Aortic remodelling in Fabry disease

Aims To evaluate thoracic aortic dilation in patients with Fabry disease (FD). Methods and results A cohort of 106 patients with FD (52 males; 54 females) from three European centres were studied. The diameter of the thoracic aorta was assessed at three levels (sinus of Valsalva, ascending aorta, and descending aorta) using echocardiograms and cardiovascular magnetic resonance imaging. Aortic dilation at the sinus of Valsalva was found in 32.7% of males and 5.6% of females; aneurysms were present in 9.6% of males and 1.9% of females. No aortic dilation was observed in the descending aorta. There was no correlation between aortic diameter at the sinus of Valsalva and cardiovascular risk factors. Conclusion Fabry disease should be considered as a cardiovascular disease that affects the heart and arterial vasculature, including the thoracic aorta. Thus, patients with FD should be closely monitored for the presence, and possible progression and complications of aortic dilation. Clinical Trial Registration: Protocol 101/01. Ethics committee, Faculty of Medicine, Lausann

Renoprotective Effect of Agalsidase Alfa: A Long-Term Follow-Up of Patients with Fabry Disease

Fabry disease is a rare lysosomal storage disorder caused by mutations in the GLA gene, which, without treatment, can cause significant renal dysfunction. We evaluated the effects of enzyme replacement therapy with agalsidase alfa on renal decline in patients with Fabry disease using data from the Fabry Outcome Survey (FOS) registry. Male patients with Fabry disease aged >16 years at agalsidase alfa start were stratified by low (0.5 g/24 h) baseline proteinuria and by 'classic' or 'non-classic' phenotype. Overall, 193 male patients with low (n = 135) or high (n = 58) baseline proteinuria were evaluated. Compared with patients with low baseline proteinuria, those with high baseline proteinuria had a lower mean +/- standard deviation baseline eGFR (89.1 +/- 26.2 vs. 106.6 +/- 21.8 mL/min/1.73 m(2)) and faster mean +/- standard error eGFR decline (-3.62 +/- 0.42 vs. -1.61 +/- 0.28 mL/min/1.73 m(2) per year; p < 0.0001). Patients with classic Fabry disease had similar rates of eGFR decline irrespective of baseline proteinuria; only one patient with non-classic Fabry disease had high baseline proteinuria, preventing meaningful comparisons between groups. In this analysis, baseline proteinuria significantly impacted the rate of eGFR decline in the overall population, suggesting that early treatment with good proteinuria control may be associated with renoprotective effects

Phenotypic characteristics of the p.Asn215Ser (p.N215S) GLA mutation in male and female patients with Fabry disease: A multicenter Fabry Registry study.

BackgroundThe p.Asn215Ser or p.N215S GLA variant has been associated with late-onset cardiac variant of Fabry disease.MethodsTo expand on the scarce phenotype data, we analyzed natural history data from 125 p.N215S patients (66 females, 59 males) enrolled in the Fabry Registry (NCT00196742) and compared it with data from 401 patients (237 females, 164 males) harboring mutations associated with classic Fabry disease. We evaluated interventricular septum thickness (IVST), left ventricular posterior wall thickness (LVPWT), estimated glomerular filtration rate and severe clinical events.ResultsIn p.N215S males, mildly abnormal mean IVST and LVPWT values were observed in patients aged 25-34 years, and values gradually increased with advancing age. Mean values were similar to those of classic males. In p.N215S females, these abnormalities occurred primarily in patients aged 55-64 years. Severe clinical events in p.N215S patients were mainly cardiac (males 31%, females 8%) while renal and cerebrovascular events were rare. Renal impairment occurred in 17% of p.N215S males (mostly in patients aged 65-74 years), and rarely in females (3%).Conclusionp.N215S is a disease-causing mutation with severe clinical manifestations found primarily in the heart. Cardiac involvement may become as severe as in classic Fabry patients, especially in males

Serum Bilirubin Levels and Promoter Variations in HMOX1

The aim of our study was to assess the possible relationships among heme oxygenase (HMOX), bilirubin UDP-glucuronosyl transferase (UGT1A1) promoter gene variations, serum bilirubin levels, and Fabry disease (FD). The study included 56 patients with FD (M : F ratio = 0.65) and 185 healthy individuals. Complete standard laboratory and clinical work-up was performed on all subjects, together with the determination of total peroxyl radical-scavenging capacity. The (GT)n and (TA)n dinucleotide variations in the HMOX1 and UGT1A1 gene promoters, respectively, were determined by DNA fragment analysis. Compared to controls, patients with FD had substantially lower serum bilirubin levels (12.0 versus 8.85 μmol/L, p=0.003) and also total antioxidant capacity (p<0.05), which showed a close positive relationship with serum bilirubin levels (p=0.067) and the use of enzyme replacement therapy (p=0.036). There was no association between HMOX1 gene promoter polymorphism and manifestation of FD. However, the presence of the TA7 allele UGT1A1 gene promoter, responsible for higher systemic bilirubin levels, was associated with a twofold lower risk of manifestation of FD (OR = 0.51, 95% CI = 0.27–0.97, p=0.038). Markedly lower serum bilirubin levels in FD patients seem to be due to bilirubin consumption during increased oxidative stress, although UGT1A1 promoter gene polymorphism may modify the manifestation of FD as well

Evaluation of the efficacy and safety of three dosing regimens of agalsidase alfa enzyme replacement therapy in adults with Fabry disease

PURPOSE: Efficacy and safety of agalsidase alfa at 0.2 mg/kg weekly were compared with 0.2 mg/kg every other week (EOW). Exploratory analyses were performed for 0.4 mg/kg weekly. PATIENTS AND METHODS: This was a 53-week, Phase III/IV, multicenter, open-label study (NCT01124643) in treatment-naïve adults (≥18 years) with Fabry disease. Inclusion criteria were left ventricular hypertrophy at baseline, defined as left ventricular mass indexed to height >50 g/m(2.7) for males and >47 g/m(2.7) for females. Primary endpoint was reduction of left ventricular mass indexed to height as assessed by echocardiography. Secondary endpoints included cardiac (peak oxygen consumption, 6-minute walk test, Minnesota Living with Heart Failure Questionnaire, New York Heart Association classification), renal (Modification of Diet in Renal Disease, estimated glomerular filtration rate), and biomarker (plasma globotriaosylceramide) assessments. Safety endpoints were adverse events and anti–agalsidase alfa antibodies. RESULTS: Twenty patients were randomized to 0.2 mg/kg EOW (mean age, 50.3 years; 70% male), 19 to 0.2 mg/kg weekly (51.8 years; 53% male), and 5 to 0.4 mg/kg weekly (49.4 years; 40% male). The mean change in left ventricular mass indexed to height by Week 53 in the 0.2-mg/kg EOW and weekly groups was 3.2 g/m(2.7) and 0.5 g/m(2.7), with no significant difference between groups. No clinically meaningful changes by Week 53 were found within or between the 0.2-mg/kg groups for peak oxygen consumption, 6-minute walk test, or Minnesota Living with Heart Failure Questionnaire. Two patients in each group improved by ≥1 New York Heart Association classification. No significant differences were found between 0.2 mg/kg EOW and weekly for mean change in estimated glomerular filtration rate (−1.21 mL/min/1.73 m(2) vs −3.32 mL/min/1.73 m(2)) or plasma globotriaosylceramide (−1.05 nmol/mL vs −2.13 nmol/mL), respectively. Infusion-related adverse events were experienced by 25% and 21% in the 0.2-mg/kg EOW and weekly groups. Tachycardia, fatigue, and hypotension were experienced by two or more patients overall. Anti–agalsidase alfa antibodies were detected in 11.4% of patients and neutralizing antibodies in 6.8%. Infusion-related reactions did not appear to be correlated with antibody status. CONCLUSION: No efficacy or safety differences were found when the approved EOW dosage of agalsidase alfa was increased to weekly administration. Exploratory analyses for 0.4 mg/kg weekly showed similar results

Early indicators of disease progression in Fabry disease that may indicate the need for disease-specific treatment initiation: findings from the opinion-based PREDICT-FD modified Delphi consensus initiative.

OBJECTIVES: The PRoposing Early Disease Indicators for Clinical Tracking in Fabry Disease (PREDICT-FD) initiative aimed to reach consensus among a panel of global experts on early indicators of disease progression that may justify FD-specific treatment initiation. DESIGN AND SETTING: Anonymous feedback from panellists via online questionnaires was analysed using a modified Delphi consensus technique. Questionnaires and data were managed by an independent administrator directed by two non-voting cochairs. First, possible early indicators of renal, cardiac and central/peripheral nervous system (CNS/PNS) damage, and other disease and patient-reported indicators assessable in routine clinical practice were compiled by the cochairs and administrator from panellists' free-text responses. Second, the panel scored indicators for importance (5-point scale: 1=not important; 5=extremely important); indicators scoring ≥3 among >75% of panellists were then rated for agreement (5-point scale: 1=strongly disagree; 5=strongly agree). Indicators awarded an agreement score ≥4 by >67% of panellists achieved consensus. Finally, any panel-proposed refinements to consensus indicator definitions were adopted if >75% of panellists agreed. RESULTS: A panel of 21 expert clinicians from 15 countries provided information from which 83 possible current indicators of damage (kidney, 15; cardiac, 15; CNS/PNS, 13; other, 16; patient reported, 24) were compiled. Of 45 indicators meeting the importance criteria, consensus was reached for 29 and consolidated as 27 indicators (kidney, 6; cardiac, 10; CNS/PNS, 2; other, 6; patient reported, 3) including: (kidney) elevated albumin:creatinine ratio, histological damage, microalbuminuria; (cardiac) markers of early systolic/diastolic dysfunction, elevated serum cardiac troponin; (CNS/PNS) neuropathic pain, gastrointestinal symptoms suggestive of gastrointestinal neuropathy; (other) pain in extremities/neuropathy, angiokeratoma; (patient-reported) febrile crises, progression of symptoms/signs. Panellists revised and approved proposed chronologies of when the consensus indicators manifest. The panel response rate was >95% at all stages. CONCLUSIONS: PREDICT-FD captured global opinion regarding current clinical indicators that could prompt FD-specific treatment initiation earlier than is currently practised

Head-to-head trial of pegunigalsidase alfa versus agalsidase beta in patients with Fabry disease and deteriorating renal function: results from the 2-year randomised phase III BALANCE study

BACKGROUND: Pegunigalsidase alfa is a PEGylated α-galactosidase A enzyme replacement therapy. BALANCE (NCT02795676) assessed non-inferiority of pegunigalsidase alfa versus agalsidase beta in adults with Fabry disease with an annualised estimated glomerular filtration rate (eGFR) slope more negative than -2 mL/min/1.73 m2/year who had received agalsidase beta for ≥1 year. METHODS: Patients were randomly assigned 2:1 to receive 1 mg/kg pegunigalsidase alfa or agalsidase beta every 2 weeks for 2 years. The primary efficacy analysis assessed non-inferiority based on median annualised eGFR slope differences between treatment arms. RESULTS: Seventy-seven patients received either pegunigalsidase alfa (n=52) or agalsidase beta (n=25). At baseline, mean (range) age was 44 (18-60) years, 47 (61%) patients were male, median eGFR was 74.5 mL/min/1.73 m2 and median (range) eGFR slope was -7.3 (-30.5, 6.3) mL/min/1.73 m2/year. At 2 years, the difference between median eGFR slopes was -0.36 mL/min/1.73 m2/year, meeting the prespecified non-inferiority margin. Minimal changes were observed in lyso-Gb3 concentrations in both treatment arms at 2 years. Proportions of patients experiencing treatment-related adverse events and mild or moderate infusion-related reactions were similar in both groups, yet exposure-adjusted rates were 3.6-fold and 7.8-fold higher, respectively, with agalsidase beta than pegunigalsidase alfa. At the end of the study, neutralising antibodies were detected in 7 out of 47 (15%) pegunigalsidase alfa-treated patients and 6 out of 23 (26%) agalsidase beta-treated patients. There were no deaths. CONCLUSIONS: Based on rate of eGFR decline over 2 years, pegunigalsidase alfa was non-inferior to agalsidase beta. Pegunigalsidase alfa had lower rates of treatment-emergent adverse events and mild or moderate infusion-related reactions. TRIAL REGISTRATION NUMBER: NCT02795676

Genetic screening of Fabry patients with EcoTILLING and HRM technology

<p>Abstract</p> <p>Background</p> <p>Anderson-Fabry disease (FD) is caused by a deficit of the α-galactosidase A enzyme which leads to the accumulation of complex sphingolipids, especially globotriaosylceramide (Gb3), in all the cells of the body, causing the onset of a multi-systemic disease with poor prognosis in adulthood. In this article, we describe two alternative methods for screening the <it>GLA </it>gene which codes for the α-galactosidase A enzyme in subjects with probable FD in order to test analysis strategies which include or rely on initial pre-screening.</p> <p>Findings</p> <p>We analyzed 740 samples using EcoTILLING, comparing two mismatch-specific<ul/>endonucleases, CEL I and ENDO-1, while conducting a parallel screening of the same samples using HRM (High Resolution Melting). Afterwards, all samples were subjected to direct sequencing. Overall, we identified 12 different genetic variations: -10C>T, -12G>A, -30G>A, IVS2-76_80del5, D165H, C172Y, IVS4+16A>G, IVS4 +68 A>G, c.718_719delAA, D313Y, IVS6-22C>T, G395A. This was consistent with the high genetic heterogeneity found in FD patients and carriers. All of the mutations were detected by HRM, whereas 17% of the mutations were not found by EcoTILLING. The results obtained by EcoTILLING comparing the CEL I and ENDO-1 endonucleases were perfectly overlapping.</p> <p>Conclusion</p> <p>On the basis of its simplicity, flexibility, repeatability, and sensitivity, we believe that<ul/>HRM analysis of the <it>GLA </it>gene is a reliable presequencing screening tool. This method can be applied to any genomic feature to identify known and unknown genetic alterations, and it is ideal for conducting screening and population studies.</p

Early indicators of disease progression in Fabry disease that may indicate the need for disease-specific treatment initiation: findings from the opinion-based PREDICT-FD modified Delphi consensus initiative

Objectives The PRoposing Early Disease Indicators for Clinical Tracking in Fabry Disease (PREDICT-FD) initiative aimed to reach consensus among a panel of global experts on early indicators of disease progression that may justify FD-specific treatment initiation. Design and setting Anonymous feedback from panellists via online questionnaires was analysed using a modified Delphi consensus technique. Questionnaires and data were managed by an independent administrator directed by two non-voting cochairs. First, possible early indicators of renal, cardiac and central/peripheral nervous system (CNS/PNS) damage, and other disease and patient-reported indicators assessable in routine clinical practice were compiled by the cochairs and administrator from panellists’ free-text responses. Second, the panel scored indicators for importance (5-point scale: 1=not important; 5=extremely important); indicators scoring ≥3 among &gt;75% of panellists were then rated for agreement (5-point scale: 1=strongly disagree; 5=strongly agree). Indicators awarded an agreement score ≥4 by &gt;67% of panellists achieved consensus. Finally, any panel-proposed refinements to consensus indicator definitions were adopted if &gt;75% of panellists agreed. Results A panel of 21 expert clinicians from 15 countries provided information from which 83 possible current indicators of damage (kidney, 15; cardiac, 15; CNS/PNS, 13; other, 16; patient reported, 24) were compiled. Of 45 indicators meeting the importance criteria, consensus was reached for 29 and consolidated as 27 indicators (kidney, 6; cardiac, 10; CNS/PNS, 2; other, 6; patient reported, 3) including: (kidney) elevated albumin:creatinine ratio, histological damage, microalbuminuria; (cardiac) markers of early systolic/diastolic dysfunction, elevated serum cardiac troponin; (CNS/PNS) neuropathic pain, gastrointestinal symptoms suggestive of gastrointestinal neuropathy; (other) pain in extremities/neuropathy, angiokeratoma; (patient-reported) febrile crises, progression of symptoms/signs. Panellists revised and approved proposed chronologies of when the consensus indicators manifest. The panel response rate was &gt;95% at all stages. Conclusions PREDICT-FD captured global opinion regarding current clinical indicators that could prompt FD-specific treatment initiation earlier than is currently practised.Instituto de Estudios Inmunológicos y Fisiopatológico