High-Risk Population Screening for Gaucher Disease: Final Results and Key Learnings from an Italian Multicenter Observational Study

Background:Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder due to the deficiency of beta-glucosidase enzyme. Its prevalence in the non-Ashkenazy Jewish population is 1:40.000-100.000, whereas in Ashkenazy Jewish 1:500-1000. Patients present several hematological symptoms, including splenomegaly (86%), anemia (64%), thrombocytopenia (56%), bleeding, and MGUS, leading them to consult a hematologist on their diagnostic pathway. However, an international survey showed that only 20% of hematologists included GD in the differential diagnosis of a patient with anemia, thrombocytopenia, hepatomegaly, splenomegaly, and bone pain (Mistry PK, Am J Hematol 2007). Indeed, GD is underdiagnosed, patients experience long diagnostic delays, and misdiagnoses, leading to inappropriate procedures, treatments, and complications that often cannot be reversed by treatment. Half of the patients are diagnosed through bone marrow biopsy, although the diagnostic gold standard is the activity of beta-glucosidase on leukocytes or fibroblasts. Among the crucial obstacles to diagnosis, physicians identify the outsourced diagnostic test and, more importantly, the lack of awareness. Thus, ten years ago, a panel of experts published two diagnostic algorithms, one for the Ashkenazi and one for the non-Ashkenazi Jewish population, to facilitate the diagnosis of GD for hematologists (Mistry PK, Am J Hematol. 2011). Newborn screening has been experimented, showing an incidence of 1:22.205 (Burlina AB, J Inherit Metab Dis 2018). However, the large-scale implementation of newborn screening should be carefully evaluated. We hypothesized that an approach that combines the use of a diagnostic algorithm and a simple and cheap test could facilitate the diagnosis. Preliminary results of this study on 196 patients have been previously published, showing a prevalence of 3.6% of GD in a high-risk population (Motta I, Eur J Haem 2016).

Aim:The aim of this study was to evaluate the prevalence of GD in a high-risk population presenting to the hematologist for splenomegaly and/or thrombocytopenia associated with other hematological signs or symptoms suggestive for GD.

Methods:We designed a multicenter observational study among hematology centers in Italy. The study enrollment started in September 2010 and closed in December 2018. Inclusion and exclusion criteria were based on the published algorithm for the non-Ashkenazi population:

• Inclusion criteria: Splenomegaly and/or thrombocytopenia plus at least one among bone pain history, anemia, MGUS, polyclonal gammopathy in under 30 yrs, splenectomy;

• Exclusion criteria: onco-hematological diseases, portal hypertension due to liver diseases, hemoglobinopathies or chronic hemolytic anemias.

The beta-glucosidase activity tests on Dried Blood Spot (DBS) were centralized at Ospedale Gaslini, Genoa (Italy).

Results:500 subjects have been enrolled. 45 have been excluded because they did not fulfill the inclusion and exclusion criteria. The mean age at enrollment was 46.9±17.4 years, 31.9% (145/455) were females. The majority of enrolled patients had splenomegaly (89.7%), and approximately half (47.9%) thrombocytopenia associated with the other signs/symptoms. Anemia was the most frequent adjunctive sign (23.1%). The prevalence of GD was 3.3% (15/455, IC 95%: 1.9-5.4) in this high-risk population. In 14/15 of these patients, the molecular analysis of GBA gene identified the mutations. GD patients showed a significantly lower PLT count compared to non-GD patients (84.000/mm3 vs. 131.000/mm3, p<0.001) and significantly higher serum ferritin levels (551 ng/dL vs. 139 ng/dL, p<0.001). The mean Hb value was 12.9±2.1 g/dL in the GD and 13.3±2.4 in the non-GD group.

Interestingly, in the non-GD group, a patient was diagnosed with Acid Sphingomyelinase Deficiency (ASMD), previously known as Niemann Pick type B, which presents with similar signs and symptoms as GD.

Conclusions:High-risk population testing is effective in identifying Gaucher disease patients who present to the hematologist because of splenomegaly and/or thrombocytopenia. The use of DBS as a first-level tool is essential to facilitate patient testing. Because of the overlapping features of GD and ASMD, patients fulfilling the criteria applied to this protocol should be tested for both beta-glucosidase and acid-sphingomyelinase activity.