A novel hereditary encephalopathy in four related Labrador Retrievers associated with a missense variant in the ALDH5A1 gene.

BACKGROUND: Hereditary neurodegenerative diseases occur in dogs, and a molecular diagnosis can be of value for treatment and prevention. HYPOTHESIS/OBJECTIVES: To describe the clinical presentation of a novel encephalopathy in 4 related Labrador Retrievers. To identify a candidate causal variant for the disease using whole genome sequencing (WGS). ANIMALS: Four related Labrador Retrievers presenting between 4 and 9 months of age. METHODS: Case information and clinical workup were recorded for the 4 dogs in this case series. Two cases underwent WGS to identify candidate causal variants that were validated by genotyping Labradors related and unrelated to the cases, and by screening WGS of other breeds/canid species. RESULTS: Clinical signs in cases included paroxysmal anxiety episodes, and focal and generalized epileptic seizures. Interictal clinical and neurological examinations were normal in all cases. Magnetic resonance imaging of the brain documented bilaterally symmetrical, T2-weighted image hyperintense, T1-weighted image isointense, and non-contrast-enhancing lesions within the lentiform nuclei, caudal colliculi, substantia nigra, and cerebellar nuclei. Investigations to exclude underlying nutritional, toxic, and metabolic causes were within normal limits. All cases had 2 copies of a missense variant in the aldehyde dehydrogenase 5 family member A1 (ALDH5A1) gene that segregated as expected in the family group and was absent in 70 unrelated Labradors and 2339 WGS of multiple breeds/canids. CONCLUSIONS AND CLINICAL IMPORTANCE: The prognosis of this novel hereditary encephalopathy in a family of Labradors appears fair with reasonable clinical response to administration of anti-seizure drugs. A missense variant in ALDH5A1 has been identified as a candidate causal variant for the disease in these dogs.