This study investigated genetic contributions to North American Holsteins affected with Spastic Syndrome. The heritability estimate for the study population was 0.26. A GWAS via the generalized quasi-likelihood logistic regression on two animal cohorts genotyped with the 50k SNP panel and imputed high density SNP panel revealed six and 18 significant SNPs for the first cohort, and 98 and 522 significant SNPs for the second cohort. Significant regions were obtained on two chromosomes, with one QTL-like peak approximately 1 megabase pair (Mb) in length, and another in a QTL-like peak approximately 20 Mb in length. Functional and in silico analyses revealed seven candidate genes for both study populations. Candidate gene function involved neurons and skeletal muscle, with two genes appearing in both lists. One compelling candidate gene produces defects in ion channels which do not produce any histopathological changes. This study suggests Spastic Syndrome is multi-genic and neuromuscular in nature.