Genomic Investigation of Vitamin E Metabolism in Horses with Equine Degenerative Myeloencephalopathy

Neurologic diseases cause horses to be unsafe for riding or handling. For this reason, neurologic horses are typically euthanized when treatment is not available. Equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (eNAD/EDM) is neurologic disorder caused by a genetic predisposition coupled with a vitamin E deficiency within the first two years of life. Clinical signs of eNAD/EDM are a symmetric ataxia, wide base stance at rest, and limb weakness. This is similar to many other neurologic diseases in horses, which complicates the diagnostic process. The complete genetic and pathologic etiology of eNAD/EDM remains unknown. Currently, eNAD/EDM can only be definitively diagnosed via postmortem evaluation of the central nervous system. This thesis provides an overview of the current body of knowledge regarding eNAD/EDM research, evaluates the prevalence based on necropsy findings, investigates the genetic basis of the disease while excluding caytaxin (ATCAY) as a likely candidate gene, and examines the metabolism of vitamin E within eNAD/EDM horses. The prevalence of eNAD/EDM has not been evaluated since 1989, when it was found to be one of the top three causes of spinal ataxia in the Eastern United States. Chapter 1 provides an overview of what is known about eNAD/EDM. In Chapter 2, we describe our retrospective study that identified eNAD/EDM as the second most common diagnosable cause of ataxia in the Western United States. In Chapter 3, a genetic investigation of eNAD/EDM in Quarter Horses revealed a 2.5 Mb region on equine chromosome 7 (ECA7) associated with the neurologic phenotype. Additional interrogation of a likely positional and functional candidate gene, caytaxin (ATCAY), excluded it as the cause of disease. Previous work exploring the absorption and transport of α-tocopherol, an isoform of vitamin E, showed that these processes are not altered in eNAD/EDM affected individuals. In Chapter 4, we show that the α-tocopherol metabolic rate is increased in eNAD/EDM affected horses as compared to unaffected horses within the first 24 hours after administration of a 5000 IU oral dose of RRR-α-tocopherol. It was hypothesized this could be due to genetic or regulatory changes. However, the location of regulatory elements within the horse genome is currently not known. In addendum a biobank was generated to be used in the functional annotation of these regulatory elements. Future work should focus on the genetic association on ECA7 to identify the genetic risk factors predisposing affected horses to development of clinical signs. Additionally, α-tocopherol metabolism needs further exploration in a larger cohort of horses to determine the precise physiological role for vitamin E in prevention of the disease