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Mutation du gène de la Glucocerebrosidase (maladie de Gaucher) et la maladie de Parkinson chez les Ashkénazes

MaladieDeGAUCHER — Mon, 02 Nov 2009 15:30:00 GMT

Article classé dans la catégorie "Parkinson et Gaucher".

Les patients atteints de maladie de Gaucher sont suceptibles d'être atteints par la maladie de Parkinson. Il a été constaté que certaines personnes hétérozygotes avec la mutation S370 sont atteints de la maladie de Parkinson.

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Ghislaine SURREL

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Volume 351:1972-1977		November 4, 2004		Number 19

Mutations in the Glucocerebrosidase Gene and Parkinson's Disease in Ashkenazi Jews

Judith Aharon-Peretz, M.D., Hanna Rosenbaum, M.D., and Ruth Gershoni-Baruch, M.D.

ABSTRACT

Background A clinical association has been reported betweentype 1 Gaucher's disease, which is caused by a glucocerebrosidasedeficiency owing to mutations in the glucocerebrosidase gene(GBA), and parkinsonism. We examined whether mutations in theGBA gene are relevant to idiopathic Parkinson's disease.

Methods A clinic-based case series of 99 Ashkenazi patientswith idiopathic Parkinson's disease, 74 Ashkenazi patients withAlzheimer's disease, and 1543 healthy Ashkenazi Jews who underwenttesting to identify heterozygosity for certain recessive diseaseswere screened for the six GBA mutations (N370S, L444P, 84GG,IVS+1, V394L, and R496H) that are most common among AshkenaziJews.

Results Thirty-one patients with Parkinson's disease (31.3 percent;95 percent confidence interval, 22.2 to 40.4 percent) had oneor two mutant GBA alleles: 23 were heterozygous for N370S, 4were heterozygous for 84GG, 3 were homozygous for N370S, and1 was heterozygous for R496H. Among the 74 patients with Alzheimer'sdisease, 3 were identified as carriers of Gaucher's disease(4.1 percent; 95 percent confidence interval, 0.0 to 8.5 percent):2 were heterozygous for N370S, and 1 was heterozygous for 84GG.Ninety-five carriers of Gaucher's disease were identified amongthe 1543 control subjects (6.2 percent; 95 percent confidenceinterval, 5.0 to 7.4 percent): 92 were heterozygous for N370S,and 3 were heterozygous for 84GG. Patients with Parkinson'sdisease had significantly greater odds of being carriers ofGaucher's disease than did patients with Alzheimer's disease(odds ratio, 10.8; 95 percent confidence interval, 3.0 to 46.6;P<0.001) or control subjects (odds ratio, 7.0; 95 percentconfidence interval, 4.2 to 11.4; P<0.001). Among the patientswith Parkinson's disease, patients who were carriers of Gaucher'sdisease were younger than those who were not carriers (mean[±SD] age at onset, 60.0±14.2 years vs. 64.2±11.7years; P=0.04).

Conclusions Our results suggest that heterozygosity for a GBAmutation may predispose Ashkenazi Jews to Parkinson's disease.

Parkinson's disease is a common neurodegenerative condition,with an estimated prevalence of approximately 1 in 100 persons.¹Parkinson's disease is characterized by resting tremor, akinesia,rigidity, and postural instability, caused by selective degenerationof dopaminergic neurons within the substantia nigra pars compactaand consequent depletion of dopamine in their striatal projections.¹Most cases of Parkinson's disease are sporadic, and familialcases are rare.²^,³ Data from twin and family studies,⁴ the mappingand cloning of PARK genes, and analysis of potential susceptibilitygenes have provided increasing evidence to indicate a causativerole for genetic factors in the disease.⁵^,⁶ There is also evidenceindicating that environmental factors play a role in the causationof Parkinson's disease.⁷ The association of parkinsonism withtype 1 Gaucher's disease has been reported.⁸^,⁹^,¹⁰^,¹¹^,¹² Thesimultaneous occurrence of Parkinson's disease and Gaucher'sdisease is marked by atypical parkinsonism generally presentingby the fourth through sixth decades of life. The combinationprogresses inexorably and is refractory to conventional antiparkinsontherapy.¹¹

Gaucher's disease, the most prevalent, recessively inheriteddisorder of glycolipid storage,¹³ is caused by a deficiencyof the lysosomal enzyme glucocerebrosidase, which normally hydrolyzesglucocerebroside to glucose and ceramide, leading to the accumulationof glucocerebroside in macrophages and resulting in multiorganinvolvement.¹³ Three phenotypes have been described that aredenoted by the absence (type 1) or presence of neurologic involvementduring childhood (type 2) or adolescence (type 3).¹³ Type 1Gaucher's disease is panethnic, but is especially prevalentamong persons of Ashkenazi Jewish descent, with a carrier rateof 1 in 17 Ashkenazi Jews.¹⁴ The N370S and 84GG mutations arethe most frequent mutations in the glucocerebrosidase gene (GBA)among Ashkenazi Jews, with rates of 1 in 17.5 for N370S and1 in 400 for 84GG in the general healthy Ashkenazi population,and are associated with mild and severe Gaucher's disease, respectively.The 84GG mutation occurs almost exclusively among AshkenaziJews.¹⁴ Other rare GBA variants identified in patients of Ashkenazidescent with Gaucher's disease include L444P, IVS2+1G" border="0">A, V394L,and R496H.

In an attempt to establish whether there is an association betweenParkinson's disease and Gaucher's disease, we determined theprevalence of mutations in the GBA gene in 99 Ashkenazi patientswith idiopathic Parkinson's disease, who had no signs or symptomsof Gaucher's disease, and compared the rate with that amongAshkenazi patients with Alzheimer's disease and among healthyAshkenazi controls.

Methods

Population

Ninety-nine Ashkenazi patients with idiopathic Parkinson's disease(55 men and 44 women) were sequentially recruited from the Cognitiveand Movement Disorder Unit at the Rambam Medical Center, Haifa,Israel, on their arrival at the clinic for follow-up or treatmentover a period of 28 months (from February 21, 2002, to April30, 2004). None had a history of neurologic or psychiatric conditionsother than Parkinson's disease. Seventy-four patients with Alzheimer'sdisease (42 men and 32 women) were similarly recruited fromthe same clinic to serve as a comparison group. The clinic servesas a secondary and tertiary referral center for patients withAlzheimer's disease and Parkinson's disease from the northernpart of Israel. Parkinson's disease was diagnosed accordingto the United Kingdom brain-bank criteria.¹⁵ Patients with Alzheimer'sdisease met the criteria for dementia of the Alzheimer's typeof the Diagnostic and Statistical Manual of Mental Disorders,4th edition,¹⁶ and the criteria for probable Alzheimer's diseaseof the National Institute of Neurological and CommunicativeDisorders and Stroke and the Alzheimer's Disease and RelatedDisorders Association.¹⁷

Information on family history, demographic characteristics,and clinical data were obtained in a uniform manner with theuse of structured questionnaires. Patients underwent a physical,neurobehavioral, and neurologic examination that incorporatedthe Unified Parkinson's Disease Rating Scale.¹⁸Patients ortheir guardians were asked to provide written informed consent,and patients were asked to provide a blood sample. All patientswere informed regarding the results of the analysis. The studywas approved by the hospital's institutional review board. Acontrol group of 1543 healthy Ashkenazi Jews from the same geographicarea who were undergoing testing to identify heterozygosityfor certain recessive diseases and who provided written informedconsent allowing the use of their DNA for research purposeswas used to determine the frequency of GBA mutations in ourgeneral population.

Detection of Mutations

DNA samples were subjected to a polymerase-chain-reaction (PCR)assay to identify six GBA mutations (N370S, L444P, 84GG, IVS2+1G" border="0">A,V394L, and R496H). PCR amplification was followed by digestionwith appropriate enzymes (Table 1), to distinguish the wild-typeallele from the mutant allele.¹⁹ Six primer pairs were usedseparately to amplify the genomic segments flanking each mutation.The PCR primers, annealing temperatures, restriction enzymes,and length of the PCR products before and after cleavage arelisted in Table 1. The L444P and R496H mutations create cleavagesites with the use of the NciI and HphI restriction enzymes,respectively. The IVS2+1G" border="0">A mutation abolishes a native restrictionsite for HphI. A mismatch introduced in either the forward orreverse primer is used to create a restriction site in eitherthe mutant PCR product (N370S and 84GG) or the normal PCR product(V394L) with the use of XhoI for N370S, BsabI for 84GG, andBanI for V394L. All mutant-allele profiles were confirmed bymeans of sequence analysis in an independent PCR assay, withthe use of an automated ABI Prism 310 Genetic Analyzer (Perkin–ElmerApplied Biosystems). No discrepancies were detected betweenthe results of cleavage analyses and the results of sequencing(Figure 1 and Figure 2).

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Table 1. Primers and Variables Used for the Detection of Mutations in the GBA Gene.

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Figure 1. PCR Analysis of the A1226G (N370S) Mutation in Patients with Parkinson's Disease.

When the mutation is present (lanes 1, 4, and 7), the enzyme (XhoI) digests a 105-bp PCR product, producing two fragments of 89 and 16 bp. The wild-type PCR product remains uncut (lanes 2, 3, 5, and 6). M denotes a 50-bp marker.

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Figure 2. Electropherogram of the Normal Sequence and the A1226G (N370S) Mutation in the GBA Gene.

The arrows show the position of the mutation.

Statistical Analysis

Differences in carrier rates among groups were analyzed by meansof the chi-square test. Differences in clinical characteristicswere compared between carriers and noncarriers by means of anindependent-sample t-test for age and a chi-square test forfamily history.

Results

Among the 99 Ashkenazi patients with Parkinson's disease, 31(31.3 percent; 95 percent confidence interval, 22.2 to 40.4percent) had a mutant GBA allele (Table 2): 23 were heterozygousfor N370S, 3 were homozygous for N370S, 1 was heterozygous forR496H, and 4 were heterozygous for 84GG. Among the 74 patientswith Alzheimer's disease, 3 were carriers of Gaucher's disease(4.1 percent; 95 percent confidence interval, 0.0 to 8.5 percent);2 were heterozygous for N370S, and 1 was heterozygous for 84GG.Among the 1543 control subjects, 95 were carriers of Gaucher'sdisease (6.2 percent; 95 percent confidence interval, 5.0 to7.4 percent); 92 were heterozygous for N370S, and 3 were heterozygousfor 84GG, findings consistent with a carrier rate of 1 in 16.7for the N370S variant and 1 in 514 for 84GG. Patients with Parkinson'sdisease had significantly greater odds of being carriers ofGaucher's disease than did patients with Alzheimer's disease(odds ratio, 10.8; 95 percent confidence interval, 3.0 to 46.6;P<0.001) or control subjects (odds ratio, 7.0; 95 percentconfidence interval, 4.2 to 11.4; P<0.001). The rate of carriageof Gaucher's disease among patients with Alzheimer's diseasedid not differ significantly from that among controls (oddsratio, 0.6; 95 percent confidence interval, 0.2 to 2.2; P=0.62).

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Table 2. Rates of Carriage of Gaucher's Disease among Patients with Parkinson's Disease, Patients with Alzheimer's Disease, and Control Subjects.

All patients with Parkinson's disease had an initially favorableresponse to dopaminergic agonists or levodopa. Among the patientswith Parkinson's disease, those who were also carriers of Gaucher'sdisease were significantly younger than those who were not carriers(mean [±SD] age at onset, 60.0±14.2 years vs.64.2±11.7 years; P=0.04). Carriers of Gaucher's diseasedid not differ significantly from noncarriers with regard tothe presence of a family history of Parkinson's disease in afirst- or second-degree relative, initial motor manifestations,or initial response to levodopa or dopaminergic agonists.

Discussion

Because parkinsonism has occasionally been described in patientswith Gaucher's disease, we evaluated the effect of GBA mutationson idiopathic Parkinson's disease. In our population of patientswith Parkinson's disease, the frequency of a mutant N370S GBAallele was 5 times that among our healthy Ashkenazi controlsubjects, and the frequency of a mutant 84GG GBA allele was21 times that among controls (P<0.001 for both comparisons).In addition, three patients with Parkinson's disease were foundto be homozygous for nonpenetrant Gaucher's disease (N370S/N370S),as compared with none of the 1543 control subjects. Since N370Scauses a mild phenotype, N370S/N370S homozygotes may remainsymptom-free, and their Gaucher's disease may escape detection.The prevalence of GBA mutations in our population of Ashkenazipatients with Parkinson's disease by far outweighs the reportedprevalence of mutations in other susceptibility genes for Parkinson'sdisease, such as parkin and synuclein.²⁰ Mutations in the GBAgene thus emerge as strong genetic determinants predisposingpeople to Parkinson's disease.

The nature of the association between Parkinson's disease andGaucher's disease remains elusive. In recent years, two hypothesesregarding the pathogenesis of Parkinson's disease have beensuggested. The first posits that misfolding and aggregationof proteins are instrumental in the death of dopaminergic neurons,and the other proposes that the culprit is oxidative stressresulting from mitochondrial dysfunction, which may also increasethe amount of misfolded proteins.²¹ The aggregation of proteinsmay lead to cell dysfunction by inhibiting the ubiquitin–proteasomesystem,²²^,²³ a finding that has been implicated in the causationof both familial and sporadic Parkinson's disease.²⁴

We speculate that the pathogenic mechanism leading to Parkinson'sdisease in carriers of mutant GBA alleles may be related tothe faulty processing of toxic, unwanted proteins, aggravatedby the relative decrease in glucocerebrosidase activity andaccumulation of glucocerebroside. Indeed, studies demonstratethat the inhibition of glucocerebrosidase and accumulation ofglucocerebroside induce apoptosis in cultured neurons by increasingthe mobilization of calcium ions from intracellular stores²⁵and that neurons with elevated levels of glucocerebroside showenhanced sensitivity to agents that induce cell death by potentiatingcalcium ions.²⁶ Moreover, mesencephalic cells, including dopaminergicneurons, can undergo apoptosis after ceramide-induced damage,²⁷suggesting that dysfunctional metabolism of sphyngolipids mayinduce the death of dopaminergic cells. However, since brainglucocerebroside levels were not consistently elevated in patientswith type 1 Gaucher's disease,²⁸ the pathogenetic relevanceof these findings remains unclear. Recent findings indicatethat Gaucher's disease and Parkinson's disease share pathophysiologicalfeatures. Unique pathological findings, such as neuronal loss,astrogliosis, and the presence of intraneuronal Lewy-body–likesynuclein inclusions specifically targeting the hippocampalCA2–3 region were recently described in both diseases.²⁹Synuclein is a neuronal protein. Mutations in the gene encoding-synuclein appear to be responsible for Parkinson's diseasein rare familial cases, and the aggregated protein is a majorcomponent of Lewy bodies, the pathological hallmark of sporadicParkinson's disease.⁵ Thus, the presence of intraneuronal Lewy-body–likesynuclein inclusions in patients with both type 1 and neuronopathicGaucher's disease points to a selective vulnerability and cytotoxicity,specifically targeting the CA2–3 region that appears tocharacterize idiopathic Parkinson's disease, diffuse Lewy-bodydementia, and according to recent reports, Gaucher's disease.

Carriage of type 1 Gaucher's disease is common in the Ashkenazipopulation. Taking into account the frequency of GBA mutationsin the general Ashkenazi population and the general prevalenceof parkinsonism,³⁰ we can extrapolate that the majority of carriersof mutant GBA alleles, in whom Parkinson's disease does notdevelop, are equipped with an efficient genetic mechanism thateither prevents the deposition and accumulation of glucocerebrosidein dopaminergic neurons or adequately degrades the glucocerebrosidethat is deposited. Alternatively, the occurrence of Parkinson'sdisease in carriers of Gaucher's disease may be accounted forby genetic variance in another gene.

In conclusion, our data indicate that some GBA mutations aregenetic susceptibility factors for Parkinson's disease. We havealso found that, in contrast to previous suggestions, heterozygosityfor a non-neuropathic GBA mutation is not an absolutely asymptomaticstate. Additional studies are needed to replicate our findings,to perform further analyses of the correlation between genotypeand phenotype, and to identify the pathogenetic mechanisms thatrender some carriers of Gaucher's disease vulnerable to Parkinson'sdisease. The clinical implications of our findings and thoseof other studies that are soon to be completed should affectthe treatment options available to patients with Parkinson'sdisease.

We are indebted to Gerald Brook, Hadas Shoshani, and Adi Sela-Goldbergfor their contributions.

Source Information

From the Department of Neurology and the Cognitive Neurology Unit (J.A.-P.) and the Departments of Hematology and Bone Marrow Transplantation (H.R.) and Human Genetics (R.G.-B.), Rambam Medical Center; and the Bruce Rappaport Faculty of Medicine, Technion–Israel Institute of Technology (J.A.-P., H.R., R.G.-B.) — both in Haifa, Israel.

Address reprint requests to Dr. Gershoni-Baruch at the Department of Medical Genetics, Rambam Medical Center, Haifa 31096, Israel, or at rgershoni@rambam.health.gov.il.

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Related Letters:

The Glucocerebrosidase Gene and Parkinson's Disease in Ashkenazi Jews
Eblan M. J., Walker J. M., Sidransky E., Zimran A., Neudorfer O., Elstein D., Schlossmacher M. G., Cullen V., Müthing J., Gershoni-Baruch R., Aharon-Peretz J., Rosenbaum H.
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N Engl J Med 2005; 352:728-731, Feb 17, 2005. Correspondence

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Di Fonzo, A., Chien, H. F., Socal, M., Giraudo, S., Tassorelli, C., Iliceto, G., Fabbrini, G., Marconi, R., Fincati, E., Abbruzzese, G., Marini, P., Squitieri, F., Horstink, M. W., Montagna, P., Libera, A. D., Stocchi, F., Goldwurm, S., Ferreira, J. J., Meco, G., Martignoni, E., Lopiano, L., Jardim, L. B., Oostra, B. A., Barbosa, E. R., The Italian Parkinson Genetics Network, , Bonifati, V. (2007). ATP13A2 missense mutations in juvenile parkinsonism and young onset Parkinson disease. Neurology 68: 1557-1562 [Abstract] [Full Text]
Goker-Alpan, O., Giasson, B. I., Eblan, M. J., Nguyen, J., Hurtig, H. I., Lee, V. M.-Y., Trojanowski, J. Q., Sidransky, E. (2006). Glucocerebrosidase mutations are an important risk factor for Lewy body disorders. Neurology 67: 908-910 [Abstract] [Full Text]
Spitz, M, Rozenberg, R, Silveira, P A A, Barbosa, E R (2006). Parkinsonism in type 1 Gaucher's disease. J. Neurol. Neurosurg. Psychiatry 77: 709-710 [Full Text]
Toft, M., Pielsticker, L., Ross, O. A., Aasly, J. O., Farrer, M. J. (2006). Glucocerebrosidase gene mutations and Parkinson disease in the Norwegian population. Neurology 66: 415-417 [Abstract] [Full Text]
Aharon-Peretz, J., Badarny, S., Rosenbaum, H., Gershoni-Baruch, R. (2005). Mutations in the glucocerebrosidase gene and Parkinson disease: Phenotype-genotype correlation. Neurology 65: 1460-1461 [Abstract] [Full Text]
Halliday, G. M., Ophof, A., Broe, M., Jensen, P. H., Kettle, E., Fedorow, H., Cartwright, M. I., Griffiths, F. M., Shepherd, C. E., Double, K. L. (2005). {alpha}-Synuclein redistributes to neuromelanin lipid in the substantia nigra early in Parkinson's disease. Brain 128: 2654-2664 [Abstract] [Full Text]
Paisan-Ruiz, C., Lang, A. E., Kawarai, T., Sato, C., Salehi-Rad, S., Fisman, G. K., Al-Khairallah, T., St George-Hyslop, P., Singleton, A., Rogaeva, E. (2005). LRRK2 gene in Parkinson disease: Mutation analysis and case control association study. Neurology 65: 696-700 [Abstract] [Full Text]
Eblan, M. J., Walker, J. M., Sidransky, E., Zimran, A., Neudorfer, O., Elstein, D., Schlossmacher, M. G., Cullen, V., Muthing, J., Gershoni-Baruch, R., Aharon-Peretz, J., Rosenbaum, H. (2005). The Glucocerebrosidase Gene and Parkinson's Disease in Ashkenazi Jews. NEJM 352: 728-731 [Full Text]

Comments and questions? Please contact us.

ACTELION, lettre du 08/09 relatif à la prescription de ZAVESCA suite à la pénurie de CEREZYME ( VESIVIRUS 2117)

MaladieDeGAUCHER — Tue, 22 Sep 2009 00:25:02 GMT

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Ghislaine SURREL

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ACTELION

AUGUST 2009

Dear Healthcare Professional:

In June 2009, Genzyme Corporation issued a press release announcing the detection of a virus in its recombinant cell cultures that produce the enzyme replacement therapy (ERT), imiglucerase. The contamination of cell cultures resulted in the immediate interruption of drug production and the subsequent supply shortage of Cerezyme® (imiglucerase) for some patients for a period of time. Since the announcement, Actelion has received direct requests from Healthcare Professionals for information regarding Zavesca® (miglustat) as an immediate option for patients who may not have access to imiglucerase treatment during the shortage.

Actelion would like to inform physicians that Zavesca® is indicated for the treatment of adult patients with mild to moderate type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option (e.g. due to constraints such as allergy, hypersensitivity or poor venous access). Zavesca® was approved and has been marketed in the United States since 2003. The decision to prescribe Zavesca® to patients is at the discretion of the treating physician. The physician should assess the risks and benefits of therapy for the individual patient.

Clinical studies where patients were switched from Cerezyme® to Zavesca® monotherapy have been conducted. One of these studies is described as follows:

The Study OGT 918-004 was a prospective, open-label, randomized clinical study over 24 months in which type 1 Gaucher patients were switched from ERT to Zavesca® monotherapy in one treatment arm. There were no significant differences for mean absolute changes in liver, spleen volume and hemoglobin concentration between the groups of patients switched to Zavesca® monotherapy and the Cerezyme® group. However, in adult type 1 Gaucher disease patients who had been treated with enzyme replacement therapy for at least 2 years, switching to Zavesca® as monotherapy was associated with decreases in platelet counts after discontinuation of enzyme replacement therapy. Platelet counts also declined after discontinuation of enzyme replacement therapy in patients originally randomized to combination therapy. [USPI; Elstein et al, Blood, 2007, 110(7):2296-2301] Important Safety Information for Zavesca®

§ Gastrointestinal disturbances (GI) such as diarrhea, flatulence and abdominal pain are the most common adverse side reactions associated with Zavesca® therapy.

— Diarrhea due to Zavesca® therapy usually responds to the introduction of a lactose-free and low carbohydrate diet and/or loperamide treatment.

§ Peripheral neuropathy has been reported in patients receiving Zavesca®.

— Patients should undergo neurological examination at the start of treatment and every 6 months thereafter; Zavesca® should be reassessed in patients who develop symptoms of peripheral neuropathy.

§ Zavesca® may cause fetal harm if administered to a pregnant woman.

— Pregnancy category X; Zavesca® is contraindicated in women who are or who may become pregnant; patients should be appraised of the potential hazard to a fetus.

§ There is a risk of impaired fertility in men.

— Men should maintain reliable contraceptive methods and not plan to conceive while taking Zavesca® and for 3 months after discontinuing treatment.

§ There is no experience with the use of Zavesca® in type 1 Gaucher disease patients under the age of 18 years.

Please consult the enclosed Zavesca® package insert for complete prescribing information. If you have additional questions or require additional information, please contact the Medical Information Department at usmedinfo@actelion.com or call toll-free (866) 228-3546 and follow the prompts for Medical Information.

Sincerely,

Kirk Taylor, MD Stefan Kolb, MD

Senior Vice President, US Medical Global Medical Leader, Zavesca®

Enclosure: Zavesca USPI 2008

Actelion Pharmaceuticals US, Inc.

SHIRE : Résultat de l'essai clinique de Phase III du Velaglucerase alfa pour la maladie de Gaucher de Type I

MaladieDeGAUCHER — Tue, 25 Aug 2009 07:21:52 GMT

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Registered in Jersey, No. 99854, 22 Grenville Street, St Helier, Jersey JE4 8PX

Shire Reports Positive Results from First of Three Phase III Trials of velaglucerase alfa for Type 1 Gaucher Disease and Provides Important Updates on Interactions with FDA
Treatment Protocol Accepted and Rolling Submission of New Drug Application Initiated

Lexington, Massachusetts, US – August 3, 2009 – Shire plc (LSE: SHP, NASDAQ: SHPGY), the global specialty biopharmaceutical company, today reported positive results from the first of three Phase III studies of velaglucerase alfa, its enzyme replacement therapy in development for the treatment of Type 1 Gaucher disease. The Company also announced that the U.S. Food and Drug Administration (FDA) has accepted its treatment protocol for velaglucerase alfa and that Shire has begun its rolling submission of the New Drug Application (NDA) for velaglucerase alfa allowed under the Fast Track process.

“We are very pleased with the progress of the velaglucerase alfa program from both a clinical and regulatory perspective,” said Sylvie Grégoire, President of Shire Human Genetic Therapies. “This data are consistent with those previously reported from the Phase I/II and extension studies. We will continue to work diligently with the FDA and other regulatory agencies to make velaglucerase alfa available as soon as possible to help meet the needs of the Gaucher community.”

Shire’s velaglucerase alfa program is the largest and most comprehensive set of Phase III clinical trials conducted to date for Gaucher disease. Over 100 patients at 24 sites in 10 countries around the world have participated in the clinical studies.

Velaglucerase alfa is made using Shire’s proprietary technology, in a human cell line. The enzyme produced has the exact human amino acid sequence and carries a human glycosylation pattern.

Phase III Study Overview and Results
The first trial in the Phase III program to be completed was a multicenter, randomized, double-blind, two dose study of velaglucerase alfa in patients with Type 1 Gaucher disease.
The primary goal of this study was to evaluate the safety and efficacy of velaglucerase alfa in 25 patients with Type 1 Gaucher disease.

Patients aged two years and older who were treatment naïve were eligible to participate in the study if they presented with disease-related anemia and had at least one of the following clinical manifestations of Gaucher disease: thrombocytopenia, moderate splenomegaly or a readily palpable enlarged liver. Patients were randomized to receive velaglucerase alfa at either 45 U/ kg or 60 U/ kg for a duration of 12 months.

In the trial, the primary endpoint was reached with patients benefiting from a clinically important and statistically significant (p<0.0001) increase in mean hemoglobin concentration compared with baseline after receiving velaglucerase alfa at 60 U/kg IV every other week for 12 months. Statistically significant improvements compared with baselines were also observed in platelet and spleen sizes, and nominally significant improvements were observed in liver size at this dose. Results were clinically important as defined by standard criteria and consistent with the previously published Phase I/II data.

At the 45 U/kg IV dose, statistically significant improvements in hemoglobin, platelet count, and spleen volume were also demonstrated. The magnitude of changes in the 45U/kg dose was also clinically important, and a trend in liver volume reduction was observed. The 60U/kg dose performed numerically as well or better than 45U/kg across all measured clinical endpoints.

The specific data from this trial will be presented at a scientific meeting later this year.

Velaglucerase alfa was found to be generally well tolerated with no drug-related serious adverse events reported in the trial. No patients withdrew from the trial due to an adverse event.

Most of the drug-related adverse events were reported in association with velaglucerase alfa infusions, all of which were mild and resolved without sequelae.

“These findings are very encouraging. They illustrate important potential benefits that velaglucerase alfa may provide to patients who are affected by Type 1 Gaucher disease,” said Dr. Atul Mehta, Clinical Director of the Lysosomal Storage Disorders Unit, Royal Free Hospital, London. “Velaglucerase alfa appears to be an excellent choice for Type 1 Gaucher patients. The prospect of having another treatment option available to help patients achieve therapeutic goals is very important and is welcomed by both the physicians and patients.”

Regulatory Updates
With regard to ongoing interactions with the FDA, Shire provided the following important updates:

The FDA has accepted Shire’s treatment protocol for velaglucerase alfa. The acceptance of the treatment protocol by the FDA will enable physicians to treat Gaucher patients with velaglucerase alfa prior to commercialization. Shire will initially provide velaglucerase alfa free of charge to patients who are enrolled in the protocol.

Shire has begun a rolling submission of a New Drug Application (NDA) to the FDA for velaglucerase alfa to treat patients with Type 1 Gaucher disease. The submission was initiated on July 30, 2009, three weeks after Shire received Fast Track designation. Fast Track designation allows a company to file the sections of the NDA as they become available and enables the agency to commence its review on a rolling basis. The company expects to complete the NDA submission by the end of this quarter.

Background on Gaucher disease
Gaucher disease is an autosomal recessive disease and the most prevalent Lysosomal Storage Disorder (LSD), with an incidence of about 1 in 20,000 live births. Despite the fact that Gaucher Disease consists of a phenotype, with varying degrees of severity, it has been sub-divided in three subtypes according to the presence or absence of neurological involvement. It is also the most common genetic disease affecting Ashkenazi Jewish people Eastern, Central and Northern European ancestry), with a carrier frequency of 1 in 10 (Dr. John Barranger and Dr. Ed Ginns 1989). This panethnic disease involves many organ systems, such as liver, spleen, lungs, brain, metabolism and bone marrow.
Gaucher Disease results from a specific enzyme deficiency in the body, caused by a genetic mutation received from both parents. The disease course is quite variable, ranging from no outward symptoms to severe disability and death. Carrier status can be detected through blood or saliva to identify potential carriers of the Gaucher gene. Gaucher Disease can be diagnosed early through a blood test.

Worldwide the diagnosed population of Gaucher Disease patients is approximately 7,000.
Based on incidence, the estimated total world population is likely to be between 10,000 and 15,000 patients.
For further information please contact:

Investor Relations Cléa Rosenfeld (Rest of the World) +44 1256 894 160
                           Eric Rojas (North America) +1 617 551 9715
Media                   Jessica Mann (Rest of the World) +44 1256 894 280
                           Jessica Cotrone (North America) +1 617 613 4640

Notes to editors

SHIRE PLC

Shire’s strategic goal is to become the leading specialty biopharmaceutical company that focuses on meeting the needs of the specialist physician. Shire focuses its business on attention deficit hyperactivity disorder (ADHD), human genetic therapies (HGT) and gastrointestinal (GI) diseases as well as opportunities in other therapeutic areas to the extent they arise through acquisitions. Shire’s in-licensing, merger and acquisition efforts are focused on products in specialist markets with strong intellectual property protection and global rights. Shire believes that a carefully selected and balanced portfolio of products with strategically aligned and relatively small-scale sales forces will deliver strong results.

For further information on Shire, please visit the Company’s website: www.shire.com.

"SAFE HARBOR" STATEMENT UNDER THE PRIVATE SECURITIES LITIGATION REFORM ACT
OF 1995

Statements included herein that are not historical facts are forward-looking statements. Such forward-looking statements involve a number of risks and uncertainties and are subject to change at any time. In the event such risks or uncertainties materialize, the Company’s results could be materially adversely affected. The risks and uncertainties include, but are not limited to, risks associated with: the inherent uncertainty of research, development, approval, reimbursement, manufacturing and commercialization of the Company’s Specialty Pharmaceutical and Human Genetic Therapies products, as well as the ability to secure and integrate new products for commercialization and/or development; government regulation of the Company’s products; the
Company’s ability to manufacture its products in sufficient quantities to meet demand; the impact of competitive therapies on the Company’s products; the Company’s ability to register, maintain and enforce patents and other intellectual property rights relating to its products; the Company’s ability to obtain and maintain government and other third-party reimbursement for its products; and other risks and uncertainties detailed from time to time in the Company’s filings with the Securities and Exchange Commission.

Press Release
www.shire.com

Protalix : FDA approuve le "treatment protocol" pour le prGCD

MaladieDeGAUCHER — Tue, 25 Aug 2009 07:02:44 GMT

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Subject: Protalix - press release: U.S. Food and Drug Administration Approves Protalix's Treatment Protocol for prGCD

CARMIEL, Israel--(BUSINESS WIRE)--Protalix BioTherapeutics, Inc. (NYSE-Amex:PLX), announced today that the U.S. Food and Drug Administration (FDA) has approved the Company’s treatment protocol for prGCD, the Company’s proprietary plant-cell expressed recombinant form of glucocerebrosidase (GCD) for the treatment of Gaucher disease. The treatment protocol allows physicians and other care-providers to treat patients of Gaucher disease with prGCD in the United States and additional countries world-wide while studies of prGCD continue as part of the Company’s ongoing pivotal Phase III clinical trial. Prior to accepting the protocol, the FDA reviewed available data from the Company’s on-going Phase III clinical development programs.

The treatment protocol is a multicenter, open-label trial designed to allow physicians and other care-providers to treat patients of Gaucher disease with prGCD during the expected shortage of Cerezyme® and thereafter. Cerezyme® is a mammalian cell expressed version of glucocerebrosidase and the only enzyme replacement therapy currently approved for Gaucher disease. The treatment protocol allows patients enrolled in the protocol to continue being treated with prGCD until its anticipated marketing approval from the FDA. The Company will provide the drug free of charge to patients enrolled in the protocol.

"We appreciate the guidance and vote of confidence provided by the FDA in establishing a treatment protocol for prGCD and are working closely with physicians and patient advocacy groups to allow Gaucher disease patients to gain access to our drug," commented Dr. David Aviezer, the Company’s President and Chief Executive Officer. "We expect to conclude our phase III pivotal study next month and are looking forward to announcing top-line results from this study in October. We anticipate filing an NDA with the FDA by the end of this year.”

About Protalix BioTherapeutics

Protalix is a biopharmaceutical company. Its goal is to become a fully integrated biopharmaceutical company focused on the development and commercialization of proprietary recombinant therapeutic proteins to be expressed through its proprietary plant cell based expression system. Protalix’s ProCellEx(TM) presents a proprietary method for the expression of recombinant proteins that Protalix believes will allow for the cost-effective, industrial-scale production of recombinant therapeutic proteins in an environment free of mammalian components and viruses. Protalix is conducting a Phase III pivotal study for its lead product candidate, prGCD, to be used in enzyme replacement therapy for Gaucher disease, a rare and serious lysosomal storage disorder in humans with severe and debilitating symptoms. Protalix and the U.S. Food and Drug Administration agreed on the final design of the pivotal Phase III clinical trial through the FDA’s Special Protocol Assessment (SPA) process. Protalix has completed enrollment for this study and is treating patients in the study in North America, South America, Israel, Europe and South Africa. The study is monitored by an independent Data Monitoring Committee, including experts in the field, who monitor the on-going safety data, which has recently held their last scheduled meeting before the end of the trial. No serious adverse events have been reported in the study. Protalix is also advancing additional recombinant biopharmaceutical drug development programs

EMEA 14-08-09 : PQuestions et réponses sur les manques de Cerezyme et Fabrazyme (virus Vesivirus 2117)

MaladieDeGAUCHER — Tue, 25 Aug 2009 06:56:10 GMT

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Ghislaine SURREL

maladies-lysosomales-subscribe@yahoogroupes.fr

European Medicines Agency

7 Westferry Circus, Canary Wharf, London E14 4HB, UK

Tel. (44-20) 74 18 84 00 Fax (44-20) 74 18 84 16

E-mail: mail@emea.europa.eu http://www.emea.europa.eu

 European Medicines Agency, 2009. Reproduction is authorised provided the source is acknowledged.

London, 14 August 2009

Doc. Ref. EMEA/510766/2009

Questions and answers on the shortages of Cerezyme and Fabrazyme

The European Medicines Agency has reviewed treatment recommendations from June 2009 on which

patients should receive Cerezyme and Fabrazyme as a priority during the shortage of these two

medicines over the next few months. The shortage, which is expected to last until the end of the year,

is happening because of a problem in a factory where the active substances for the medicines are

made.

The company has informed the Agency that the supply shortage of Cerezyme is more severe than it

previously thought. Because of this, the Agency is now recommending the following:

• for Cerezyme, only patients at greatest need of treatment will receive Cerezyme but at a reduced

dosage;

• for Fabrazyme, the recommendations given in June 2009 remain the same. They are ensuring that

patients at greatest need of treatment continue to receive this medicine until the shortage is

resolved.

What are Cerezyme and Fabrazyme?

Cerezyme and Fabrazyme are medicines that are used in two rare, inherited, life-threatening diseases

in which patients have a lack of an enzyme involved in the breakdown of fatty substances in the body:

• Cerezyme is used in patients with Gaucher disease, a disease in which patients do not have enough

of an enzyme called alglucerase. Cerezyme contains imiglucerase, which is a copy of the natural

enzyme;

• Fabrazyme is used in patients with Fabry disease, a disease in which patients do not have enough of

an enzyme called alpha-galactosidase A. Fabrazyme contains agalsidase beta, which is a copy of

the natural enzyme.

In both medicines, the replacement enzyme is made by a method known as ‘recombinant DNA

technology’: the enzymes are made by cells that have received genes (DNA) that makes them able to

produce the enzymes. The cells are grown in special tanks called ‘bioreactors’ over a three- to

four-month process, and the enzyme is extracted from the culture at regular intervals during the

process.

Cerezyme has been authorised since November 1997 and Fabrazyme since August 2001. Both

medicines are marketed in all Member States of the European Union.

What is the problem with Cerezyme and Fabrazyme?

Earlier this year, Genzyme, the company that makes Cerezyme and Fabrazyme, became aware of

reduced yields from the bioreactors used to produce Cerezyme and Fabrazyme at their production site

in Allston Landing in the United States of America. The company found out that the bioreactors were

contaminated with a virus (a calicivirus of the type Vesivirus 2117). This virus is not known to cause

disease in humans, but it can attack the cells used to produce these medicines. The contamination has

an impact on cell growth, affecting the quantity, but not the quality, of the enzymes produced by the

cells.

In June 2009, in order to sanitise the production facilities and conduct an investigation to prevent the

contamination from re-occurring, the company had to stop the production of new batches of Cerezyme

and Fabrazyme for an extended period of time. As a result of the supply shortage of both medicines,

the company, in agreement with the Agency, recommended some temporary changes to the way

Cerezyme and Fabrazyme were prescribed and used.

Although manufacturing is resuming, Genzyme has now informed the European Medicines Agency

that the stocks of Cerezyme are lower than it said they were in June. Therefore the recommendations

on the use of Cerezyme have had to be revised. These changes should be implemented immediately.

What are the recommendations while the shortages are ongoing?

Revised recommendations for Cerezyme

For Cerezyme, priority is given to infants, children and adolescents, and adults with severe, life-

threatening disease progression:

• infants, children and adolescents should receive Cerezyme at a reduced dose or at a reduced

infusion frequency. However, no patient should be treated at a dose lower than 15 units per

kilogram body weight every two weeks, or alternative treatment should be considered.

• adult patients with severe, life-threatening disease progression should receive Cerezyme at a

reduced dose or at a reduced infusion frequency. However, no patient should be treated at a dose

lower than 15 U/kg every four weeks, or alternative treatment should be considered.

In adult patients without severe, life-threatening disease progression, alternative treatment such as

miglustat should be considered or treatment should be interrupted. Adults who demonstrate

progression to severe, life-threatening disease should re-initiate treatment with Cerezyme.

Recommendations for Fabrazyme

For Fabrazyme, as in June 2009, priority is given to children and adolescents, and adult male

patients, who should continue to receive Fabrazyme as one infusion every two weeks.

However, adult female patients, in whom the disease is less severe, may receive Fabrazyme at a

reduced dose.

All patients will be closely monitored while treatment is suspended or while they are receiving

reduced doses of Cerezyme or Fabrazyme. Reporting of side effects will continue as normal, with

doctors recording the batch numbers of the medicines in each patient’s records.

These changes will need to continue until end of 2009 when the shortages are to be resolved.

What are the recommendations for prescribers?

• Doctors who look after patients with Gaucher or Fabry disease should be aware of the shortages,

and should consider which patients should be switched to the reduced dose or other treatment.

What are the recommendations for patients with Gaucher disease who receive Cerezyme?

• Young patients with the disease (infants, children and adolescents) and adult patients with severe,

life-threatening disease progression should be contacted by their doctor to discuss their treatment

options. While the shortages are ongoing, they may be treated at a different frequency and with a

reduced dose.

• Adult patients without severe, life-threatening disease progression should be contacted by their

doctor to discuss the possibility of switching to alternative treatments (e.g. miglustat) or suspending

treatment.

• Patients who have any questions should speak to their doctor or pharmacist.

What are the recommendations for patients with Fabry disease who receive Fabrazyme?

• There are no consequences for young patients with the disease (infants, children and adolescents)

or for adult male patients.

• Adult female patients with Fabry disease should be contacted by their doctor to discuss their

treatment options. While the shortages are ongoing, they may be treated at the same frequency

(every two weeks) but with a reduced dose.

• Patients who have any questions should speak to their doctor or pharmacist.

What will happen next?

Genzyme is sending specific communications to all Cerezyme prescribers on how to select patients for

dose reduction, switch to alternative treatment or suspension of treatment, according to the new

recommendations. Genzyme has informed the Agency that no changes to the June recommendations

are required for Fabrazyme.

Genzyme has also informed the Agency that these stock-sparing measures will have no impact on the

supplies to ongoing clinical trials.

The European Medicines Agency will update this document as new information becomes available.

Production de l'enzyme recombinant GCD exprimé dans des cellules de carrots

MaladieDeGAUCHER — Sat, 22 Aug 2009 09:06:39 GMT

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Ghislaine SURREL

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Plant Biotechnol J. 2007 Sep;5(5):579-90. Epub 2007 May 24.

Production of glucocerebrosidase with terminal mannose glycans for enzyme replacement therapy of Gaucher's disease using a plant cell system.

Shaaltiel Y, Bartfeld D, Hashmueli S, Baum G, Brill-Almon E, Galili G, Dym O, Boldin-Adamsky SA, Silman I, Sussman JL, Futerman AH, Aviezer D.

Protalix Biotherapeutics, 2 Snunit Street, Science Park, Carmiel 20100, Israel.

Gaucher's disease, a lysosomal storage disorder caused by mutations in the gene encoding glucocerebrosidase (GCD), is currently treated by enzyme replacement therapy using recombinant GCD (Cerezyme) expressed in Chinese hamster ovary (CHO) cells. As complex glycans in mammalian cells do not terminate in mannose residues, which are essential for the biological uptake of GCD via macrophage mannose receptors in human patients with Gaucher's disease, an in vitro glycan modification is required in order to expose the mannose residues on the glycans of Cerezyme. In this report, the production of a recombinant human GCD in a carrot cell suspension culture is described. The recombinant plant-derived GCD (prGCD) is targeted to the storage vacuoles, using a plant-specific C-terminal sorting signal. Notably, the recombinant human GCD expressed in the carrot cells naturally contains terminal mannose residues on its complex glycans, apparently as a result of the activity of a special vacuolar enzyme that modifies complex glycans. Hence, the plant-produced recombinant human GCD does not require exposure of mannose residues in vitro, which is a requirement for the production of Cerezyme. prGCD also displays a level of biological activity similar to that of Cerezyme produced in CHO cells, as well as a highly homologous high-resolution three-dimensional structure, determined by X-ray crystallography. A single-dose toxicity study with prGCD in mice demonstrated the absence of treatment-related adverse reactions or clinical findings, indicating the potential safety of prGCD. prGCD is currently undergoing clinical studies, and may offer a new and alternative therapeutic option for Gaucher's disease.

Publication Types:

Research Support, Non-U.S. Gov't

PMID: 17524049 [PubMed - indexed for MEDLINE]

FDA : traitement SHIRE et PROTALIX

MaladieDeGAUCHER — Sat, 22 Aug 2009 08:58:20 GMT

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Current Drug Shortages

Drug Name

Company

Drug Name

Cerezyme (imiglucerase) Injection

Updated 8/21/2009

Genzyme Corporation

For inquiries contact Genzyme Medical Information: medinfo@genzyme.com

or 1-800-745-4447, option 2

Manufacturing delays

Please see Dear Doctor letter, Dear Patient letter, and Request Form also visit the Website: Genzyme supply update for additional information.

Please see the following link Treatment Protocol of Velaglucerase Alfa (this is a treatment protocol available under IND)

Please see the following link: Expanded Access Trial of Plant Expressed Recombinant Glucocerebrosidase (prGCD) in Patients With Gaucher Disease for information about prGCD, also called Taliglucerase Alfa (this is a treatment protocol available under IND

http://www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm050792.htm#cerezyme

PROTALIX : Accés étendu à l'essai de Glucocerebrosidase (prGCD) Recombinant dans la maladie de Gaucher

MaladieDeGAUCHER — Sat, 22 Aug 2009 08:34:07 GMT

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Expanded Access Trial of Plant Expressed Recombinant Glucocerebrosidase (prGCD) in Patients With Gaucher Disease
Expanded access is currently available for this treatment.

Verified by Protalix, August 2009

First Received: August 18, 2009 No Changes Posted

Sponsored by:	Protalix
Information provided by:	Protalix
ClinicalTrials.gov Identifier:	NCT00962260

Purpose

This is an open-label expanded access trial of prGCD in patients with Gaucher disease who require enzyme replacement therapy (ERT) and who have been treated with imiglucerase but for whom the dose has been reduced or discontinued due to shortage of the product.

Condition	Intervention
Gaucher Disease	Drug: Plant cell expressed recombinant glucocerebrosidase (prGCD)

Study Type:	Expanded Access
Official Title:	An Open-label Expanded Access Trial of Plant Cell Expressed Recombinant Human Glucocerebrosidase (prGCD) in Patients With Gaucher Disease Who Require Enzyme Replacement Therapy

Resource links provided by NLM:

Genetics Home Reference related topics: Chanarin-Dorfman syndrome cholesteryl ester storage disease Farber lipogranulomatosis Gaucher disease primary carnitine deficiency succinic semialdehyde dehydrogenase deficiency

MedlinePlus related topics: Gaucher's Disease

Drug Information available for: Alglucerase Imiglucerase

U.S. FDA Resources

Further study details as provided by Protalix:

Intervention Details:
Drug: Plant cell expressed recombinant glucocerebrosidase (prGCD)

Intravenous infusion every two weeks at the dose level equal to each patient's previous imiglucerase dose before reduction or discontinuation due to shortage

Detailed Description:
Gaucher disease, the most prevalent lysosomal storage disorder, is caused by mutations in the human glucocerebrosidase gene (GCD), which have been mapped to chromosome 1 q21-q31, leading to reduced activity of the lysosomal enzyme glucocerebrosidase and thereby to the accumulation of substrate glucocerebroside (GlcCer) in the cells of the monocyte-macrophage system. This accumulation leads to the visceral manifestations of hepatosplenomegaly, anemia and thrombocytopenia, as well as to the skeletal features and less frequently also to lung involvement.
prGCD is a plant cell expressed recombinant glucocerebrosidase enzyme for the treatment of Gaucher disease.
Expression of proteins in plant cell culture is highly efficient, does not require post-expression modification of the protein, and is not susceptible to contamination by agents such as viruses that are pathological to humans.
prGCD safety will be observed in this treatment protocol of patients with non-neuronopathic Gaucher disease who require enzyme replacement therapy. Eligible patients will receive intravenous (IV) infusions of prGCD every two weeks. The dose of prGCD will be equal to each patient's previous imiglucerase dose before reduction or discontinuation due to shortage. The infusions will be administered at the selected medical center.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Bot

Criteria
Inclusion Criteria:

Males and females, 18 years or older
Diagnosis of Gaucher disease treated historically with imiglucerase
Able to provide written informed consent

Exclusion Criteria:

Currently taking another experimental drug for any condition
History of allergy to carrots
Presence of anti-glucocerebrosidase (GCD) antibodies
Previous infusion reaction suspected to be allergic in nature to Cerezyme® or Ceredase® or receiving premedication to prevent infusion reactions
Allergy to beta-lactam antibiotics
Presence of any medical, emotional, behavioral or psychological condition that in the judgment of the Investigator would interfere with the patient's compliance with the requirements of the study.

Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00962260

Contacts

Contact: Raul Chertkoff, MD

+972 (4) 988-9488

raul@protalix.com

Sponsors and Collaborators
Protalix

More Information

Publications:

Shaaltiel Y, Bartfeld D, Hashmueli S, Baum G, Brill-Almon E, Galili G, Dym O, Boldin-Adamsky SA, Silman I, Sussman JL, Futerman AH, Aviezer D. Production of glucocerebrosidase with terminal mannose glycans for enzyme replacement therapy of Gaucher's disease using a plant cell system. Plant Biotechnol J. 2007 Sep;5(5):579-90. Epub 2007 May 24.

Aviezer D, Brill-Almon E, Shaaltiel Y, Hashmueli S, Bartfeld D, Mizrachi S, Liberman Y, Freeman A, Zimran A, Galun E. A plant-derived recombinant human glucocerebrosidase enzyme--a preclinical and phase I investigation. PLoS ONE. 2009;4(3):e4792. Epub 2009 Mar 11.

Responsible Party:	Protalix Ltd ( Einat Brill Almon, PhD )
Study ID Numbers:	PB-06-004
Study First Received:	August 18, 2009
Last Updated:	August 18, 2009
ClinicalTrials.gov Identifier:	NCT00962260 History of Changes
Health Authority:	United States: Food and Drug Administration; Israel: Ministry of Health

Keywords provided by Protalix:

                  glucocerebrosidase
                  enzyme replacement therapy
                  Gaucher disease
                  plant cell culture

                  splenomegaly
                  hepatomegaly
                  anemia
                  thrombocytopenia

Study placed in the following topic categories:

                  Lipid Metabolism, Inborn Errors
                  Sphingolipidoses
                  Metabolic Diseases
                  Lysosomal Storage Diseases
                  Anemia
                  Sphingolipidosis
                  Central Nervous System Diseases
                  Brain Diseases
                  Lymphatic Diseases
                  Metabolism, Inborn Errors

                  Thrombocytopenia
                  Genetic Diseases, Inborn
                  Splenomegaly
                  Lipidoses
                  Brain Diseases, Metabolic, Inborn
                  Gaucher Disease
                  Metabolic Disorder
                  Hepatomegaly
                  Lipid Metabolism Disorders
                  Brain Diseases, Metabolic

Additional relevant MeSH terms:

                  Lipid Metabolism, Inborn Errors
                  Sphingolipidoses
                  Metabolic Diseases
                  Reticuloendotheliosis
                  Lysosomal Storage Diseases, Nervous System
                  Lysosomal Storage Diseases
                  Nervous System Diseases
                  Central Nervous System Diseases
                  Brain Diseases

                  Lymphatic Diseases
                  Metabolism, Inborn Errors
                  Genetic Diseases, Inborn
                  Brain Diseases, Metabolic, Inborn
                  Lipidoses
                  Gaucher Disease
                  Lipid Metabolism Disorders
                  Brain Diseases, Metabolic

ClinicalTrials.gov processed this record on August 21, 2009

Contact Help Desk
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http://www.clinicaltrials.gov/ct2/show/NCT00962260?term=prgcd

Treatment Protocol of Velaglucerase Alfa for Patients With Type 1 Gaucher Disease

MaladieDeGAUCHER — Tue, 18 Aug 2009 23:03:00 GMT

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Ghislaine SURREL

maladies-lysosomales-subscribe@yahoogroupes.fr

Treatment Protocol of Velaglucerase Alfa for Patients With Type 1 Gaucher Disease

Expanded access is currently available for this treatment.

Verified by Shire Human Genetic Therapies, Inc., August 2009

First Received: August 5, 2009 Last Updated: August 6, 2009 History of Changes

Sponsored by:	Shire Human Genetic Therapies, Inc.
Information provided by:	Shire Human Genetic Therapies, Inc.
ClinicalTrials.gov Identifier:	NCT00954460

Purpose

Gaucher disease is a rare lysosomal storage disorder caused by the deficiency of the enzyme glucocerebrosidase (GCB). Due to the deficiency of functional GCB, glucocerebroside accumulates within macrophages leading to cellular engorgement, organomegaly, and organ system dysfunction. The purpose of this treatment protocol is to observe the safety of velaglucerase alfa in patients with type 1 Gaucher disease who are either treatment naive (newly diagnosed) or who are currently being treated with the Enzyme Replacement Therapy (ERT) imiglucerase.

Condition	Intervention
Gaucher Disease, Type 1	Drug: velaglucerase alfa

Study Type:

Expanded Access

Official Title:

Multicenter Open-Label Treatment Protocol to Observe the Safety of Gene-Activated™ Human Glucocerebrosidase (GA-GCB, Velaglucerase Alfa) ERT in Newly Diagnosed or Previously Treated (With Imiglucerase) Patients With Type

1 Gaucher Disease

Resource links provided by NLM:

MedlinePlus related topics: Gaucher's Disease

Drug Information available for: Alglucerase Imiglucerase

U.S. FDA Resources

Further study details as provided by Shire Human Genetic Therapies, Inc.:

Intervention Details:

Drug: velaglucerase alfa

up to 60 U/kg, every other week via intravenous infusion

Detailed Description:

Type 1 Gaucher disease, the most common form, accounts for more than 90% of all cases of Gaucher disease and does not involve the CNS. Typical manifestations of type 1 Gaucher disease include hepatomegaly, splenomegaly, thrombocytopenia, bleeding tendencies, anemia, hypermetabolism, skeletal pathology, growth retardation, pulmonary disease, and decreased quality of life. Velaglucerase alfa (Gene-Activated™ human glucocerebrosidase;GA-GCB) is produced in a continuous human cell line using proprietary gene-activation technology and has an identical amino acid sequence to the naturally occurring human enzyme. Velaglucerase alfa contains terminal mannose residues that target the enzyme to the macrophages-the primary target cells in Gaucher disease. This treatment protocol will observe the safety of velaglucerase alfa in patients with type 1 Gaucher disease who are either treatment naive (newly diagnosed) or who are currently being treated with the Enzyme Replacement Therapy (ERT) imiglucerase.

Patients currently being treated with ERT for their Gaucher disease will receive the same number of units of velaglucerase alfa per month as their imiglucerase dose for doses between 30-120 U/kg/month. For patients who experienced dose reductions in their imiglucerase treatment due to supply constraints the pre-reduction monthly dose may be used to determine the monthly dose of velaglucerase alfa.

Eligibility

Ages Eligible for Study:	3 Years and older
Genders Eligible for Study:	Both

Criteria

Inclusion Criteria:

The patient has a documented diagnosis of type 1 Gaucher disease

The patient is > 2 years of age

The patient has NOT previously experienced an anaphylactic or anaphylactoid reaction to another ERT including imiglucerase

Women of child-bearing potential must agree to use a medically acceptable method of contraception at all times during the study; and must have a negative result to a pregnancy test as required throughout their participation in the study. Male patients must use a medically acceptable method of birth control throughout their participation in the study and must report their partner's pregnancy.

The patient is sufficiently cooperative to participate in this treatment plan as judged by the Investigator

If the patient is naïve or new to treatment, the patient has one or more of the following (in absence of the following criteria, please call the sponsor for treatment justification):
- Gaucher disease-related anemia
- Moderate splenomegaly (2 to 3 cm below the left costal margin), by palpation
- Gaucher disease-related thrombocytopenia
- Gaucher disease-related palpable enlarged liver

Exclusion Criteria: None

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00954460

Contacts

Contact: Dan Madden (One Path)

1-866-888-0660

Sponsors and Collaborators

Shire Human Genetic Therapies, Inc.

More Information

No publications provided

Responsible Party:	Shire Human Genetic Therapies, Inc. ( Gabriel M. Cohn, M.D., MBA, FACMG, FACOG )
Study ID Numbers:	HGT-GCB-058
Study First Received:	August 5, 2009
Last Updated:	August 6, 2009
ClinicalTrials.gov Identifier:	NCT00954460 History of Changes
Health Authority:	United States: Food and Drug Administration

Keywords provided by Shire Human Genetic Therapies, Inc.:

Enzyme Replacement Therapy
Gaucher disease
glucocerebrosidase
beta-glucocerebrosidase
Acid beta-glucocerebrosidase

glucosylceramidase
D-glucosyl-N-acylsphingosine glucohydrolase
gene activation
human

Study placed in the following topic categories:

Lipid Metabolism, Inborn Errors
Sphingolipidoses
Metabolic Diseases
Lysosomal Storage Diseases
Sphingolipidosis
Central Nervous System Diseases
Brain Diseases
Lymphatic Diseases

Metabolism, Inborn Errors
Genetic Diseases, Inborn
Brain Diseases, Metabolic, Inborn
Lipidoses
Gaucher Disease
Metabolic Disorder
Lipid Metabolism Disorders
Brain Diseases, Metabolic

Additional relevant MeSH terms:

Lymphatic Diseases
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Brain Diseases, Metabolic, Inborn
Lipidoses
Gaucher Disease
Lipid Metabolism Disorders
Brain Diseases, Metabolic

ClinicalTrials.gov processed this record on August 18, 2009

Lettre de Genzyme du 3/08/09 aux US docteurs sur la gestion du stock et attente de la la FDA concernant la GENZ-112638

MaladieDeGAUCHER — Tue, 18 Aug 2009 22:56:00 GMT

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Ghislaine SURREL

maladies-lysosomales-subscribe@yahoogroupes.fr

Genzyme Corporation

500 Kendall Street

Cambridge, MA 02142

Tel 617-252-7500

August 3, 2009

RE: Revised Cerezyme® (imiglucerase for injection) Supply Management plan effective August 3, 2009

Dear Doctor:

As we previously informed you, we are in a period of temporary shortage of Cerezyme while we interrupt production to remediate a viral contamination of our manufacturing facility in Allston, Massachusetts.

Throughout this period, our overarching objective has been to protect the most vulnerable Gaucher patients.

On June 22, Genzyme convened a Cerezyme Stakeholders Working Group (including physicians and patient advocacy leaders) to develop a set of recommendations (a “Guidance”) for patient management designed to conserve supply for the most vulnerable patients. Across the U.S., physicians have begun to implement these recommendations. However, due to the complexities and time required to make these changes, we have not yet seen an adequate reduction in the usage of Cerezyme.

The projected levels of Cerezyme inventory are at a point where there is a high risk of not maintaining supply sufficient to protect the most vulnerable patients in August. The Cerezyme Stakeholders Working Group and FDA have been updated regarding this situation. As a result we have decided to begin more actively managing Cerezyme supply in order to preserve supply for the most vulnerable patients.

As of Monday August 3, 2009, Genzyme will implement a revised supply management plan which has been reviewed by the CSWG and which continues to have as its main objective conservation of Cerezyme supply for the most vulnerable patients.

The most vulnerable Gaucher patients will be defined as: infants, children and adolescents (≤18 years old) and patients with type 2 or 3 Gaucher disease. These patients should continue receiving Cerezyme according to their current dose and frequency, without any interruptions, and shipments will continue to these patients.

In addition, Genzyme will implement a Cerezyme Emergency Access Program (CEAP) which is designed to enable physicians to request Cerezyme for a limited number of other adult patients with life- threatening clinical situations defined as one or more of the following:

Platelet count ≤20,000/uL and/or documented bleeding diathesis Impending emergency non-elective surgery (e.g., splenectomy) Documented history of rapid and life-threatening disease progression following dose-reduction or treatment interruption.

Other life-threatening clinical situation which requires Cerezyme

The number of qualifying patients who will be able to receive Cerezyme through CEAP will depend on inventory levels. The CEAP form with instructions regarding the process is enclosed.

Other adult patients (>18 years old) will not receive shipments of Cerezyme as of August 3rd, in order to conserve supply for the most vulnerable patients defined above.

This revised supply management plan will be in effect through the month of August. At that point, the situation will be reassessed in consultation with the Cerezyme Stakeholders Working Group and the FDA, and we will inform the Gaucher community about any changes to the plan.

We anticipate having additional information to share with the community at that time regarding the availability of additional inventory of Cerezyme that is not currently approved for finishing and release by FDA. In addition, Genzyme has submitted a treatment IND for our investigational oral small molecule to treat Gaucher disease, GENZ-112638, and we anticipate a response from FDA regarding that treatment protocol by the end of August. In the meantime, if you need any further information, please contact Genzyme Medical Information (medinfo@genzyme.com or 800-745-4447, option 2). A copy of the Cerezyme US Prescribing Information is included with this letter.

We acknowledge that this has been a challenging period for the entire Gaucher community. As of today, the sanitization of the Allston facility has been completed, and the process of restarting production of Cerezyme has already begun. Throughout this time, thank you for working together with us to protect the most vulnerable patients until the supply of Cerezyme is fully restored.

Sincerely,

John Yee, MD, MPH

VP, Global Medical Affairs

Genzyme Corporation

Fabrazyme® (agalsidase beta) Update: Initial adoption of the Fabry Stakeholders Working Group Guidance appears to be strong, with many indications that physicians and patients have chosen to alter their treatment plans by missing a dose, reducing their dose, or changing the frequency of infusions. At this time, there is not a need to revise this Guidance. However, during this period of supply constraint, there continues to be a need for physicians to make the appropriate clinical decisions for each Fabry patient in consideration of the Fabry Stakeholders Working Group Guidance until the Fabrazyme supply is fully restored.

CZ-US-P067-08-09