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Metabolic Disorders Gaucher Disease A Rare Condition in Haematological Practice – Gaucher Disease Maria-Domenica Cappellini Centro Anemie Congenite, Ospedale Maggiore Policlinico IRCCS, University of Milan, Italy Abstract Gaucher disease, which is caused by an inherited glucocerebrosidase deficiency, is the most prevalent lysosomal storage disease worldwide. Estimated prevalence of Gaucher disease is 1:50,000 in most countries and the disease has its highest incidence in the Ashkenazi Jewish population. Type 1 (non-neuropathic) Gaucher disease is by far the most common form. Gaucher disease type 1 should be considered in cases of unexplained splenomegaly with or without bleeding diathesis, skeletal manifestations or hepatomegaly. Diagnosis is made by demonstrating decreased glucocerebrosidase activity in peripheral blood leucocytes. Dried blood spots can be used for screening but conventional enzyme assay on heparinised blood is essential. Patients with Gaucher disease may have extensive organ involvement despite relatively minor overt symptomatology. Evidence suggests that Gaucher disease may remain undiagnosed for years, leading to severe complications that are preventable or reversible with enzyme replacement therapy. These complications include avascular necrosis, severe bleeding, chronic bone pain, pathological fractures, growth failure, liver pathology and life-threatening sepsis. Most patients with Gaucher disease are initially evaluated by a haematologist–oncologist. Improved education is needed to enable prompt detection of Gaucher disease. An increased risk of multiple myeloma and haematological and non-haematological malignancies has been reported in type 1 Gaucher disease. This review aims to offer familiarisation with a rare disorder in haematological practice, focusing on adult patient management. Keywords Gaucher disease, glucocerebrosidase, cancer, haematological malignancy, multiple myeloma, monoclonal gammopathy of undermined significance (MGUS), diagnosis, splenomegaly, thrombocytopenia Disclosure: Maria-Domenica Cappellini has the following conflicts of interest to declare: Sanofi/Genzyme advisory board, Novartis advisory board. Acknowledgements: Editorial assistance was provided by Catherine Amey at Touch Medical Media, London, UK, funded by Genzyme, a Sanofi Company. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. Received: 23 April 2015 Accepted: 13 May 2015 Citation: European Oncology & Haematology, 2015;11(1):15–20 Correspondence: Maria-Domenica Cappellini, Centro Anemie Congenite, Ospedale Maggiore Policlinico IRCCS, University of Milan, Italy. E: maria.cappellini@unimi.it Support: The publication of this article was supported by Genzyme, a Sanofi Company. Genzyme were given the opportunity to review the article for scientific accuracy before submission. Any resulting changes were made at the author’s discretion. Gaucher disease (OMIM #230800) is an inherited deficiency of lysosomal enzyme acid ß-glucosidase (glucocerbrosidase, GBA1; EC 3.2.1.45) due to mutations in the glucocerebrosidase gene, GBA1. 1 Genetic mutations affect the enzyme’s catalytic function, intracellular stability or subcellular trafficking. 2–4 Such enzyme deficiency results in the accumulation of glucocerebroside in lysosomes of macrophages (known as Gaucher cells, Figure 1), which are observed in many organs, primarily in the bone marrow, liver, spleen and lymph node parenchyma. The finding of an association between the GBA mutation in the heterozygous state and Parkinson’s disease indicates that there may be pathogenic roles for GBA mutations beyond enzyme deficiency. 5–7 Gaucher cells are typically 20–100 µm in diameter with eccentrically placed nuclei and cytoplasm with characteristic crinkles and striations. 8–10 However, untreated patients with type 1 Gaucher disease have recently been shown to display a considerable proportion of Gaucher cells with atypical cytomorphology. 11 The glucocerebroside concentration in spleens can be increased 10  to 1,000-fold, but high levels may also be present in the bone Tou ch ME dical ME d ia marrow and liver. 12 Glucosylceramide accumulation leads to variable combinations of: 13 • Splenomegaly with abdominal discomfort, often the presenting symptom of Gaucher disease. 14 • Anaemia with chronic fatigue. 15 • Spontaneous bruising and bleeding – due to thrombocytopenia and/or Gaucher disease-associated coagulopathy. 16 This is initially a result of enhanced blood cell clearance by the enlarged spleen. At a later disease stage, or in patients who have undergone a splenectomy, replacement of the bone marrow by Gaucher cells adds to cytopenia development. • Hepatomegaly and abnormal liver function. • Diverse bone disease manifestations, including chronic bone pain, acute bone crises, defective bone mineralisation, infarction, osteonecrosis, osteolysis and pathological fractures. 17 Skeletal disease affects more than 80 % of patients with Gaucher disease and can have a major impact on patient quality of life. 18,19 • Impaired neutrophil function and neutropenia may cause an increased susceptibility to infection. 20 15