***TASK*** the task is to summarize an input biomedical literature in six sentences 
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    Input: Summary Background . Fabry disease is an X-linked genetic disorder result ing in the accumulation of glycosphingolipids in various organs , leading to exercise intolerance and early mortality . Enzyme replacement therapy ( ERT ) has recently been approved for use in Fabry patients . Goals of study . To assess baseline cardiopulmonary exercise characteristics in both invasive and noninvasive tests and to study the impact of ERT on exercise . Methods . A total of 15 patients with Fabry disease underwent baseline cardiopulmonary exercise tests .  Six patients were r and omized 2:1 to receive either ERT or placebo . We performed serial cardiopulmonary exercise tests at baseline and every 3 months over a period of at least 18 months . The baseline test was compared to the last two exercise tests for each patient . Results . Mean age was 32 years .  Mean VO2 max was 1.680 ± 0.67 L/min and increased by 0.459 ± 0.64 L/min in the patients receiving ERT  . Mean VO2 max was 1.462 ± 0.25 L/min and decreased by 0.116 ± 0.44 L/min in patients on placebo . Mean oxygen pulse ( VO2/HR ) increased by 1.71 with enzyme , but increased only 0.025 in patients taking placebo . Estimated stroke volume ( SV ) increased by 10 ml in patients on ERT . Conclusions . In this small cohort , exercise tolerance increased in patients receiving enzyme replacement therapy . Cardiopulmonary exercise testing is a useful test in measuring the response to therapy in Fabry disease patients Background —Fabry disease is an X-linked lysosomal deficiency of & agr;-galactosidase A that results in cellular accumulation of galacto-conjugates such as globotriosylceramide , particularly in blood vessels . It is associated with early-onset stroke and kidney and heart failure . Methods and Results —Using [ 15O ] H2O and PET , we found increased resting regional cerebral blood flow in Fabry disease without evidence of occlusive vasculopathy or cerebral hypoperfusion . Because nitric oxide is known to play an important role in vascular tone and reactivity , we studied plasma nitrate , nitrite , and low-molecular-weight S-nitrosothiol levels by chemiluminescence . Skin biopsy specimens and archived brain tissue were also examined immunohistochemically for nitrotyrosine . Plasma nitrate , nitrite , and low-molecular-weight S-nitrosothiol were in the normal range ; however , enhanced nitrotyrosine staining was observed in dermal and cerebral blood vessels . After a double-blind , placebo-controlled trial of & agr;-galactosidase A therapy , the resting regional cerebral blood flow in the treated group was significantly reduced , with a notable decrease of nitrotyrosine staining in dermal blood vessels . Conclusions —These findings suggest a chronic alteration of the nitric oxide pathway in Fabry disease , with critical protein nitration that is reversible with enzyme replacement therapy Background and Purpose — Fabry disease is an X-linked inherited disorder result ing from a deficiency of & agr;-galactosidase A. Cerebrovascular disease in Fabry disease includes small-vessel disease and larger-vessel ectasia in a predominantly posterior distribution . We assessed transcranial Doppler ( TCD ) blood flow velocities in naive and enzyme-treated Fabry patients . Methods — TCD was used to noninvasively examine patients with Fabry disease for abnormal cerebral blood flow velocities . TCD measurements were also made during CO2 retention by breathholding to examine cerebrovascular vessel reactivity .  Twenty-six patients were enrolled in a 6-month , double-blind , placebo-controlled trial of enzyme replacement therapy consisting of biweekly intravenous & agr;-galactosidase A infusions , with a subsequent 18-month follow-up in an open-label trial . Statistical analysis consisted of applying a mixed-effects ANOVA model for correlated outcomes . Results — Peak velocity , mean velocity , pulsatility index , and resistance index were found to be significantly higher in patients compared with control subjects . When the individual vessels were considered , elevated flow velocities were found in the middle cerebral M1 branch and the posterior cerebral artery . Enzyme replacement therapy significantly decreased peak , mean , and end-diastolic velocities and flow acceleration at the 18-month follow-up time point . Conclusions — Patients with Fabry disease have elevated cerebral blood flow velocities . These velocities significantly improved with enzyme replacement therapy Background Two different enzyme preparations , agalsidase alfa ( ReplagalTM , Shire ) and beta ( FabrazymeTM , Genzyme ) , are registered for treatment of Fabry disease . We compared the efficacy of and tolerability towards the two agalsidase preparations administered at identical protein dose in a r and omized controlled open label trial . Methodology /Principal Findings Thirty-four Fabry disease patients were treated with either agalsidase alfa or agalsidase beta at equal dose of 0.2 mg/kg biweekly . Primary endpoint was reduction in left ventricular mass after 12 and 24 months of treatment . Other endpoints included occurrence of treatment failure ( defined as progression of cardiac , renal or cerebral disease ) , glomerular filtration rate , pain , anti-agalsidase antibodies , and globotriaosylceramide levels in plasma and urine . After 12 and 24 months of treatment no reduction in left ventricular mass was seen , which was not different between the two treatment groups . Also , no differences in glomerular filtration rate , pain and decline in globotriaosylceramide levels were found . Antibodies developed only in males ( 4/8 in the agalsidase alfa group and 6/8 in the agalsidase beta group ) . Treatment failure within 24 months of therapy was seen in 8/34 patients : 6 male patients ( 3 in each treatment group ) and 2 female patients ( both agalsidase alfa ) . The occurrence of treatment failures did not differ between the two treatment groups ; χ2 = 0.38 p = 0.54 . Conclusion Our study revealed no difference in reduction of left ventricular mass or other disease parameters after 12 and 24 months of treatment with either agalsidase alfa or beta at a dose of 0.2 mg/kg biweekly . Treatment failure occurred frequently in both groups and seems related to age and severe pre-treatment disease . Trial Registration International St and ard R and omized Clinical Trial IS RCT CONTEXT Fabry disease is a metabolic disorder without a specific treatment , caused by a deficiency of the lysosomal enzyme alpha-galactosidase A ( alpha-gal A ) . Most patients experience debilitating neuropathic pain and premature mortality because of renal failure , cardiovascular disease , or cerebrovascular disease . OBJECTIVE To evaluate the safety and efficacy of intravenous alpha-gal A for Fabry disease . DESIGN AND SETTING Double-blind placebo-controlled trial conducted from December 1998 to August 1999 at the Clinical Research Center of the National Institutes of Health . PATIENTS Twenty-six hemizygous male patients , aged 18 years or older , with Fabry disease that was confirmed by alpha-gal A assay . INTERVENTION A dosage of 0.2 mg/kg of alpha-gal A , administered intravenously every other week ( 12 doses total ) . MAIN OUTCOME MEASURE Effect of therapy on neuropathic pain while without neuropathic pain medications measured by question 3 of the Brief Pain Inventory ( BPI ) . RESULTS Mean ( SE ) BPI neuropathic pain severity score declined from 6.2 ( 0.46 ) to 4.3 ( 0.73 ) in patients treated with alpha-gal A vs no significant change in the placebo group ( P = .02 ) . Pain-related quality of life declined from 3.2 ( 0.55 ) to 2.1 ( 0.56 ) for patients receiving alpha-gal A vs 4.8 ( 0.59 ) to 4.2 ( 0.74 ) for placebo ( P = .05 ) . In the kidney , glomeruli with mesangial widening decreased by a mean of 12.5 % for patients receiving alpha-gal vs a 16.5 % increase for placebo ( P = .01 ) . Mean inulin clearance decreased by 6.2 mL/min for patients receiving alpha-gal A vs 19.5 mL/min for placebo ( P = .19 ) . Mean creatinine clearance increased by 2.1 mL/min ( 0.4 mL/s ) for patients receiving alpha-gal A vs a decrease of 16.1 mL/min ( 0.3 mL/s ) for placebo ( P = .02 ) . In patients treated with alpha-gal A , there was an approximately 50 % reduction in plasma glycosphingolipid levels , a significant improvement in cardiac conduction , and a significant increase in body weight . CONCLUSION Intravenous infusions of alpha-gal A are safe and have widespread therapeutic efficacy in Fabry disease We prospect ively evaluated the effect of enzyme replacement therapy ( ERT ) on the intraepidermal nerve fiber density ( IENFD ) and thermal threshold in patients with Fabry disease , an X-linked disorder associated with a painful small-fiber neuropathy and decreased linear IENFD in a length-dependent pattern . Twenty-five hemizygous male patients with Fabry disease were enrolled in a 6-month , r and omized , placebo-controlled ERT trial of 0.2 mg/kg of alpha-galactosidase A ( agalsidase-alfa ) every 2 weeks followed by an additional 12 months of open-label ERT for both population s. IENFD and thermal threshold were measured in the distal thigh at baseline , 6 months , and 18 months from initiation of the trial . We found no significant difference in IENFD between the treatment groups at 6 months . After an additional year of ERT , there was a significant reduction in IENFD in the patient group as a whole , attributable to the declining glomerular filtration rate . Thermal thresholds remained unchanged . We conclude that epidermal nerve fiber regeneration , as measured in the distal thigh , does not occur in this patient population after 12 - 18 months of ERT The earliest clinical signs of Fabry disease often manifest as dermatologic disturbances such as angiokeratomata , hypohidrosis , acroparesthesias , and impaired thermal and vibration detection . These disturbances are caused by cellular globotriaosylceramide accumulation in the skin due to deficient lysosomal alpha-galactosidase A activity . In this histologic study , we analyzed pre- and post-treatment dermatologic biopsies from 58 Fabry patients enrolled in a 5 mo , Phase 3 double-blind , r and omized , placebo-controlled trial followed by a 30 mo open label extension study of recombinant human alpha-galactosidase A ( r-halphaGalA ) , administered i.v . at 1 mg per kg every 2 wk . Baseline evaluations revealed globotriaosylceramide in multiple dermal cell types ( vascular endothelial cells , vascular smooth muscle cells , perineurium ) . Five months of r-halphaGalA treatment in the Phase 3 trial result ed in complete clearance of globotriaosylceramide from the superficial capillary endothelium in all treatment patients and in only 1 ( 3 % ) placebo patient ( p<0.001 ) . The placebo group achieved similar results after 6 mo of r-halphaGalA in the open label trial . The capillary endothelium remained free of globotriaosylceramide for up to 30 mo into the extension study among 39 of 40 ( 98 % ) patients who underwent biopsies . Globotriaosylceramide clearance from deep vascular endothelial cells was similarly robust . Vascular smooth muscle cells and perineurium demonstrated moderate clearance . These findings suggest that long-term treatment with r-halphaGalA may halt the progression of pathology and prevent the dermatologic disturbances in Fabry patients , and that periodic dermal biopsies can serve as a reliable monitor of sustained efficacy Context Fabry disease is an X-linked storage disorder characterized by deficient lysosomal enzyme activity and excessive deposition of glycosphingolipids in vascular endothelial cells . Contribution In this double-blind multicenter trial , 82 adults with kidney dysfunction from Fabry disease were r and omly assigned to infusions of enzyme replacement with agalsidase beta or placebo every 2 weeks for up to 35 months . Agalsidase beta reduced the frequency of and delayed the time to clinical events ( composite outcome of renal , cardiac , and cerebrovascular events and death ) and caused infusion reactions more often than placebo . Caution Most clinical events in the small trial were worsening kidney function . Implication Agalsidase beta may slow disease progression in patients with advanced Fabry disease . The Editors Fabry disease is a rare , X-linked lysosomal storage disorder caused by deficient activity of the lysosomal enzyme -galactosidase A ( -Gal A ) . The result ant progressive accumulation of its substrates ( globotriaosylceramide and related glycosphingolipids ) has profound clinical consequences , particularly in the vascular endothelial cells of the kidney and heart ( 1 , 2 ) . Early manifestations typically include deb 
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A meta- analysis showed increased odds for fever , rigors , development of IgG antibodies to agalsidase , and no significant association with development of hypertension or reduction in the QRS complex duration on electrocardiogram .
The available evidence suggests that response to ERT is variable across patient subgroups and that agalsidase may slow progression of FD , with slight improvement of existing changes .