Clinical, Electrophysiological, and Serum Biochemical Measures of Progressive Neurological and Hepatic Dysfunction in Feline Niemann-Pick Type C Disease

Abstract

Niemann-Pick type C (NP-C) disease is a neurovisceral lysosomal storage disease characterized by neurological 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 neurological 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 post-rotatory 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 weeks. Central nervous system 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 neurological 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.

Identification of Niemann-Pick C1 disease biomarkers through sphingolipid profiling

“…Concomitant with the lipid accumulation, brains of Npc1 Ϫ / Ϫ mice exhibit microglial activation and infi ltration and expression of pro-infl ammatory mediators (16)(17)(18). The clinical, neuropathological, and biochemical abnormalities present in juvenile-onset patients are similarly faithfully modeled in a naturally-occurring feline model of NPC disease, which has a missense mutation in the Npc1 gene ( 19,20 ). Intervention with miglustat, an inhibitor of glycosphingolipid biosynthesis, or 2-hydroxypropyl-␤ -cyclodextrin (HP-␤ -CD), a cholesterol-binding agent, alleviates neuronal ganglioside (miglustat and HP-␤ -CD) and cholesterol (HP-␤ -CD) storage in the NPC1 mouse model, and markedly prolongs survival in NPC1 mouse and cat models (21)(22)(23)(24)(25)(26).…”

Niemann-Pick C disease and mobilization of lysosomal cholesterol by cyclodextrin

“…These studies have been particularly useful for understanding in which cells of the brain loss of NPC function is the most detrimental (see Loss of NPC Function in Cells of the Brain). As an alternative to mouse models of NPC disease, an NPC1-defi cient feline model was established ( 78,79 ) and has provided valuable information relevant to human NPC disease. Other models that have been used to elucidate pathways defective in NPC disease are mutants of yeast ( 80 ) and Drosophila ( 81,82 ).…”

Longitudinal changes in cerebellar and subcortical volumes in adult-onset Niemann–Pick disease type C patients treated with miglustat

“…The reasons for these apparently contradictory findings are unclear. It is possible that the non-progression of clinical ataxia as measured by the BARS in the patient group, in spite of cerebellar volume loss, could reflect an effect of treatment on other brain regions known to be affected in NPC, such as neurons in the basal ganglia [7,21], brainstem and vestibular system [22,25], or connecting white matter tracts [7,20]. The Iturriaga scale is a composite of a number of different motor deficits (manipulation, ambulation, language, and swallowing), and thus is presumed to reflect a broader range of motor circuits within the wider brain, and thus may capture a broader range of treatment effects in the CNS.…”