Three major clinical variants of
Gaucher disease have been defined: Type I, chronic nonneuronopathic; Type II, acute neuronopathic; and Type III, subacute neuronopathic. In a search for the underlying molecular basis of the
neurological manifestations, the concentration and composition of
cholesterol,
phospholipids,
neutral glycosphingolipids, and
gangliosides were examined in cerebral and cerebellar cortices of five cases of Type II, eight cases of Type III, and one case of presumed Type I/III. In Type II the concentration of
glucosylceramide was 140-530 mumol/kg in cerebral cortex and 51-450 mumol/kg in cerebellar cortex, the highest values found in the most fulminant cases. These concentrations were 20-80 times greater than normal in cerebral cortex and 5-40 times normal in cerebellar cortex. In type III the concentration of
glucosylceramide was 37-65 and 59-1750 mumol/kg in cerebral and cerebellar cortex, respectively. The highest concentrations were found in the cerebellum of patients who had survived
splenectomy for several years. The
ceramide composition of the accumulated
glucosylceramide suggested that brain
gangliosides were the major precursors of the
glucosylceramide in brains of Type II but in cerebellar cortex in Type III was partly of extracerebral origin. The levels of
lactosylceramide and oligohexaosylceramides were slightly raised in all brain specimens from the Gaucher cases. The
ganglioside concentration was normal, whereas there was a certain increase in the proportion of GM2 and GM3
gangliosides. The brain
glycosphingolipid changes in the Type I/III case were similar but slightly less than those in Type III cases of corresponding age.
Glucosylsphingosine (
psychosine), never detected in normal human brain, was demonstrated in brains from all the Gaucher cases. The
psychosine concentration was highest in Type II cases, 3.8-8.8 and 3.9-12.3 mumol/kg in cerebral and cerebellar cortex, respectively, with the highest values found in the most fulminant cases. In type III the
psychosine concentration varied more widely, 0.8-4.6 and 1.4-6.3 mumol/kg in cerebral and cerebellar cortex, respectively. The lowest value, 0.7 mumol/kg, was found in the Type I/III case. Our method detected
psychosine down to 0.01 mumol/kg, which means that the concentration of
psychosine was increased at least 100- to 1000-fold in Gaucher grey matter. We suggest that the accumulation of the cell-toxic substance
psychosine is the basis for the extensive neuronal cell loss in
Gaucher disease, which is most striking in Type II disease.