Bone complications occur frequently in Gaucher disease (GD) and reduce the quality of life of these patients. Skeletal involvement is an important indication for treatment to ameliorate symptoms and reduce the risk of irreversible and debilitating disease. Bone biomarkers have been used to assess disease status and the response to therapy in a number of bone disorders. Here, we examine the literature for evidence of abnormalities in bone turnover markers in patients with type 1 GD to assess whether they might be useful for the assessment of bone involvement in GD. We have found that bone biomarkers in GD show highly variable results which do not currently support their routine use for clinical assessment of bone status, as an indication for therapy initiation, or for monitoring the response to therapy. A greater understanding of bone markers and their relation to the bone manifestations of GD is required.
3780 Background: Gaucher Disease (GD) is an autosomal recessive hereditary disorder of glycosphingolipid metabolism, characterized by accumulation of glucosylceramide in cells of the reticulo-endothelial system, due to the deficient activity of the lysosomal enzyme glucocerebrosidase. Bone manifestations are frequent in GD; nevertheless the pathophysiology of skeletal involvement is still not well understood. Aim: to investigate the role of the bone turnover biochemical markers in GD. In particular we evaluated markers involved in bone formation: Osteoprotegerin (OPG), carboxyterminal propeptide of type I procollagen (PICP), osteocalcin (OST) and in bone resorption: receptor activator of nuclear factor (NF)-kb ligand (RANKL), tartrate resistant acid phosphatase (TRAP5b). Methods: Bone turnover biochemical markers were evaluated on sera obtained from 5 GD patients and 5 healthy subjects matched for age and sex, by Elisa commercial available kits according to the manufacturers‘ instructions. Results: In GD patients we observed an increase of RANKL and a significant reduction of OPG, with a consequent significantly lower OPG/RANKL ratio. Despite of higher levels of TRAP5b and lowest levels of PICP in GD compared to healthy subjects the differences did not achieve statistical significance, likely due to the small number of subjects involved in the study. No differences we observed in serum levels of OST compared with controls. Data (means ± DS) are reported in Table 1. Conclusions: Our data confirm the presence of unbalanced bone turnover in GD patients, characterized by an altered modulation of the OPG/RANKL system (due mainly to reduced expression of OPG, besides increased production of RANKL), an increased resorption phase (TRAP5b) and a decreased neoformation phase (PICP), all of them contributing to skeletal alterations characteristics of these patients. Disclosures: No relevant conflicts of interest to declare.
INTRODUCTION: Gaucher disease (GD) is a rare, autosomal recessive genetic disorder. It is due to a deficiency of the lysosomal enzyme, glucocerebrosidase, which leads to an accumulation of its substrate, glucosylceramide, in tissue macrophage with damage to hematological, visceral, and skeletal organ systems. Although GD has a continuous spectrum of severity, it is traditionally classified into three forms: type 1 (chronic; lacking early onset neuronopathy), type 2 (acute; with early onset neuronopathy),and type 3 (chronic; with early onsetneuronopathy). Type 1GD accounts for more than 90% all GD patients. Its prevalence world-wide is 1 in 50,000-100,000 but it is as high as ~1 in 850 in individuals of Ashkenazi heritage. Type 1 GD is frequently associated to monoclonal gammopathies; despite the emergence of theories advanced to explain these observations, the cause remains unknown. OBJECTIVE: Aim of the ongoing observational study is to determine the prevalence of unrecognized type I GD in a selected Italian population with MGUS. MATERIALS AND METHODS: From January 2018, dried blood spots (DBS) sample from patients with laboratory evidence of MGUS coming from five hematology units of Sicily and Calabria were collected and tested for the acid β-glucosidase enzyme activity. The study was approved by the local institutional review board. All patients provided informed consent for the prospective collection of their data. In case of DBS positive result, a confirmatory test was carried over and, if GD was confirmed, the patient was referred to one of the Regional Reference Centers for Metabolic Disease, as for current clinical practice in Italy. RESULTS: To date, 308 patients with MGUS were enrolled; acid β-glucosidase enzyme activity was low in 22 patients (7%). Sequence analysis of GBA gene was performed in these selected patients, but we have found only 4 patients with heterozygous mutation in the GBA1 gene, 1 homozygous(c.1226A>G -N370S) and 1 compound heterozygous (c.1226A>G -N370S and c.1448T>C -L444P); the last 2 patients had signs of GD (hepato-splenomegaly and mild thrombocytopenia). CONCLUSIONS: Type 1 GD remains a rare lysosomal storage disorder but preliminary results of our observational study show that it should be considered in the diagnostic framework of patients with MGUS, particularly when other GD symptoms are present. Disclosures Conticello: Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Di Raimondo:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy; Amgen: Consultancy, Honoraria, Research Funding.
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