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IntroductionGaucher disease, a relatively common recessively inherited lysosomal storage disorder, is caused by a deficiency in the enzyme glucocerebrosidase, encoded by the GBA gene. 1 Deficient enzymatic activity of glucocerebrosidase results in the lysosomal accumulation of its substrate glucosylceramide, most prominently in macrophages. Three variants of Gaucher disease are generally distinguished based on the absence (type 1) or presence of central nervous system involvement 1 (types 2 and 3). In the much more common type 1 variant of Gaucher disease, glycosphingolipidladen macrophages, referred to as Gaucher cells, accumulate in the visceral tissues liver, spleen, and bone marrow, inducing a pleiotropic array of symptoms, including hepatosplenomegaly and pancytopenia. In addition, type 1 Gaucher patients often develop bone complications: bone pain and crises, avascular necrosis, and pathologic fractures. 1 Two different types of therapeutic intervention are available for type 1 patients. One relies on chronic intravenous administration of recombinant glucocerebrosidase, denoted enzyme replacement therapy (ERT). 2 Two recombinant enzyme preparations are now registered for ERT in type 1 Gaucher disease: imiglucerase (Cerezyme; Genzyme Corp) and velaglucerase alfa (Vpriv; Shire HGT). 3 A third enzyme, a plant-cellexpressed recombinant glucocerebrosidase, is under clinical development (Taliglucerase; Protalix/Pfizer). 3 The other therapeutic intervention is based on oral administration of the iminosugar N-butyldeoxinojirimycin (Miglustat; Zavesca, Actelion). 4 This compound is thought to effectively lower synthesis of the accumulating metabolite, glucosylceramide, by inhibiting its synthesizing enzyme, glucosylceramide synthase. 5 The clinical responses to ERT are fast and impressive, such as significant corrections in hepatosplenomegaly, improvement of hematologic parameters and reduction of bone marrow infiltration as seen by magnetic resonance imaging. 6 The response to miglustat treatment is less prominent, and its use is authorized for mildly to moderately affected patients who are unsuitable for ERT (EMA) or in whom ERT is not a therapeutic option (FDA). 7 Future use of such small compounds for treating patients with a neuronopathic course of Gaucher disease is appealing given their potential to penetrate the brain (in contrast to recombinant enzyme). 8 The availability of costly therapies has stimulated searches for plasma biomarkers that can assist in clinical management of individual patients. Several circulating protein markers for Gaucher cells have meanwhile been identified (for a review see Aerts et al 9 ). It has been demonstrated that the enzyme chitotriosidase 10 and the chemokine CCL18 11 are produced by Gaucher cells and secreted into the circulation. Both proteins are candidate biomarkers since their plasma concentrations are markedly increased in symptomatic type 1 Gaucher patients and vary This article contains a data supplement.The publication costs of this article were defrayed in part b...

In nonneuronopathic type 1 Gaucher disease (GD1), mutations in the glucocerebrosidase gene (GBA1) gene result in glucocerebrosidase deficiency and the accumulation of its substrate, glucocerebroside (GL-1), in the lysosomes of mononuclear phagocytes. This prevailing macrophage-centric view, however, does not explain emerging aspects of the disease, including malignancy, autoimmune disease, Parkinson disease, and osteoporosis. We conditionally deleted the GBA1 gene in hematopoietic and mesenchymal cell lineages using an Mx1 promoter. Although this mouse fully recapitulated human GD1, cytokine measurements, microarray analysis, and cellular immunophenotyping together revealed widespread dysfunction not only of macrophages, but also of thymic T cells, dendritic cells, and osteoblasts. The severe osteoporosis was caused by a defect in osteoblastic bone formation arising from an inhibitory effect of the accumulated lipids LysoGL-1 and GL-1 on protein kinase C. This study provides direct evidence for the involvement in GD1 of multiple cell lineages, suggesting that cells other than macrophages may be worthwhile therapeutic targets.

Mutations in GBA1 gene that encodes lysosomal glucocerebrosidase result in Type 1 Gaucher Disease (GD), the commonest lysosomal storage disorder; the most prevalent disease mutation is N370S. We investigated the heterogeneity and natural course of N370S GD in 403 patients. Demographic, clinical, and genetic characteristics of GD at presentation were examined in a cross-sectional study. In addition, the relative risk (RR) of cancer in patients compared with age-, sex-, and ethnic-group adjusted national rates of cancer was determined. Of the 403 patients, 54% of patients were homozygous (N370S/N370S) and 46% were compound heterozygous for the N370S mutation (N370S/other). The majority of N370S/N370S patients displayed a phenotype characterized by late onset, predominantly skeletal disease, whereas the majority of N370S/other patients displayed early onset, predominantly visceral/hematologic disease, P < 0.0001. There was a striking increase in lifetime risk of multiple myeloma in the entire cohort (RR 25, 95% CI 9.17-54.40), mostly confined to N370S homozygous patients. The risk of other hematologic malignancies (RR 3.45, 95% CI 1.49-6.79), and overall cancer risk (RR 1.80, 95% CI 1.32-2.40) was increased. Homozygous N370S GD leads to adult-onset progressive skeletal disease with relative sparing of the viscera, a strikingly high risk of multiple myeloma, and an increased risk of other cancers. High incidence of gammopathy suggests an important role of the adaptive immune system in the development of GD. Adult patients with GD should be monitored for skeletal disease and cancers including multiple myeloma. Am. J. Hematol. 84:208-214, 2009. V