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

Gaucher disease (GD) leads to accumulation of glucosylceramide (GL1) and its deacylated lysolipid, glucosylsphingosine (lyso-GL1) which is implicated in mediating immune dysregulation and skeletal disease. The aim of our study was to assess plasma Lyso-GL1 as a biomarker of GD and its response to therapy. Plasma lyso-GL1 in 169 patients with GD type 1 (GD1) was measured by LC-MS/MS. Significant predictors of were assessed by Pearson’s correlation coefficient, Wilcoxon Mann Whitney test and multiple linear regression. Propensity scores were used to match patients on treatment mode: Enzyme Replacement Therapy (ERT) vs Eliglustat Tartrate SRT (ELI-SRT). Lyso-GL1 levels in healthy controls on average was 1.5 ng/ml (1.3 – 1.7; 95% CI). In untreated GD patients, the levels were massively elevated (180.9 ng/ml: 95% CI, 145.4 – 216.5) and ERT resulted in marked reduction (89 ng/ml: 95% CI, 69.2 – 129.4) (p<0.001). Lyso-GL1 correlated with chitotriosidase (r=0.59 p<0.001), CCL18 (r= 0.62 p <0.001), hepatomegaly (r=0.28 p<0.001), splenomegaly (r=0.27 p=0.003), splenectomy (p=0.01) and treatment mode (p<0.001). By multiple linear regression, the strongest predictors of lyso-GL1 were age (p<0.001), splenectomy (p=0.02), Chitotriosidase (p<0.001) and CCL18 levels (p=0.001). After propensity score matching to obtain comparable groups of patients on ERT vs ELI-SRT, lyso-GL1 levels were lower among patients receiving ELI-SRT by 113 ng/ml (95% CI: 136 – 90.3 ng/ml p<0.001). Plasma lyso-GL1 is a key biomarker of GD. ERT reduced lyso-GL1 levels. By propensity scoring, ELI-SRT resulted in greater reduction of lyso-GL1 than ERT.

In Gaucher disease, defective lysosomal glucocerebrosidase due to mutations in the GBA1 gene results in lysosomal accumulation of glucocerebroside in mononuclear phagocytes and a multisystemic phenotype. Observations of occurrence of Parkinson's disease in some patients with non-neuronopathic type 1 Gaucher disease (GD1) and their first degree relatives has led to the identification of GBA1 heterozygous mutations as a genetic risk factor for idiopathic Parkinson's disease (PD). However, the magnitude of risk of PD in patients with known GD1 has not been determined, and it is not known whether GD1/PD represents a specific sub-phenotype of GD1 with distinctive genotype/phenotype characteristics. We estimated the risk of PD in a cohort of 444 consecutively evaluated patients with GD1 compared to that in the general population. Eleven patients developed parkinsonian syndrome during a 12-year follow-up period. The adjusted life-time NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript risk ratio of PD in GD1 compared to that in the general population was 21.4 [95% confidence interval (95% CI) 10.7-38.3], with a higher risk in men compared to women. In our cohort, GD1/Parkinson's disease phenotype (GD1/PD) was characterized by higher GD1 severity score, due to higher incidence of avascular osteonecrosis. The clinical spectrum of PD varied from mild to potentially life-threatening disease. All but one patient with GD1/PD phenotype had at least one N370S GBA1 allele. In conclusion, compared to the general population, patients with GD1 have an almost 20-fold increased life-time risk of developing PD.

Gaucher disease (GD) is a progressive macrophage lipidosis capable of causing disabling and life-threatening complications. Anecdotal experiences suggest that GD may go undiagnosed for many years, leading to severe complications that are preventable or reversible by enzyme replacement therapy (ERT) with imiglucerase. We conducted surveys of patients and Hematology-Oncology specialists to assess the frequency of diagnostic delays. Additionally, we report a series of patients who suffered diagnostic delays and as a result developed disabilities including potentially life-threatening manifestations of GD. Of 136 patients surveyed, the average time from first appearance of GD symptoms to final diagnosis was 48.7 ± 123.6 months. More than two-thirds were evaluated and managed by a Hematologist-Oncologist (Hem-Onc). A global survey of 406 Hem-Oncs found that only 20% considered GD in the differential diagnosis for all of its classic symptoms (cytopenia, hepatosplenomegaly, bone pain); the diagnosis considered most likely included leukemia, lymphoma, and multiple myeloma. To illustrate actual consequences of diagnostic delays, we describe 14 patients with GD who suffered from symptoms for up to 10 years before correct diagnosis. Diagnostic delays led to complications that are preventable or reversible with ERT (i.e., avascular necrosis, severe bleeding, chronic bone pain, life-threatening sepsis, pathologic fractures, growth failure, liver pathology). Patients homozygous for N370S mutation in this series were vulnerable to diagnostic delays. In conclusion, prolonged diagnostic delays occur in GD and may result in severe disease manifestations. Our findings suggest that physician education will increase the likelihood of prompt detection of GD and improve its management with ERT with imiglucerase when indicated. Am. J. Hematol. 82:697-701, 2007. V

Key Points• A new subset of human and murine type II NKT-T FH cells against Gaucher lipids that regulate B-cell immunity.• A novel pathway for B-cell help providing a mechanism underlying chronic B-cell activation and gammopathy in metabolic lipid disorders.Chronic inflammation including B-cell activation is commonly observed in both inherited (Gaucher disease [GD]) and acquired disorders of lipid metabolism. However, the cellular mechanisms underlying B-cell activation in these settings remain to be elucidated. Here, we report that b-glucosylceramide 22:0 (bGL1-22) and glucosylsphingosine (LGL1), 2 major sphingolipids accumulated in GD, can be recognized by a distinct subset of CD1d-restricted human and murine type II natural killer T (NKT) cells. Human bGL1-22-and LGL1-reactive CD1d tetramer-positive T cells have a distinct T-cell receptor usage and genomic and cytokine profiles compared with the classical type I NKT cells. In contrast to type I NKT cells, bGL1-22-and LGL1-specific NKT cells constitutively express T-follicular helper (T FH ) phenotype. Injection of these lipids leads to an increase in respective lipidspecific type II NKT cells in vivo and downstream induction of germinal center B cells, hypergammaglobulinemia, and production of antilipid antibodies. Human bGL1-22-and LGL1-specific NKT cells can provide efficient cognate help to B cells in vitro. Frequency of LGL1-specific T cells in GD mouse models and patients correlates with disease activity and therapeutic response. Our studies identify a novel type II NKT-mediated pathway for glucosphingolipid-mediated dysregulation of humoral immunity and increased risk of B-cell malignancy observed in metabolic lipid disorders. (Blood. 2015;125(8):1256-1271