A patient is described whose clinical course and pathologic features, including massive brain storage of GM2 ganglioside in grey matter, are identical with those of classical Tay-Sachs disease despite normal levels of beta -N-acetyl hexosaminidase and normal isozyme distribution. The kinetic properties and thermolability of the patient's hexosaminidase are normal. Crude extracts of a postmortem sample of patient's liver can catalyze the hydrolysis of 5.1 pmoles of labeled GM2 ganglioside/16 h/mg of protein (control liver = 69.9 pmoles/16 h/mg). Addition of partially purified human liver hexosaminidase A activator protein stimulated the hydrolysis of substrate by the patients liver extract by 27-fold compared to 3-fold for control livers. Measurement of "activator" in enriched fractions of patient's and control liver showed a reduced (25-30% of control) amount of stimulation of hexosaminidase A catalyzed hydrolysis of GM2 ganglioside as well as of Asialo-GM2 ganglioside. The addition of sphingomyelin to reaction mixtures, which is known to inhibit surfactant stimulation of hexosaminidase A, reduced activation of hexosaminidase A by patient's liver preparation to undetectable levels. Polyacrylamide gel electrophoresis of enriched preparations of control and patient's liver showed a rapidly migrating protein band in control liver corresponding to the activator protein and the absence of this protein band in the patient's liver.