GM ₂ Ganglioside Lysosomal Storage Disease in Cats with α-Hexosaminidase Deficiency

Abstract

Two kitteens with progressive neurologic disease had increased concentrations of GM2 ganglioside in their cerebral cortex. Examination under the light microscope revealed cytoplasmic vacuolation of neurons and hepatocytes. Transmission and scanning electron microscopy demosntrated cytoplasmic inclusions encompassed by membranes in various central nervous system cell types and in hepatocytes. Beta-D-N-acetyl-hexosaminidase activity was reduced to about 1.0 percent of normal in brain, liver, and cultured skin fibroblasts of the diseased kittens; both major electrophoretic forms, A and B, of the enzyme were deficient. In fibroblasts from the parents of the diseased kittens, this enzyme activity was intermediate between that of affected and normal cats, suggesting an autosomal recessive mode of inheritance of the enzyme defect. Histopahtological and ultrastructural lesions, glycolipid storage, enzyme defect, and pattern of inheritance are similar to those of human GM2 gangliosidosis type 2.

126. Comparative Analysis of brain lipids in Mice, Cats, and Humans with Sandhoff disease

“…In contrast to a previous study, which showed that GM2 was about 42% of the total brain ganglioside distribution in the SD cat, we show that GM2 accounts for 67% of the total ganglioside distribution in the SD cat (19). The ganglioside distribution in the SD cat in the previous study was analyzed at an earlier age (11 weeks), which could account for the lower GM2 distribution (19). For our study, we analyzed the total brain ganglioside distribution at a similar time-point in disease progression in the SD mouse, cat, and human, and we showed that GM2 accumulation in the SD cat is intermediate between the SD mouse and the SD patient.…”

“…The SD cats were obtained from the fG M2 Baker colony and have been previously described (17,19). Sequence analysis determined that the causative mutation in this domestic shorthair SD cat resulted from a 25-base-pair inversion at the 3' end of the Hexb gene (16).…”

“…While the CNS GM2 accumulation has been reported for the mouse and cat models of SD and in the patient (11,(19)(20)(21)(22), the comparative total lipid analysis has never been done. In particular, our objective was to analyze similar brain regions, at a similar phenotypic timepoint, using the same methodology to compare the total lipid distribution between mice, cats, and humans with SD.…”

“…The brain weight of the mouse is around 0.4 grams while an infantile human brain weighs around 400 grams, representing a 1000-fold difference in size (13)(14)(15). A naturally occurring, authentic model of SD in cats (fG M2 Baker) has been previously characterized and could potentially serve as an intermediate model between mouse and man (16)(17)(18)(19). Although the feline brain is closer in size and complexity to the human brain, it is not clear how the mouse and the cat animal models of SD compare to the human patient.…”

Rapid and Simple Polymerase Chain Reaction—Based Diagnostic Assays for GM2 Gangliosidosis Variant 0 (Sandhoff-Like Disease) in Japanese Domestic Cats

“…Therefore, deleterious mutations in the HEXB gene encoding the b-subunit of Hex molecules affect both Hex A and Hex B, producing the null (0) variant of GM2 gangliosidosis (human Sandhoff disease) and lysosomal storage of undegraded GM2 ganglioside in neurons as a major storage material. 5 In domestic animals, naturally occurring Sandhoff-like disease has been reported in only 2 canine breeds (i.e., a Golden Retriever 18 and toy Poodles 16 ) and 4 feline breeds or families (i.e., domestic cats in the United States, 4 Korat cats, 13 Japanese domestic cats, 19 and European Burmese cats 3 ). At present, the pathogenic mutations in all 4 feline families have been identified, 3,8,11,12 but not in canine breeds.…”