Primary Dysautonomia (PD), distinct from the entity called familial dysautonomia, is a condition that runs in families in which the autonomic nervous system (ANS) does not function correctly leading to a range of disabling disease symptoms. Despite the known fact that PD exhibits Mendelian inheritance patterns, an underlying genetic origin has not been identified. Treatments are solely based on alleviating symptomatology and there is no rationale for effectuating a cure. To help fill this knowledge gap and start identifying contributing factors to PD, we closely followed 69 families with a dominant Mendelian inheritance pattern of multiple shared symptoms including chronic orthostatic intolerance, chronic fatigue, primary focal hyperhidrosis, chronic itch, and generalized anxiety. We initiated whole-exome sequencing in these families with resulting data suggesting a causal relationship between PD and an autosomal dominant inheritance pattern of mutations in genes encoding voltage-gated sodium (Na_V) channels. This outcome is strengthened by the fact that we have treated family members with Na_V channel modulators which resolved many of their complaints. Based on preliminary results, we hypothesize that what appears pathophysiologically to link the diffuse autonomic symptoms, is a disease model in which mutations in Na_V channels can transform the ANS into an oversensitive hypervigilant nervous system that over time develops persistent disease. To start investigating the involvement of Na_V channel genes in PD, we devised a strategy to help elucidate the link between our targets and overactivation of the sympathetic nervous system. Our approach will create realistic animal models in which human therapeutics can be tested. We expect to generate the first genetic and physiological insights into the relationship between PD and the ANS which, in turn, can help lay the foundation for a treatment that dramatically improves the quality of life of these patients.