Kurzfassung

Background: Gaucher Disease (GD) is a rare autosomal recessive hereditary disorder of glycosphingolipid metabolism, characterized by the accumulation of glucosylceramide in cells of the reticulo-endothelial system, due to deficient activity of the lysosomal enzyme, beta-glucosidase (glucocerebrosidase, EC 3.2.1.45). The clinical picture is different according to the three types of Gaucher disease: type I can manifest at any age and lacks neurological symptoms, whereas type 2 and type 3 are...Background: Gaucher Disease (GD) is a rare autosomal recessive hereditary disorder of glycosphingolipid metabolism, characterized by the accumulation of glucosylceramide in cells of the reticulo-endothelial system, due to deficient activity of the lysosomal enzyme, beta-glucosidase (glucocerebrosidase, EC 3.2.1.45). The clinical picture is different according to the three types of Gaucher disease: type I can manifest at any age and lacks neurological symptoms, whereas type 2 and type 3 are characterized by the presence of neurological involvement.
Gaucher disease type 1 is the most frequent form and presents with a broad spectrum of clinical manifestations varying in severity, age of manifestation, rate of progression and organs affected. Common manifestations are anaemia, thrombocytopenia, hepato-splenomegaly and bone disease. The skeletal manifestations of GD, which may lead to significant pain, disability and a progressive reduction in quality of life include abnormal bone remodelling, osteopenia, osteoporosis, lytic lesions, avascular necrosis, pathological fractures and vertebral collapse.
Enzyme replacement therapy (ERT) can improve some skeletal symptoms of GD, such as bone pain and bone crises after 1-2 years of treatment. However, BMD response can be slower and some bone complications, such as avascular necrosis, are irreversible despite optimal treatment.  Skeletal response to treatment is variable in GD on an individual basis and the pathophysiology of bone disease in Gaucher patients is not completely understood. Infiltration of Gaucher cells in the bone marrow exert a compressive effect but may also activate the production of inflammatory cytokines and / or accelerate bone turnover.  Signaling networks between osteoclasts and osteoblasts are central to the regulation of bone turnover. Activated osteoclasts have a role in regulating the activity of other cells, including osteoblast precursors, by participating in immune responses and by secreting cytokines that may affect their own function and those of other cells. Osteoclast formation, is dependent on the cytokine RANKL through binding to its cognate receptor RANK on the surface of osteoclast precursors while osteoprotegerin (OPG), a decoy receptor for RANKL, inhibits osteoclast differentiation and osteoclast activity.
A previous review of the current literature investigating bone disease and bone markers in Gaucher disease type 1 yields insufficient evidence for a good characterization of bone disease in terms of predictive markers and concludes that a greater understanding of bone markers and their relation to bone manifestations of GD is required. Most studies include rather small number of patients to allow conclusive remarks.  Our group investigated for the first time the impact of the FokI polymorphism in the gene of the vitamin D receptor on bone mass and bone dynamics under treatment (abstract DGIM, A. Zimmermann, poster price 2013). Further SNPs with impact on BMD and osteoporotic fracture risk had been described: vitamin D receptor (VDR), estrogen a receptor (ERa), collagen type I a1 gene (COL1A1), calcitonin receptor (CTR), osteoprotegerin (OPG). However, the current literature lacks data on genetic variability in skeletal involvement and response to treatment due to possible SNPs in genes relevant to bone mass in GD patients.
By analyzing bone disease in the context of genetic background and SNPs with possible impact on bone mass, we hope to be able to better understand the variability of bone disease response under ERT and hopefully identify predictive markers of good or poor response, in the setting of a pilot- explorative investigation.
Aim of study:
We aim to collect real life data from Romanian patients with Gaucher disease type 1 and to investigate dynamic changes of bone disease in these patients under ERT by assessment of BMD and bone markers in relation to:
SNPs with impact on bone mass;
clinical variables;
parameters of disease severity;
parameters of lipid and carbohydrate metabolism, of subclinical inflammation and adipokine profile (*).We aim to investigate bone disease and predictive biomarkers after appropriate substitution in vitamin D deficient patients and under antiresorptive treatment with bisphosphonates if osteoporosis is present (according to current guidelines in treatment of osteoporosis).
The choice of focusing on bone disease in this data collection under ERT is based on the fact that, while blood count and visceromegaly commonly displays a good response under ERT, bone response is often variable under treatment with up to date not well understood causality. Furthermore, the genetic background of the Romanian population is a particular one.
 
(*) Zimmermann A, Grigorescu-Sido P, Rossm,ann H, Lackner KJ, Drugan C, Al Khzouz C, Bucerzan S, Nascu I, Zimmermann T, Leucuta D, Weber MM. Dynamic changes of lipid profile in Romanian patients with Gaucher disease type 1 under enzyme replacement therapy: a prospective study. J Inherit Metab Dis 2013;36(3):555-63. doi: 10.1007/s10545-012-9529-3. 
 » weiterlesen» einklappen