ABSTRACT
Niemann-Pick disease type C (NPC disease) is an incurable cellular lipid-trafficking disorder characterized by neurodegeneration and intralysosomal accumulation of cholesterol and glycosphingolipids. Treatment with miglustat, a small imino sugar that reversibly inhibits glucosylceramide synthase, which is necessary for glycosphingolipid synthesis, has been shown to benefit patients with NPC disease. The mechanism(s) and extent of brain cellular changes underlying this benefit are not understood. To investigate the basis of the efficacy of miglustat, cats with disease homologous to the juvenile-onset form of human NPC disease received daily miglustat orally beginning at 3 weeks of age. The plasma half-life of miglustat was 6.6 ± 1.1 hours, with a tmax, Cmax, and area under the plasma concentration-time curve of 1.7 ± 0.6 hours, 20.3 ± 4.6 µg/mL, and 104.1 ± 16.6 µg hours/mL, respectively. Miglustat delayed the onset of neurological signs and increased the lifespan of treated cats and was associated with decreased GM2 ganglioside accumulation in the cerebellum and improved Purkinje cell survival. Ex vivo examination of microglia from the brains of treated cats revealed normalization of CD1c and class II major histocompatibility complex expression, as well as generation of reactive oxygen species. Together, these results suggest that prolonged Purkinje cell survival, reduced glycosphingolipid accumulation, and/or the modulation of microglial immunophenotype and function contribute to miglustat-induced neurological improvement in treated cats.
Subject(s)
1-Deoxynojirimycin/analogs & derivatives , Brain/pathology , Cat Diseases , Enzyme Inhibitors/administration & dosage , Microglia/drug effects , Niemann-Pick Disease, Type C , Purkinje Cells/drug effects , 1-Deoxynojirimycin/administration & dosage , 1-Deoxynojirimycin/blood , Animals , Antigens, CD/metabolism , Area Under Curve , Brain/drug effects , Case-Control Studies , Cats , Cell Survival/drug effects , Cholesterol/metabolism , Enzyme Inhibitors/blood , Follow-Up Studies , Gangliosidoses, GM2/metabolism , Microglia/metabolism , Niemann-Pick Disease, Type C/drug therapy , Niemann-Pick Disease, Type C/genetics , Niemann-Pick Disease, Type C/veterinary , Phagocytosis/drug effects , Phenotype , Postmortem Changes , Purkinje Cells/metabolism , Reactive Oxygen Species/metabolism , Sphingomyelins/metabolism , Sphingosine/metabolism , Time FactorsABSTRACT
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.
