GM2 gangliosidoses, cats also get it-at least in the model

Molecular Genetics and Metabolism 2025

Sidney J. Beecy a, Amanda L. Gross b, Anne S. Maguire b,c, Leah M.K. Hoffman b, Elise B. Diffie b,Paul Cuddon b, Pamela Kell d, Xuntian Jiang d, Heather L. Gray-Edwards a,*,Douglas R. Martin

Background
GM2 activator protein (GM2A) deficiency is a rare lysosomal storage disorder related to GM2 gangliosidoses, including Tay-Sachs and Sandhoff diseases. GM2A is an essential accessory protein for hydrolyzing GM2 ganglioside via lysosomal β-N-acetylhexosaminidase. Deficiency results in progressive neurodegeneration, typically fatal in humans during early childhood. The study characterizes a feline model of GM2A deficiency to provide benchmarks for translational therapeutic research.

Methods
Researchers utilized a colony of GM2A-deficient cats bred at Auburn University. Clinical features, enzyme activities, metabolite levels, and neuroimaging data were examined using methods such as:
-MRI and magnetic resonance spectroscopy (MRS) for structural and biochemical analysis.
-Electroencephalography (EEG) to evaluate cortical activity.
-Cerebrospinal fluid (CSF) analysis for enzymatic biomarkers.
-Histopathology for tissue changes. Biochemical assays included ganglioside quantification, lysosomal enzyme activities, and liquid chromatography-tandem mass spectrometry (LC-MS/MS).

Results
-Neuroimaging and Biochemical Markers: GM2A-deficient cats displayed white matter hyperintensity on T2-weighted MRI and altered brain metabolites, with gliosis markers (myoinositol) elevated and neuronal markers (N-acetylaspartate) reduced.

-Biochemical Findings: Significant accumulation of GM2 and GA2 gangliosides and increased lyso-platelet activating factor (lyso-PAF) levels were observed, serving as potential disease biomarkers.

-CSF Enzymes: Elevated aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) levels in CSF indicated neuronal damage.

-Histopathology: Widespread neuron enlargement and lipid storage in the central nervous system and liver were noted.

Limitations
The study was limited to a feline model, which may not fully replicate human disease phenotypes. Certain advanced biomarkers and therapeutic responses remain unvalidated in clinical settings.

Conclusions
The feline GM2A model recapitulates key clinical and biochemical aspects of the human disorder, making it a valuable tool for developing and testing novel therapies. Elevated lyso-PAF and altered metabolites offer promising biomarkers for disease progression and therapeutic efficacy. Continued research may guide therapeutic advancements for GM2A deficiency in humans.

T2-weighted, ultra-high field 7 T MRI of a normal cat (left) and GM2A deficient cat (right) at the level of the thalamus and parietal cortex (top), or cerebellum (bottom). Normal white matter is hypointense to (darker than) gray matter, but the GM2A brain has white matter (arrowheads) that is either hyperintense to (lighter than) or isointense to gray matter. These abnormalities reflect both lipid accumulation in gray matter and myelin loss from white matter. Brain atrophy is not pronounced in GM2A cats, which have approximately normal gyrus width, sulcus depth and CSF volume.

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