Cerebellar involvement in murine sphingomyelinosis: a new model of Niemann-Pick disease.

Mice with sphingomyelinosis (spm) with a C57BL/KsJ inbred background showed hepatosplenomegaly as early as four weeks (wk) of age and cerebellar signs around seven wk. Almost all animals died by 14 wk. Sudanophilic lipid accumulated in the liver, spleen, and lymph nodes as well as in the brain. The striking neuropathological change was a marked atrophy of the cerebellum, where Purkinje cells were predominantly involved. Loss of Purkinje cells started at the age of six wk before the cerebellar signs had become evident clinically. The cell loss appeared to be more marked in the vermis than in the hemispheres. Cytoplasmic inclusions in most cells consisted of myelin figures composed of concentric membranous lamellae. These inclusions were found mainly in the Purkinje cells at an early stage; thereafter, they were widely distributed in the granule cells, Golgi cells, some glial cells, macrophages and endothelial cells. The neuronal inclusions were frequently located in the vicinity of the Golgi apparatus; there were no unusual mitochondrial configurations. The clinicopathological characteristics of the mutant mice are similar to those of the human Niemann-Pick disease type C.