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

Abstract

Glucosylceramide lipidosis results from a defective lysosomal degradation of this glycolipid. Lipid degradation is controlled by two components, the enzyme beta-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 patients have been described with normal enzyme levels and mutations in the gene for the sphingolipid activator protein 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 progressive horizontal ophthalmoplegia, pyramidal and cerebellar signs, and died at the age of 15.5 years. Neuropathological studies demonstrated neuronal cell loss and neuronophagia, massive intraneuronal lipid storage and lack of perivascular Gaucher cells. Electron microscopy examination showed different types of storage including lipofuscin 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 fractions 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 consequences of mutant sphingolipid activator proteins is critical to a better understanding of the physiological significance of these proteins.

Lysosomal storage diseases: Diagnostic confirmation and management of presymptomatic individuals

“…10,127 In addition, patients with saposin C deficiency will be missed by determination of ␤-glucosidase enzymatic activity. 129,131,135 Abnormally low enzymatic test results can be further corroborated by the demonstration of increased glucosylceramide levels. 136 Reflecting the high levels of macrophage activation in GD patients, chitotriosidase 137 and CCL18/ PARC/MIP-418 138 show moderate to massive elevations in almost all patients.…”

Multi-system disorders of glycosphingolipid and ganglioside metabolism

“…Purkinje cell death is detected in 60 day old NPC1 mice that store cholesterol and multiple GSLs (GM2, GM3, GlcCer, and LacCer) ( 260 ). Decreased Purkinje cell numbers occur in human Sap C defi ciency ( 262 ) and Sap C Ϫ / Ϫ mice ( 193 ). Purkinje cell loss is also observed in Sap D-deficient mice ( 98 ).…”

“…In GM1 and GM2 gangliosidosis, axonal spheroids and dendritogenesis correlate with progressive ganglioside accumulation ( 271 ). In humans and mice with Sap C defi ciency, the soma of neurons and Purkinje cells have normal initial ultrastructure, but inclusion bodies and focal swellings of dendrites develop ( 193,262 ). Dysregulation of autophagosomes in axonal termini has been implicated in axon degeneration ( 272 ) but has not been explored in GSL LSDs.…”

A mutation within the saposin D domain in a Gaucher disease patient with normal glucocerebrosidase activity

“…In the present work we describe the identification of the second mutant allele in the last patient. The clinical and pathological data of this patient, who meets the clinical criteria of GD but has normal acid b-glucosidase activity, were previously described (Christomanou et al 1989;Pampols et al 1999).…”