Clinical and Genetic Investigation of Equine Neuroaxonal Dystrophy

Equine neuroaxonal dystrophy (NAD) is a neurodegenerative disease characterized by the insidious onset of ataxia during the first year of life. NAD is considered the basic underlying disease of equine degenerative myeloencephalopathy (EDM). A definitive diagnosis of NAD/EDM requires histologic evaluation of the caudal medulla and cervicothoracic spinal cord. Strong evidence has suggested that NAD/EDM is an inherited disorder and there appears to be a role for vitamin E acting as an environmental modifier to determine the overall severity of the phenotype of horses affected with NAD/EDM.;Within this dissertation, the clinical phenotype in both the Quarter horse and Lusitano breed, consisting of a symmetric ataxia and inconsistent menace reflex, is examined. Electroretinography, cerebrospinal fluid (CSF) analyses and histologic assessment of peripheral nerves and muscle in both breeds does not demonstrate any abnormalities and an antemortem diagnostic test remains unavailable. The mode of inheritance appears to be autosomal dominant with incomplete penetrance. Tocopherol-associated transfer protein (TTPA), a gene that is mutated in a similar disease in humans, is not causative for NAD/EDM. A genome wide association study revealed a significant subchromosomal region of association on chromosome 8 at 62 Mb. Sequencing of candidate genes PIK3C3 and RIT2 in this region have not demonstrated any putative mutations for NAD/EDM. The concentrations of alpha-tocopherol in serum and CSF appear to decrease in healthy unaffected Quarter horses during the first 6 months of life and NAD/EDM affected foals demonstrate lower serum and CSF concentrations than unaffected foals during this developmental window. Future research aimed at further defining the role of alpha-tocopherol and dysregulation of genes within the central nervous system is required.