Publications by authors named "Laura van Dussen"

18 Publications

  • Page 1 of 1

Influence of sex and phenotype on cardiac outcomes in patients with Fabry disease.

Heart 2021 Feb 10. Epub 2021 Feb 10.

Endocrinology and Metabolism, Amsterdam UMC Locatie AMC, Amsterdam, The Netherlands

Objective: This study describes the influence of sex and disease phenotype on the occurrence of cardiac events in Fabry disease (FD).

Methods: Cardiac events from birth to last visit (median age 50 years) were recorded for 213 patients with FD. Patients were categorised as follows : men with classical FD (n=57), men with non-classical FD (n=26), women with classical FD (n=98) and women with non-classical FD (n=32), based on the presence of classical FD symptoms, family history (men and women), biomarkers and residual enzyme activity (men). Event rates per 1000 patient-years after the age of 15 years and median event-free survival (EVS) age were presented. Influence of disease phenotype, sex and their interaction was studied using Firth's penalised Cox regression.

Results: The event rates of major cardiovascular events (combined endpoint cardiovascular death (CVD), heart failure (HF) hospitalisation, sustained ventricular arrhythmias (SVAs) and myocardial infarction) were 11.0 (95% CI 6.6 to 17.3) in men with classical FD (EVS 55 years), 4.4 (95% CI 2.5 to 7.1) in women with classical FD (EVS 70 years) and 5.9 (95% CI 2.6 to 11.6) in men with non-classical FD (EVS 70 years). None of these events occurred in women with non-classical FD. Sex and phenotype significantly influenced the risk of major adverse cardiovascular event. CVD was the leading cause of death (75%) to which HF contributed most (42%). The overall rate of SVA was low (14 events in nine patients (4%)).

Conclusions: Sex and phenotype greatly influence the risk and age of onset of cardiac events in FD. This indicates the need for patient group-specific follow-up and treatment.
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http://dx.doi.org/10.1136/heartjnl-2020-317922DOI Listing
February 2021

Predicting the Development of Anti-Drug Antibodies against Recombinant alpha-Galactosidase A in Male Patients with Classical Fabry Disease.

Int J Mol Sci 2020 Aug 12;21(16). Epub 2020 Aug 12.

Department of Endocrinology and Metabolism, Amsterdam University Medical Centers (AUMC), University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.

Fabry Disease (FD) is a rare, X-linked, lysosomal storage disease that mainly causes renal, cardiac and cerebral complications. Enzyme replacement therapy (ERT) with recombinant alpha-galactosidase A is available, but approximately 50% of male patients with classical FD develop inhibiting anti-drug antibodies (iADAs) that lead to reduced biochemical responses and an accelerated loss of renal function. Once immunization has occurred, iADAs tend to persist and tolerization is hard to achieve. Here we developed a pre-treatment prediction model for iADA development in FD using existing data from 120 classical male FD patients from three European centers, treated with ERT. We found that nonsense and frameshift mutations in the α-galactosidase A gene ( = 0.05), higher plasma lysoGb3 at baseline ( < 0.001) and agalsidase beta as first treatment ( = 0.006) were significantly associated with iADA development. Prediction performance of a Random Forest model, using multiple variables (AUC-ROC: 0.77) was compared to a logistic regression (LR) model using the three significantly associated variables (AUC-ROC: 0.77). The LR model can be used to determine iADA risk in individual FD patients prior to treatment initiation. This helps to determine in which patients adjusted treatment and/or immunomodulatory regimes may be considered to minimize iADA development risk.
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http://dx.doi.org/10.3390/ijms21165784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460974PMC
August 2020

Improvement in bone marrow infiltration in patients with type I Gaucher disease treated with taliglucerase alfa.

J Inherit Metab Dis 2018 11 31;41(6):1259-1265. Epub 2018 Jul 31.

Academic Medical Centre, Amsterdam, Netherlands.

Preliminary data suggest a positive effect of taliglucerase alfa on the bone marrow infiltration of Gaucher cells. In this investigator-initiated study, we report the impact of taliglucerase alfa on the bone marrow fat fraction (FF) in 26 patients assessed by quantitative chemical shift imaging (QCSI). Of 15 treatment-naïve patients (median age 48 [range 24-68] years), eight had baseline FF ≤ 0.3, six of those with a FF ≤ 0.23 ('bone at risk'). All significantly improved from a median baseline FF of 0.24 (0.15-0.32) to 1st year FF of 0.37 (0.25-0.54) and 2nd year FF of 0.42 (0.27-0.59) (p = 0.01). Among the 11 'switch-over' patients (median age 42 [range 33-69] years; median imiglucerase exposure 8 [range 1-17] years), eight had baseline FF ≤ 0.3, five of those with FF < 0.23. All, but one, significantly improved from a median baseline FF of 0.17 (0.08-0.28) to 1st year FF of 0.3 (0.05-0.34) and 2nd year FF of 0.34 (0.08-0.44) (p = 0.03). Two elderly female patients (age 43 and 58 years, with 17 years imiglucerase exposure) who remained at the same enzyme replacement therapy dose, increased from baseline FF of 0.13 and 0.19 to 0.26 at 1 year. Although the number of observations is small, we hypothesize that switching to taliglucerase may result in an improved bone marrow response. A larger study is needed to assess the early benefit of taliglucerase alfa in adult patients with type 1 Gaucher disease on the bone marrow compartment.
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http://dx.doi.org/10.1007/s10545-018-0195-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6326976PMC
November 2018

Hepatocellular carcinoma in Gaucher disease: an international case series.

J Inherit Metab Dis 2018 09 8;41(5):819-827. Epub 2018 Feb 8.

Department of Internal Medicine, division of Endocrinology & Metabolism, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.

Gaucher disease (GD) is associated with an increased risk for malignancies. Next to hematological malignancies, the development of solid tumors in several organs has been described. The liver is one of the major storage sites involved in GD pathogenesis, and is also affected by liver-specific complications. In this case series, we describe 16 GD type 1 (GD1) patients from eight different referral centers around the world who developed hepatocellular carcinoma (HCC). Potential factors contributing to the increased HCC risk in GD patients are studied. Eleven patients had undergone a splenectomy in the past. Liver cirrhosis, one of the main risk factors for the development of HCC, was present in nine out of 14 patients for whom data was available. Three out of seven examined patients showed a transferrin saturation > 45%. In these three patients the presence of iron overload after histopathological examination of the liver was shown. Chronic hepatitis C infection was present in three of 14 examined cases. We summarized all findings and made a comparison to the literature. We recommend that GD patients, especially those with prior splenectomy or iron overload, be evaluated for signs of liver fibrosis and if found to be monitored for HCC development.
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http://dx.doi.org/10.1007/s10545-018-0142-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133179PMC
September 2018

Lung Transplantation in Gaucher Disease: A Learning Lesson in Trying to Avoid Both Scylla and Charybdis.

Chest 2016 Jan 6;149(1):e1-5. Epub 2016 Jan 6.

Department of Respiratory Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. Electronic address:

Gaucher disease (GD), a lysosomal storage disorder, may result in end-stage lung disease. We report successful bilateral lung transplantation in a 49-year-old woman with GD complicated by severe pulmonary hypertension and fibrotic changes in the lungs. Before receiving the lung transplant, the patient was undergoing both enzyme replacement therapy (imiglucerase) and triple pulmonary hypertension treatment (epoprostenol, bosentan, and sildenafil). She had a history of splenectomy, severe bone disease, and renal involvement, all of which were related to GD and considered as relative contraindications for a lung transplantation. In the literature, lung transplantation has been suggested for severe pulmonary involvement in GD but has been reported only once in a child. To our knowledge, until now, no successful procedure has been reported in adults, and no reports deal with the severe potential posttransplantation complications specifically related to GD.
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http://dx.doi.org/10.1016/j.chest.2015.09.011DOI Listing
January 2016

Short-Term Effect of Estrogen on Human Bone Marrow Fat.

J Bone Miner Res 2015 Nov 14;30(11):2058-66. Epub 2015 Jul 14.

Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.

Bone marrow fat, an unique component of the bone marrow cavity increases with aging and menopause and is inversely related to bone mass. Sex steroids may be involved in the regulation of bone marrow fat, because men have higher bone marrow fat than women and clinical observations have suggested that the variation in bone marrow fat fraction is greater in premenopausal compared to postmenopausal women and men. We hypothesized that the menstrual cycle and/or estrogen affects the bone marrow fat fraction. First, we measured vertebral bone marrow fat fraction with Dixon Quantitative Chemical Shift MRI (QCSI) twice a week during 1 month in 10 regularly ovulating women. The vertebral bone marrow fat fraction increased 0.02 (95% CI, 0.00 to 0.03) during the follicular phase (p = 0.033), and showed a nonsignificant decrease of 0.02 (95% CI, -0.01 to 0.04) during the luteal phase (p = 0.091). To determine the effect of estrogen on bone marrow fat, we measured vertebral bone marrow fat fraction every week for 6 consecutive weeks in 6 postmenopausal women before, during, and after 2 weeks of oral 17-β estradiol treatment (2 mg/day). Bone marrow fat fraction decreased by 0.05 (95% CI, 0.01 to 0.09) from 0.48 (95% CI, 0.42 to 0.53) to 0.43 (95% CI, 0.34 to 0.51) during 17-β estradiol administration (p < 0.001) and increased again after cessation. During 17-β estradiol administration the bone formation marker procollagen type I N propeptide (P1NP) increased (p = 0.034) and the bone resorption marker C-terminal crosslinking telopeptides of collagen type I (CTx) decreased (p < 0.001). In conclusion, we described the variation in vertebral bone marrow fat fraction among ovulating premenopausal women. And among postmenopausal women, we demonstrated that 17-β estradiol rapidly reduces the marrow fat fraction, suggesting that 17-β estradiol regulates bone marrow fat independent of bone mass.
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http://dx.doi.org/10.1002/jbmr.2557DOI Listing
November 2015

Modelling Gaucher disease progression: long-term enzyme replacement therapy reduces the incidence of splenectomy and bone complications.

Orphanet J Rare Dis 2014 Jul 24;9:112. Epub 2014 Jul 24.

Long-term complications and associated conditions of type 1 Gaucher Disease (GD) can include splenectomy, bone complications, pulmonary hypertension, Parkinson disease and malignancies. Enzyme replacement therapy (ERT) reverses cytopenia and reduces organomegaly. To study the effects of ERT on long-term complications and associated conditions, the course of Gaucher disease was modelled.
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http://dx.doi.org/10.1186/s13023-014-0112-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4226965PMC
July 2014

Cost-effectiveness of enzyme replacement therapy for type 1 Gaucher disease.

Orphanet J Rare Dis 2014 Apr 14;9:51. Epub 2014 Apr 14.

Clinical Research Unit, Academic Medical Center, PO Box 22660, 1100 DD Amsterdam, The Netherlands.

Objective: To evaluate the cost-effectiveness of enzyme replacement therapy (ERT) compared to standard medical care without ERT in the Dutch cohort of patients with type 1 Gaucher disease (GD I).

Design: Cost-effectiveness analysis was performed using a life-time state-transition model of the disease's natural course. Transition probabilities, effectiveness data and costs were derived from retrospective data and prospective follow-up of the Dutch study cohort.

Setting: The tertiary referral center for Gaucher disease in the Netherlands.

Participants: The Dutch cohort of patients with GD I.

Intervention: ERT versus standard medical care without ERT in symptomatic patients.

Main Outcome Measures: Years free of end organ damage (YFEOD) (splenectomy, bone complication, malignancy, multiple complications), quality adjusted life years (QALY), and costs.

Results: Over an 85 year lifetime, an untreated GD I patient will generate 48.9 YFEOD and 55.86 QALYs. Starting ERT in a symptomatic patient increases the YFEOD by 12.8 years, while the number of QALYs gained increases by 6.27. The average yearly ERT medication costs range between € 124,000 and € 258,000 per patient. The lifetime costs of ERT starting in the symptomatic stage are € 5,716,473 against € 171,780 without ERT, a difference of € 5,544,693. Consequently, the extra costs per additional YFEOD or per additional QALY are € 434,416 and € 884,994 respectively. After discounting effects by 1.5% and costs by 4% and under a reasonable scenario of ERT unit cost reduction by 25%, these incremental cost-effectiveness ratios could decrease to € 149,857 and € 324,812 respectively.

Discussion: ERT is a highly potential drug for GD I with substantial health gains. The conservatively estimated incremental cost-effectiveness ratios are substantially lower than for Pompe and Fabry disease. We suggest that the high effectiveness has contributed importantly to acceptance of reimbursement of ERT for GD I. The present study may further support discussions on acceptable price limits for ultra-orphan products.
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http://dx.doi.org/10.1186/1750-1172-9-51DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4022049PMC
April 2014

Malignancies and monoclonal gammopathy in Gaucher disease; a systematic review of the literature.

Br J Haematol 2013 Jun 18;161(6):832-42. Epub 2013 Apr 18.

Department of Endocrinology and Metabolism, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.

Gaucher disease is an autosomal, recessively inherited, lysosomal storage disease, which has been associated with gammopathies and malignancies. This report represents the results of a systematic review of the literature on the prevalence of monoclonal gammopathies and malignancies in Gaucher disease. A PubMed search identified 365 studies, of which 80 reported on concomitant Gaucher disease and malignancies and/or gammopathies (15 cohort/cross sectional studies, and 65 case reports/series). Based on these studies, we conclude that compared to the general population, Gaucher patients have an increased risk of cancer in general [pooled relative risk of 1·70 (95% confidence interval 1·27-2·31)], and multiple myeloma and haematological malignancies in particular (estimated risk between 25·0 and 51·1 and 3·5 and 12·7, respectively). In addition, an increased risk has been reported for hepatocellular carcinoma and renal cell carcinoma. Several factors have been hypothesized to play a role in the pathophysiology. These include: splenectomy, immune dysregulation, endoplasmic reticulum stress, genetic modifiers, altered iron metabolism and insulin resistance.
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http://dx.doi.org/10.1111/bjh.12335DOI Listing
June 2013

Liver fibrosis in type I Gaucher disease: magnetic resonance imaging, transient elastography and parameters of iron storage.

PLoS One 2013 15;8(3):e57507. Epub 2013 Mar 15.

Department of Radiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Long term liver-related complications of type-1 Gaucher disease (GD), a lysosomal storage disorder, include fibrosis and an increased incidence of hepatocellular carcinoma. Splenectomy has been implicated as a risk factor for the development of liver pathology in GD. High ferritin concentrations are a feature of GD and iron storage in Gaucher cells has been described, but iron storage in the liver in relation to liver fibrosis has not been studied. Alternatively, iron storage in GD may be the result of iron supplementation therapy or regular blood transfusions in patients with severe cytopenia. In this pilot study, comprising 14 type-1 GD patients (7 splenectomized, 7 non-splenectomized) and 7 healthy controls, we demonstrate that liver stiffness values, measured by Transient Elastography and MR-Elastography, are significantly higher in splenectomized GD patients when compared with non-splenectomized GD patients (p = 0.03 and p = 0.01, respectively). Liver iron concentration was elevated (>60±30 µmol/g) in 4 GD patients of whom 3 were splenectomized. No relationship was found between liver stiffness and liver iron concentration. HFE gene mutations were more frequent in splenectomized (6/7) than in non-splenectomized (2/7) participants (p = 0.10). Liver disease appeared more advanced in splenectomized than in non-splenectomized patients. We hypothesize a relationship with excessive hepatic iron accumulation in splenectomized patients. We recommend that all splenectomized patients, especially those with evidence of substantial liver fibrosis undergo regular screening for HCC, according to current guidelines.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057507PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3598804PMC
September 2013

Effects of switching from a reduced dose imiglucerase to velaglucerase in type 1 Gaucher disease: clinical and biochemical outcomes.

Haematologica 2012 Dec 6;97(12):1850-4. Epub 2012 Jul 6.

Department of Endocrinology and Metabolism, Academic Medical Centre, Amsterdam, The Netherlands.

This paper describes the effects of a switch to velaglucerase alfa in a group of adult patients with type 1 Gaucher disease, all of whom had previously had their dose reduced as a consequence of the worldwide imiglucerase shortage. Thirty-two patients from two large European Gaucher centers switched to treatment with velaglucerase alfa after 1-8.5 months of dose reduction. The course of important Gaucher disease parameters was studied at four time points: one year before the shortage, just before the shortage, before a switch to velaglucerase and after up to one year of treatment with velaglucerase. These parameters included hemoglobin concentration, platelet count, plasma chitotriosidase activity in all patients, and spleen and liver volumes (as well as bone marrow fat fraction images) in 10 patients. Decreases in platelet counts as a result of reduced treatment with imiglucerase were quickly restored on treatment with velaglucerase alfa. Chitotriosidase activity declined overall after switching. Five out of 10 patients had an increase in liver volume of at least 10% after six months of velaglucerase treatment, which was reversible in 3. Most patients received infusions at home and no important side effects were observed. Velaglucerase alfa appears to be a safe and effective alternative for imiglucerase.
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http://dx.doi.org/10.3324/haematol.2011.059071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3590092PMC
December 2012

Characteristics of type I Gaucher disease associated with persistent thrombocytopenia after treatment with imiglucerase for 4-5 years.

Br J Haematol 2012 Aug 29;158(4):528-38. Epub 2012 May 29.

Department of Internal Medicine, Division of Endocrinology and Metabolism, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.

The characteristics of Gaucher disease (GD) associated with persistent thrombocytopenia despite imiglucerase enzyme therapy in type 1 GD (GD1) were investigated by retrospective analysis of International Collaborative Gaucher Group (ICGG) Registry data. The study involved 1016 GD1 patients with an intact spleen for whom date of diagnosis, therapy initiation, and platelet counts were known, and who received continuous imiglucerase therapy for 4 to 5 years. These patients were stratified by last platelet count: ≥ 120 × 10(9) /l (n = 772); ≥ 100 to <120 × 10(9) /l (n = 94); ≥ 80 to <100 × 10(9) /l (n = 80); and <80 × 10(9) /l (n = 70; 20 with <60 × 10(9) /l) and characterized by initial and cumulative average imiglucerase dose, body mass index, platelet count, anaemia, hepatomegaly, splenomegaly, and skeletal assessments at baseline and after 4-5 years of therapy. Statistically significant associations were found between persistent thrombocytopenia and baseline platelet count (<80 × 10(9) /l), splenomegaly, and anaemia (all P < 0·0001). After 4-5 years, statistically significant associations were found with splenomegaly (P < 0·0001), anaemia (P < 0·0001), white blood cell count (P = 0·049), hepatomegaly (P = 0·004) and bone pain (P = 0·035). Exponential platelet decay in relation to splenomegaly suggests that platelets increase only when spleen volume decreases substantially.
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http://dx.doi.org/10.1111/j.1365-2141.2012.09175.xDOI Listing
August 2012

Elevated plasma glucosylsphingosine in Gaucher disease: relation to phenotype, storage cell markers, and therapeutic response.

Blood 2011 Oct 25;118(16):e118-27. Epub 2011 Aug 25.

Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands.

Gaucher disease, caused by a deficiency of the lysosomal enzyme glucocerebrosidase, leads to prominent glucosylceramide accumulation in lysosomes of tissue macrophages (Gaucher cells). Here we show glucosylsphingosine, the deacylated form of glucosylceramide, to be markedly increased in plasma of symptomatic nonneuronopathic (type 1) Gaucher patients (n = 64, median = 230.7 nM, range 15.6-1035.2 nM; normal (n = 28): median 1.3 nM, range 0.8-2.7 nM). The method developed for mass spectrometric quantification of plasma glucosylsphingosine is sensitive and robust. Plasma glucosylsphingosine levels correlate with established plasma markers of Gaucher cells, chitotriosidase (ρ = 0.66) and CCL18 (ρ = 0.40). Treatment of Gaucher disease patients by supplementing macrophages with mannose-receptor targeted recombinant glucocerebrosidase results in glucosylsphingosine reduction, similar to protein markers of Gaucher cells. Since macrophages prominently accumulate the lysoglycosphingolipid on glucocerebrosidase inactivation, Gaucher cells seem a major source of the elevated plasma glucosylsphingosine. Our findings show that plasma glucosylsphingosine can qualify as a biomarker for type 1 Gaucher disease, but that further investigations are warranted regarding its relationship with clinical manifestations of Gaucher disease.
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http://dx.doi.org/10.1182/blood-2011-05-352971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3685900PMC
October 2011

Spontaneous regression of disease manifestations can occur in type 1 Gaucher disease; results of a retrospective cohort study.

Blood Cells Mol Dis 2010 Mar 13;44(3):181-7. Epub 2010 Jan 13.

Department of Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands.

Gaucher disease (GD) is a lysosomal storage disorder, caused by deficient activity of the enzyme glucocerebrosidase. GD is classically divided into three major phenotypes. The most prevailing form is type 1, which presents with variable hepatosplenomegaly, cytopenia, and/or bone disease. In adult patients with mild manifestations, progress of disease might be slow or even absent. As a consequence, treatment with intravenous enzyme replacement or substrate reduction is not always necessary. In the Netherlands, the follow-up of GD patients is centralized, which allows detailed investigation of untreated patients. A retrospective study was conducted in 18 type 1 GD patients, (2 teenagers: 15 and 16 years of age at first visit) who were not treated for at least one year. The chitotriosidase activity, platelet count, hemoglobin level, lumbar bone marrow fat content measured with quantitative chemical shift imaging (QCSI), liver ratio (ml/kg body weight), and spleen volume were recorded. Criteria were developed to score regression, stability or progression of disease. During a mean follow up of 4.5 years (range 1.1-12.2) seven patients (39%) showed spontaneous regression of GD. Eight patients (44%) were stable. Two patients had progressive disease, solely based upon a sustained increase in chitotriosidase activity. A pediatric patient had an increase in splenomegaly but an improvement in bone marrow fat fraction, probably due to aging. Nine patients fulfilled the local criteria to start treatment at first visit, of whom six started treatment within 1.1 to 6.8 years. The other three refused therapy, but nevertheless showed stability or even regression of the disease during a follow up of 4.6, 9.5 and 11.4 years respectively. None of the parameters was predictive of progression or regression of disease. In conclusion, GD in adults can, in some cases, regress spontaneously. No parameters for accurately predicting future disease course exist.
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http://dx.doi.org/10.1016/j.bcmd.2009.12.006DOI Listing
March 2010

Force majeure: therapeutic measures in response to restricted supply of imiglucerase (Cerezyme) for patients with Gaucher disease.

Blood Cells Mol Dis 2010 Jan 4;44(1):41-7. Epub 2009 Oct 4.

Department of Endocrinology and Metabolism, Academic Medical Centre, F5-170, PO Box 22660, 1100 DD Amsterdam, The Netherlands.

Gaucher disease is the first lysosomal disorder for which clinically effective enzyme replacement therapy has been introduced. Lifelong treatment with imiglucerase, the recombinant glucocerebrosidase manufactured by the Genzyme Corporation (MA, USA), is administered intravenously - usually at biweekly intervals. An acute shortage of imiglucerase (to 20% of prior global supply) has occurred as a result of viral contamination of the production facility; production was halted, and a full supply of imiglucerase is not anticipated until January 2010. An urgent meeting of physicians, researchers, and patients was convened through the agency of the European Working Group for Gaucher Disease; this was instigated by patients internationally represented by the European Gaucher Alliance. Here we present a position statement based on the findings of the group, with key recommendations about identification and monitoring of at-risk patients threatened by the abrupt withdrawal of treatment, the equitable distribution of residual imiglucerase - and access to alternative treatments including those that have completed phase III clinical trials but have not yet been licensed.
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http://dx.doi.org/10.1016/j.bcmd.2009.09.006DOI Listing
January 2010

Enzyme therapy for the treatment of type 1 Gaucher disease: clinical outcomes and dose - response relationships.

Expert Opin Pharmacother 2009 Nov;10(16):2641-52

Academic Medical Center, Division of Endocrinology and Metabolism, Department of Internal Medicine, F5-170, PO Box 22660, 1100 DD Amsterdam, The Netherlands.

Background: Enzyme therapy for Gaucher disease has improved the lives of many patients, by reducing the burden of their disease. Several studies have sought to determine to what extent optimal clinical outcomes are a function of the prescribed enzyme dose and its resultant costs.

Objective: Issues concerning dose - response relationships during initial and maintenance treatment phases and currently applied treatment goals have been addressed.

Methods: All studies that aimed to describe the efficacy of different doses of treatment and approaches for maintenance, such as lowering the dose or changing to less frequent infusions and the effects of drug interruptions, were reviewed.

Results/conclusion: Dose - response relationships do exist, but doses between 30 and 60 U/kg per month may be sufficient in a large majority of patients. Goals of treatment should include important clinical end points, such as enhanced quality of life and decreased risk for malignancies and other morbidities. The relationship between these important end points and treatment schedules deserve further study.
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http://dx.doi.org/10.1517/14656560903270520DOI Listing
November 2009

Gaucher disease: a model disorder for biomarker discovery.

Expert Rev Proteomics 2009 Aug;6(4):411-9

Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.

Gaucher disease is an inherited lysosomal storage disorder, characterized by massive accumulation of glucosylceramide-laden macrophages in the spleen, liver and bone marrow as a consequence of deficient activity of glucocerebrosidase. Gaucher disease has been the playground to develop new therapeutic interventions such as enzyme-replacement therapy and substrate-reduction therapy. The availability of these costly therapies has stimulated research regarding suitable biomarkers to monitor onset and progression of disease, as well as the efficacy of therapeutic intervention. Given the important role of storage cells in the pathology, various attempts have been made to identify proteins in plasma or serum reflecting the body burden of these pathological cells. In this review, the existing data regarding biomarkers for Gaucher disease, as well as the current application of biomarkers in clinical management of Gaucher patients are discussed. Moreover, the use of several modern proteomic technologies for the identification of Gaucher biomarkers is reviewed.
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http://dx.doi.org/10.1586/epr.09.54DOI Listing
August 2009