Neuronopathic juvenile glucosylceramidosis due to sap-C deficiency: clinical course, neuropathology and brain lipid composition in this Gaucher disease variant

Glucosylceramide lipidosis results from a defective lysosomal degradation o f this glycolipid. Lipid degradation is controlled by two components, the e nzyme beta-glucocerebrosidase and a sphingolipid activator protein. While m ost Gaucher cases are due to mutations within the gene that codes for the l ysosomal enzyme, only two patients have been described with normal enzyme l evels and mutations in the gene for the sphingolipid activator protein C (s ap-C). Here we present the detailed neurological manifestations, neuropatho logical findings and brain lipid composition in one sap-C-deficient patient . The patient was an 8-year-old boy who presented with transient losses of consciousness, myoclonic jerks and generalized seizures resistant to all an tiepileptic drugs. He developed progressive horizontal ophthalmoplegia, pyr amidal and cerebellar signs, and died at the age of 15.5 years. Neuropathol ogical studies demonstrated neuronal cell loss and neuronophagia, massive i ntraneuronal lipid storage and lack of perivascular Gaucher cells. Electron microscopy examination showed different types of storage including lipofus cin granules as well as the cytosomes with parallel arrays of bilayers that are assumed to be formed by stored lipids. General brain lipid composition did not show a remarkable increase or loss of any of the major lipid fract ions but the glucosylceramide concentration in the cortex of several anatom ical regions showed a striking increase. Fatty acid composition of the cera mide moiety clearly suggests that gangliosides are the main precursors in t he cerebral cortex, while it implies an additional and distinct source in t he cerebellum. Studying the phenotypic consequences of mutant sphingolipid activator proteins is critical to a better understanding of the physiologic al significance of these proteins.