Feline sphingolipidosis resembling Niemann-Pick disease type C

Abstract

A 9-week old domestic short-hair kitten with progressive neurological dysfunction had histopathological lesions consistent with a lysosomal storage disease. Light microscopy of the brain, spinal cord, and ganglia revealed distention and vacuolation of many neuronal populations, and extensive neuroaxonal dystrophy. Large numbers of foamy macrophages were observed in the liver, spleen, lymph nodes, and lung. Hepatocytes appeared pale and swollen. Ultrastructural examination of all affected tissues and organs revealed heterogeneous membranous inclusions. Lipid analysis of liver revealed an excess of cholesterol, glucosylceramide, lactosylceramide and phospholipids including sphingomyelin. There was some increase in the levels of brain GM2 and GM3 gangliosides. Sphingomyelinase activity in liver was partially deficient or low normal. Skin fibroblasts were cultured from two affected cats from the colony established with littermates of the subject of this report. The cultured skin fibroblasts had partially decreased sphingomyelinase activity and a greatly decreased ability to esterify exogenous cholesterol. Clinical, morphological, and biochemical findings suggest that this cat had sphingolipidosis similar to human Niemann-Pick disease type C, a disease not previously described in the cat. The feline form of this storage disease may provide a useful model for studies on the human disease.

Metabolic abnormalities in feline Niemann‐Pick type C heterozygotes

“…Numerous features of this feline lipid storage disorder and human NPC are remarkably similar, and include onset and progression of clinical neurological signs and autosomal recessive inheritance. Neurovisceral storage is evident by light microscopy, with progressive neuronal cell loss, axonal spheroids, and ectopic neurites demonstrated (Lowenthal et at 1990;Brown et al 1994a,b). Biochemical analysis of storage material consists of unesterified cholesterol, glycolipids, sphingomyelin and other phospholipids in viscera, and gangliosides and glycolipids in the central nervous system (Lowenthal et al 1990;Brown et al 1994a,b).…”

“…A feline model of NPC has been established and characterized (Lowenthal and Walkley 1989;Lowenthal et al 1990;Brown et al 1994a,b;Mufiana et al 1994). Numerous features of this feline lipid storage disorder and human NPC are remarkably similar, and include onset and progression of clinical neurological signs and autosomal recessive inheritance.…”

Recognition and Diagnosis of Lysosomal Storage Diseases in the Cat and Dog

“…[2][3][4] Later, behavioral abnormalities and seizures may be seen, although these changes may also be found earlier in diseases such as globoid cell leukodystrophy in the Poodle, 21 fucosidosis, 1 and ceroid lipofuscinosis. 33,34 Neurovisceral phenotypes, so common in humans, are encountered in cats (examples include Niemann-Pick type C 26 and some cases of ␣-mannosidosis 2,46 ) and dogs (the canine G M1 gangliosidoses [10][11][12] ). Phenotypic heterogeneity is such, however, that a milder form of ␣-mannosidosis has been reported in domestic long-hair cats that lacks the skeletal pathology, ocular abnormalities, and hepatomegaly found in other feline models of the disease.…”

“…abnormalities of myelination in the peripheral and central nervous systems. Three cats with Niemann-Pick type A were reported with a demyelinating polyneuropathy, 47 although other cats with Niemann-Pick type A 23,24 and cats with Niemann-Pick type C 26,45 showed predominantly cerebellar signs or signs suggestive of more generalized central nervous system pathology.…”

Bidirectional links between Alzheimer's disease and Niemann–Pick type C disease

“…NPC is an autosomal recessive inherited panethnic disease caused by mutations in NPC1 (95% of families) or less frequently in HE1, referred to as NPC2 gene Naureckiene et al, 2000). In addition to human NPC1 disease, feline and murine models of NPC disease are also known, both of which were discovered after occurring spontaneously in normal mouse and cat colonies Lowenthal et al, 1990;Morris et al, 1982;Somers et al, 1999). NPC1/2 genes do not encode lysosomal enzymes unlike other genes involved in lysosomal storage diseases.…”