Clinical and biochemical pathophysiology of ataxia in the sphingolipidoses

The sphingolipidoses are best defined as lysosomal storage disorders. Their manifestations can be explained on the basis of a few key principles that should all be verified before making a diagnosis. A genetic mutation may reduce the activity of a lysosomal hydrolase. Mutations of the hydrolases, respecting the active site, would not compromise their activity as tested in vitro but might interfere with the lysosomal functions. The undegraded substrates accumulate in the tissues where they are normally synthesized or taken up. The site and rate of storage define the clinical expression of the defect, which may include ataxia. Detailed, comprehensive, multidisciplinary studies emphasize the great complexity of the lysosomal storage disorders and the nonspecificity of single clinical, pathological, ultrastructural, or biochemical criteria. The possibility of inducing storage by chemical means points to aspects of the lysosomal physiology that have been neglected so far but that might also have genetic expression. Lysosomal hydrolases function in a controlled environment dependent on the lysosomal membrane, pH, and hypothetical dispersing agents. Any of these factors conceivably may be genetically impaired and give rise to apparently nonspecific storage.