2nd litter, and 4 from the 3rd litter had severe diffuse spongy degeneration of the white matter of the brain and spinal cord. An inherited basis for this syndrome was suspected. The purpose of this study was to evaluate the pups with currently available screening tests for the metabolic, biochemical, infectious, and toxicologic causes of leukodystrophy seen in humans and animals. Computed tomography scans revealed diffuse hypomyelination in the affected pup. Complete postmortem examination, including histopathology and electron microscopy, delineated a leukodystrophy resembling human Canavan's disease, but amino acid and organic acid metabolism abnormalities were not detected. No etiology for Shetland Sheepdog leukodystrophy has been found, but this condition represents another familial disease in the purebred dog population.

Magnetic resonance imaging of spongy degeneration of the central nervous system in a Labrador Retriever.

A 7-month-old, neutered female Labrador Retriever was evaluated for tetraparesis and subtle cerebellar dysfunction. Clinical signs progressed over a period of 6 weeks to severe ataxia, hypermetria, intention tremors, and finally non-ambulatory tetraparesis. On magnetic resonance imaging of the brain there were large, bilaterally symmetrical, ovoid lesions in the region of the deep cerebellar nuclei that were hyperintense on T2-weighted and proton density images and hypointense on T1-weighted images. There were similar but smaller bilaterally symmetrical lesions present within the thalamus. Euthanasia was performed and lesions consistent with the previously described spongy degeneration of Labrador Retrievers were identified. This disease and its relation to similar human heritable leukodystrophies are discussed.