Niemann-Pick type C (NP-C) disease is a neurovisceral lysosomal storage disease characterized by neurologic dysfunction, hepatosplenomegaly, and early death. Natural history studies are very difficult to perform due to the low incidence and high heterogeneity of disease in the human population. Sixteen cats with a spontaneously occurring missense mutation in NPC1 were evaluated over time to define the progression of neurologic and hepatic disease. Affected cats had remarkably regular onsets of specific signs of cerebellar and vestibular system dysfunction with progressive severity of dysfunction quantified by postrotatory nystagmus and brain stem auditory evoked response measures. NP-C disease cats also showed increasing serum activity of alanine aminotransferase, asparate aminotransferase, and cholesterol with advancing age. Affected cats lived to a mean age of 20.5 +/- 4.8 wk. CNS and hepatic lesions were similar to those described in human patients. These data are the first to document progressive hepatic disease in the feline model and demonstrate the importance of liver disease as part of the NP-C disease phenotype. Both neurologic and hepatic measures of disease onset and severity can be used as a baseline with which to assess the efficacy of experimental therapies of NP-C disease in the feline model.