Late onset Tay-Sachs disease in mice with targeted disruption of the Hexa gene: behavioral changes and pathology of the central nervous system.

Tay-Sachs disease is an autosomal recessive neurodegenerative disease resulting from a block in the hydrolysis of GM2 ganglioside, an intermediate in ganglioside catabolism. The mouse model of Tay-Sachs disease (Hexa -/-) has been described as behaviorally indistinguishable from wild type until at least 1 year of age due to a sialidase-mediated bypass of the metabolic defect that reduces the rate of GM2 ganglioside accumulation. In this study, we have followed our mouse model to over 2 years of age and have documented a significant disease phenotype that is reminiscent of the late onset, chronic form of human Tay-Sachs disease. Onset occurs at 11-12 months of age and progresses slowly, in parallel with increasing storage of GM2 ganglioside. The disease is characterized by hind limb spasticity, weight loss, tremors, abnormal posture with lordosis, possible visual impairment, and, late in the disease, muscle weakness, clasping of the limbs, and myoclonic twitches of the head. Immunodetection of GM2 ganglioside showed that storage varies widely in different regions, but is most intense in pyriform cortex, hippocampus (CA3 field, subiculum), amygdala, hypothalamus (paraventricular supraoptic, ventromedial and arcuate nuclei, and mammilary body), and the somatosensory cortex (layer V) in 1- to 2-year-old mutant mice. We suggest that the Tay-Sachs mouse model is a phenotypically valid model of disease and may provide for a reliable indicator of the impact of therapeutic strategies, in particular geared to the late onset, chronic form of human Tay-Sachs disease.