Current Opinion in Hematology:
MYELOID BIOLOGY: Edited by David C. Dale
Haematological manifestations and complications of Gaucher disease
Hughes, Derralynn A.a; Pastores, Gregory M.b
aDepartment of Haematology, Lysosomal Storage Disorders Unit, Royal Free Hospital and University College Medical School, London, UK
bDepartments of Neurology and Pediatrics, Neurogenetics Unit, University School of Medicine, NYU at Rivergate, New York, USA
Correspondence to Dr Derralynn A. Hughes, Department of Haematology, Lysosomal Storage Disorders Unit, Royal Free Hospital and University College Medical School, London, UK. Tel: +44 207 472 6588; fax: +44 207 830 2092; e-mail: email@example.com
Purpose of review: Gaucher disease is a rare inherited disorder of sphingolipid metabolism resulting in the accumulation of glucocerebroside substrate in cells throughout the reticuloendothelial system and clinical manifestations including cytopenias, organomegaly and bone disease. The clinical presentation is very variable and little has been understood of the determinants of heterogeneity or biological features that influence disease severity.
Recent findings: This review explores the haematological features of Gaucher disease in the context of new insights into the underlying cellular physiopathlogy. Careful examination of registry data has furthered understanding of individual risk factors for bone complications including fractures and osteonecrosis and for reduced or delayed response to enzyme replacement therapy. Analysis of substrates and their derivatives have added to possible biomarkers for assessment of disease burden and response to treatment and strikingly, in view of its rarity a genome-wide association study has identified a hitherto unsuspected gene as a potential modifier of severity.
Summary: Improved understanding of biological and clinical risk factors for severe manifestations of Gaucher disease will allow rational assessment of patients and suggests potential nonsubstrate directed adjuvant strategies to consider in the management of this condition.
Gaucher disease is an inherited disorder of sphingolipid metabolism, caused by deficiency of the lysosomal enzyme glucocerebrosidase (GBA). The resultant accumulation of the incompletely metabolized substrate, glucocerebroside, in cells of monocyte/macrophage lineage leads to anaemia, thrombocytopenia, hepatosplenomegaly, and bone complications such as osteonecrosis . Patients with type 1 Gaucher disease have also been shown to have a higher risk for gallstone formation, multiple myeloma and Parkinsonism.
Gaucher disease is an extremely heterogeneous condition with severe early manifestations in some, whereas others may exhibit a lifelong asymptomatic course. Primary neurologic involvement is encountered in a subset of patients, classified as having acute type 2 and subacute type 3 Gaucher disease. For the purposes of this review, the main focus will be on insights into type 1 Gaucher disease pathophysiology and possible determinants of severity.
INHERITANCE AND GENETICS
Gaucher disease is inherited as an autosomal recessive trait. Patients with type 1 Gaucher disease can present at any age from childhood to adulthood. Age at onset is partly influenced by the underlying mutations. Four common genotypes account for the majority of cases, namely N370S/N370S, N370S/L444P, N370S/84gg and L444P/L444P. N370S, commonly referred to as the mild allele, when found precludes the development of primary central nervous system disorder associated with type 2 and 3 Gaucher disease. Patients homozygous for the N370S mutation tend to follow a mild disease course with a later age of onset and slower progression, when compared with other combination of mutations. On the other hand, those with the L444P/L444P genotype tend to have severe disease, with neurologic complications in a significant proportion . There can be exceptions, and indeed some patients homozygous for N370S can show significant disorder. The basis for these observations is not fully understood; however, a recent genome-wide association study (GWAS) has revealed the surprising finding that the pattern of expression of a gene known as CLN8 may be a potential modifier. Loss of function mutations in CLN8 causes a late-infantile onset form of neuronal ceroid-lipofuscinosis. CLN8 may function as a sphingolipid sensor and/or be involved in glycosphingolipid trafficking, metabolic pathways implicated in Gaucher disease. The GWAS report, which examined a cohort of 139 N370S homozygous Ashkenazi Jewish patients, found overexpression of CLN8 may have a positive/protective modifying effect [3▪▪].
A significant number of patients with Gaucher disease seen by haematologists are detected by bone marrow biopsy, which reveals the presence of characteristic lipid-engorged macrophage expressing acid phosphatase, CD68, CD14 and HLA class II, but not CD11b, CD40 or dendritic cell markers. Additionally, Gaucher cells expressed CD163, CCL18 and interleukin-1 receptor antagonist, characteristic of alternatively activated or M2 macrophages . Pseudo-Gaucher cells, which represent macrophages induced by increased turnover in rapidly dividing tumour cells, have been described in several haematologic malignancies. They are indistinguishable by light microscope examination from typical Gaucher cells , and on electron microscopy they show heterogenous inclusions, cell debris and dense fibrillary bodies compared with typical tubular inclusions in Gaucher cells.
Anaemia, thrombocytopenia and to a lesser extent leukopenia are a consequence of bone marrow infiltration, compounded by splenic sequestration, and may be observed simultaneously or independently . Thirty-six per cent of patients enrolled in the international Gaucher registry were anaemic at diagnosis; however, there is no direct correlation between the degree of splenomegaly and cytopenia  suggesting that other mechanisms may be involved. These may include Gaucher cell infiltration into bone marrow , iron deficiency, alterations in iron metabolism and transport, vitamin B12 deficiency  and autoimmune haemolytic anaemia . Serum ferritin levels are often elevated, whereas other parameters such as serum iron, transferrin saturation coefficient and transferrin levels are normal. Clinical, biological and iron studies undertaken in 54 Gaucher disease patients (median age 32 years, range 12–73 years) did not show any differences between those with and those without hyperferritinaemia (defined as >400 and ≤400 μg/l, respectively) [11–13].
Severe thrombocytopenia (platelets less than 60 000/μl) was demonstrated in 15% of patients enrolled in the International Collaborative Gaucher Group Gaucher Registry, 45% had moderate thrombocytopenia (platelets >60 000 to <120 000 per μl) and 40% mild thrombocytopenia (platelets >120 000 to <150 000 per μl) . As with anaemia, thrombocytopenia is also related to hypersplenism and/or infiltration of bone marrow, but with no direct correlation to the degree of splenomegaly . Patients with Gaucher disease and autoimmune haemolytic anaemia or idiopathic thrombocytopenic purpura have also been described, and therefore immune complications should be excluded in atypical cases wherein the clinical course is associated with rapid decline in blood counts or failure to improve with Gaucher-specific therapy [16▪].
Treatment of Gaucher disease-related anaemia has depended historically on blood product transfusions, splenectomy and more recently enzyme replacement therapy to restore haemoglobin to agreed therapeutic targets . Anaemic Gaucher disease patients are able to mount an appropriate erythropoietin (EPO) response ; however, there is little data regarding the use of EPO to treat anaemia since the introduction of enzyme replacement therapy (ERT). In type 2 Gaucher disease, the most severe phenotype characterized by anaemia and neurological dysfunction, and endoplasmic reticulum (ER) stress, exogenous EPO-stimulated signalling pathways enhanced the expression of GBA, reduced ER stress marker protein levels, and enhanced the proliferation rate of type 2 Gaucher disease patient cells [19▪].
Patients with Gaucher disease are at risk for bleeding, caused primarily by severe thrombocytopenia; however, it has been noted that the extent of the bleeding tendency is out of proportion to the platelet count suggesting concurrent abnormalities of platelet function and coagulation factors. For example, there may be coinheritance of genetic factor XI deficiency among Ashkenazi Jewish patients. A study of coagulation and fibrinolysis in 30 type 1 Gaucher disease patients revealed activated partial thromboplastin time (aPTT) and prothrombin time (PT) were prolonged in 42 and 38%, respectively. Markers for activation of coagulation (thrombin–antithrombin complex) and fibrinolysis (PAP complex, fibrin cleavage product D-dimer) were significantly elevated, especially in the splenectomized patients. In these patients, the deficiencies were attributed to consumption of coagulation factors caused by ongoing low-level coagulation activation, possibly due to mononuclear cell activation . Furthermore, elevated D-dimer levels have been correlated with development of osteonecrosis . In a study of newly diagnosed and previously treated Egyptian patients, factors II, V and VII and fibrinogen were deficient in all newly diagnosed patients and factors V, VII, VIII, X, XI and XII were noted to be reduced to various extents in patients receiving ERT . In another case, a 15-year-old boy was reported to present with epistaxis, prolonged aPPT and reduced factor VIII and Von Willebrand levels which improved after desmopressin. This was thought to be an acquired type I von Willebrand disease as aPTT, PT, vWfAg, vWf Rcof, factor VIII level and bleeding times were all normal at different times .
Type 1 Gaucher disease patients have also been found to have platelet function abnormalities including significantly lower platelet adhesion, associated with mucosal bleeding; mixing tests showed that the reduced adhesion was an intrinsic platelet defect and was not affected by the use of disease-specific ERT .
Abnormalities of haemostatic factors, reduced platelet numbers and dysfunction result in increased risk of bleeding, for example, during dental and major surgical procedures. Attention to local haemostasis has allowed safe invasive procedures, with platelet transfusions being given only to patients considered high risk on the basis of a bleeding score [25▪]. Pregnancy also has the potential to exacerbate Gaucher disease manifestations, and the risk of bleeding during delivery may be increased in women with Gaucher disease. In one study, 78.6% of women with impaired platelet aggregation developed postpartum haemorrhage during at least one delivery, as opposed to 16.7% of those with normal platelet function tests. Enzyme replacement therapy before and during pregnancy has demonstrated benefits in reducing the risk of spontaneous abortion and Gaucher disease-related complications, especially bleeding during delivery and postpartum [26,27].
Enlargement of the liver and spleen are common in untreated Gaucher disease type 1, and splenic nodules which can be mistaken for malignancy may be seen, particularly in individuals with massive splenomegaly (Fig. 1). Liver function is usually normal, although hyperbilirubinaemia may be observed in patients of Askenazi Jewish ancestry due to Gilbert syndrome. Earlier reports of abnormalities in liver function tests may in some part have been due to hepatitis, acquired with blood transfusion. There are several reports of patients with Gaucher disease and hepatic failure who have undergone liver transplantation, although in most cases a secondary problem has been identified (e.g. hepatitis C) .
Bone involvement is a source of significant morbidity among untreated patients with progressive disease (Fig. 2). Reported complications include osteoporosis, vertebral compression fracture and osteonecrosis of the femoral head. Clinically, patients may experience an episode of bone pain (‘bone crisis’) involving one limb or joint, not unlike that observed in patients with sickle cell anaemia. Local findings such as erythema and swelling require distinction from osteomyelitis. Recent work has more clearly defined the risk factors for significant bone disease, including splenectomy, and importantly confirmed the relationship between low bone density and fracture risk in Gaucher disease [29▪▪]. The underlying pathophysiology of Gaucher disease bone manifestations is still the focus of active research. Recent work in a murine model of Gaucher disease has demonstrated abnormalities of osteoblast differentiation indicating that bone formation as well as degradation may be affected and importantly that Gaucher disease may involve cells outside of the reticuloendothelial system . Characerization of mesenchymal stromal cells (MSC) obtained from adult patients with type 1 Gaucher disease revealed a three-fold increase in cellular glucocerebroside content. Although affected MSCs have a typical MSC marker phenotype and normal osteocytic and adipocytic differentiation, there was a marked increase in cyclo-oxygenase-2, prostaglandin E2, interleukin-8 and CCL2 production compared with normal controls . These changes suggest a potential role of mesenchymal-derived cells in the genesis of skeletal disease and gammopathy observed in Gaucher disease patients, in addition to the primary macrophage transformation related to lipid storage.
Gaucher disease is frequently associated with immunologic abnormalities, for example, hypergammaglobulinaemia, polyclonal gammopathy and benign monoclonal gammopathy. Studies have also shown an increased rate of various malignancies and in particular multiple myeloma [32–35]. A patient with Gaucher disease and a selective accumulation of IgM kappa in Gaucher cells but without serum monoclonal gammopathies has recently been described . Furthermore, the JAK2V617F mutation has been found in a patient with splenomegaly and hypersplenism associated with Gaucher disease. The authors speculate that the progression to myeloid metaplasia–myelofibrosis may have been abetted by an abnormal bone marrow milieu attributable to Gaucher cell infiltration .
Patients with Gaucher disease have also been found to have an increased risk for Parkinson's disease, and conversely GBA mutations have been identified in Parkinson's disease patients, with Parkinson's disease patients over five-times more likely to carry GBA mutations than the general healthy population. Studies have shown Gaucher disease patients generally have an earlier onset of Parkinson's disease and more cognitive impairment than those without GBA mutations [38,39]. The basis for the relationship is not fully understood, but studies have indicated the presence of a GBA mutation and/or lipid accumulation may inhibit the clearance of and/or promote the aggregation of α-synuclein [40▪▪].
BIOMARKERS AND SEVERITY
Assessment of disease severity is based on a comprehensive evaluation, including blood tests, MRI or ultrasound for measurement of liver and spleen volume, and a combination of modalities to evaluate trabecular and compact bone disease, including radiographs, bone densitometry by dual energy X-ray absorptiometry and MRI to assess the severity of bone marrow infiltration. Several scoring systems have been developed, more recently incorporating quantitative assessments of organ volume and bone disease [1,41,42].
The utility of a number of biomarkers correlating with baseline disease severity and treatment effects have been evaluated (Fig. 3). The activity of serum chitotriosidase enzyme is increased in Gaucher disease patients , and less markedly so in other lysosomal storage disorders wherein macrophages are activated including Niemann–Pick disease, GM1-gangliosidosis and Krabbe disease. Among Gaucher disease patients, there are no known differences in clinical presentation or course among 40% of white extraction who are heterozygous or homozygous for a common null mutation, c.1049_1072dup24 (dup24) . The plasma chemokine CCL18 has also been found to be elevated in Gaucher disease and decreases during therapy .
Other markers found elevated in patients include tartrate-resistant acid phosphatase, angiotensin converting enzyme, and macrophage inflammatory protein (MIP)1α and β. The significance of these findings is uncertain, although elevated MIP1α has been correlated with severity of bone disease . Despite the presence of significant bone involvement, evaluation of markers of bone turnover in blood and urine has not shown a consistent pattern of abnormalities. These observations have limited their use in the follow up of individual patients [47,48▪].
Levels of the glucocerbrosidase substrate, glucosylceramide, in the plasma of untreated patients are on average three-fold increased compared with controls, and correlate with disease severity and biomarker changes. Gaucher-specific therapies, as expected, resulted in decreases in plasma glucosylceramide which may, therefore, be useful for disease monitoring . Recently glucosylsphingosine, the deacylated form of glucosylceramide, has also been found markedly elevated in plasma of symptomatic type 1 Gaucher patients, correlating with other biomarkers and declining with therapy [50▪].
Intravenously administered ERT has been shown to be safe and effective in reversing and/or stabilizing several cardinal features of Gaucher disease, associated with an improvement in health-related quality of life . Currently, there are three recombinant enzyme formulations, distinguished by the cell lines from which they have been generated: imiglucerase (Chinese Hamster Ovary cells) , velaglucerase (human cells)  and taliglucerase (carrot cells) .
The introduction of ERT has obviated the need for measures such as splenectomy, previously undertaken in symptomatic patients. Studies have shown enzyme dose–response relationships, although a range of doses has been used to start therapy with outcomes that are largely satisfactory in most treated individuals. Antibodies, primarily IgG, against the various recombinant enzyme formulations have been detected, and except in isolated report of patients with neutralizing antibodies, their presence does not appear to adversely influence outcome . Most patients tolerate the infusions, and most of those who experience adverse reactions during an infusion can continue with treatment, administered at a slower rate and with the use of premedications, primarily antihistamine, occasionally steroid.
Recent studies of patients on ERT have begun to examine determinants of outcome. Understandably, preexisting disorder is likely a major factor, with osteonecrosis and focal splenic lesions due to fibrosis not reversible with therapies targeted at reducing or eliminating substrate burden . These factors have to be considered in setting therapeutic goals, and when contemplating dose adjustments once disease stability has been achieved. For instance, thrombocytopenia may persist in patients with massive splenomegaly at the time of treatment initiation, with platelets increasing only when spleen volume has decreased substantially [16▪]. Moreover, the presence of focal splenic lesions also appear to influence final platelet counts.
Oral substrate reduction therapy is an alternative approach, based on partial inhibition of substrate synthesis as a means of reducing substrate burden to match the residual activity of the mutant enzyme. Miglustat, an iminosugar, is the first oral treatment to become available [57,58]. A second agent, eliglustat, currently in clinical trials, has also been shown to be effective [59,60].
Gaucher disease is a rare inherited disorder but, whilst specific therapy by enzyme replacement has now been available for two decades, aspects of pathophysiology and in particular determination of disease severity remain incompletely understood. Recent studies have improved knowledge of clinical and biological factors, which can be used to measure and predict disease severity. Further research should now be directed towards the mechanisms by which such factors such as the CLN8 gene and deacylated substrate glocosylsphingosine relate to disease manifestations, which may serve as potential new therapeutic targets to optimize outcome.
Conflicts of interest
D.A.H. has received travel and research grants, honoraria for speaking and advisory boards from Genzyme, Shire HGT and Actelion, and consultancy fees via UCL business from Shire HGT and Actelion.
G.M.P. is the recipient of research grants/support from Actelion, Amicus, Biomarin, Genzyme/Sanofi, Protalix/Pfizer, and Shire HGT, pharmaceutical/biotechnology companies engaged in drug development programmes for the lysosomal storage disorders.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 70–71).
1. Zimran A, Kay A, Gelbart T, et al. Gaucher disease. Clinical, laboratory, radiologic, and genetic features of 53 patients. Medicine (Baltimore) 1992; 71:337–353.
2. Pastores GM, Hughes DA. Gaucher Disease (February 2011) in: Gene reviews at genetests – medical genetics information resource. Copyright, University of Washington, Seattle; 1997–2010. http://www.genetests.org
. [Accessed 21 July, 2011]
3▪▪. Zhang CK, Stein PB, Liu J, et al. Genome-wide association study of N370S homozygous Gaucher disease reveals the candidacy of CLN8 gene as a genetic modifier contributing to extreme phenotypic variation. Am J Hematol 2012; 87:377–383.
An important study by whole-genome genotyping for more than 500 000 single nucleotide polymorphisms (SNPs) in 139 patients with Gaucher disease. Several SNPs in linkage disequilibrium within the CLN8 gene locus were associated with the Gaucher disease type 1 severity. Results indicated that increased expression of CLN8 may protect against severe Gaucher disease type 1. In an in-vitro cell model of Gaucher disease, CLN8 expression was increased especially in the presence of glucosylsphingosine. CLN8 is, therefore, a candidate modifier gene for Gaucher disease type 1.
4. Boven LA, van Meurs M, Boot RG, et al. Gaucher cells demonstrate a distinct macrophage phenotype and resemble alternatively activated macrophages. Am J Clin Pathol 2004; 122:359–369.
5. Alterini R, Rigacci L, Stefanacci S. Pseudo- Gaucher cells in the bone marrow of a patient with centrocytic nodular non-Hodgkin's lymphoma. Haematologica 1996; 81:282–283.
6. Zimran A, Altarescu G, Rudensky B, et al. Survey of hematological aspects of Gaucher disease. Hematology 2005; 10:151–156.
7. Gielchinsky Y, Elstein D, Hadas-Halpern I, et al. Is there a correlation between degree of splenomegaly, symptoms and hypersplenism? A study of 218 patients with Gaucher disease. Br J Haematol 1999; 106:812–816.
8. Poll LW, Koch JA, Willers R, et al. Correlation of bone marrow response with hematological, biochemical, and visceral responses to enzyme replacement therapy of nonneuronopathic (type 1) Gaucher disease in 30 adult patients. Blood Cells Mol Dis 2002; 28:209–220.
9. Gielchinsky Y, Elstein D, Green R, et al. High prevalence of low serum vitamin B12 in a multiethnic Israeli population. Br J Haematol 2001; 115:707–709.
10. Haratz D, Manny N, Raz I. Autoimmune hemolytic anemia in Gaucher's disease. Klin Wochenschrift 1990; 68:94–95.
11. Grosbois B, Revest M, Decaux O. Major hyperferritinemia, autoimmune thrombocytopenic purpura and lymphocytic lymphoma in Gaucher disease. Presse Med 2009; 38 (Suppl 2:2):S56–S57.
12. Mekinian A, Stirnemann J, Belmatoug N, et al.
Ferritinemia during type 1 Gaucher disease: mechanisms and progression under treatment. Blood Cells Mol Dis 2012; 49:53–57.
13. Stein P, Yu H, Jain D, Mistry PK. Hyperferritinemia and iron overload in type 1 Gaucher disease. Am J Hematol 2010; 85:472–476.
14. Hughes DA, Capellini MD, Berger M, et al
. Recommendations for the management of haematological and onco-haematological aspects of Gaucher disease. Br J Haematol 2007; 138:676–686.
15. Weinreb NJ, Charrow J, Andersson HC, et al. Effectiveness of enzyme replacement therapy in 1028 patients with type 1 Gaucher disease after 2 to 5 years of treatment: a report from the Gaucher Registry. Am J Med 2002; 113:112–119.
16▪. Hollak CE, Belmatoug N, Cole JA, et al. Characteristics of type I Gaucher disease associated with persistent thrombocytopenia after treatment with imiglucerase for 4-5 years. Br J Haematol 2012; 158:528–538.
A registry analysis of platelet responses to ERT. The authors suggest that platelet responses may only be seen once spleen volume has passed a substantial threshold.
17. Pastores GM, Weinreb NJ, Aerts H, et al. Therapeutic goals in the treatment of Gaucher disease. Semin Hematol 2004; 41 (4 Suppl 5):4–14.
18. Sidransky E, Ginns EI. Erythropoietin levels in Gaucher patients. Am J Hematol 1992; 40:153–154.
19▪. Cha JR, Kim SJ, Heo TH. Protective effect of recombinant human erythropoietin in type II Gaucher disease patient cells by scavenging endoplasmic reticulum stress. Biomed Pharmacother 2011; 65:364–368.
Explores the effect of recombinant EPO on type 2 Gaucher disease cells, finding a number of beneficial effects which not only suggest therapeutic strategies but insights into pathology in Gaucher disease type 2.
20. Hollak CE, Levi M, Berends F, et al. Coagulation abnormalities in type 1 Gaucher disease are due to low-grade activation and can be partly restored by enzyme supplementation therapy. Br J Haematol 1997; 96:470–476.
21. Shitrit D, Rudensky B, Zimran A, Elstein D. D-dimer assay in Gaucher disease: correlation with severity of bone and lung involvement. Am J Hematol 2003; 73:236–239.
22. Deghady A, Marzouk I, El-Shayeb A, Wali Y. Coagulation abnormalities in type 1 Gaucher disease in children. Pediatr Hematol Oncol 2006; 23:411–417.
23. Tavil B, Balci YI, Karacan C, et al. Acquired von Willebrand disease in a Turkish boy with Gaucher disease. Pediatr Hematol Oncol 2007; 24:317–319.
24. Spectre G, Roth B, Ronen G, et al. Platelet adhesion defect in type I Gaucher disease is associated with a risk of mucosal bleeding. Br J Haematol 2011; 153:372–378.
25▪. Givol N, Goldstein G, Peleg O, et al. Thrombocytopenia and bleeding in dental procedures of patients with Gaucher disease. Haemophilia 2012; 18:117–121.
Suggests rational basis for calculation of bleeding risk in Gaucher disease patients prior to dental surgery and strategies to avoid platelet transfusion.
26. Granovsky-Grisaru S, Belmatoug N, vom Dahl S, et al. The management of pregnancy in Gaucher disease. Eur J Obstet Gynecol Reprod Biol 2011; 156:3–8.
27. Simchen MJ, Oz R, Shenkman B, et al. Impaired platelet function and peripartum bleeding in women with Gaucher disease. Thromb Haemost 2011; 105:509–514.
28. Ayto RM, Hughes DA, Jeevaratnam P, et al. Long-term outcomes of liver transplantation in type 1 Gaucher disease. Am J Transplant 2010; 10:1934–1939.
29▪▪. Khan A, Hangartner T, Weinreb NJ, et al. Risk factors for fractures and avascular osteonecrosis in type 1 Gaucher disease: a study from the International Collaborative Gaucher Group (ICGG) Gaucher Registry. J Bone Miner Res 2012; 27:1839–1848.
Registry analysis of risk factors for fractures and avascular necrosis. After controlling for sex, year of birth, treatment status and splenectomy status, concurrent anaemia was found to be associated with an increased risk for avascular necrosis. Low bone mineral density of the lumbar spine was a strong risk factor for fractures of the spine and femur in Gaucher disease type 1 demonstrating this relationship for the first time in Gaucher disease.
30. Mistry PK, Liu J, Yang M, et al. Glucocerebrosidase gene-deficient mouse recapitulates Gaucher disease displaying cellular and molecular dysregulation beyond the macrophage. Proc Natl Acad Sci U S A 2010; 107:19473–19478.
31. Campeau PM, Rafei M, Boivin MN, et al. Characterization of Gaucher disease bone marrow mesenchymal stromal cells reveals an altered inflammatory secretome. Blood 2009; 114:3181–3190.
32. Grosbois B, Rose C, Noël E, et al. Investigators of the French Observatoire on Gaucher Disease. Gaucher disease and monoclonal gammopathy: a report of 17 cases and impact of therapy. Blood Cells Mol Dis 2009; 43:138–139.
33. de Fost M, Out TA, de Wilde FA, et al. Immunoglobulin and free light chain abnormalities in Gaucher disease type I: data from an adult cohort of 63 patients and review of the literature. Ann Hematol 2008; 87:439–449.
34. Costello R, O’Callaghan T, Sébahoun G. Gaucher disease and multiple myeloma. Leuk Lymphoma 2006; 47:1365–1368.
35. Rosenbloom BE, Becker P, Weinreb N. Multiple myeloma and Gaucher genes. Genet Med 2009; 11:134.
36. Alterini R, Rigacci L, Stefanacci S, et al. Immunohistochemistry applied to the study of bone marrow Gaucher 's cells: a case report. Eur J Histochem 1999; 43:235–239.
37. Webb BD, Weinreb NJ, Botti AC, et al. JAK2V617F mutation and myeloproliferative malignancy in a patient with Type 1 Gaucher disease. Blood Cells Mol Dis 2011; 46:103–104.
38. Bultron G, Kacena K, Pearson D, et al. The risk of Parkinson's disease in type 1 Gaucher disease. J Inherit Metab Dis 2010; 33:167–173.
39. Almeida Mdo R. Glucocerebrosidase involvement in Parkinson disease and other synucleinopathies. Front Neurol 2012; 3:65.
40▪▪. Mazzulli JR, Xu YH, Sun Y, et al. Gaucher disease glucocerebrosidase and a-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell 2011; 146:37–52.
Demonstrates that loss of GBA activity in primary cultures or human induced pluripotent stem cell-generated neurons causes accumulation of α-synuclein and results in neurotoxicity; conversely, α-synuclein was found to unhibit the lysosomal activity of normal GBA in neurons and idiopathic Parkinson's disease brain.
41. Weinreb NJ, Cappellini MD, Cox TM, et al. A validated disease severity scoring system for adults with type 1 Gaucher disease. Genet Med 2010; 12:44–51.
42. Di Rocco M, Giona F, Carubbi F, et al. A new severity score index for phenotypic classification and evaluation of responses to treatment in type I Gaucher disease. Haematologica 2008; 93:1211–1218.
43. Hollak CE, van Weely S, van Oers MH, Aerts JM. Marked elevation of plasma chitotriosidase activity. A novel hallmark of Gaucher disease. J Clin Invest 1994; 93:1288–1292.
44. Grace ME, Balwani M, Nazarenko I, et al. Type 1 Gaucher disease: null and hypomorphic novel chitotriosidase mutations: implications for diagnosis and therapeutic monitoring. Hum Mutat 2007; 28:866–873.
45. Boot RG, Verhoek M, de Fost M, et al. Marked elevation of the chemokine CCL18/PARC in Gaucher disease: a novel surrogate marker for assessing therapeutic intervention. Blood 2004; 103:33–39.
46. van Breemen MJ, de Fost M, Voerman JS, et al. Increased plasma macrophage inflammatory protein (MIP)-1alpha and MIP-1beta levels in type 1 Gaucher disease. Biochim Biophys Acta 2007; 1772:788–796.
47. van Dussen L, Lips P, Everts VE, et al. Markers of bone turnover in Gaucher disease: modeling the evolution of bone disease. J Clin Endocrinol Metab 2011; 96:2194–2205.
48▪. Deegan PB, Pavlova E, Tindall J, et al. Osseous manifestations of adult Gaucher disease in the era of enzyme replacement therapy. Medicine (Baltimore) 2011; 90:52–60.
A detailed description of bone disease in 100 Gaucher disease patients including residual manifestations despite enzyme replacement. Suggests temporal and causal relationship between splenectomy and osteonecrosis.
49. Groener JE, Poorthuis BJ, Kuiper S, et al. Plasma glucosylceramide and ceramide in type 1 Gaucher disease patients: correlations with disease severity and response to therapeutic intervention. Biochim Biophys Acta 2008; 1781:72–78.
50▪. Dekker N, van Dussen L, Hollak CE, et al. Elevated plasma glucosylsphingosine in Gaucher disease: relation to phenotype, storage cell markers, and therapeutic response. Blood 2011; 118:e118–e127.
Uses mass spectrometric methods to demonstrate glucosylsphingosine, the deacylated form of glucosylceramide, to be markedly increased in plasma of symptomatic nonneuronopathic Gaucher disease patients; ERT results in reduction. The authors suggest it qualifies as a biomarker but in fact may also be important in pathology.
51. Starzyk K, Richards S, Yee J, et al. The long-term international safety experience of imiglucerase therapy for Gaucher disease. Mol Genet Metab 2007; 90:157–163.
52. Weinreb N, Taylor J, Cox T, et al. A benchmark analysis of the achievement of therapeutic goals for type 1 Gaucher disease patients treated with imiglucerase. Am J Hematol 2008; 83:890–895.
53. Zimran A, Altarescu G, Philips M, et al. Phase 1/2 and extension study of velaglucerase alfa replacement therapy in adults with type 1 Gaucher disease: 48-month experience. Blood 2010; 115:4651–4656.
54. Zimran A, Brill-Almon E, Chertkoff R, et al. Pivotal trial with plant cell-expressed recombinant glucocerebrosidase, taliglucerase alfa, a novel enzyme replacement therapy for Gaucher disease. Blood 2011; 118:5767–5773.
55. Zhao H, Bailey LA, Grabowski GA. Enzyme therapy of Gaucher disease: clinical and biochemical changes during production of and tolerization for neutralizing antibodies. Blood Cells Mol Dis 2003; 30:90–96.
56. Stein P, Malhotra A, Haims A, et al. Focal splenic lesions in type I Gaucher disease are associated with poor platelet and splenic response to macrophage-targeted enzyme replacement therapy. J Inherit Metab Dis 2010; 33:769–774.
57. Giraldo P, Alfonso P, Atutxa K, et al. Real-world clinical experience with long-term Miglustat maintenance therapy in type 1 Gaucher disease: the ZAGAL project. Haematologica 2009; 94:1771–1775.
58. Hollak CE, Hughes D, van Schaik IN, et al. Miglustat (Zavesca) in type 1 Gaucher disease: 5-year results of postauthorisation safety surveillance programme. Pharmacoepidemiol Drug Saf 2009; 18:770–777.
59. Lukina E, Watman N, Arreguin EA, et al. Improvement in hematological, visceral, and skeletal manifestations of Gaucher disease type 1 with oral eliglustat tartrate (Genz-112638) treatment: 2-year results of a phase 2 study. Blood 2010; 116:4095–4098.
60. Peterschmitt MJ, Burke A, Blankstein L, et al. Safety, tolerability, and pharmacokinetics of eliglustat tartrate (Genz-112638) after single doses, multiple doses, and food in healthy volunteers. J Clin Pharmacol 2011; 51:695–705.
Gaucher; pathophysiology; sphingolipid
© 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
Highlight selected keywords in the article text.