ABSTRACT
Canine leukoencephalomyelopathy (LEMP) is a juvenile-onset neurodegenerative disorder of the CNS white matter currently described in Rottweiler and Leonberger dogs. Genome-wide association study (GWAS) allowed us to map LEMP in a Leonberger cohort to dog chromosome 18. Subsequent whole genome re-sequencing of a Leonberger case enabled the identification of a single private homozygous non-synonymous missense variant located in the highly conserved metallo-beta-lactamase domain of the N-acyl phosphatidylethanolamine phospholipase D (NAPEPLD) gene, encoding an enzyme of the endocannabinoid system. We then sequenced this gene in LEMP-affected Rottweilers and identified a different frameshift variant, which is predicted to replace the C-terminal metallo-beta-lactamase domain of the wild type protein. Haplotype analysis of SNP array genotypes revealed that the frameshift variant was present in diverse haplotypes in Rottweilers, and also in Great Danes, indicating an old origin of this second NAPEPLD variant. The identification of different NAPEPLD variants in dog breeds affected by leukoencephalopathies with heterogeneous pathological features, implicates the NAPEPLD enzyme as important in myelin homeostasis, and suggests a novel candidate gene for myelination disorders in people.
Subject(s)
Demyelinating Diseases/genetics , Dog Diseases/genetics , Leukoencephalopathies/veterinary , Myelin Sheath/pathology , Phospholipase D/genetics , Animals , Demyelinating Diseases/pathology , Disease Models, Animal , Dog Diseases/blood , Dog Diseases/pathology , Dogs , Genome-Wide Association Study , Haplotypes , Humans , Leukoencephalopathies/blood , Leukoencephalopathies/genetics , Leukoencephalopathies/pathology , Mutation, Missense , Polymorphism, Single Nucleotide , Whole Genome SequencingABSTRACT
BACKGROUND: The diagnosis of feline epilepsy of unknown cause (EUC) requires a thorough diagnostic evaluation, otherwise the prevalence of EUC could be overestimated. HYPOTHESIS: Feline EUC is a clinically defined disease entity, which differs from feline hippocampal necrosis by the absence of magnetic resonance imaging (MRI) signal alteration of the hippocampus. The objectives of this study were (1) to evaluate the prevalence of EUC in a hospital population of cats by applying well-defined inclusion criteria, and (2) to describe the clinical course of EUC. ANIMALS: Eighty-one cats with recurrent seizures. METHODS: Retrospective study--medical records were reviewed for cats presented for evaluation of recurrent seizures (2005-2010). Inclusion criteria were a defined diagnosis based on laboratory data, and either MRI or histopathology. Final outcome was confirmed by telephone interview with the owner. Magnetic resonance images were reviewed to evaluate hippocampal morphology and signal alterations. RESULTS: Epilepsy of unknown cause was diagnosed in 22% of cats with epilepsy. Physical, neurologic, and laboratory examinations, and either 1.5 T MRI and cerebrospinal fluid analysis or postmortem examination failed to identify an underlying cause. Cats with EUC had a higher survival rate (P < .05) and seizure remission occurred frequently (44.4%). CONCLUSION AND CLINICAL IMPORTANCE: A detailed clinical evaluation and diagnostic imaging with MRI is recommended in any cat with recurrent seizures. The prognosis of cats with normal MRI findings and a clinical diagnosis of EUC are good. Standardized imaging guidelines should be established to assess the hippocampus in cats.
