- Email: [email protected]
Management of patients with Gaucher's disease: Clinical perspectives
European Journal of Internal Medicine 17 (2006) S9 – S12 www.elsevier.com/locate/ejim
Management of patients with Gaucher's disease: Clinical perspectives Gregory Pastores Department of Neurology, New York University School of Medicine, New York, USA
Abstract Gaucher's disease is a clinically heterogeneous disorder, including neuropathic and non-neuropathic variants. Among patients with nonneuropathic (type I disease), the wide variability in age of onset and the differential pattern and severity of disease expression complicate decision-making in relation to treatment. Optimal care may necessitate both palliative and adjunctive therapies. In the more mildly affected patient without clear signs of disease progression, the main issue is the appropriate time to intervene. In moderately to severely affected patients, the challenges include selection of an optimal treatment regimen and dealing with residual disease burden. Eventually, in wellcontrolled patients, guidance will be required on long-term maintenance regimens that will have to take the cost of care into consideration. Guidelines reached by consensus will hopefully reduce variation in clinical practice and promote integrated care pathways. © 2006 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. Keywords: Gaucher's disease; Patient management; Therapeutic goals; Quality of life
1. Introduction As outlined in the first two presentations, Gaucher's disease is recognised as an inborn error of metabolism specifically affecting the catabolism of glycosphingolipid. The clinical manifestations reflect the cellular sites of lipid storage involving cells of monocyte macrophage lineage. There are currently two treatment options: enzyme replacement therapy and substrate reduction. This presentation gives a personal perspective on the issues relating to the management of Gaucher's disease, including lessons learned through involvement with the care of patients since 1990, and a discussion on ways of optimising the outcome for these patients. 2. Management of Gaucher's disease Gaucher's disease is a disorder that has a wide variability in chronicity and clinical expression. It therefore presents challenges in diagnosis and management, and necessitates an understanding of the drivers of morbidity, methods of disease assessment and interpretation of the derived information. It is necessary to assess the pattern and severity of disease, and E-mail address: [email protected].
determine what the findings represent in terms of risk of complications in the paediatric versus the adult patient. It is very important to emphasise that in a disorder such as Gaucher's disease there can be discordance between the systems involved. Patients can encounter significant haematological problems and splenomegaly with very minimal bone disease, but the opposite is also true as patients can have significant bone disease and yet only very mild or moderate haematological or visceral problems. Against this background, there needs to be an increased understanding of the role of surrogate markers, not only in diagnosis, but in the serial monitoring of outcome, whether a patient is receiving treatment or not. Once it is felt that treatment is indicated, it is very important to establish therapeutic goals that meet not only the physician's but the patient's expectations, as treatment regimens are likely to be a life-long commitment. 3. Investigations of natural history In terms of investigations of the natural history, Gaucher's disease can be considered to result from progressive substrate accumulation which, to some extent, is influenced by residual enzyme activity that is also dependent on the underlying causal mutation or gene defects. We know that onset of these
0953-6205/$ - see front matter © 2006 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2006.07.004
S10
G. Pastores / European Journal of Internal Medicine 17 (2006) S9–S12
Fig. 1. Investigations of natural history.
diseases can be in adulthood and can be a latent period during which time the patient may be asymptomatic. As shown in Fig. 1, a threshold of substrate accumulation is ultimately breached, accounting for full-blown disease with its wide variability of expression. More work needs to be done to understand what those factors are that ultimately influence disease phenotype in an individual, and a clearer understanding of the diagnostic modalities such as MRI or sophisticated imaging will be needed to define the pattern. It is currently very difficult not only to stage patients but also to obtain information of prognostic value. Once appreciation of the risk of complication is achieved, it is desirable to intervene a lot earlier in a patient's disease course. 4. Mechanisms of disease Although we think of Gaucher's disease as a lysosomal storage disorder, substrate accumulation and the associated mechanical consequences are not the sole mechanisms of disease. There is a cascade of downstream events resulting from substrate accumulation and perhaps chronic macrophage activation that in the end may prove to be important. The need to understand what these other mechanisms are will educate us about the kind of adjunctive therapies and traditional pharmacological agents that one can use as supplementary treatment to achieve optimal outcome.
progression to one that is sub-clinical. Failure to achieve this point may result in a disease that can be associated with significant residual disease burden; however, if treatment is truly effective prior to the onset of established necrotic and fibrotic changes, the resolution of clinical problems is possible. This is illustrated in Fig. 2. The concept of residual disease burden to some extent determines expectations of responses to therapy directed at either correcting the underlying enzyme deficiency or reducing substrate accumulation. One should recognise that there are irreversible aspects associated with this storage problem due to necrosis and fibrosis from either vascular or inflammatory mechanisms. In the bone, which is the major source of morbidity for Type I Gaucher's disease, one can encounter femoral head necrosis ultimately associated with subchondral joint collapse and, in some patients with severe osteopenia or osteoporosis, the development of pathological fractures. As emphasised in the presentation of the French observatoire of Gaucher's disease there has to be, in parallel with traditional methods of monitoring, an appreciation of how these complications can impact on the patient's physical and functional well being, from pain, limitation in joint motion and also impaired gait. As a consequence, when the introduction of treatment is delayed, patients may require sustained or other resources such as pain medication, physical therapy and joint replacement. As part of the assessment of cost-effectiveness, a comprehensive approach to patient care must consider Quality of Adjusted Life Years. It also has to take into consideration, in economic terms, discounting for the use of adjunctive therapies. The general concepts of patient management should also encompass appropriate genetic counselling for this autosomal recessive trait and identification of other family members at risk. These efforts will hopefully lead to development of guidelines relating to the care individuals who are affected and perhaps consideration of preventive approaches for carrier couples at risk of having an affected child. For long-term health outcomes, it is necessary to intervene with directed therapies aimed at correcting the underlying enzyme deficiency or reducing the substrate load, but in some cases we may need to use more than one strategy
5. Gaucher's disease care plan Most of the 300 patients at the New York University clinic are of Ashkenazi Jewish descent and have primarily the nonneuropathic Type I disease. As a result of screening programmes and extended family screening, it is possible to identify asymptomatic individuals. Whether asymptomatic or already with problems, the biochemical diagnosis is established before proceeding with clinical evaluations, and appropriate genetic counselling is offered. If Gaucher's disease in the individual patient is considered to be a progressive disorder in an ideal world she/he would be treated prior to the onset of symptoms with safe and effective therapy in order to intervene and alter the course of disease away from
Fig. 2. Therapeutic approaches.
G. Pastores / European Journal of Internal Medicine 17 (2006) S9–S12
S11
6. A look ahead
Fig. 3. Health-related quality of life (SF36) GD = Gaucher's disease, ERT = Enzyme replacement therapy.
and adjunctive therapies aimed at reducing the likelihood of complications. Fig. 3 illustrates data from a 1998 study by John E. Ware and colleagues who developed the SF36, an instrument for health-related quality of life. It shows the physical burden associated with Gaucher's disease in terms of physical function, bodily pain and vitality, compared to the general US population. Fig. 3 also shows data from 55 patients from the NYU clinic who received enzyme replacement therapy, and shows that treatment not only stabilises the disease but also actually reverses it to the extent that the curve is superimposed onto that for the general population [1]. This is probably also a result of aggressive anti-inflammatory therapy and high-quality nursing care to address anxieties from this chronic condition. When therapeutic goals are set, there must an understanding that the disease is not only heterogeneous in terms of its presentation but in fact also in its response to therapy. Using spleen size as a surrogate for the patient's overall response to therapy, the response to enzyme replacement therapy is encouraging. There is a progressive decline in splenomegaly that is actually maintained despite reduction in the initial doses of the enzyme. However, there is a broad range of responses initially from 10–65% during the first 6 months of therapy. The response is not necessarily associated with dose so enzyme dosage should necessarily be driven by the severity of a patient's disease, but there should be goals in terms of a time-scale for the desired outcome. In most cases the response is maintained as long as most patients receive a reasonable dose. It is also worthy of note that, in patients with or without an intact spleen, the reduction in liver volume is not related to the initial dose of enzyme replacement therapy. Regardless of initiating doses there is a convergence of response that occurs around a 12-month time point. Furthermore, there appears to be a relationship between baseline organ volumes and the percentage reduction [2].
Looking ahead to the future, it is clear that there is a need for greater experience and systematic data collection such as the evidence based observatoire data to assist with making decisions regarding the management of patients. We need to update the Gaucher disease severity scoring system to facilitate communication regarding phenotypes, and determine whether phenotypes are, in fact, different between populations such as those we see in the Asia and continental Europe or North America. When looking at the response to different therapeutic options it is encouraging to realise that there is ongoing surveillance that will represent avenues for collaboration efforts in the future. For these efforts to succeed, it is necessary to reformulate therapeutic guideline that map out the treatment algorithm incorporating not only enzyme replacement therapy but also substrate reduction therapy. Registry programs do indeed encourage evidence-based management, and importantly, when guidelines are reached by consensus, it reduces variability in clinical practice. The hope is that through this mechanism we will foster integrated care pathways. Carriers, who on average have only 50% of the healthy individual's enzyme activity, experience no substrate accumulation. Substrate accumulation is only encountered when the residual activity is extremely low, as occurs in patients with null alleles. There is a hypothetical level of substrate solubility and ultimately an irreversible threshold is reached when symptoms become evident. By supplementing some of the enzyme activity within an affected individual through protein replacement, the rate of substrate accumulation can be reduced and a therapeutic response achieved. Until recently most patients were on enzyme replacement therapy. Increasingly we are seeing patients managed with substrate reduction therapy, which interestingly also appears to enhance residual enzyme activity. The lysosome is an organelle that maintains an acidified environment, and proteins that are delivered to the lysosome are rapidly degraded. There are certain diseases that result from misfolding of a protein preventing its targeted delivery to
Fig. 4. Conceptual treatment approach.
S12
G. Pastores / European Journal of Internal Medicine 17 (2006) S9–S12
the lysosome. Certain small molecules can attach to the active site of the misfolded protein allowing that protein to assume its functional confirmation and full or enhanced activity within the target organelle. The “chemical chaperone” is usually a small molecule which can mimic the protein's natural substrate [3]. Small molecules that can also cross the blood–brain barrier could potentially advance what is achievable with enzyme replacement therapy in the management of patients with neuropathic involvement [4]. 7. Conceptual treatment approach Fig. 4 shows a conceptual treatment approach. Hopefully over the next few years it will be possible to refine the treatment guidelines with greater experience. If the starting point is a patient diagnosed with Gaucher's disease in whom we have assessed the pattern or the severity of the disease as stable or slowly progressing, serial observation and palliative care may be appropriate. If, over the course of monitoring, there are clear signs of progression and the development of symptoms, it may be necessary to introduce directed therapies and, depending on physician and patient preferences and the therapeutic goals, consider primarily enzyme replacement therapy or in some cases substrate reduction. On the other hand, if patients have more moderate or severe disease, enzyme replacement therapy is the preferred choice. However, in certain cases in which it is unsuitable because of, for example, needle phobia or allergic reactions to this protein, substrate reduction therapy may be considered. In either situation, where there is disease remission or stabilisation, either a reduction in the dose or frequency of enzyme replacement therapy or a switch to substrate reduction the-
rapy could be considered. In any case, serial observation is important. These questions will be the subject of clinical trials in the near future. In moderate to severe cases in whom the response to the initial regimen of enzyme replacement is not adequate, there may be a need to adjust dosage and/or frequency of infusion, and assess for antibody formation. The possibility of an intercurrent disease process such as lymphoma and multiple myeloma that can have clinical features that overlap with Gaucher's disease must also be excluded. If the patient's status is unchanged despite optimised enzyme replacement therapy, it may be considered whether combination therapy would lead to a remission or stabilisation of the patient's disease course. If enzyme replacement therapy is continued, it may be appropriate to adjust the dosage and/or frequency. Alternatively, consideration could be given to the long-term management by substrate reduction therapy alone, bearing in mind that there is an increasing appreciation that substrate reduction therapy may also result in enzyme enhancement. References [1] Damiano AM, Pastores GM, Ware Jr JE. The health-related quality of life of adults with Gaucher's disease receiving enzyme replacement therapy: results from a retrospective study. Qual Life Res Jul 1998;7 (5):373–86. [2] Pastores GM, Sibille AR, Grabowski GA. Therapy in Gaucher's disease type 1: dosage efficacy and adverse effects in 33 patients treated for 6 to 24 months. Blood Jul 15 1993;82(2):408–16. [3] Alonso P, Pampin S, Estrada J. Miglustat works as a chaperone for mutated acid beta-glucosidase in cells transfected with several GD mutation. Blood Cells Mol Dis 2005(35):268–76. [4] Dwek RA, Butters TD, Platt FM, Zitzmann N. Targeting glycosylation as a therapeutic approach. Nat Rev 2002;1:65–75.
Management of patients with Gaucher's disease: Clinical perspectives Gregory Pastores Department of Neurology, New York University School of Medicine, New York, USA
Abstract Gaucher's disease is a clinically heterogeneous disorder, including neuropathic and non-neuropathic variants. Among patients with nonneuropathic (type I disease), the wide variability in age of onset and the differential pattern and severity of disease expression complicate decision-making in relation to treatment. Optimal care may necessitate both palliative and adjunctive therapies. In the more mildly affected patient without clear signs of disease progression, the main issue is the appropriate time to intervene. In moderately to severely affected patients, the challenges include selection of an optimal treatment regimen and dealing with residual disease burden. Eventually, in wellcontrolled patients, guidance will be required on long-term maintenance regimens that will have to take the cost of care into consideration. Guidelines reached by consensus will hopefully reduce variation in clinical practice and promote integrated care pathways. © 2006 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. Keywords: Gaucher's disease; Patient management; Therapeutic goals; Quality of life
1. Introduction As outlined in the first two presentations, Gaucher's disease is recognised as an inborn error of metabolism specifically affecting the catabolism of glycosphingolipid. The clinical manifestations reflect the cellular sites of lipid storage involving cells of monocyte macrophage lineage. There are currently two treatment options: enzyme replacement therapy and substrate reduction. This presentation gives a personal perspective on the issues relating to the management of Gaucher's disease, including lessons learned through involvement with the care of patients since 1990, and a discussion on ways of optimising the outcome for these patients. 2. Management of Gaucher's disease Gaucher's disease is a disorder that has a wide variability in chronicity and clinical expression. It therefore presents challenges in diagnosis and management, and necessitates an understanding of the drivers of morbidity, methods of disease assessment and interpretation of the derived information. It is necessary to assess the pattern and severity of disease, and E-mail address: [email protected].
determine what the findings represent in terms of risk of complications in the paediatric versus the adult patient. It is very important to emphasise that in a disorder such as Gaucher's disease there can be discordance between the systems involved. Patients can encounter significant haematological problems and splenomegaly with very minimal bone disease, but the opposite is also true as patients can have significant bone disease and yet only very mild or moderate haematological or visceral problems. Against this background, there needs to be an increased understanding of the role of surrogate markers, not only in diagnosis, but in the serial monitoring of outcome, whether a patient is receiving treatment or not. Once it is felt that treatment is indicated, it is very important to establish therapeutic goals that meet not only the physician's but the patient's expectations, as treatment regimens are likely to be a life-long commitment. 3. Investigations of natural history In terms of investigations of the natural history, Gaucher's disease can be considered to result from progressive substrate accumulation which, to some extent, is influenced by residual enzyme activity that is also dependent on the underlying causal mutation or gene defects. We know that onset of these
0953-6205/$ - see front matter © 2006 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2006.07.004
S10
G. Pastores / European Journal of Internal Medicine 17 (2006) S9–S12
Fig. 1. Investigations of natural history.
diseases can be in adulthood and can be a latent period during which time the patient may be asymptomatic. As shown in Fig. 1, a threshold of substrate accumulation is ultimately breached, accounting for full-blown disease with its wide variability of expression. More work needs to be done to understand what those factors are that ultimately influence disease phenotype in an individual, and a clearer understanding of the diagnostic modalities such as MRI or sophisticated imaging will be needed to define the pattern. It is currently very difficult not only to stage patients but also to obtain information of prognostic value. Once appreciation of the risk of complication is achieved, it is desirable to intervene a lot earlier in a patient's disease course. 4. Mechanisms of disease Although we think of Gaucher's disease as a lysosomal storage disorder, substrate accumulation and the associated mechanical consequences are not the sole mechanisms of disease. There is a cascade of downstream events resulting from substrate accumulation and perhaps chronic macrophage activation that in the end may prove to be important. The need to understand what these other mechanisms are will educate us about the kind of adjunctive therapies and traditional pharmacological agents that one can use as supplementary treatment to achieve optimal outcome.
progression to one that is sub-clinical. Failure to achieve this point may result in a disease that can be associated with significant residual disease burden; however, if treatment is truly effective prior to the onset of established necrotic and fibrotic changes, the resolution of clinical problems is possible. This is illustrated in Fig. 2. The concept of residual disease burden to some extent determines expectations of responses to therapy directed at either correcting the underlying enzyme deficiency or reducing substrate accumulation. One should recognise that there are irreversible aspects associated with this storage problem due to necrosis and fibrosis from either vascular or inflammatory mechanisms. In the bone, which is the major source of morbidity for Type I Gaucher's disease, one can encounter femoral head necrosis ultimately associated with subchondral joint collapse and, in some patients with severe osteopenia or osteoporosis, the development of pathological fractures. As emphasised in the presentation of the French observatoire of Gaucher's disease there has to be, in parallel with traditional methods of monitoring, an appreciation of how these complications can impact on the patient's physical and functional well being, from pain, limitation in joint motion and also impaired gait. As a consequence, when the introduction of treatment is delayed, patients may require sustained or other resources such as pain medication, physical therapy and joint replacement. As part of the assessment of cost-effectiveness, a comprehensive approach to patient care must consider Quality of Adjusted Life Years. It also has to take into consideration, in economic terms, discounting for the use of adjunctive therapies. The general concepts of patient management should also encompass appropriate genetic counselling for this autosomal recessive trait and identification of other family members at risk. These efforts will hopefully lead to development of guidelines relating to the care individuals who are affected and perhaps consideration of preventive approaches for carrier couples at risk of having an affected child. For long-term health outcomes, it is necessary to intervene with directed therapies aimed at correcting the underlying enzyme deficiency or reducing the substrate load, but in some cases we may need to use more than one strategy
5. Gaucher's disease care plan Most of the 300 patients at the New York University clinic are of Ashkenazi Jewish descent and have primarily the nonneuropathic Type I disease. As a result of screening programmes and extended family screening, it is possible to identify asymptomatic individuals. Whether asymptomatic or already with problems, the biochemical diagnosis is established before proceeding with clinical evaluations, and appropriate genetic counselling is offered. If Gaucher's disease in the individual patient is considered to be a progressive disorder in an ideal world she/he would be treated prior to the onset of symptoms with safe and effective therapy in order to intervene and alter the course of disease away from
Fig. 2. Therapeutic approaches.
G. Pastores / European Journal of Internal Medicine 17 (2006) S9–S12
S11
6. A look ahead
Fig. 3. Health-related quality of life (SF36) GD = Gaucher's disease, ERT = Enzyme replacement therapy.
and adjunctive therapies aimed at reducing the likelihood of complications. Fig. 3 illustrates data from a 1998 study by John E. Ware and colleagues who developed the SF36, an instrument for health-related quality of life. It shows the physical burden associated with Gaucher's disease in terms of physical function, bodily pain and vitality, compared to the general US population. Fig. 3 also shows data from 55 patients from the NYU clinic who received enzyme replacement therapy, and shows that treatment not only stabilises the disease but also actually reverses it to the extent that the curve is superimposed onto that for the general population [1]. This is probably also a result of aggressive anti-inflammatory therapy and high-quality nursing care to address anxieties from this chronic condition. When therapeutic goals are set, there must an understanding that the disease is not only heterogeneous in terms of its presentation but in fact also in its response to therapy. Using spleen size as a surrogate for the patient's overall response to therapy, the response to enzyme replacement therapy is encouraging. There is a progressive decline in splenomegaly that is actually maintained despite reduction in the initial doses of the enzyme. However, there is a broad range of responses initially from 10–65% during the first 6 months of therapy. The response is not necessarily associated with dose so enzyme dosage should necessarily be driven by the severity of a patient's disease, but there should be goals in terms of a time-scale for the desired outcome. In most cases the response is maintained as long as most patients receive a reasonable dose. It is also worthy of note that, in patients with or without an intact spleen, the reduction in liver volume is not related to the initial dose of enzyme replacement therapy. Regardless of initiating doses there is a convergence of response that occurs around a 12-month time point. Furthermore, there appears to be a relationship between baseline organ volumes and the percentage reduction [2].
Looking ahead to the future, it is clear that there is a need for greater experience and systematic data collection such as the evidence based observatoire data to assist with making decisions regarding the management of patients. We need to update the Gaucher disease severity scoring system to facilitate communication regarding phenotypes, and determine whether phenotypes are, in fact, different between populations such as those we see in the Asia and continental Europe or North America. When looking at the response to different therapeutic options it is encouraging to realise that there is ongoing surveillance that will represent avenues for collaboration efforts in the future. For these efforts to succeed, it is necessary to reformulate therapeutic guideline that map out the treatment algorithm incorporating not only enzyme replacement therapy but also substrate reduction therapy. Registry programs do indeed encourage evidence-based management, and importantly, when guidelines are reached by consensus, it reduces variability in clinical practice. The hope is that through this mechanism we will foster integrated care pathways. Carriers, who on average have only 50% of the healthy individual's enzyme activity, experience no substrate accumulation. Substrate accumulation is only encountered when the residual activity is extremely low, as occurs in patients with null alleles. There is a hypothetical level of substrate solubility and ultimately an irreversible threshold is reached when symptoms become evident. By supplementing some of the enzyme activity within an affected individual through protein replacement, the rate of substrate accumulation can be reduced and a therapeutic response achieved. Until recently most patients were on enzyme replacement therapy. Increasingly we are seeing patients managed with substrate reduction therapy, which interestingly also appears to enhance residual enzyme activity. The lysosome is an organelle that maintains an acidified environment, and proteins that are delivered to the lysosome are rapidly degraded. There are certain diseases that result from misfolding of a protein preventing its targeted delivery to
Fig. 4. Conceptual treatment approach.
S12
G. Pastores / European Journal of Internal Medicine 17 (2006) S9–S12
the lysosome. Certain small molecules can attach to the active site of the misfolded protein allowing that protein to assume its functional confirmation and full or enhanced activity within the target organelle. The “chemical chaperone” is usually a small molecule which can mimic the protein's natural substrate [3]. Small molecules that can also cross the blood–brain barrier could potentially advance what is achievable with enzyme replacement therapy in the management of patients with neuropathic involvement [4]. 7. Conceptual treatment approach Fig. 4 shows a conceptual treatment approach. Hopefully over the next few years it will be possible to refine the treatment guidelines with greater experience. If the starting point is a patient diagnosed with Gaucher's disease in whom we have assessed the pattern or the severity of the disease as stable or slowly progressing, serial observation and palliative care may be appropriate. If, over the course of monitoring, there are clear signs of progression and the development of symptoms, it may be necessary to introduce directed therapies and, depending on physician and patient preferences and the therapeutic goals, consider primarily enzyme replacement therapy or in some cases substrate reduction. On the other hand, if patients have more moderate or severe disease, enzyme replacement therapy is the preferred choice. However, in certain cases in which it is unsuitable because of, for example, needle phobia or allergic reactions to this protein, substrate reduction therapy may be considered. In either situation, where there is disease remission or stabilisation, either a reduction in the dose or frequency of enzyme replacement therapy or a switch to substrate reduction the-
rapy could be considered. In any case, serial observation is important. These questions will be the subject of clinical trials in the near future. In moderate to severe cases in whom the response to the initial regimen of enzyme replacement is not adequate, there may be a need to adjust dosage and/or frequency of infusion, and assess for antibody formation. The possibility of an intercurrent disease process such as lymphoma and multiple myeloma that can have clinical features that overlap with Gaucher's disease must also be excluded. If the patient's status is unchanged despite optimised enzyme replacement therapy, it may be considered whether combination therapy would lead to a remission or stabilisation of the patient's disease course. If enzyme replacement therapy is continued, it may be appropriate to adjust the dosage and/or frequency. Alternatively, consideration could be given to the long-term management by substrate reduction therapy alone, bearing in mind that there is an increasing appreciation that substrate reduction therapy may also result in enzyme enhancement. References [1] Damiano AM, Pastores GM, Ware Jr JE. The health-related quality of life of adults with Gaucher's disease receiving enzyme replacement therapy: results from a retrospective study. Qual Life Res Jul 1998;7 (5):373–86. [2] Pastores GM, Sibille AR, Grabowski GA. Therapy in Gaucher's disease type 1: dosage efficacy and adverse effects in 33 patients treated for 6 to 24 months. Blood Jul 15 1993;82(2):408–16. [3] Alonso P, Pampin S, Estrada J. Miglustat works as a chaperone for mutated acid beta-glucosidase in cells transfected with several GD mutation. Blood Cells Mol Dis 2005(35):268–76. [4] Dwek RA, Butters TD, Platt FM, Zitzmann N. Targeting glycosylation as a therapeutic approach. Nat Rev 2002;1:65–75.