ACADM Frameshift Variant in Cavalier King Charles Spaniels with Medium-Chain Acyl-CoA Dehydrogenase Deficiency.

A 3-year-old, male neutered Cavalier King Charles Spaniel (CKCS) presented with complex focal seizures and prolonged lethargy. The aim of the study was to investigate the clinical signs, metabolic changes and underlying genetic defect. Blood and urine organic acid analysis revealed increased medium-chain fatty acids and together with the clinical findings suggested a diagnosis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. We sequenced the genome of the affected dog and compared the data to 923 control genomes of different dog breeds. The ACADM gene encoding MCAD was considered the top functional candidate gene. The genetic analysis revealed a single homozygous private protein-changing variant in ACADM in the affected dog. This variant, XM_038541645.1:c.444_445delinsGTTAATTCTCAATATTGTCTAAGAATTATG, introduces a premature stop codon and is predicted to result in truncation of ~63% of the wild type MCAD open reading frame, XP_038397573.1:p.(Thr150Ilefs*6). Targeted genotyping of the variant in 162 additional CKCS revealed a variant allele frequency of 23.5% and twelve additional homozygous mutant dogs. The acylcarnitine C8/C12 ratio was elevated ~43.3 fold in homozygous mutant dogs as compared to homozygous wild type dogs. Based on available clinical and biochemical data together with current knowledge in humans, we propose the ACADM frameshift variant as causative variant for the MCAD deficiency with likely contribution to the neurological phenotype in the index case. Testing the CKCS breeding population for the identified ACADM variant is recommended to prevent the unintentional breeding of dogs with MCAD deficiency. Further prospective studies are warranted to assess the clinical consequences of this enzyme defect.

Risk factors associated with short-term mortality and recurrence of status epilepticus in dogs.

BACKGROUND: Status epilepticus (SE) is an emergency associated with serious consequences for both patient and owner. Data regarding risk factors for short-term mortality or recurrence in dogs with SE is limited. OBJECTIVE: Identify risk factors associated with short-term mortality (euthanasia or spontaneous death) and recurrence of SE in dogs. ANIMALS: One hundred twenty-four client-owned dogs that sustained an episode of SE. METHODS: Retrospective multicenter study using data collected from medical records of dogs presented in SE to the contributing institutions. Multivariable logistic regression analysis was performed using a manual backwards stepwise approach to identify risk factors associated with short-term mortality and recurrence of SE after discharge. RESULTS: Short-term mortality for affected dogs was 29.8%. Factors significantly associated with short-term mortality included increased patient age, shorter duration of hospitalization, development of SE before arrival, and SE caused by a potentially fatal etiology. Status epilepticus recurred in 27% of dogs that survived to discharge. Factors significantly associated with recurrence of SE included prior history of pharmacoresistant epilepsy and predominance of a focal seizure phenotype. CONCLUSIONS AND CLINICAL IMPORTANCE: Our results may be used to inform clinicians and dog owners regarding risk factors for both short-term mortality and recurrence in dogs with SE.

Peri-ictal magnetic resonance imaging characteristics in dogs with suspected idiopathic epilepsy.

BACKGROUND: The pathophysiology of changes in magnetic resonance imaging (MRI) detected after a seizure is not fully understood. OBJECTIVE: To characterize and describe seizure-induced changes detected by MRI. ANIMALS: Eighty-one client-owned dogs diagnosed with idiopathic epilepsy. METHODS: Data collected retrospectively from medical records and included anatomical areas affected, T1-, T2-weighted and T2-FLAIR (fluid-attenuated inversion recovery) appearance, whether changes were unilateral or bilateral, symmetry, contrast enhancement, mass effect, and, gray and white matter distribution. Diffusion- and perfusion weighted maps were evaluated, if available. RESULTS: Seizure-induced changes were T2-hyperintense with no suppression of signal on FLAIR. Lesions were T1-isointense (55/81) or hypointense (26/81), local mass effect (23/81) and contrast enhancement (12/81). The majority of changes were bilateral (71/81) and symmetrical (69/71). The most common areas affected were the hippocampus (39/81) cingulate gyrus (33/81), hippocampus and piriform lobes (32/81). Distribution analysis suggested concurrence between cingulate gyrus and pulvinar thalamic nuclei, the cingulate gyrus and parahippocampal gyrus, hippocampus and piriform lobe, and, hippocampus and parahippocampal gyrus. Diffusion (DWI) characteristics were a mixed-pattern of restricted, facilitated, and normal diffusion. Perfusion (PWI) showed either hypoperfusion (6/9) or hyperperfusion (3/9). CONCLUSIONS AND CLINICAL IMPORTANCE: More areas, than previously reported, have been identified that could incur seizure-induced changes. Similar to human literature, DWI and PWI changes have been identified that could reflect the underlying metabolic and vascular changes.

An Inversion Disrupting FAM134B Is Associated with Sensory Neuropathy in the Border Collie Dog Breed.

Sensory neuropathy in the Border Collie is a severe neurological disorder caused by the degeneration of sensory and, to a lesser extent, motor nerve cells with clinical signs starting between 2 and 7 months of age. Using a genome-wide association study approach with three cases and 170 breed matched controls, a suggestive locus for sensory neuropathy was identified that was followed up using a genome sequencing approach. An inversion disrupting the candidate gene FAM134B was identified. Genotyping of additional cases and controls and RNAseq analysis provided strong evidence that the inversion is causal. Evidence of cryptic splicing resulting in novel exon transcription for FAM134B was identified by RNAseq experiments. This investigation demonstrates the identification of a novel sensory neuropathy associated mutation, by mapping using a minimal set of cases and subsequent genome sequencing. Through mutation screening, it should be possible to reduce the frequency of or completely eliminate this debilitating condition from the Border Collie breed population.