P931: PROSPECTIVE OBSERVATIONAL MULTICENTER STUDY OF GAUCHER DISEASE PREVALENCE IN PATIENTS AFFECTED BY MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE

Abstract

Background: Gaucher disease (GD) is a rare, autosomal recessive genetic disorder, caused by deficiency of glucocerebrosidase, leading to glucosylceramide accumulation in tissue macrophages of hematological, visceral, and skeletal organ systems. Type 1 GD accounts for more than 90% all patients. Monoclonal gammopathy of undetermined significance is the most common plasma cell disorder, occurring in 3% of the population older than 50 years and is typically detected as an incidental finding. Type 1 GD It is frequently associated with polyclonal and monoclonal gammopathy (MGUS) and is hypothetically caused by long-term immune activation due to accumulated lysolipids, particularly glucosylsphingosine, although the cause remains unknown. Aims: We evaluated the prevalence of GD in MGUS patients, particularly when other signs and symptoms are present, in order to determine its potential usefulness as screening tool and inclusion in diagnostic framework of GD. Methods: Between January 2018 and February 2022, dried blood spots (DBS) samples were collected and tested for the acid β-glucosidase (glucocerebrosidase) enzyme activity from MGUS patients, both adult and pediatric, followed in seven hematology units of Sicily, Calabria and Naples. The glucocerebrosidase activity was measured with multiplexed tandem mass spectrometry (MS/MS) using the NeoLSD® assay system, and pathological range was within 0.2 and 2.5 nmol/h/ml. In case of DBS positive result, a confirmatory test was carried over in order to confirm the diagnosis of GD. The study was approved by the local institutional review board and supported by Sanofi Genzyme. All patients provided informed consent for the prospective collection of their data. Results: A total of 600 patients with MGUS was enrolled at last study update. Around half of the study population was male, with median age of 65 years. Immunoglobulin G was most frequently isolated with serum immunofixation, median level of monoclonal protein was 0.66 g/dL, while median kappa and lambda values based on monoclonal serum free light chain type were 24.8 mg/L and 32.7 mg/L, respectively. Out of 161 patients with available complete blood count median hemoglobin value was 13.5 g/dL with 15 patients having less than 11 g/dL, median platelet count was 224.000/mmc with 10 patients having less than 100.000/mmc platelets and median neutrophil count of 4.280/mmc and seven patients with less than 2.000/mmc neutrophils. Median ferritin level was 77 ng/mL, with more than 400 ng/mL in 10 patients. The median glucocerebrosidase activity in the entire cohort was 6.9 nmol/h/ml (range 0.3-58.8), with thirteen patients having pathological enzyme activity (median value 1.8 nmol/h/ml, range 0.2-2.5). Sequence analysis of GBA gene evidenced compound heterozygous mutation of the GBA1 gene in three patients (c.1226A>G - N370S and c.1448T>C -L444P in two and c.1226A>G -N370S and c.355G>A -G119R in one respectively), and homozygous mutation (c.1226A>G -N370S) in one patient associated with glucocerebrosidase activity below normal limits. All three patients with compound heterozygous mutational status had signs of GD (hepatosplenomegaly and mild thrombocytopenia). As for the rest of the MGUS patients, in a total of 114 patients sequence analysis evidenced single heterozygous mutation in 16 patients. Summary/Conclusion: Although type 1 GD remains a rare lysosomal storage disorder, patients with the diagnosis of MGUS could be considered for GD screening with DBS, especially when other symptoms (thrombocytopenia, splenomegaly, hyperferritinemia) are present.