review Gaucher disease: pathological mechanisms and modern management Marina Jmoudiak and Anthony H Futerman Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel Summary Gaucher disease, the most common lysosomal storage disorder, is caused by the defective activity of the lysosomal enzyme, acid-b-glucosidase (GlcCerase), leading to accumulation of glucosylceramide (GlcCer), particularly in cells of the macrophage lineage Nearly 200 mutations in GlcCerase have been described, but for the most part, genotype-phenotype correlations are weak, and little is known about the down-stream biochemical changes that occur upon GlcCer accumulation that result in cell and tissue dysfunction In contrast, the clinical course of Gaucher disease has been well described, and at least one treatment is available, namely enzyme replacement therapy One other treatment, substrate reduction therapy, has recently been marketed, and others are in early stages of development This review, after discussing pathological mechanisms, evaluates the advantages and disadvantages of existing therapies Keywords: Gaucher disease, lysosomal storage disease, glucocerebrosidase, enzyme replacement therapy, macrophage Gaucher disease (GD) is a lysosomal storage disorder (LSD) These metabolic disorders are caused by mutations in genes encoding a single lysosomal enzyme or cofactor, resulting in intracellular accumulation of undegraded substrates (Neufeld, 1991; Futerman & van Meer, 2004) Most LSDs, including GD, are inherited in an autosomal recessive fashion In GD, 200 different mutations have been described in the gene encoding lysosomal glucocerebrosidase (glucosylceramidase, GlcCerase) (Beutler & Grabowski, 2001), and as a result, glucosylceramide (GlcCer, glucosylcerebroside) is degraded much more slowly than in normal cells and accumulates intracellularly, primarily in cells of mononuclear phagocyte origin These GlcCer-laden macrophages are known as ‘Gaucher cells’, and are the classical hallmark of the disease Since GlcCer is an important constituent of biological membranes and is a key intermediate in the biosynthetic and degradative pathways of complex Correspondence: A.H Futerman, Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel glycosphingolipids (Fig 1), its accumulation in GD is likely to have severe pathological consequences Historically, and from the clinical point of view, GD has been divided into three major subtypes, namely types 1, and 3, although a recent trend is to consider GD as a continuum of disease states (Goker-Alpan et al, 2003) Type is the most common form of GD and is essentially a macrophage disorder, lacking primary central nervous system involvement Patients with type GD display a large variety of symptoms, ranging from patients who are entirely asymptomatic to those that display child-onset disease Clinical manifestations normally begin with splenomegaly and hepatomegaly, anaemia and thrombocytopenia Bone manifestations include osteopenia, lytic lesions, pathological fractures, chronic bone pain, acute episodes of excruciating bone crisis, bone infarcts, osteonecrosis and skeletal deformities (Zimran, 1997) Lung involvement includes interstitial lung disease (Zimran, 1997) and pulmonary hypertension has also been reported in a small number of patients with type GD (Elstein et al, 1998) Type GD (Beutler & Grabowski, 2001), the acute neuronopathic form, is characterized by neurological impairment in addition to visceral symptoms The neurological symptoms start with oculomotor abnormalities followed by brainstem involvement, and these patients usually die within the first 2–3 years of life Type GD is also characterized by neurological involvement but neurological symptoms generally appear later in life than in type disease, and include abnormal eye movements, ataxia, seizures, and dementia, with patients surviving until their third or fourth decade (Erikson et al, 1997) Recently, a clinical association has been reported between the presence of mutations in the GlcCerase gene and Parkinsonism (Aharon-Peretz et al, 2004; Lwin et al, 2004) Although it is generally assumed that the severity of GD depends on levels of residual GlcCerase activity (Beutler & Grabowski, 2001), this has been difficult to prove for most mutations (Meivar-Levy et al, 1994) Likewise, genotypephenotype correlations are poor, although certain mutations are known to predispose to certain disease types Thus, homozygosity for L444P normally results in neuronopathic disease whereas the presence of even one mutant allele for E-mail: tony.futerman@weizmann.ac.il doi:10.1111/j.1365-2141.2004.05351.x ª 2005 Blackwell Publishing Ltd, British Journal of Haematology, 129, 178–188 Review Sphinganine Dihydroceramide synthase Sphingomyelin Dihydroceramide Dihydroceramide desaturase Fig Metabolic relationships of GlcCer GlcCer is formed from ceramide by the action of glucosylceramide synthase Its degradation, by GlcCerase, is defective in GD GlcCer is the precursor of a number of complex glycosphingolipids, whose defective degradation leads to other LSDs (Futerman & van Meer, 2004) Enzymes of the biosynthetic pathway are shown in italics, and degradative enzymes with the associated disease, in bold N370S normally prevents neurological involvement Remarkably, phenotype severity may vary even among siblings or in identical twins (Lachmann et al, 2004) In this review, we will first discuss the secondary biochemical pathways that may be involved in development of disease pathology (Futerman & van Meer, 2004), and then discuss disease management and possible new therapeutic options, a number of which have been proposed over the past few years Pathological mechanisms Glucosylceramide accumulation GlcCer was first characterized as the accumulating lipid in GD in 1934 (Aghion, 1934) and is now known to accumulate in essentially every tissue where its levels have been measured By way of example, GlcCer accumulates to levels of 30–40 mmol/kg tissue in spleen obtained from all three types of GD, and glucosylsphingosine (GlcSph), the deacylated form of GlcCer, which is usually not detectable in normal tissues, accumulates to lower but significant levels of 0Ỉ1–0Ỉ2 mmol/ kg (Nilsson et al, 1982a) Interestingly, GlcSph is found at higher levels in the brains of type and patients with GD (Orvisky et al, 2002) suggesting a potential pathological role for this lipid in types and GD (Suzuki, 1998) The fatty acid composition of GlcCer differs between the brain and peripheral systems, with a prevalence of stearic acid in the central nervous system and palmitic acid in GlcCer of peripheral tissues, implying a different metabolic or cellular origin of GlcCer in different tissues (Gornati et al, 2002) GlcCer levels are also elevated in the plasma of patients with GD (Nilsson e as ) lin ye k A/B om ic ing -P ph ann S m e (Ni SM Galactosyl- Ga/Cersythase Ceramide ceramide β-galactosidase (Krabbe disease) GlcCer synthase e s tha syn Cera (Farb midase er dis ease) Glucosylceramidase (Gaucher disease) Sphingosine Glucosylceramide Lactosylceramide Complex glycosphingolipids et al, 1982b; Gornati et al, 1998) Finally, changes in the levels of other glycosphingolipids have also been reported in some cases of GD, but there is no clear consensus about the extent or significance of these changes Despite the elevated levels of GlcCer in GD tissues, it appears that GlcCer levels are nevertheless not sufficiently high enough to account for changes in tissue mass and/or tissue pathology Thus, whereas the size of the spleen increases up to 25-fold in patients with GD, GlcCer accounts for 12 years Indeed, the success story of ERT should act as a stimulus for the development of ERT for other LSDs (Desnick & Schuchman, 2002), and potentially for other metabolic disorders caused by enzyme deficiencies The history of ERT has been extensively reviewed (see, for instance Brady, 1997, 2003, Desnick & Schuchman, 2002; Sly, 2004) Vital to the success of ERT is the ability to target GlcCerase to macrophages via the mannose receptor found at high levels on the macrophage surface Uptake of GlcCerase is achieved with a high efficiency by remodelling its oligosaccharide chains to expose core mannose residues, by sequential enzymatic modification using sialidase, b-galactosidase and b-N-acetylglucosaminidase (http://www.cerezyme.com/healthcare/about/ cz_hc_aboutcz.asp) This modified enzyme is endocytosed after it binds to cell-surface mannose receptors and is subsequently delivered to lysosomes where it supplements the defective enzyme (Grabowski & Hopkin, 2003) The importance of uptake by mannose receptors is reinforced by studies showing that up-regulation of the mannose receptor can improve the delivery of recombinant b-glucosidase to Gaucher macrophages (Zhu et al, 2003), and can, therefore, improve the efficacy of ERT However, a recent report has suggested the absence of mannose receptors on splenic Gaucher cells, but demonstrated their abundance on the surrounding myeloid cells (Boven et al, 2004) Reduction in organ volumes, improvement in haematological parameters, and amelioration of bone pain using ERT have dramatically improved the quality of life for many patients with GD (Charrow et al, 2000; Weinreb et al, 2002) Data collated in the Gaucher Registry has summarized the effects of 2–5 years of treatment on specific manifestations of type GD Anaemic patients show an increase of haemoglobin concentrations to normal or near normal levels within 6–12 months, with a sustained response throughout years Thrombocytopenia in patients with intact spleens responds most significantly during the first years, with slower improvement thereafter In cases of severe baseline thrombocytopenia, chances of achieving a normal platelet count are lower In splenectomised patients, platelet counts normalize within 6–12 months Hepatomegaly and splenomegaly decrease by up to 60%, but spleen and liver volumes nevertheless remain significantly above normal size Children receiving ERT also show improvement and the prevention of development of complications that can otherwise occur in later life, particularly skeletal abnormalities, even in patients with severe underlying disease (Cohen et al, 1998; Dweck et al, 2002) However, it should be noted that ERT is essentially of no use for treating the neurological symptoms in type and GD since it does not cross the blood–brain barrier (Desnick & Schuchman, 2002), although visceral symptoms, with the exception of lung involvement, are improved (Bove et al, 1995; Altarescu et al, 2001) 182 Despite the notable success of ERT in treating patients with type GD, it would be lax of the medical and research community to rest on their laurels and not to attempt to improve ERT by the production of second generation enzymes For instance, although few systematic studies have been published examining the fate of GlcCerase after infusion (the main study was performed with CeredaseÒ (Genzyme, Corporation), a first-generation, placental GlcCerase), it is rapidly cleared from blood (within a few minutes), and has a half-life in the bone marrow of only 14 h (Beutler & Grabowski, 2001) Engineering a more stable enzyme, or an enzyme with a higher catalytic activity, could reduce the number of infusions and potentially also reduce cost, and the recent availability of the 3D-structure of GlcCerase should help in this regard (Dvir et al, 2003) Moreover, CerezymeÒ generally has a poor effect on bones and lungs in patients with pre-existing lesions, does not cross the blood–brain barrier, and, of no less importance, is expensive and therefore unavailable to patients in poor countries, imposing a disproportionate burden on the health care budget of a number of countries with limited resources (Beutler, 1994) It should be stressed that the GD market is relatively small in terms of numbers of patients (about 3000 patients receive CerezymeÒ world-wide), but it is our contention that basic research to improve the efficacy of ERT, or to develop novel and alternative treatments (see below) is essential to further improve the quality of life of patients with type GD Substrate reduction therapy A new treatment has recently become available for type GD, namely substrate reduction therapy (SRT) using N-butyldeoxynojirimycin (NB-DNJ: ZavescaÒ; Actelion Pharmaceuticals, Allschwill, Switzerland) (Lachmann, 2003) NB-DNJ is an inhibitor of GlcCer synthase, the enzyme responsible for GlcCer synthesis and hence synthesis of all GlcCer-based glycolipids (Fig 1), and was originally shown to delay neurological deterioration in Sandhoff mice (Platt et al, 1997), a model of a GM2 gangliosidosis Since GlcCer synthesis is reduced, levels of its accumulation are lowered A non-comparative phase I/II study in adult patients with mild to moderate type GD who were unable or unwilling to receive ERT demonstrated the clinical feasibility of SRT Reductions in liver and spleen volumes were observed, although haematological responses were less impressive (Cox et al, 2000) Other clinical trials have been, or are being performed with ZavescaÒ (Heitner et al, 2002; Zimran & Elstein, 2003), and a position statement on its use in treating type GD was recently published (Cox et al, 2003) Unlike CerezymeÒ, ZavescaÒ is given orally and does cross the blood–brain barrier (Platt et al, 1997), and clinical trials are currently also underway using ZavescaÒ for type GD However, ZavescaÒ causes a number of side-effects (Futerman et al, 2004), and therefore attempts are ongoing to develop other GlcCer-synthase inhibitors for SRT (Abe et al, 2001) Moreover, long-term reduction in glycolipid levels could ª 2005 Blackwell Publishing Ltd, British Journal of Haematology, 129, 178–188 Review Table II Indications for choice of currently available GD treatments Enzyme replacement therapy using CerezymeÒ Substrate reduction therapy using ZavescaÒ First-line treatment for Gaucher disease Second treatment option when ERT is unavailable or unsuitable Mild disease Non-paediatric disease Slower response option Patient must use contraceptives Severe disease Paediatric disease Need for prompt response Patients planning to have children or unable/unwilling to use contraceptives Lack of improvement/side effects with SRT treatment Supplemental to ERT in severe cases affect a variety of cell functions because of the essential roles that these lipids play in normal cell physiology (Buccoliero & Futerman, 2003; Futerman & Hannun, 2004) Due to these problems, ZavescaÒ has been approved in Europe (including Israel) and in the USA only for patients for whom ERT is ‘unsuitable’ or ‘not a therapeutic option’ respectively (Table II) Thus, ZavescaÒ is clearly not the last word in SRT Other management and treatment options In addition to the treatments listed above, both of which are directed at reducing GlcCer levels, a number of other management and treatment options are used either alone, or together with ERT or SRT, to alleviate specific disease symptoms Bone disease Bone disease usually designates the advanced stages of GD, but susceptibility to fractures and avascular necrosis can be the first sign of GD in otherwise asymptomatic patients Treatment of bone manifestations is mostly directed at the prevention of irreversible complications, and ERT is often of limited influence on bone density (Schiffmann et al, 2002) The use of biphosphonates, which act directly on osteoclasts (Toyras et al, 2003), is an effective and safe means to increase bone density and prevent complications (Samuel et al, 1994; Wenstrup et al, 2004) Orthopaedic intervention may be necessary in cases of pathologic fractures or avascular necroses Supportive management for bone pains or bone crises may also be required Splenectomy Once the most popular GD treatment, because of the absence of other options, splenectomy is now performed only in cases of severe thrombocytopenia or symptomatic organomegaly that are unresponsive to ERT Bleeding tendency As mentioned above, defective platelet function, coagulation factor abnormalities and non-corrected thrombocytopenia may cause increased bleeding risk in GD patients, demanding appropriate evaluation and preparation before surgical procedures Bone marrow replacement Attempts to treat GD by bone marrow transplantation (BMT) have been reported (Ringden et al, 1995), and BMT has been shown to abolish haematological and visceral disease (Tsai et al, 1992; Young et al, 1997) In addition, some effect on limiting neurological deterioration has been reported in type GD (Krivit et al, 1999), but in general, BMT is not normally considered as a realistic treatment for GD Pulmonary hypertension Pulmonary evaluation should include a Doppler echocardiogram to estimate right ventricular systolic pressure (Weinreb et al, 2004) Risk factors for severe, life-threatening pulmonary hypertension include mutations other than N370S, a family history of pulmonary hypertension, angiotensin converting enzyme I gene polymorphism, asplenia and female sex (Mistry et al, 2002) Neuronopathic GD management A patient with GD and neurological involvement is defined as having neuronopathic disease, i.e type or It has been suggested that these patients, along with patients having mutations that are known to predispose to neuronopathic disease, should undergo thorough neurological evaluation and monitoring (Vellodi et al, 2001) The best current treatment option is high-dose ERT for visceral symptoms and supportive treatment for neurological disease if required Some of the new treatment options, such as SRT, may eventually prove useful for treating patients with type and GD Others A clinical association has been reported between the presence of mutations in the GlcCerase gene and Parkinsonism (Aharon-Peretz et al, 2004; Lwin et al, 2004) but no management options, apart from those routinely used for Parkinsons disease, have yet been suggested Likewise, patients with haematological malignancies are normally referred to an oncologist or haematologist Developing management and treatment options The past few years have seen a tremendous effort in the attempt to develop new treatments for GD and other LSDs Much of the impetus for these advances is derived from the limitations of ERT, as discussed above, and the lack of usefulness of ERT for LSDs in which the brain is affected, but has also derived from renewed interest in the structure, intracellular transport, stability and activity of GlcCerase, and other lysosomal hydrolases affected in other LSDs (Futerman & van Meer, 2004) Chemical chaperones (enzyme enhancement therapy) Amongst the potential exciting advances in GD treatment is the recent proof of concept that chemical chaperones can be used to stabilize or reactivate improperly-folded GlcCerase (Fan, 2003; Desnick, 2004) Some GD mutations result in improperly-folded GlcCerase that is retarded in the endoplasmic reticulum and degraded there, and chaperones, in ª 2005 Blackwell Publishing Ltd, British Journal of Haematology, 129, 178–188 183 Review principle, enhance normal trafficking of the enzyme through the secretory pathway, and thus increase its level in lysosomes Proof of principle was obtained by incubating cultured cells expressing a mutant GlcCerase (N370S) with sub-optimal concentrations of a GlcCerase inhibitor, N-nonyl-deoxynojirimycin, which resulted in elevated enzyme activity (Sawkar et al, 2002) Likewise, incubation with N-octyl-b-valienamine, another GlcCerase inhibitor, increased the protein level of a mutant GlcCerase and up-regulated cellular enzyme activity (Lin et al, 2004) Importantly, it should be emphasized that a modest increase in GlcCerase activity should be sufficient to achieve a therapeutic effect Clearly, a substantial amount of work is required before this approach will provide a therapeutic option for GD (e.g optimization of inhibitor levels in animal studies rather than in cultured cells, and determination of efficacy in reducing GlcCer storage in the primary cell types and tissues affected in GD), but this approach nevertheless holds great promise for GD and other LSDs Gene therapy Also holding great promise is gene therapy, which would of course be the ultimate treatment for GD However, it has been largely unsuccessful to date in human patients, although GlcCer storage can be significantly reduced in cultured cells by gene transfer For instance, recombinant adeno-associated viral vectors containing human GlcCerase driven by the human elongation factor 1-a promoter have recently been used and shown to elevate GlcCerase levels in both normal and Gaucher fibroblasts (Hong et al, 2004); moreover, intravenous administration of vectors to wild-type mice resulted in increased GlcCerase activity that persisted for over 20 weeks Other vectors have been used (i.e Kim et al, 2004, and reviewed in Cabrera-Salazar et al, 2002), but the likelihood of gene therapy becoming a viable option for GD in the near future in human patients remains small This is also true for other LSDs (D’Azzo, 2003; Eto et al, 2004), and presents a major challenge for the future Conclusion and future prospects In this review, we have discussed the little that is known about the pathological mechanisms leading from GlcCer accumulation in macrophages and other cells, to disease development The relative lack of knowledge is somewhat surprising, and might be due, at least in part, to the availability of ERT, and thus the feeling in the medical and research community that there is little need to understand the basic mechanisms of disease development and progression However, a renewed interest in GD, and in the biology of other LSDs, is apparent from the recent scientific literature, and it is to be hoped that the coming years will lead not only to new therapies based 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