Clinical and biochemical abnormalities in a feline model of GM2 activator deficiency.

Abstract

Though it has no catalytic activity toward GM2 ganglioside, the GM2 activator protein (GM2A) is essential for ganglioside hydrolysis by facilitating the action of lysosomal ß-N-acetylhexosaminidase. GM2A deficiency results in death in early childhood due to rapid central nervous system deterioration similar to the related GM2 gangliosidoses, Tay-Sachs disease and Sandhoff disease. This manuscript further characterizes a feline model of GM2A deficiency with a focus on clinical and biochemical parameters that may be useful as benchmarks for translational therapeutic research. The GM2A deficient cat has clinical features consistent with the human condition, including isointensity of gray and white matter of the brain on T2-weighted MRI; MR spectroscopic changes of brain metabolites consistent with gliosis, neuronal injury and demyelination; rhythmical slowing of cerebral cortical activation on electroencephalography; and elevation of aspartate aminotransferase and lactate dehydrogenase in cerebrospinal fluid. Biochemically, the brain of GM2A deficient cats has storage of GM2 and GA2 ganglioside coincident with increased hexosaminidase activity toward a standard synthetic substrate. Also, the brain of GM2A deficient cats has increased levels of lyso-platelet activating factor and lyso-phosphatidylcholine, which may serve as novel biomarkers of disease progression and provide insights into pathogenic mechanisms.