British Journal of Radiology 75 (2002),A2-A12 © 2002 The British Institute of Radiology
Skeletal aspects of Gaucher disease: a review
R J Wenstrup, MD1,
M Roca-Espiau, MD2,
N J Weinreb, MD3 and
B Bembi, MD4
1 Children's Foundation Research Hospital, Cincinnati, Ohio, USA, 2 Department of Radiology, Musculoskeletal MRI Section, Hospital Miguel Servet, Zaragoza, Spain, 3 University Gaucher Research Foundation Inc., University Gaucher Treatment Center, Tamarac, Florida, USA and 4 Burlo Garofolo Institute, Trieste, Italy
Correspondence: Dr Richard J Wenstrup, Division and Program in Human Genetics, Children's Hospital Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229, USA. Tel. +1 513 636 7290; Fax +1 513 636 7297; email wensr0{at}chmcc.org
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Abstract
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In Gaucher disease, a genetic deficiency in the activity of the lysosomal enzyme ß-glucocerebrosidase (acid ß-glucosidase) causes monocytes and macrophages to store excessive amounts of glucocerebroside in lysosomes. The resulting distended cells are called Gaucher cells, and the pathology associated with this condition stems from the accumulation of Gaucher cells in organ systems. The skeletal manifestations are probably the most disabling aspect of the disease. Patients commonly experience bone pain, some suffer bone crises, and up to 20% have impaired mobility. Radiological findings include Erlenmeyer flask deformity, osteopenia, osteosclerosis, osteonecrosis, fractures and bone marrow infiltration. Findings from the Gaucher Registry show that nearly all patients with Gaucher disease have radiological evidence of skeletal involvement, and the majority have a history of serious skeletal complications. Skeletal involvement follows three basic processes: focal disease (irreversible lesions such as osteonecrosis and osteosclerosis), local disease (reversible abnormalities adjacent to heavily involved marrow such as cortical thinning and long bone deformity) and generalized osteopenia. Infarctions are involved in some of the skeletal manifestations, but the mechanisms causing high rates of bone turnover and failure of remodelling are not known. The availability of a ß-glucocerebrosidase-deficient mouse model of Gaucher disease with long-term survival should help elucidate the skeletal pathology in Gaucher disease and may ultimately lead to improved management of skeletal complications.
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Introduction to Gaucher disease
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Gaucher disease is the most prevalent inherited, lysosomal storage disease [1]. Although it occurs most commonly in Ashkenazic Jews, in whom one of every 400–600 people are believed to be affected, Gaucher disease is a pan-ethnic disorder found in one of every 40,000–60,000 people in the general world population [2].
Gaucher disease results from mutations that confer a deficient level of activity of ß-glucocerebrosidase (acid ß-glucosidase; EC 3.2.1.45), a membrane-bound lysosomal enzyme [3]. This deficiency leads to accumulation of the lipid glucocerebroside in the lysosomes of monocytes and macrophages. The monocytes and macrophages that are engorged with glucocerebroside are called Gaucher cells. The symptoms and pathology of Gaucher disease result from the accumulation of Gaucher cells in various organ systems [4].
The symptoms, organ involvement and clinical course of Gaucher disease vary greatly among individual patients. More than 100 different mutations of the ß-glucocerebrosidase gene, located on the long arm of chromosome 1, have been identified and linked to ß-glucocerebrosidase deficiency [5]. The most common mutant alleles among patients with Gaucher disease include N370S, L444P, R463C, c.84-85insG, IVS2+1G
A, and c.1263-1317del [5, 6]. Although there is some correlation between genotype and phenotype, it is generally not possible to predict organ involvement and disease severity from mutation analysis [5–7].
Despite the heterogeneity of Gaucher disease, three basic clinical forms have been distinguished based on the degree of neurological involvement. Most patients with Gaucher disease have the non-neuronopathic form, which is sometimes referred to as type 1. The remainder of patients with Gaucher disease have the acutely neuronopathic form (type 2) or the subacutely neuronopathic form (type 3) [8]. With the acutely neuronopathic form, the neurological symptoms may include cranial nerve and extrapyramidal tract involvement. Neurological deterioration progresses quickly, and death from apnoea or aspiration usually occurs in early childhood [9]. With the subacutely neuronopathic form, the neurological symptoms can include myoclonic seizures or horizontal supranuclear gaze paresis [10].
Systemic symptoms are more common than neurological involvement in patients with Gaucher disease. The organs affected by Gaucher disease include the spleen, liver, lung, kidney, bone and bone marrow, and patients may exhibit hepatosplenomegaly, anaemia, thrombocytopenia and skeletal and bone marrow pathology [4]. The effects of Gaucher disease on the skeleton are probably the least understood aspects of the disease, but are the most disabling and have a negative impact on the patient's quality of life [11, 12].
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Skeletal symptoms and radiological findings
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The skeletal aspects of Gaucher disease include a diverse array of symptomatic and radiological findings. A thorough assessment of the skeleton is important for newly diagnosed patients because they may have bone complications in the absence of visceral disease or skeletal symptoms.
Bone pain is common among patients with Gaucher disease. This pain varies in severity, can be acute or chronic, and may not correlate with radiological findings. Bone crises, which are acute episodes of severe skeletal pain and fever accompanied by leucocytosis and elevated erythrocyte sedimentation rates, are also reported. Plain radiography may show periosteal elevation [13], a radionuclide bone scan may show photopenia [14] and MRI may show an increased T2-weighted signal at the site of a bone crisis (Figure 1
). Although the signs and symptoms of a bone crisis may mimic those of osteomyelitis, toxaemia is not present and blood cultures are negative. Terms such as pseudo-osteomyelitis and aseptic osteomyelitis have therefore been used to describe this condition [15]. Osteomyelitis has also been reported among patients with Gaucher disease [16], and it is important to distinguish between the two conditions because untreated osteomyelitis is life-threatening.
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Figure 1. Magnetic resonance image of a bone crisis in Gaucher disease, with a high T2-weighted signal in the bone marrow of the left femoral head and neck, indicating oedema.
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Erlenmeyer flask deformity is also common in patients with Gaucher disease, but it is neither symptomatic nor pathognomonic. This deformity results from the impairment of remodelling of the metaphyseal region of tubular bones and is manifested as a flaring of the distal lateral aspects of the femur and proximal tibia (Figure 2a).
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Figure 2. Plain radiographs of skeletal complications in Gaucher disease. (a) Erlenmeyer flask deformity of femur; (b) osteopenia of femur; (c) osteosclerosis of hip.
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Osteopenia is nearly universal in children and adults with Gaucher disease, and is associated with an increased risk for bone fractures. Osteopenia may be found adjacent to sites of bone marrow infiltration but is not limited to these areas. It can affect trabecular and cortical bone in a localized or diffuse manner (Figure 2b
) and can be detected as a decrease in bone mineral density (BMD) using dual-energy X-ray absorptiometry (DXA) [17].
Osteosclerosis can occur as aberrant remodelling after bone infarction with deposition of calcium into the bone. Such infarction is often associated with a high degree of pain. Osteosclerosis occurs in patients with severe bone disease but may also be observed in patients with mild bone disease [12]. Plain radiography is the best method for imaging osteosclerosis (Figure 2c). On MRI, osteosclerosis appears as an abnormal low signal intensity on T1- and T2-weighted images, comparable with Gaucher-infiltrated marrow. This finding must therefore be correlated with areas of increased bone density due to calcium hydroxyapatite deposition on plain radiography.
Osteonecrosis, also called avascular necrosis, is probably the most clinically significant and disabling skeletal manifestation in Gaucher disease [12, 18]. Osteonecrosis is bone death, believed to be secondary to ischaemia due to chronic infarction, and once the necrotic process starts, it cannot be reversed. It affects predominantly the femoral head, proximal humerus and vertebral bodies, and can result in fracture and joint collapse.
The Ficat staging system describes the progression of osteonecrosis using clinical signs and symptoms and radiographic findings. Ficat Stage 0 (early osteonecrosis) is asymptomatic and the radiograph shows normal bone, although necrosis is detected on bone biopsy. Patients at Stage I experience pain and a decreased range of motion, while radiography may show normal bone or subtle signs of osteoporosis and loss of cortical or trabecular clarity. Stage II is characterized by the clinical symptoms along with mixed sclerosis and osteoporosis. In Stage III, there is fracture of the femoral head "subchondral crescent" but maintenance of the joint space. Finally, in Stage IV, cortical collapse with secondary degenerative joint disease occurs [19].
MRI is more sensitive than plain radiography for demonstrating osteonecrosis (Figure 3a,b) and can detect very early stages of necrosis (Figure 3c). Progression of the central lesion of osteonecrosis has been described using the Mitchell classification system [20]. In this system, Class A is early osteonecrosis, which is manifested as a high intensity T1-weighted signal and an intermediate intensity T2 signal, indicative of elevated fat concentration. Class B produces high intensity T1- and T2-weighted signals, indicating blood infiltration. Class C results in a low intensity T1-weighted signal and a high intensity T2-weighted signal, owing to fluid infiltration. Class D is the most advanced state of osteonecrosis, manifested as low intensity T1- and T2-weighted signals resulting from fibrous tissue. These various marrow signal changes frequently co-exist.
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Figure 3. Osteonecrosis in Gaucher disease. (a) Plain radiograph of osteonecrosis affecting both femoral heads (particularly the right); (b) magnetic resonance image of the same patient shown in (a); (c) magnetic resonance T1-weighted image showing early stage osteonecrosis of the left femoral head in another patient with Gaucher disease.
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The skeletal complications of Gaucher disease are accompanied by an increased risk of fracture. These fractures are associated with considerable pain and disability, particularly when the spinal column is involved (Figure 4).
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Figure 4. Magnetic resonance T1-weighted sagittal image of the thoracic spine, showing a compression fracture in the mid/lower thoracic spine with posterior displacement of the vertebral fractured body into the spinal canal.
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Bone marrow is affected because of infiltration with Gaucher cells, which then replace the normal marrow cells [21, 22]. The infiltration may cause ischaemia and as a result oedema, and is accompanied by pain. Bone adjacent to marrow infiltration may exhibit cortical thinning, osteopenia and long bone deformity. Although it has been suggested that marrow infiltration extends from the axial to the appendicular skeleton [22], it is not known where the process of marrow infiltration commences. There can be significant variability between individuals, particularly with respect to focal areas of marrow infiltration. Advanced stages of bone marrow infiltration are generally accompanied by fracture and osteonecrosis, and rarely by osteomyelitis [22]. In adults, bone marrow involvement is manifested on MRI as decreased T1- and decreased or increased T2-weighted signals (Figure 5a,b), and can give rise to a homogenous or heterogenous pattern (Figure 5c).
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Figure 5. Magnetic resonance images of bone marrow infiltration in Gaucher disease. (a) T1- and (b) T2-weighted images of the spinal column illustrating the reduced signal intensities; (c) T1-weighted image of the left and right femur illustrating a heterogenous pattern of marrow infiltration.
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Prevalence of skeletal involvement—data from the Gaucher Registry
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The most comprehensive data on the prevalence of skeletal involvement in Gaucher disease have been compiled in the Gaucher Registry [23]. The Gaucher Registry is an international, observational, longitudinal database established by The Genzyme Corporation in 1991 for the purpose of collecting clinical information on patients with Gaucher disease. The registry is open to all physicians managing patients with Gaucher disease. In 2000, an analysis of physician participation by specialty showed participation by haematologists/oncologists (46%), paediatricians (17%), geneticists (16%), family/general practitioners (10%) and others (11%). The scientific direction for the Gaucher Registry is guided by a group of academically recognized experts on Gaucher disease. The Gaucher Registry has three objectives:- To provide reports on individual patient outcomes for referring physicians and to aggregate data to help develop guidelines for monitoring patients and assessing therapies
- To increase the knowledge of the variability, progression and natural history of Gaucher disease among patients not receiving enzyme replacement therapy (ERT)
- To evaluate and monitor the long-term effectiveness of ERT
Participating physicians are asked to provide information on patient demographics, medical history, treatment regimens and outcomes. The voluntary nature of the physician participation means that the data in the registry may not be representative of the entire Gaucher disease patient population. Another limitation of the Gaucher Registry is that data are unverified and sometimes incomplete, and the methodology is not standardized or reviewed by reference panels. Because of limitations in resources and technology, some physicians may not be able to comply with the established guidelines for disease assessment (for example, MRI is not universally available). Nevertheless, the Gaucher Registry is the largest database for this rare disease, and it has made it possible to pool and analyse data from case reports and small institutional cohorts of patients [23].
Data for 2004 patients from 39 countries were included in the Gaucher Registry during the year 2000, with most from the United States (43%) and Israel (18%). 79% were adults (aged 
18 years), and female and male patients were almost equally represented. The overwhelming majority (94%) had type 1 disease, 69% had not had a splenectomy and 77% were receiving ERT (ERT+). Of patients with type 1 disease included in the Registry in 2000, 75% were ERT+, and the mean age at first infusion was 30.6 years (range, 0–84 years) [24].
At baseline (when first included in the registry for ERT– patients and just prior to the first infusion for ERT+ patients), bone pain and bone crisis were more prevalent in the ERT+ patient group (Table 1). The proportion of patients with a history of bone pain increased with age up to 60 years in both the ERT+ and ERT– groups (Figure 6). The incidence of radiological findings of skeletal involvement among patients in the Gaucher Registry in 2000 are given in Table 1. Regardless of treatment status, most patients with type 1 disease had radiological evidence of skeletal involvement. Radiological bone manifestations were more common among the ERT+ patients prior to the start of ERT than among the ERT– patients. In general, patients with skeletal involvement are more likely to receive ERT because of the overall severity of their disease than those without bone complications. The most common skeletal findings for both groups were Erlenmeyer flask deformity, bone marrow infiltration and osteopenia. Although infarction, avascular necrosis and new fractures were not as common, these findings affected a considerable proportion of both ERT+ and ERT– patients (Table 1).
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Figure 6. Data on bone pain from the Gaucher Registry. Proportion of patients with a history of bone pain at baseline (i.e. when first included in the registry for ERT– patients and just prior to the first infusion for ERT+ patients) according to age and enzyme replacement therapy (ERT) status.
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20.8% of the 602 patients with type 1 disease for whom baseline data on mobility were available had some degree of disability. 12.0% of those patients walked with some difficulty, 7.1% required an orthopaedic aid to walk, 1.2% required a wheelchair and 0.5% were bedridden.
These data from the Gaucher Registry indicate that bone involvement confers pain and discomfort in most patients and is associated with varying degrees of disability. Other findings from the Registry indicate that the skeletal aspects of the disease have a much greater impact on patients' quality of life than the haematological and visceral aspects, and that skeletal manifestations are commonly seen in patients with normal haematology (data not shown). It is therefore important that physicians should not focus on the haematological and visceral complications to the exclusion of skeletal involvement when assessing the indications for ERT as well as the response to treatment.
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Pathophysiology of skeletal disease
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At least three different disease processes contribute to the skeletal manifestations in Gaucher disease. These processes are focal disease, local disease and generalized osteopenia. Focal disease consists of osteonecrosis and osteosclerosis. It is characterized by infarctions caused by Gaucher cells, thrombosis and possibly inflammatory processes. Local disease includes cortical thinning and long bone deformity. This process occurs in areas adjacent to bone marrow infiltration. Generalized osteopenia is believed to result from abnormally high rates of bone resorption and reduced rates of bone formation. It progresses with ageing and correlates with overall disease severity.
The pathophysiology of bone involvement in Gaucher disease is not well understood. The basis of bone complications in Gaucher disease is believed to be the infiltration of Gaucher cells into bone and bone marrow. Marrow expansion resulting from infiltration by Gaucher cells may cause vascular occlusion and compression, and increased intraosseous pressure, although no direct data exist to show this. The mechanisms by which Gaucher cells displace normal bone marrow cells and cause oedema and ischaemia are also not known. Furthermore, not all of the bone complications are caused by infarction of Gaucher cells. 99Tcm bone scanning indicates that areas of focal and local skeletal disease have increased vascularity [12]. No data exist to show that Gaucher cells directly erode bone. Osteoclasts have not been observed with glucocerebroside storage, and osteoclasts in the affected areas have shown normal cellular morphology. Affected bone exhibited normal static indices, i.e. ratios of osteoid volume to surface area and trabecular surface area to volume [12]. Preliminary data from a study of the effects of bisphosphonates on lumbar BMD suggests that there is a high turnover rate for bone and a reduced rate of bone deposition in patients with Gaucher disease [25]. Other evidence for aberrant osteoclast activity are the impaired bone remodelling, osteosclerosis and evidence of woven bone and increased mineralization rates [12].
One hypothesized mechanism for the skeletal pathology in Gaucher disease is that the Gaucher cells interfere with the proper functioning of osteoclasts and osteoblasts through paracrine effectors, for example, via cytokines and lysosomal enzymes. Osteoclast activity is regulated by a variety of substances including interleukin-1 (IL-1), IL-6 and tumour necrosis factor (TNF). These cytokines are produced by monocytes and macrophages as well as other cells, and they stimulate osteoclast activity indirectly through effects on osteoblasts. Furthermore, these substances have been associated with skeletal diseases characterized by inflammation, bone resorption and/or lytic lesions. IL-1 has been implicated in rheumatoid arthritis [26], osteoarthritis [27] and multiple myeloma [28]. Interleukin-6 has been associated with multiple myeloma [28] and post-menopausal osteoporosis [29]. Tumour necrosis factor has been linked to rheumatoid arthritis and osteoarthritis [26, 27]. Some limited data suggest that serum levels of these cytokines may be up-regulated in patients with Gaucher disease, although the results are conflicting. Barak et al found increased serum levels of IL-1ß, IL-6 and TNF-alpha [30], while Allen et al observed that serum levels of IL-6 were increased but IL-1ß and TNF-alpha levels were normal [31], and Hollak found that IL-6 and TNF-alpha levels were normal [45]. In another report, monocytes from patients with Gaucher disease were found to express elevated levels of mRNA for IL-1ß but not for IL-6 or IL-8 [32]. The evidence supporting a role for lysosomal enzymes is limited. The results of an in vitro study suggest that Gaucher cells may secrete lysosomal enzymes that attract and activate osteoclasts [33].
Research into the pathophysiology of skeletal involvement in Gaucher disease has been hampered by the lack of an appropriate animal model. Mouse models of Gaucher disease have been produced [34, 35], but unfortunately these animals die within 1–2 days after birth and therefore have not been suitable for studying skeletal disease. More recently, a long-living ß-glucocerebroside-deficient mouse line has been developed. These animals exhibit glucocerebroside storage with a pattern of organ system involvement similar to that for patients with Gaucher disease and have a normal lifespan. Using these mice, it should be possible to perform BMD analyses, histomorphometric analyses, osteoclast cell culture studies and other tests. One intriguing type of study would be to investigate the mechanism of bone turnover in Gaucher disease by analysing this process in mice produced by crossing ß-glucocerebroside-deficient mice with mice from a strain that is deficient for osteoclasts.
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Bone biochemical markers in Gaucher disease
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Bone turnover is defined as the simultaneous processes of bone formation (the production of bone matrix and subsequent calcification) and bone resorption (removal of bone by osteoblast-produced proteases and osteoclast-mediated acid decalcification and proteolytic digestion). Knowledge of the biochemical processes of bone formation and resorption is being used to develop bone biochemical marker assays to monitor bone turnover in such diseases as osteoporosis [36]. Bone biochemical marker assays do not expose patients to radiation and are relatively inexpensive, repeatable and quantitative. Some of these bone biochemical marker assays may be used to predict the risk of fractures and monitor the response to treatment in patients with osteoporosis [36, 37], and the clinical usefulness of these assays for patients with Gaucher disease is under investigation.
Many bone markers are components of Type I collagen, which constitutes 90% of bone protein. Some bone collagen components contain post-translational modifications highly specific to bone and thus may be useful for monitoring bone changes in Gaucher disease. Some of these markers are measured in urine, which necessitates 24-hour specimen collection and normalization of values to creatinine levels (requiring another assay). There is therefore interest in biochemical markers that can be assayed in serum samples [37].
The clinical utility of bone biochemical markers in Gaucher disease has yet to be firmly established, although some of these molecules could have potential application (Table 2).
Procollagen carboxy-terminal propeptide (PICP) is a bone formation marker [37, 38]. During the process of collagen formation, osteoblasts secrete procollagen molecules that then undergo further biochemical modification. PICP is a cleavage product of the procollagen molecule. It is produced in bone and in other soft tissues, such as skin and muscle. This peptide is specific for collagen formation, but it is not specific for bone formation. It is stable at room temperature and can be assayed from serum samples.
The pyridinium crosslinks pyridinoline (Pyrilink) and deoxypyridinoline (Pyrilink-D) are components of mature collagen that result from the binding of lysine and hydroxylysine residues that join the separate triple-helix strands. The crosslinks are highly specific for collagen degradation and are separated from collagen during bone turnover and resorption of all Type I collagen-containing connective tissues, of which bone represents a major fraction. The crosslink Pyrilink is produced primarily by bone and cartilage, and Pyrilink-D is primarily produced by bone. Although these markers are assayed in urine samples, Pyrilink and Pyrilink-D are currently the most useful among the most frequently used biochemical markers for monitoring bone resorption in patients with osteoporosis and metastatic cancer [36, 39, 40].
Crosslinked Type I collagen C-terminal telopeptide (CTX) and N-terminal telopeptide (NTX) are collagen degradation products with attached crosslinks that are released during bone resorption. The NTX peptides contain a crosslink found almost exclusively in bone and are more specific to bone than any of the other currently used resorption markers. These peptides were first discovered in urine, but they can also be assayed in serum [37, 38, 40]. Elevated serum CTX and NTX levels have been observed in patients with post-menopausal osteoporosis, metastatic cancer and Paget's disease [40].
Bone sialoprotein (BSP) is produced by osteoblasts and odontoblasts and by some osteoclast-like and malignant cell lines. It constitutes approximately 5% of the non-collagenous bone protein and appears to function in adhesion. Elevated serum BSP has been associated with increased bone turnover rates and has been proposed to be a biochemical marker for bone resorption [37]. As with CTX and NTX, elevated serum BSP levels have been found in patients with post-menopausal osteoporosis, metastatic cancer and Paget's disease [40].
Stowens et al [12] did not find evidence of increased urinary bone resorption markers in a large cohort of patients with Gaucher disease. Definitive studies on the effects of ERT on bone formation markers have not been done. However, patients with Gaucher disease receiving ERT have shown significant improvement in BMD and demonstrated decreases in urinary hydroxyproline, a collagen-specific (but not bone-specific) amino acid that for many years was used to measure bone resorption activity [41–43].
At present, no significant correlations have been found between levels of bone resorption markers and skeletal disease measures in individual patients with Gaucher disease. These markers have not yet proved useful for monitoring the response to ERT in individual patients, although a number of current studies are assessing the effects of ERT on bone markers. In the future, a combined analysis using BMD data obtained with DXA and bone turnover data using serum NTX and osteocalcin may provide greater predictive value than either measurement alone.
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Conclusion
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The skeletal manifestations of Gaucher disease are associated with considerable morbidity. Not only do patients commonly experience bone pain, but they are also at risk of pathological fractures, orthopaedic interventions and irreversible damage such as avascular necrosis. As such, the skeletal complications of Gaucher disease can interfere with the activities of daily living, restrict mobility and therefore decrease the patient's quality of life to a greater extent than the visceral and haematological aspects of the disease [11, 12]. Physicians must therefore not focus solely on the visceral and haematological aspects of the disease, but must also assess and treat the skeletal components.
A better understanding of the pathophysiology of the skeletal complications of Gaucher disease may improve disease management. While infarctions are involved in some of the skeletal manifestations, other unknown mechanisms, possibly involving IL-1, IL-6 and TNF, contribute to high rates of bone turnover and failure of remodelling. The recent availability of the long-living ß-glucocerebrosidase-deficient mouse, an animal model of Gaucher disease, should aid in the research of skeletal pathology in Gaucher disease.
Radiological imaging techniques, such as MRI and DXA, are used to monitor bone marrow infiltration and BMD, respectively, in patients with Gaucher disease, but highly sensitive quantitative methods need to be developed [44]. An optimal quantitative method would enable the detection of early stages of skeletal involvement, the estimation of the risk of complications and irreversible damage, and the assessment of response to ERT. Along with research into quantitative radiological methods, which are described in Chapter 2, biochemical markers of bone turnover such as PICP and the bone resorption markers Pyrilink, Pyrilink-D, CTX, NTX and BSP are being investigated. Analysis of bone biomarker levels in conjunction with BMD measurements may provide a more accurate estimation of fracture risk.
In summary, the skeletal aspects of Gaucher disease are associated with significant morbidity, and further research into the pathophysiology of the skeletal aspects and development of quantitative methods for monitoring the skeleton in patients with Gaucher disease will aid in the assessment and treatment of these patients.
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Acknowledgments
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We would like to thank and acknowledge the invaluable input from Pilar Geraldo, MD (Hospital Miguel Servet, Zaragoza, Spain), Neal Mantick (Gaucher Registry) and Karen Walton-Bowen (Genzyme Corp.).
Received for publication November 2, 2001.
Revision received January 3, 2002.
Accepted for publication January 14, 2002.
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L W Poll, M Maas, M R Terk, M Roca-Espiau, B Bembi, G Ciana, and N J Weinreb
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Abstract
Introduction to Gaucher disease
