Abstract Glucosylceramide lipidosis results from a de- fective lysosomal degradation of this glycolipid. Lipid degradation is controlled by two components, the enzyme β-glucocerebrosidase and a sphingolipid activator protein. While most Gaucher cases are due to mutations within the gene that codes for the lysosomal enzyme, only two pa- tients have been described with normal enzyme levels and mutations in the gene for the sphingolipid activator pro- tein C (sap-C). Here we present the detailed neurological manifestations, neuropathological 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 antiepileptic drugs. He developed progres- sive horizontal ophthalmoplegia, pyramidal and cerebellar signs, and died at the age of 15.5 years. Neuropathologi- cal studies demonstrated neuronal cell loss and neu- ronophagia, massive intraneuronal lipid storage and lack of perivascular Gaucher cells. Electron microscopy exam- ination showed different types of storage including lipo- fuscin granules as well as the cytosomes with parallel ar- rays of bilayers that are assumed to be formed by stored lipids. General brain lipid composition did not show a re- markable increase or loss of any of the major lipid frac- tions but the glucosylceramide concentration in the cortex of several anatomical regions showed a striking increase. Fatty acid composition of the ceramide moiety clearly suggests that gangliosides are the main precursors in the cerebral cortex, while it implies an additional and distinct source in the cerebellum. Studying the phenotypic conse- quences of mutant sphingolipid activator proteins is criti- cal to a better understanding of the physiological signifi- cance of these proteins. Key words Neuronopathic Gaucher disease · Sphingolipid activator proteins (SAPs) · Glucocerebrosidase activator protein (sap-C) · Glucosylceramide · Gaucher brain Introduction Gaucher disease or glucosylceramidosis is characterized by the accumulation of glucosylceramide, primarily in the lysosomes of cells of the monocyte/macrophage system, caused by deficient activity of the lysosomal enzyme β- glucocerebrosidase (EC 3.2.1.45) [3]. Clinically, patients can be divided into three major phe- notypes: chronic non-neuronopathic (type 1); acute neu- ronopathic (type 2) (infantile), and subacute neuronopathic (type 3) (juvenile) [12]. Glucosylceramide accumulates largely in the spleen and liver in the three types with the main clinical differences being derived from the alterations in the nervous system. Since the isolation of the glucosyl- ceramidase gene, genetic heterogeneity has been widely studied in Gaucher disease patients and genotype/pheno- type relationships studied; correlation between mutations and a neuronopathic phenotype are often unclear [3]. For a number of years it has been known that hydroly- sis of glucosylceramide in vivo involves another compo- T. Pàmpols · M. Pineda · M. L. Girós · I. Ferrer · V. Cusi · A. Chabás · F. X. Sanmarti · M. T. Vanier · H. Christomanou Neuronopathic juvenile glucosylceramidosis due to sap -C deficiency: clinical course, neuropathology and brain lipid composition in this Gaucher disease variant Acta Neuropathol (1999) 97 : 91–97 © Springer-Verlag 1999 Received: 28 July 1997 / Revised: 22 June 1998 / Revised, accepted: 10 July 1998 CASE REPORT T. Pàmpols () · M. L. Girós · A. Chabás Institut de Bioquímica Clínica, Corporació Sanitària, C/. Mejía Lequerica, s/n, Edifici Helios III, Planta baixa, E-08028 Barcelona, Spain e-mail: tpampols@medicina.ub.es, Fax: +34-93-227-56-68 M. Pineda · F. X. Sanmarti Servicio de Neurología, Hospital de Sant Joan de Déu, Barcelona, Spain I. Ferrer Unidad de Neuropatología, Departamento de Anatomía Patológica, Hospital Principes de España, Hospitalet del Llobregat, Spain V. Cusi Servicio de Anatomía Patológica Hospital de Sant Joan de Déu, Barcelona, Spain M. T. Vanier INSERM U 189, Lyon-Sud Medical School and Fondation Gillet-Mérieux, Lyon-Sud University Hospital, Oullins, France H. Christomanou Laboratory of Neurochemistry and Molecular Biology, Oceanographic Biochemical Studies, Athens, Greece