Safety and Efficacy of Recombinant Human -Galactosidase A Replacement Therapy in Fabry's Disease
Christine M. Eng, M.D., Nathalie Guffon, M.D., William R. Wilcox, M.D., Ph.D., Dominique P. Germain, M.D., Ph.D., Philip Lee, M.R.C.P., D.M., Ph.D., Steve Waldek, M.B., B.Ch., Louis Caplan, M.D., Gabor E. Linthorst, M.D., Robert J. Desnick, Ph.D., M.D., for the International Collaborative Fabry Disease Study Group
Background Fabry's disease, lysosomal -galactosidase A deficiency,results from the progressive accumulation of globotriaosylceramideand related glycosphingolipids. Affected patients have microvasculardisease of the kidneys, heart, and brain.
Methods We evaluated the safety and effectiveness of recombinant-galactosidase A in a multicenter, randomized, placebo-controlled,double-blind study of 58 patients who were treated every 2 weeksfor 20 weeks. Thereafter, all patients received recombinant-galactosidase A in an open-label extension study. The primaryefficacy end point was the percentage of patients in whom renalmicrovascular endothelial deposits of globotriaosylceramidewere cleared (reduced to normal or near-normal levels). We alsoevaluated the histologic clearance of microvascular endothelialdeposits of globotriaosylceramide in the endomyocardium andskin, as well as changes in the level of pain and the qualityof life.
Results In the double-blind study, 20 of the 29 patients inthe recombinant -galactosidase A group (69 percent) had no microvascularendothelial deposits of globotriaosylceramide after 20 weeks,as compared with none of the 29 patients in the placebo group(P<0.001). Patients in the recombinant -galactosidase A groupalso had decreased microvascular endothelial deposits of globotriaosylceramidein the skin (P<0.001) and heart (P<0.001). Plasma levelsof globotriaosylceramide were directly correlated with clearanceof the microvascular deposits. After six months of open-labeltherapy, all patients in the former placebo group and 98 percentof patients in the former recombinant -galactosidase A groupwho had biopsies had clearance of microvascular endothelialdeposits of globotriaosylceramide. Mild-to-moderate infusionreactions (i.e., rigors and fever) were more common in the recombinant-galactosidase A group than in the placebo group.
Conclusions Recombinant -galactosidase A replacement therapycleared microvascular endothelial deposits of globotriaosylceramidefrom the kidneys, heart, and skin in patients with Fabry's disease,reversing the pathogenesis of the chief clinical manifestationsof this disease.
Fabry's disease is an X-linked inborn error of glycosphingolipidcatabolism due to deficient lysosomal -galactosidase A activity.1In patients with the classic form of the disease, progressiveaccumulation of globotriaosylceramide and related glycosphingolipidsin vascular endothelial lysosomes of the kidneys, heart, skin,and brain leads to the main disease manifestations. The clinicalonset is in childhood and is characterized by severe acroparesthesias,angiokeratoma, corneal and lenticular opacities, and hypohidrosis.Over time, microvascular disease of the kidneys, heart, andbrain progresses, leading to early death.1 Treatment is limitedto symptomatic management of pain and the end-stage complicationsof renal failure, cardiac disease, and strokes.
Early trials demonstrated the feasibility of enzyme replacementto correct the metabolic defect in Fabry's disease.2,3,4 A phase1 trial demonstrated reductions of globotriaosylceramide inthe liver and in urinary sediment with a single dose of recombinant-galactosidase A.5 A phase 1 and 2 open-label dose-escalationstudy of replacement therapy with recombinant -galactosidaseA in 15 male patients with classic Fabry's disease demonstratedthat repeated administration (a total of five infusions) wassafe and effective in clearing plasma globotriaosylceramideand microvascular endothelial deposits of globotriaosylceramidefrom target tissues.6 Plasma and tissue clearance of globotriaosylceramidewas observed for all dose regimens, and the effect was mostpronounced at higher doses. Therefore, we evaluated the safetyand efficacy of recombinant -galactosidase A replacement therapyin Fabry's disease in a multicenter, randomized, double-blind,placebo-controlled trial and subsequent open-label study.
Methods
Patients
Eligible patients had an enzymatically confirmed diagnosis ofclassic Fabry's disease, had a level of activity of -galactosidaseA of less than 1.5 nmol per hour per milliliter in plasma orless than 4 nmol per hour per milligram in leukocytes,7 andwere at least 16 years old. Patients were excluded if theirserum creatinine concentration exceeded 2.2 mg per deciliter(194.5 µmol per liter), if they were undergoing dialysis,or if they had undergone kidney transplantation.
Clinical and Biochemical Assessments
Evaluations including a medical history taking, routine chemicalanalyses, and hematologic indexes were obtained and a physicalexamination was performed at base line and before each infusion.Echocardiograms were obtained and plasma and 24-hour urinarysediments were collected at base line, after week 20 of thedouble-blind study, and after six months of open-label treatment.Glomerular filtration rates were measured in terms of inulinclearance at base line and after six months of the extensionstudy. Concentrations of globotriaosylceramide in plasma, tissue,and urinary sediment8 were determined by a quantitative enzyme-linkedimmunosorbent assay (ELISA).9 Before each infusion, the presenceor absence of antibody against recombinant -galactosidase Awas assessed by ELISA, and the results were confirmed by a radioimmunoprecipitationassay.10
Study Protocol
Enrollment in the double-blind study began on March 22, 1999,and ended on December 3, 1999. The open-label study began onOctober 26, 1999. Patients were randomly assigned to receiverecombinant -galactosidase A (agalsidase beta; Fabrazyme, Genzyme,Cambridge, Mass.) at a dose of 1 mg per kilogram of body weightor placebo (phosphate-buffered mannitol). Both agents were administeredintravenously at a rate of 0.25 mg per minute every other weekfor 20 weeks (for a total of 11 infusions). Before each infusionpatients were pretreated with 1000 mg of acetaminophen and 25to 50 mg of hydroxyzine. Ibuprofen, prednisone, or both werealso used in a few patients for infusion-related reactions.After the double-blind trial, all patients received recombinant-galactosidase A in an open-label fashion at a dose of 1 mgper kilogram every other week, but the infusion rates were increasedas tolerated, reducing the length of the infusion. The institutionalreview boards at all sites approved the double-blind and open-labelprotocols, and all patients gave written informed consent.
Tissue Assessments
Kidney specimens were obtained by ultrasound-guided biopsy,heart specimens were obtained through an endomyocardial catheterwith the use of a bioptome, and 3-mm skin specimens were obtainedby punch biopsy at base line, after infusion 11 (week 20), andafter six months of the open-label study. Tissue sections (1µm) were stained with methylene blue–azure II. Eachof the three types of biopsy specimen was assessed for microvascularendothelial deposits of globotriaosylceramide by a differentgroup of three pathologists. None of the nine pathologists wereaware of the patients' treatment assignments or the times atwhich the specimens were obtained.
Specimens with no microvascular endothelial deposits of globotriaosylceramideor only trace amounts (normal or nearly normal) were given ascore of 0; specimens in which the majority of vessels had evidenceof a single endothelial inclusion were given a score of 1; specimensthat contained multiple vessels with multiple sites of singleor multiple inclusions were given a score of 2; and specimensthat had large accumulations of inclusions with some clustersat the juxtanuclear region and around cytoplasmic borders andbulging of the vessel lumens were given a score of 3. Renal-biopsyspecimens that were initially given a score of 0 or 1 were reevaluatedby the three renal pathologists with the use of a slightly modifiedscoring system. In this system, specimens with no inclusionswere given a score of 0; those with one small granule (approximately0.2 µm) were designated as having trace evidence; thosewith multiple discrete granules were given a score of 1; thosewith single or multiple aggregates of granules were given ascore of 2; and those with aggregates of granules within theendothelium that caused the distortion of the luminal endothelialcell surface were given a score of 3.
Evaluation of Efficacy
An average of 233 capillaries in each renal-biopsy specimenwere assessed by each renal pathologist. The primary efficacyend point of the double-blind study required more than 50 percentof the renal interstitial capillaries in each specimen to havea score of 0, less than 5 percent to have a score of 1 or greater,and the remainder to be designated as having trace evidenceof microvascular endothelial deposits of globotriaosylceramideafter week 20. For each biopsy specimen, a majority score wasdetermined from the three pathologists' scores.
Secondary end points were also assessed at base line and afterthe week-20 infusion and consisted of the composite score formicrovascular endothelial deposits of globotriaosylceramidein the heart, kidney, and skin specimens (scores were calculatedper organ and summed for all organs) and the change from baseline in the concentrations of globotriaosylceramide in urinarysediment and kidney specimens and the level of pain, as assessedby the short form of the McGill Pain Questionnaire.11 Scoreson this questionnaire can range from 0 to 45, with higher scoresindicating severe pain intensity.
Statistical Analysis
We used chi-square tests to analyze the proportion of patientsin the recombinant -galactosidase A group and the placebo groupwith a renal-biopsy score of 0 after week 20 of the double-blindstudy and after six months of the open-label study. We usedtwo-sample, two-tailed tests for all analyses. A P value of0.05 or less was considered to indicate statistical significance.Changes in the concentrations of globotriaosylceramide in urinarysediment and kidney specimens on ELISA were ranked individually,and the rank-sum score for each patient was obtained. We useda two-sample Wilcoxon rank-sum test to assess the change frombase line to the end of the double-blind study (after week 20).We used t-tests to compare the mean change in the level of painfrom base line to the end of the double-blind study (after week20) for each treatment group. The Genzyme Biostatistics groupheld the data and analyzed the data, with the help of consultingacademic biostatisticians.
We used the 36-item Medical Outcomes Study Short-Form GeneralHealth Survey (SF-36)12 to evaluate the patients' quality oflife. This multi-item scale measures eight health-related aspects:physical function, social function, physical role, emotionalrole, mental health, energy, pain, and general health perception.Scores on each aspect can range from 0 (worst) to 100 (best).The results were evaluated according to established guidelines,12and we used a Wilcoxon signed-rank test to compare the meanchange in scores from base line in each group. We used an analysisof variance to compare the differences between groups in thechanges in the mean glomerular filtration rate from base lineto six months of the open-label study.
Results
Characteristics of the Patients
The base-line characteristics of the 58 patients assigned tothe two treatment groups were similar (Table 1).
Table 1. Base-Line Characteristics of the Patients.
Double-Blind Study
Renal Capillary Endothelial Clearance of Globotriaosylceramide
The primary efficacy end point was the percentage of patientsin each group who were free of microvascular endothelial depositsof globotriaosylceramide in renal-biopsy specimens (i.e., whohad a score of 0) after 20 weeks of treatment (11 infusions)in the double-blind study. The end point was reached by 20 ofthe 29 patients in the recombinant -galactosidase A group (69percent), as compared with none of the 29 patients in the placebogroup (P<0.001; odds ratio, 0.0). Eight of the remainingnine patients in the recombinant -galactosidase A group hada score of 1 (the scores of six of these patients had improved,and the scores of two had not changed). The ninth patient hada missing biopsy specimen and so was assigned a score of 3.An analysis of sensitivity, in which a maximum of 1 percentof the capillaries could be given a score of 1 or greater, asopposed to the original requirement of less than or equal to5 percent, did not change the outcome (P<0.005). These resultsfor the three renal pathologists were uniform.
Secondary End Points
The individual scores for the kidney-, heart-, and skin-biopsyspecimens as well as the composite scores for all three typesof specimens were compared at base line and after the week-20infusion (Table 2). Although both groups had similar base-linescores for each type of specimen (P=0.53), the patients in therecombinant -galactosidase A group had significantly lower scoresfor each type of specimen after the week-20 infusion than didthe patients in the placebo group (P<0.001 for all threecomparisons). In addition, the median percent changes in thekidney and urinary concentrations of globotriaosylceramide differedbetween the patients in the recombinant -galactosidase A groupand the patients in the placebo group (23.3 percent decreasevs. 42.8 percent increase and 34.1 percent decrease vs. 6.2percent decrease, respectively). The rank-sum scores for kidneyand urinary-sediment concentrations of globotriaosylceramidehad decreased significantly in the recombinant -galactosidaseA group, but not in the placebo group (median change, 32.5 percentdecrease vs. 48.0 percent decrease; P=0.003).
Table 2. Mean Changes in Individual and Composite Scores for Microvascular Endothelial Deposits of Globotriaosylceramide in Kidney-, Heart-, and Skin-Biopsy Specimens from Base Line to after the Week-20 Infusion.
Although both groups had low scores on all five scales of theshort form of the McGill Pain Questionnaire at base line, statisticallysignificant decreases in the scores were observed at week 20in both treatment groups (Figure 1). There was no significantdifference between groups after week 20 in any pain assessment(P>0.05 for all comparisons), possibly because of a placeboeffect.
Figure 1. Change in Levels of Pain from Base Line to Week 20 of the Double-Blind Study in the Recombinant -Galactosidase A Group (Panel A) and the Placebo Group (Panel B).
The short form of the McGill Pain Questionnaire was used to assess the level of sensory pain, affective pain, pain as measured on a visual analogue scale (VAS), and the present pain intensity (PPI). On this scale, higher scores indicate greater pain. The total pain score is the sum of the sensory and affective pain scores. There were significant reductions in all the mean pain measures within each treatment group, but no significant differences between the two groups.
Clearance of Globotriaosylceramide in Plasma
Figure 2 shows clearance of globotriaosylceramide from plasmaby week 14 of treatment with recombinant -galactosidase A; incontrast, the plasma concentrations in the placebo group didnot change significantly during the double-blind study (P<0.001for the comparison between the groups). Plasma concentrationsof globotriaosylceramide were undetectable (<1.2 ng per microliter)after week 20 in all 20 patients who had no microvascular endothelialdeposits of globotriaosylceramide in renal-biopsy specimensafter week 20 of treatment. Five of eight patients in the recombinant-galactosidase A group who had a renal score of 1 after week20 had undetectable plasma concentrations of globotriaosylceramideafter week 20, and three had concentrations ranging from 12to 94 percent (mean, 35.3 percent) of their base line values.The patient who had been assigned a score of 3 because of amissing biopsy specimen at week 20 had a plasma globotriaosylceramideconcentration of 3.9 ng per microliter.
Figure 2. Median Plasma Concentrations of Globotriaosylceramide in the Recombinant -Galactosidase A Group and the Placebo Group in the Double-Blind Study and the Open-Label Study.
Plasma levels of globotriaosylceramide were determined by a quantitative enzyme-linked immunosorbent assay at base line and week 20 of the double-blind study and after six months of open-label treatment. Plasma globotriaosylceramide values that were below the limit of detection (<1.2 ng per microliter) were recorded as 0. All patients who had been in the placebo group during the double-blind study received recombinant -galactosidase A during the open-label study.
Quality of Life
Patients in the recombinant -galactosidase A group had significantimprovements in two components of the SF-36 (physical role andemotional role), whereas patients in the placebo group had significantimprovements in the physical role and body-pain components ofthe SF-36.
Open-Label Extension Study
All 58 patients enrolled in the open-label study. After sixmonths of treatment with recombinant -galactosidase A, 98 percentof patients in whom a biopsy was performed at this time (42of 43) had a score of 0 on histologic analysis of microvascularendothelial deposits of globotriaosylceramide in kidney specimens,96 percent (45 of 47) had such results for skin specimens, and75 percent (24 of 32) had such results for heart specimens (Table 3).The results were similar when the analysis included onlythe patients who crossed over from placebo to recombinant -galactosidaseA: 100 percent, 96 percent, and 67 percent, respectively. In95 percent of the patients who had had a biopsy during the open-labelstudy and who received recombinant -galactosidase A during thedouble-blind study, the renal scores were maintained or furtherdecreased after six months of open-label treatment. In addition,renal function, as measured by the glomerular filtration rate,did not change substantially from base line in either groupafter week 20 of the double-blind study (P=0.19) or after sixmonths of open-label treatment (P=0.81).
Table 3. Number of Patients with a Score of 0 on Histologic Analysis of Microvascular Capillary Endothelial Deposits of Globotriaosylceramide in Biopsy Specimens after 20 Weeks of Double-Blind Treatment and 6 Months of Open-Label Treatment with Recombinant -Galactosidase A.
Safety
No significant changes from base line in the echocardiograms,electrocardiograms, or other safety assessments in either groupwere observed after week 20 of the double-blind study or aftersix months of the open-label study. The infusions were generallywell tolerated. Rigors and fever were the only treatment-relatedadverse events that occurred significantly more frequently inthe recombinant -galactosidase A group than in the placebo groupduring the double-blind study (P=0.004) (Table 4). Althoughnot considered to be related to recombinant -galactosidase Atherapy, skeletal pain was the only other adverse event thatoccurred more frequently among enzyme-treated patients duringthe double-blind study (P=0.02). Transient mild-to-moderateinfusion-associated reactions occurred in 59 percent of patients(34 of 58) during double-blind or open-label treatment. Reducingthe infusion rate, administering preventive medications, orboth measures controlled these reactions. A single patient hada positive skin test to recombinant -galactosidase A after hiseighth infusion during the open-label study, and treatment wasdiscontinued.
Table 4. Adverse Events That Occurred in at Least 10 Percent of Patients in the Recombinant -Galactosidase A Group during the Double-Blind Study.
IgG seroconversion occurred in 51 of the 58 patients who receivedrecombinant -galactosidase A (88 percent) during the study.Seroconversion did not affect the primary or secondary efficacyend points. For example, the distribution of the scores forrenal specimens (0 vs. not 0) did not differ significantly betweenpatients who did seroconvert and those who did not. In addition,8 of 29 patients in the original recombinant -galactosidaseA group who had renal scores of 1 after week 20 had a reductionin their scores to 0 during the open-label study. IgG titershad decreased in 15 of 26 patients in the recombinant -galactosidaseA group (58 percent) who seroconverted during the double-blindstudy when the titers were assessed after 12 months of treatment.In addition, one IgG-positive patient with a low titer becameseronegative during this period. These observations serve toreduce concern about potential reactions associated with seroconversion.
Discussion
During the past decade the safety and effectiveness of enzyme-replacementtherapy have been demonstrated in patients with type 1 Gaucher'sdisease.13,14 In patients with this lysosomal storage disease,the infusion of human placental or recombinant acid -glucosidasemetabolized the accumulated substrate, reversed the disease-relatedabnormalities, and markedly improved the quality of life.13,14We report the results of a randomized, double-blind, placebo-controlledtrial and the first six months of an open-label extension studythat demonstrate the safety and effectiveness of enzyme replacementin a second lysosomal disorder, Fabry's disease.
In patients with classic Fabry's disease, the chief debilitatingmanifestations result primarily from the progressive accumulationof microvascular endothelial deposits of globotriaosylceramide,leading to ischemia and infarction, particularly in the kidneys,heart, and brain.1 In contrast, patients with the cardiac variantof the disease have residual -galactosidase A activity (<10percent of normal levels) and do not have vascular endothelialaccumulation of glycosphingolipid.1,15,16 In these patients,left ventricular hypertrophy and mild proteinuria typicallydevelop late in life, the life span is normal, and the classicmanifestations of the disease, including angiokeratoma, acroparesthesias,hypohidrosis, and renal failure, are absent.1 Thus, the reversalof the underlying vascular endothelial abnormalities in patientswith classic Fabry's disease should be therapeutic.
We found that 11 infusions of recombinant -galactosidase A ata dose of 1 mg per kilogram over a 20-week period safely andeffectively cleared the abnormalities in the capillary endotheliumof the kidneys, heart, and skin of patients with classic Fabry'sdisease. The primary efficacy end point of our study directlyaddressed a fundamental cause of the most common and devastatingfeature of classic Fabry's disease: renal failure. After 20weeks of treatment, complete or almost complete clearance ofthe accumulated renal microvascular endothelial deposits ofglobotriaosylceramide was achieved in 69 percent of the patientsin the recombinant -galactosidase A group, as compared withnone of the patients in the placebo group (P<0.001). In addition,the concentration of globotriaosylceramide was significantlyreduced in the urinary sediment of patients in the recombinant-galactosidase A group, providing indirect evidence of the clearanceof glycosphingolipids in renal tubules. Similar results wereachieved with respect to the clearance of microvascular endothelialdeposits of globotriaosylceramide from the heart (P<0.001)and skin (P<0.001).
The open-label extension study confirmed the results of thedouble-blind study and demonstrated that clearance was maintainedor that microvascular endothelial deposits of globotriaosylceramidewere further reduced in all three types of specimens assessedin patients who were treated with recombinant -galactosidaseA for about one year. Notably, the percentage of patients withclearance of the microvascular endothelial deposits of globotriaosylceramidein the endomyocardium increased from 67 percent after 20 weeksto 82 percent after 6 months of open-label treatment, indicatingthat the clearance of globotriaosylceramide may be tissue specific,depending on the dose and duration of treatment, the level ofenzyme uptake, and the degree of substrate accumulation. Takentogether, the results of the double-blind and open-label studiesconfirm that recombinant -galactosidase A replacement therapycleared the accumulated microvascular endothelial deposits ofglobotriaosylceramide and reversed the chief underlying abnormalityin Fabry's disease. On the basis of the results of the preclinical,17phase 1 and 2 dose-escalation,6 and double-blind studies, theplasma globotriaosylceramide level may be correlated with theaccumulation of this glycosphingolipid in tissue and may providea noninvasive indicator of systemic substrate clearance, analogousto serum glucose levels in patients with diabetes.
Most patients with the classic form of the disease have episodicacroparesthesias that are debilitating and markedly impair theirquality of life. Patients in a phase 1 and 2 open-label studyreported decreased severity of pain related to Fabry's disease.6In our double-blind study, the severity of pain and the qualityof life, as assessed by standardized instruments, were significantlyimproved in both groups, making it impossible to differentiatetreatment-related effects from a placebo effect. For ethicalreasons, patients who had been dependent on prophylactic drugs,analgesics, or both for years continued to take such medicationsduring the study, a factor that may have minimized base-linescores and subsequent differences between groups. Studies areneeded to determine the long-term effects of treatment withrecombinant -galactosidase A, perhaps with the use of instrumentsspecifically designed to assess pain related to Fabry's diseaseand quality-of-life issues.
In general, the infusions were well tolerated, and all 58 patientscompleted the double-blind trial and entered the open-labelstudy. The possibility of infusion-related reactions was anticipated,since patients with classic Fabry's disease have no detectable-galactosidase A activity, protein, or both.1 Therefore, wepurposely kept the infusion rates slow to maintain blinding,and we administered prophylactic medications to all patientsto minimize any infusion-related reactions. During the open-labelstudy, we increased the infusion rates, and in the case of manypatients, the infusion lasted two hours. In 88 percent of patients,IgG antibodies against recombinant -galactosidase A developed;however, seroconversion did not affect primary or secondaryefficacy results, nor did the antibodies have a neutralizingeffect, as occurs in patients with hemophilia A in whom inhibitorsdevelop.18,19 After approximately one year of treatment withrecombinant -galactosidase A, IgG titers had decreased in 58percent of patients with seroconversion and became undetectablein one patient. On the basis of previous experience with long-termenzyme-replacement therapy,10,20 such findings suggest thatimmunologic tolerance may develop in these patients.
In conclusion, we found that a dose of 1 mg of recombinant -galactosidaseA per kilogram every other week for about six months to oneyear safely and effectively reversed the accumulation of microvascularendothelial deposits of globotriaosylceramide in the kidneys,heart, and skin. Continued treatment may be required to reducethe deposition of glycosphingolipids in other types of cells,to which less enzyme is delivered,17 particularly renal tubularepithelial cells, podocytes, and cardiomyocytes. Further experiencewill determine effective regimens for initial reversal and subsequentcontrol of the accumulated glycosphingolipids in the capillaryendothelium and other types of cells.
Supported in part by a Merit Award from the National Institutesof Health (5 R37 DK34045), by grants from the National Institutesof Health (5 M01 RR00071 and 5 M01 RR00425, to the General ClinicalResearch Centers at the Mount Sinai School of Medicine and Cedars–SinaiMedical Center, and 5 P30 HD28822, to the Mount Sinai ChildHealth Research Center), and by a grant from Genzyme Corporation.
Dr. Desnick has received grant support from and serves as aconsultant to Genzyme.
We are indebted to the patients who participated in the studyand to the outstanding nursing staffs of the General ClinicalResearch Centers at all the investigational sites.
Source Information
From the Mount Sinai School of Medicine, New York (C.M.E., R.J.D.); Hôpital Edouard Herriot, Lyons, France (N.G.); Cedars–Sinai Burns and Allen Research Institute, UCLA School of Medicine, Los Angeles (W.R.W.); Hôpital Européen Georges Pompidou, Paris (D.P.G.); University College London Hospitals, London (P.L.); Hope Hospital, Salford, Manchester, United Kingdom (S.W.); Beth Israel Deaconess Medical Center, Boston (L.C.); and Academisch Medisch Centrum, Amsterdam (G.E.L.).
Address reprint requests to Dr. Desnick at the Department of Human Genetics, Box 1498, Mount Sinai School of Medicine, Fifth Ave. at 100th St., New York, NY 10029, or at rjd.fabry{at}mssm.edu.
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Appendix
In addition to the authors, the following members of the InternationalCollaborative Fabry Disease Study Group participated in thestudy: Investigators — M. Banikazemi, J. Ibraham, andA.P. Cheng (New York); L.J. Raffel (Los Angeles); P. Cochat(Lyons, France); M. Azizi and X. Jeunemaitre (Paris); A. Vellodi(London); J.E. Wraith (Manchester, United Kingdom); C.J. Chaves,K.B. Kanis, I. Linfante, and R. Llinas (Boston); D.K. Bosman,H.S.A. Heymans, C.E.M. Hollak, and F.A. Wijburg (Amsterdam);Expert pathologists — Kidney: R.B. Colvin (Boston); S.Dikman (New York), and H. Rennke (Boston); Heart: H.T. Aretz(Boston), J. Fallon (New York), and R. Mitchell (Boston); Skin:H.R. Beyers and S. Granler (Boston) and R. Phelps (New York);and General Pathology: R.E. Gordon (New York); Specialty consultants— S. Brodie, S.A. Gass, M. Goldman, D. Mehta, and J. Winston(New York); R. Bouvier, B.P. Denis, L. Dubourg, A. Fouilhoux,A. Hadj-Aïssa, M. Laville, I. Maire, B. Ranchin, and M.T.Vanier (Lyons, France); A. Hickey, J. Jordan, S. Jordan, S.S.Khan, and E. Maguen (Los Angeles); C. Amrein, B. Diebold, J.N.Fiessinger, M. Froissart, J.P. Grunfeld, J. Julien, L.H. Noel,C. Orssaud, and L. Poenaru (Paris); M.H. Griffiths, D. Holdright,N. Phelps-Brown, S. Sporton, R. Woolfson, V.C. Worthington,and E.P. Young (London); M. Bhushan, A. Cooper, E. O'Riordan,R. Radford, S.G. Ray, and R.S. Reeve (Manchester, United Kingdom);F.G. Berson, M.S. Kruskall, and W.J. Manning (Boston); W.J.W.Bos, D.K. Bosman, F.J.W. ten Kate, R.T. Krediet, K.I. Lie, J.J.Piek, L.J.J.M. Prick, and J.H.S. Smitt (Amsterdam); Study coordinatorsand nurses — M. Nunn, A. Nieto, R.A. Denchy, and A. Kowalski(New York); J. Exantus, M.T. Dupret, S. Garnier, and S. Walbilic(Lyons, France); A.G. Verne and B. Williams (Los Angeles); M.C.Bernard and V. Remones (Paris); J. Morrison, D.G. Burke, L.G.Fulford, M. Jackson, R. Lobo, S. Sporton, and V.C. Worthington(London); B.M. Kenny (Manchester, United Kingdom); L. Baron(Boston); A. Vyth (Amsterdam); Genzyme personnel — R.Moscicki, T. Braakman, M. Goldberg, M. O'Callaghan, R. Cintron,S. Richards, P.K. Tandon, M.A. Fitzpatrick, M. Yelmene, andM. Nichols.
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(2003). {alpha}-Galactosidase A deficiency in Dutch patients on dialysis: a critical appraisal of screening for Fabry disease. Nephrol Dial Transplant
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[Abstract][Full Text]
Linthorst, G. E., Hollak, C. E. M., Korevaar, J. C., van Manen, J. G., Aerts, J. M. F. G., Boeschoten, E. W.
(2003). {alpha}-Galactosidase A deficiency in Dutch patients on dialysis: a critical appraisal of screening for Fabry disease. Nephrol Dial Transplant
18: 1581-1584
[Abstract][Full Text]
Nagueh, S F
(2003). Fabry disease. Heart
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Morrone, A, Cavicchi, C, Bardelli, T, Antuzzi, D, Parini, R, Di Rocco, M, Feriozzi, S, Gabrielli, O, Barone, R, Pistone, G, Spisni, C, Ricci, R, Zammarchi, E
(2003). Fabry disease: molecular studies in Italian patients and X inactivation analysis in manifesting carriers. J. Med. Genet.
40: e103-103
[Full Text]
Burns, T. M., Ryan, M. M., Darras, B., Jones, H. R. Jr
(2003). Current Therapeutic Strategies for Patients With Polyneuropathies Secondary to Inherited Metabolic Disorders. Mayo Clin Proc.
78: 858-868
[Abstract]
Takanashi, J.-i., Barkovich, A. J., Dillon, W. P., Sherr, E. H., Hart, K. A., Packman, S.
(2003). T1 Hyperintensity in the Pulvinar: Key Imaging Feature for Diagnosis of Fabry Disease. Am. J. Neuroradiol.
24: 916-921
[Abstract][Full Text]
Pieroni, M., Chimenti, C., Ricci, R., Sale, P., Russo, M. A., Frustaci, A.
(2003). Early Detection of Fabry Cardiomyopathy by Tissue Doppler Imaging. Circulation
107: 1978-1984
[Abstract][Full Text]
Lee, K., Jin, X., Zhang, K., Copertino, L., Andrews, L., Baker-Malcolm, J., Geagan, L., Qiu, H., Seiger, K., Barngrover, D., McPherson, J. M., Edmunds, T.
(2003). A biochemical and pharmacological comparison of enzyme replacement therapies for the glycolipid storage disorder Fabry disease. Glycobiology
13: 305-313
[Abstract][Full Text]
Waldek, S.
(2003). PR Interval and the Response to Enzyme-Replacement Therapy for Fabry's Disease. NEJM
348: 1186-1187
[Full Text]
Park, J., Murray, G. J., Limaye, A., Quirk, J. M., Gelderman, M. P., Brady, R. O., Qasba, P.
(2003). Long-term correction of globotriaosylceramide storage in Fabry mice by recombinant adeno-associated virus-mediated gene transfer. Proc. Natl. Acad. Sci. USA
100: 3450-3454
[Abstract][Full Text]
Wenger, D. A., Coppola, S., Liu, S.-L.
(2003). Insights Into the Diagnosis and Treatment of Lysosomal Storage Diseases. Arch Neurol
60: 322-328
[Abstract][Full Text]
Desnick, R. J., Brady, R., Barranger, J., Collins, A. J., Germain, D. P., Goldman, M., Grabowski, G., Packman, S., Wilcox, W. R.
(2003). Fabry Disease, an Under-Recognized Multisystemic Disorder: Expert Recommendations for Diagnosis, Management, and Enzyme Replacement Therapy. ANN INTERN MED
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[Abstract][Full Text]
Eitzman, D. T., Bodary, P. F., Shen, Y., Khairallah, C. G., Wild, S. R., Abe, A., Shaffer-Hartman, J., Shayman, J. A.
(2003). Fabry Disease in Mice Is Associated With Age-Dependent Susceptibility to Vascular Thrombosis. J. Am. Soc. Nephrol.
14: 298-302
[Abstract][Full Text]
Breunig, F., Wanner, C.
(2003). Enzyme replacement therapy for Fabry disease: proving the clinical benefit. Nephrol Dial Transplant
18: 7-9
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De Schoenmakere, G., Chauveau, D., Grunfeld, J.-P.
(2003). Enzyme replacement therapy in Anderson-Fabry's disease: beneficial clinical effect on vital organ function. Nephrol Dial Transplant
18: 33-35
[Abstract][Full Text]
Kingdon, E J, Holt, S G, Burns, A
(2002). Renal involvement in an Anderson-Fabry heterozygote. Postgrad. Med. J.
78: 759-759
[Full Text]
-Galactosidase A Replacement Therapy in Fabry's Disease
-glucosidase metabolized the accumulated substrate, reversed the disease-related abnormalities, and markedly improved the quality of life.13,14 We report the results of a randomized, double-blind, placebo-controlled trial and the first six months of an open-label extension study that demonstrate the safety and effectiveness of enzyme replacement in a second lysosomal disorder, Fabry's disease. 
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