RALGAPA1 Deletion in Belgian Shepherd Dogs with Cerebellar Ataxia.

Several genetically distinct forms of cerebellar ataxia exist in Belgian shepherd dogs. We investigated a litter in which two puppies developed cerebellar ataxia. The clinical signs stabilized at around six weeks of age, but remained visible into adulthood. Combined linkage and homozygosity mapping delineated a 5.5 Mb critical interval. The comparison of whole-genome sequence data of one affected dog to 929 control genomes revealed a private homozygous ~4.8 kb deletion in the critical interval, Chr8:14,468,376_14,473,136del4761. The deletion comprises exon 35 of the RALGAPA1 gene, XM_038544497.1:c.6080-2893_6944+1003del. It is predicted to introduce a premature stop codon into the transcript, truncating ~23% of the wild-type open reading frame of the encoded Ral GTPase-activating protein catalytic subunit α 1, XP_038400425.1:(p.Val2027Glnfs*7). Genotypes at the deletion showed the expected co-segregation with the phenotype in the family. Genotyping additional ataxic Belgian shepherd dogs revealed three additional homozygous mutant dogs from a single litter, which had been euthanized at five weeks of age due to their severe clinical phenotype. Histopathology revealed cytoplasmic accumulation of granular material within cerebellar Purkinje cells. Genotyping a cohort of almost 900 Belgian shepherd dogs showed the expected genotype-phenotype association and a carrier frequency of 5% in the population. Human patients with loss-of-function variants in RALGAPA1 develop psychomotor disability and early-onset epilepsy. The available clinical and histopathological data, together with current knowledge about RALGAPA1 variants and their functional impact in other species, suggest the RALGAPA1 deletion is the likely causative defect for the observed phenotype in the affected dogs.

Atypically located arachnoid cyst in a five-year-old cat.

Arachnoid cysts are cystic lesions that occur in spinal or intracranial locations in the leptomeningeal space. Four intracranial cases have been described in cats, three of which were diagnosed by imaging techniques alone. We now report the clinical, gross and histopathological findings in a 5-year-old, male-neutered European Shorthair cat that presented with chronic, asymmetrical encephalopathy. Using magnetic resonance imaging, a focal, fluid-filled cavity that did not show contrast enhancement was identified in the left temporal and piriform lobes. Necropsy confirmed the presence of a cystic, meningeal cavity filled with clear, serous fluid. Histologically, the cyst had an irregular, hypereosinophilic surface and single psammoma bodies with moderate perivascular oedema in the adjacent neuroparenchyma. Immunohistochemical evidence of meningeal tissue surrounding the cyst confirmed the diagnosis of an arachnoid cyst, which should be considered as a differential diagnosis of intracranial, fluid-filled cavities.

Behavioral Changes Under Levetiracetam Treatment in Dogs.

In veterinary medicine levetiracetam (LEV) is a well-tolerated antiepileptic drug (AED) with only mild to moderate side effects. Behavioral changes are rarely reported in animals. In contrast, in human medicine the impact of LEV on behavior has frequently been described. Since in the Clinic for Small Animals at the University of Veterinary Medicine Hannover single canine patients were observed with behavioral abnormalities after LEV treatment, it was hypothesized that levetiracetam induces behavioral changes or causes an intensifying of pre-existing behavioral abnormalities in dogs with epileptic seizures. This monocentric retrospective study evaluated the incidence of behavioral changes in epileptic dogs treated with the antiepileptic drug LEV based on information obtained in a questionnaire completed by dog owners. Eighty-four client-owned dogs with recurrent seizures receiving LEV as monotherapy, add on treatment or pulse therapy met inclusion criteria. Approximately half of the dogs in the study population were reported to have preexisting behavioral changes before treatment with LEV, and some of these dogs were reported to experience a worsening of behavioral changes (14/44) or the emergence of new behaviors after initiation of LEV therapy (4/44). One quarter of the dogs without pre-existing behavioral abnormalities developed behavioral changes associated with the administration of LEV (10/40). Based on these results, the authors conclude that behavioral changes can occur in dogs being administered LEV, and this should be taken into consideration when discussing treatment options with owners.

TSEN54 missense variant in Standard Schnauzers with leukodystrophy.

We report a hereditary leukodystrophy in Standard Schnauzer puppies. Clinical signs occurred shortly after birth or started at an age of under 4 weeks and included apathy, dysphoric vocalization, hypermetric ataxia, intension tremor, head tilt, circling, proprioceptive deficits, seizures and ventral strabismus consistent with a diffuse intracranial lesion. Magnetic resonance imaging revealed a diffuse white matter disease without mass effect. Macroscopically, the cerebral white matter showed a gelatinous texture in the centrum semiovale. A mild hydrocephalus internus was noted. Histopathologically, a severe multifocal reduction of myelin formation and moderate diffuse edema without inflammation was detected leading to the diagnosis of leukodystrophy. Combined linkage analysis and homozygosity mapping in two related families delineated critical intervals of approximately 29 Mb. The comparison of whole genome sequence data of one affected Standard Schnauzer to 221 control genomes revealed a single private homozygous protein changing variant in the critical intervals, TSEN54:c.371G>A or p.(Gly124Asp). TSEN54 encodes the tRNA splicing endonuclease subunit 54. In humans, several variants in TSEN54 were reported to cause different types of pontocerebellar hypoplasia. The genotypes at the c.371G>A variant were perfectly associated with the leukodystrophy phenotype in 12 affected Standard Schnauzers and almost 1000 control dogs from different breeds. These results suggest that TSEN54:c.371G>A causes the leukodystrophy. The identification of a candidate causative variant enables genetic testing so that the unintentional breeding of affected Standard Schnauzers can be avoided in the future. Our findings extend the known genotype-phenotype correlation for TSEN54 variants.