193 results on '"Germain DP"'
Search Results
2. Buts thérapeutiques dans la maladie de Gaucher
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P. Mistry and Germain Dp
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Pediatrics ,medicine.medical_specialty ,Acid beta-glucosidase ,Imiglucerase ,business.industry ,Anemia ,Gastroenterology ,Disease ,medicine.disease ,Asymptomatic ,Safety profile ,Quality of life ,Tolerability ,Internal Medicine ,Medicine ,medicine.symptom ,business ,medicine.drug - Abstract
Evidence-based therapeutic goals have been developed by European and North American experts in the field of Gaucher disease (GD, lysosomal acid beta glucosidase deficiency, OMIM 230 800) in an attempt to reverse the entire disease phenotype, improve quality of life and prevent life-threatening complications. Patients with GD usually have maximal clinical benefit when enzyme replacement treatment (ERT) efficiency is administered at the optimal time i.e. generally during the asymptomatic phase of the disease. Currently, imiglucerase is the standard of care for type 1 GD due to its high efficiency at improving bleeding tendencies, anemia, reversing heptosplenomegaly and part of skeletal damages and eliminating bone crises. ERT has also demonstrated a remarkable safety profile with tolerability at 3 years greater than 99%. Treatment of GD is a lifelong treatment that patients should not interrupt without a careful monitoring of the disease evolution.
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- 2007
3. Kidney transplantation in patients with Fabry disease
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Cybulla M, Walter KN, Schwarting A, Divito R, Feriozzi S, Sunder Plassmann G, Binder C, Kotanko P, Kroepfl T, Plecko B, Bodamer O, Hauser AC, Kleinert J, Kristoferitsch W, Schreiber W, Georges B, Nassogne MC, Pirson Y, Dehout F, Henry F, Roland D, Vauthier L, Goyens P, Mazoin N, Van Maldergem L, Eyskens F, Bultas J, Karetová D, Linhart A, Dostalova G, Choukroun G, Berthelot J, Hardy P, Carey Reomonnay S, Lacombe D, Bataille P, Benziane S, Mittelberger JM, Thevenot C, Dobbelaere D, Hachulla E, Dussol B, Reade R, Khau van Kien A, Kaminsky P, Guyot C, Lino M, Ghafari T, Germain DP, Knebelmann B, Lidove O, Ouali N, Touati G, Monlun E, Jaussaud R, Richalet B, Klotz V, Andres E, Caraman D, Bazex J, Perrichot R, Hennermann J, von Arnim Baas A, Stolz S, Hoffmann B, Chrobot E, Grabbe S, Jansen T, Neumann HP, Schluh G, Gal A, Muschol N, Shäfer E, Ullrich K, Das A, Illsinger S, Lücke T, Bähner F, Baron K, Beck M, Bruns K, Delgado Sanchez S, Hartung R, Kalkum G, Kampmann C, Keilmann A, Lackner K, Pitz S, Whybra C, Wiethoff C, Koletzko B, Pontz B, Böttcher T, Miethe S, Rolfs A, Davydenko I, Wanner C, Maródi L, Gabrielli O, Gobbi S, Concolino D, Zampetti A, Borsini W, Buchner S, Menni F, Parini R, Ravaglia R, Santus F, Di Vito R, Burlina A, Burlina AP, Manara R, Antuzzi D, Castorina M, Ricci R, Kaarbøe Ø, Skarbøvik A, Houge G, Svarstad E, Tøndel C, Barba MA, Botella R, Franco A, Torras J, Gómez Huertas E, Torregrosa V, Fernández V, Paniagua J, Rodriguez F, Herrera J, Febrer I, Perez Garcia A, Martin I, Barbado FJ, Garcia de Lorenzo A, López M, González J, Ballarin J, Torra R, Hernández S, Ara J, Bonal J, Pintos G, Andreu J, Rivera A, Oqvist B, Huyen Do U, Barbey F, Hayoz D, Theytaz J, Schärer M, Schulthess G, Steinmann B, Walter K, Widmer U, Hollak C, Ormel E, van Duinen A, Vetter A, Corcoran M, Cox TM, Deegan P, Ramaswami U, Wright N, Baker R, Blincoe M, Bruce R, Burns A, Close L, Davey C, Elliott J, Elliott P, Evans S, Ginsberg L, Hajioff D, Hughes D, Ioannidis A, Keshav S, Mehta A, Milligan A, Orteu C, Richfield L., STRISCIUGLIO, PIETRO, Cybulla, M, Walter, Kn, Schwarting, A, Divito, R, Feriozzi, S, Sunder Plassmann, G, Binder, C, Kotanko, P, Kroepfl, T, Plecko, B, Bodamer, O, Hauser, Ac, Kleinert, J, Kristoferitsch, W, Schreiber, W, Georges, B, Nassogne, Mc, Pirson, Y, Dehout, F, Henry, F, Roland, D, Vauthier, L, Goyens, P, Mazoin, N, Van Maldergem, L, Eyskens, F, Bultas, J, Karetová, D, Linhart, A, Dostalova, G, Choukroun, G, Berthelot, J, Hardy, P, Carey Reomonnay, S, Lacombe, D, Bataille, P, Benziane, S, Mittelberger, Jm, Thevenot, C, Dobbelaere, D, Hachulla, E, Dussol, B, Reade, R, Khau van Kien, A, Kaminsky, P, Guyot, C, Lino, M, Ghafari, T, Germain, Dp, Knebelmann, B, Lidove, O, Ouali, N, Touati, G, Monlun, E, Jaussaud, R, Richalet, B, Klotz, V, Andres, E, Caraman, D, Bazex, J, Perrichot, R, Hennermann, J, von Arnim Baas, A, Stolz, S, Hoffmann, B, Chrobot, E, Grabbe, S, Jansen, T, Neumann, Hp, Schluh, G, Gal, A, Muschol, N, Shäfer, E, Ullrich, K, Das, A, Illsinger, S, Lücke, T, Bähner, F, Baron, K, Beck, M, Bruns, K, Delgado Sanchez, S, Hartung, R, Kalkum, G, Kampmann, C, Keilmann, A, Lackner, K, Pitz, S, Whybra, C, Wiethoff, C, Koletzko, B, Pontz, B, Böttcher, T, Miethe, S, Rolfs, A, Davydenko, I, Wanner, C, Maródi, L, Gabrielli, O, Gobbi, S, Concolino, D, Strisciuglio, Pietro, Zampetti, A, Borsini, W, Buchner, S, Menni, F, Parini, R, Ravaglia, R, Santus, F, Di Vito, R, Burlina, A, Burlina, Ap, Manara, R, Antuzzi, D, Castorina, M, Ricci, R, Kaarbøe, Ø, Skarbøvik, A, Houge, G, Svarstad, E, Tøndel, C, Barba, Ma, Botella, R, Franco, A, Torras, J, Gómez Huertas, E, Torregrosa, V, Fernández, V, Paniagua, J, Rodriguez, F, Herrera, J, Febrer, I, Perez Garcia, A, Martin, I, Barbado, Fj, Garcia de Lorenzo, A, López, M, González, J, Ballarin, J, Torra, R, Hernández, S, Ara, J, Bonal, J, Pintos, G, Andreu, J, Rivera, A, Oqvist, B, Huyen Do, U, Barbey, F, Hayoz, D, Theytaz, J, Schärer, M, Schulthess, G, Steinmann, B, Walter, K, Widmer, U, Hollak, C, Ormel, E, van Duinen, A, Vetter, A, Corcoran, M, Cox, Tm, Deegan, P, Ramaswami, U, Wright, N, Baker, R, Blincoe, M, Bruce, R, Burns, A, Close, L, Davey, C, Elliott, J, Elliott, P, Evans, S, Ginsberg, L, Hajioff, D, Hughes, D, Ioannidis, A, Keshav, S, Mehta, A, Milligan, A, Orteu, C, and Richfield, L.
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- 2009
4. Fabry disease: a review of current management strategies
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Mehta, A, Beck, M, Eyskens, F, Feliciani, Claudio, Kantola, I, Ramaswami, U, and Germain, Dp
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genetic disorder ,fabry ,Settore MED/35 - MALATTIE CUTANEE E VENEREE - Published
- 2010
5. COMMENTARY
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Koletzko, B, primary and Germain, DP, additional
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- 2007
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6. Endothelial markers and homocysteine in patients with classic Fabry disease
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Demuth, K, primary and Germain, DP, additional
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- 2007
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7. Gaucher's disease: a paradigm for interventional genetics
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Germain, DP, primary
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- 2004
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8. Fabry disease: a functional and anatomical study of cardiac manifestations in 20 hemizygous male patients
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Senechal, M, primary and Germain, DP, additional
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- 2002
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9. Arterial remodelling in Fabry disease
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Boutouyrie, P, primary, Laurent, S, additional, Laloux, B, additional, Lidove, O, additional, Grunfeld, JP, additional, and Germain, DP, additional
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- 2002
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10. Co‐occurrence and contribution of Fabry disease and Klippel–Trénaunay–Weber syndrome to a patient with atypical skin lesions
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Germain, DP, primary
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- 2001
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11. Pathological Case of the Month
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Germain Dp and Pope Fm
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medicine.medical_specialty ,business.industry ,Pediatrics, Perinatology and Child Health ,Medicine ,business ,Pseudoxanthoma elasticum ,medicine.disease ,Dermatology ,Pathological - Published
- 1997
12. Fabry disease: a functional and anatomical study of cardiac manifestations in 20 hemizygous male patients.
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Senechal, M and Germain, DP
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- *
GLYCOSPHINGOLIPIDS , *HYDROLASES - Abstract
Fabry disease (FD, OMIM 301500) is an X-linked disorder of glycosphingolipid metabolism resulting from the deficient activity of α-galactosidase A, a lysosomal acid hydrolase, leading to progressive lysosomal accumulation of incompletely metabolized neutral glycosphingolipids. Cardiac involvement is frequent. The objective of this study was to characterize the cardiac abnormalities in male patients affected with classic Fabry disease and define the context in which the clinicians were able to make the diagnosis. Clinical evaluation, laboratory tests, electrocardiography (ECG) and echocardiography were performed in 20 hemizygous men (mean age 39 years, range 12–65 years). The context of diagnosis was obtained by review of patients' charts. Left ventricular hypertrophy (LVH) and/or concentric remodeling were found in 12 patients (60%). Structural changes in mitral and aortic valves were found in 25% and 10% of cases, respectively. The sensitivity of the ECG Romhilt–Estes score for LVH was high (80%). Short PR interval (40%), ST segment abnormalities and conduction delay were frequent on ECG. Left ventricular mass index, ECG scores for LVH and systolic pulmonary pressure correlated positively with age. There was no relation between classic vascular risk factors and coronary artery disease, transient ischemic attack (TIA) or stroke. Diagnosis of Fabry disease was frequently suggested by nephrologists, dermatologists or geneticists. Echocardiograph and ECG abnormalities are frequently observed in patients with Fabry disease. Cardiologists should be aware of the diagnosis of Fabry disease in patients presenting with LVH, concentric remodeling, mitral and aortic valve thickening on echocardiography, short PR interval and conduction defects on ECG. [ABSTRACT FROM AUTHOR]
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- 2003
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13. Foreword.
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Germain DP
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- 2008
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14. Prognostic indicators of renal disease progression in adults with Fabry disease: natural history data from the Fabry Registry
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Stephen Waldek, Christoph Wanner, Alberto Ortiz, Michael Mauer, Gabor E. Linthorst, Dominique P. Germain, Andreas L. Serra, Dana Beitner-Johnson, David G. Warnock, Renzo Mignani, Roberta Lemay, Bruno Cianciaruso, João Paulo Oliveira, Bojan Vujkovac, László Maródi, Endocrinology, Wanner, C, Oliveira, Jp, Ortiz, A, Mauer, M, Germain, Dp, Linthorst, Ge, Serra, Al, Maródi, L, Mignani, R, Cianciaruso, Bruno, Vujkovac, B, Lemay, R, Beitner Johnson, D, Waldek, S, and Warnock, Dg
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Adult ,Male ,medicine.medical_specialty ,Epidemiology ,Urinary system ,Urology ,Renal function ,Critical Care and Intensive Care Medicine ,Klinikai orvostudományok ,Excretion ,chemistry.chemical_compound ,renal disease ,Internal medicine ,medicine ,Humans ,Enzyme Replacement Therapy ,Registries ,Transplantation ,Creatinine ,Proteinuria ,business.industry ,Fabry Registry ,Enzyme replacement therapy ,Original Articles ,Orvostudományok ,Middle Aged ,medicine.disease ,Prognosis ,Fabry disease ,Natural history ,Endocrinology ,chemistry ,Nephrology ,Disease Progression ,Fabry Disease ,Kidney Failure, Chronic ,Female ,Kidney Diseases ,medicine.symptom ,business ,Glomerular Filtration Rate - Abstract
Background and objectives: These analyses were designed to characterize renal disease progression in untreated adults with Fabry disease. Design, setting, participants, & measurements: Data from the Fabry Registry for 462 untreated adults (121 men and 341 women) who had at least two estimated GFR (eGFR) values over a span of ≥12 months before starting enzyme replacement therapy were included. Results: Most men (86 of 121, 71%) had more rapid loss of kidney function than the normal adult population (loss of eGFR > −1 ml/min per 1.73 m2 per year), whereas fewer women (133 of 341, 39%) had rapid loss of kidney function. Patients with rapid progression had significantly higher mean averaged urinary protein to urinary creatinine ratios (UP/Cr) than patients with slower progression (1.5 versus 0.2 for men; 1.4 versus 0.5 for women; P < 0.0001). Patients were grouped into quartiles based on averaged UP/Cr; renal function in men declined more rapidly with higher UP/Cr, with the steepest declines observed in men with UP/Cr > 1.5 (mean eGFR slope, −5.6 ml/min per 1.73 m2 per year; n = 30). eGFR slope declined more slowly in women, with the steepest declines observed in women with UP/Cr > 1.2 (mean eGFR slope, −1.3 ml/min per 1.73 m2 per year; n = 85). Regression models of eGFR slope indicated that UP/Cr is the most important indicator of renal disease progression in adult Fabry patients. In women, lower baseline eGFR and age were also associated with renal disease progression. Women who had clinical events had more rapid loss of kidney function. Conclusions: Urinary protein excretion is strongly associated with renal disease progression in men and women with Fabry disease.
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- 2010
15. End-stage renal disease in patients with Fabry disease: natural history data from the Fabry Registry
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Dominique P. Germain, Renzo Mignani, Bruno Cianciaruso, João Paulo Oliveira, Bojan Vujkovac, Christoph Wanner, Alberto Ortiz, Stephen Waldek, David G. Warnock, Jacobo Villalobos, Marta Cizmarik, Ortiz, A, Cianciaruso, Bruno, Cizmarik, M, Germain, Dp, Mignani, R, Oliveira, Jp, Villalobos, J, Vujkovac, B, Waldek, S, Wanner, C, and Warnock, Dg
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Adult ,Male ,medicine.medical_specialty ,Pediatrics ,Adolescent ,Fabry's disease ,medicine.medical_treatment ,urologic and male genital diseases ,Nephropathy ,End stage renal disease ,Young Adult ,Risk Factors ,medicine ,Humans ,Enzyme Replacement Therapy ,Renal replacement therapy ,Registries ,Stroke ,Kidney transplantation ,Aged ,Retrospective Studies ,Transplantation ,business.industry ,Age Factors ,Fabry Registry ,Enzyme replacement therapy ,Middle Aged ,medicine.disease ,Fabry disease ,female genital diseases and pregnancy complications ,Surgery ,Renal Replacement Therapy ,Nephrology ,Cardiovascular Diseases ,alpha-Galactosidase ,Disease Progression ,Fabry Disease ,Kidney Failure, Chronic ,Female ,End Stage Renal Disease ,business ,Kidney disease - Abstract
BACKGROUND: Fabry disease, an X-linked lysosomal storage disorder caused by deficiency of alpha-galactosidase activity, is associated with progressive loss of kidney function. This study was undertaken to characterize Fabry disease among patients who reached end-stage renal disease. METHODS: Data from 2,712 patients in the Fabry Registry were analysed to identify clinical characteristics of patients who received renal replacement therapy (RRT) during the natural history period (i.e. prior to any enzyme replacement therapy). RESULTS: A total of 213 patients [186 of 1,359 males (14%) and 27 of 1,353 females (2%)] received RRT at a median age of 38 years in both males and females. Males who received RRT were diagnosed at a median age of 35 years, compared to 23 years for non-RRT males. Sixty-one males and 10 females were not diagnosed with Fabry disease until after they had received RRT. Compared to other Fabry Registry patients, a higher percentage of RRT patients also experienced either a serious cardiovascular event or a stroke. Ninety-two of 186 males who had RRT (50%) experienced a cardiac event or stroke, compared to 230 of 1,173 non-RRT males (20%). Ten of 27 RRT females (37%) had experienced a cardiac event or stroke, compared to 226 of 1,326 non-RRT females (17%). Patients who had RRT experienced cardiovascular events and strokes at earlier ages than did patients who had not received RRT, and most received RRT before having a cardiac event or stroke. CONCLUSIONS: While all Fabry patients are at risk of cardiovascular events and strokes, patients with Fabry nephropathy who develop kidney failure appear to have concurrent involvement of other major organ systems. It is important that Fabry patients are diagnosed early and that their renal function is monitored carefully
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- 2009
16. Prevalence of Fabry disease in patients with chronic pain: Lessons from the DOUFAB and DOUFABIS studies.
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Angelini C, Bar C, Baudier MP, Fergelot P, Lancelot G, Rooryck C, Germain DP, Jabbour F, Blanchet AS, Cauchie A, Sarrazin E, Bellance R, Lefaucheur JP, Bismuth J, Ranque-Garnier S, Corand V, Coupry I, and Goizet C
- Abstract
Background: Fabry disease (FD) is a rare X-linked lysosomal disorder caused by alpha-galactosidase deficiency consecutive to a pathogenic variant in the GLA gene. Age at onset is highly variable, with a wide clinical spectrum including frequent renal, cardiac, skin and nervous system manifestations. Since pain can be an indicator of underlying FD, we wanted to estimate the prevalence of FD in a population of chronic pain patients., Methods: Two studies, DOUFAB and DOUFABIS, were carried out in expert centers for chronic pain to assess the prevalence of FD by measuring alpha galactosidase A activity in men and analysing the GLA gene in women., Results: Analysis of 893 patients, essentially adults, led to the diagnosis of FD in one female patient, now treated with enzyme replacement therapy., Conclusions: The prevalence of FD is estimated about 1/1000 in our population of men and women suffering from various chronic pain. This is nearly the prevalence of FD observed in other previously screened high-risk populations with renal failure., Significance: Although a systematic search for FD does not seem relevant in the context of unexplained chronic pain in adults, a positive family history of FD or the presence of additional FD related organ features must lead to consider this rare disease diagnosis. Therefore, pain specialists need to be aware of main features of FD, including pain characteristics., (© 2024 The Author(s). European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation ‐ EFIC ®.)
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- 2024
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17. 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.
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Wallace EL, Goker-Alpan O, Wilcox WR, Holida M, Bernat J, Longo N, Linhart A, Hughes DA, Hopkin RJ, Tøndel C, Langeveld M, Giraldo P, Pisani A, Germain DP, Mehta A, Deegan PB, Molnar MJ, Ortiz D, Jovanovic A, Muriello M, Barshop BA, Kimonis V, Vujkovac B, Nowak A, Geberhiwot T, Kantola I, Knoll J, Waldek S, Nedd K, Karaa A, Brill-Almon E, Alon S, Chertkoff R, Rocco R, Sakov A, and Warnock DG
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- Humans, Male, Adult, Female, Middle Aged, Adolescent, Young Adult, Treatment Outcome, Fabry Disease drug therapy, alpha-Galactosidase therapeutic use, alpha-Galactosidase administration & dosage, alpha-Galactosidase adverse effects, alpha-Galactosidase genetics, Glomerular Filtration Rate drug effects, Enzyme Replacement Therapy methods, Isoenzymes therapeutic use, Isoenzymes adverse effects, Isoenzymes administration & dosage, Recombinant Proteins administration & dosage, Recombinant Proteins therapeutic use, Recombinant Proteins adverse effects
- Abstract
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 m
2 /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., Competing Interests: Competing interests: ELW has consulting agreements and/or grants with Sanofi, Protalix, Chiesi, Idorsia, 4DMT, Amicus and Natera. OG-A has conducted contracted research, received consulting fees and/or served on advisory boards with Amicus, Freeline, Genentech, Protalix, Sangamo, Sanofi, Takeda, 4DMT and Avrobio. WRW has been or is currently involved in clinical trials and/or registries with Alexion, Amicus, BioMarin, Chiesi, Freeline, Idorsia, Orphazyme, Pfizer, Protalix, Sanofi, Sangamo, Takeda and 4DMT. He has received honoraria from Alexion, Amicus, BioMarin, Sanofi, Spark and Takeda, and research funding from Amicus and Takeda. MH received speaker-related fees from Protalix and has been, or is currently, involved in clinical trials with Sanofi, Sangamo, Avrobio, Protalix and Idorsia (no direct funding received for these trials because they are institution directed). JB receives research support from Avrobio, BioMarin Pharmaceutical, Chiesi Farmaceutici, Idorsia Pharmaceuticals, Pfizer, Protalix Biotherapeutics, Sangamo Therapeutics, Sanofi, Takeda, Travere Therapeutics; and has received a speaker honorarium from the Fabry Support and Information Group; and has participated in advisory boards for Chiesi USA, Sanofi and Takeda. NL receives research support from and has participated in advisory boards for Amicus, Astellas, Avrobio, BioMarin Pharmaceutical, Homology, Horizon, Moderna, Pfizer, Protalix Biotherapeutics, PTC Biotherapeutics, Reneo, Sanofi, Takeda and Ultragenyx (no direct funding is received because they are institution directed). DH has received honoraria for speaking and consulting fees for advisory boards from Protalix, Takeda, Sanofi, Freeline and Sangamo, administered through University College London consultants and used in part to support research in lysosomal storage diseases. PG has been involved in premarketing studies with Genzyme, Protalix and Idorsia, and has received grants from Sanofi-Genzyme and Takeda; monies received for these activities have been deposited into the Spanish Foundation for the Study and Treatment of Gaucher Disease (FEETEG) to contribute to the development of research in lysosomal storage disorders. MJM, DO, MM, BAB, JK, TG and KN have no disclosures. RJH has received consulting fees from Alexion, Amicus Therapeutics, Inc., Avrobio, Chiesi, Sangamo, Sanofi/Genzyme, and Takeda; advisory fees from Alexion, Amicus Therapeutics, Inc., and Sanofi/Genzyme; speakers' bureau fees from Alexion and Sanofi/Genzyme and grants/research funding from Alexion, Amicus Therapeutics, Inc., Idorsia, Protalix, Sangamo, Sanofi/Genzyme and Takeda. CT has received honoraria, travel support, and/or participated as an investigator in clinical studies supported by Protalix, Sanofi, Idorsia, Takeda, Amicus, Freeline and Acelink. All received honoraria went to her institution Haukeland University Hospital. AL has received consultancy and speaker's honoraria from Amicus Therapeutics, Sanofi, Takeda, 4DMT and Chiesi. PD has been a paid consultant with Sanofi; received speaker honoraria from Sanofi and Takeda and participated in an advisory board with Protalix. AJ has received a grant from Amicus and consultancy and speaker’s honoraria from Takeda, Sanofi and Amicus. VK is an advisory board member for the Sanofi-Genzyme North American Pompe Registry. She is the principal investigator for Sanofi-Genzyme Lysosomal Storage Disease registry at UC Irvine. She has received education grants, lecturing honoraria, and research support from Sanofi-Genzyme. She participates as an investigator in clinical studies supported by Protalix, Sanofi, Idorsia, Chiesi Farmaceutici and Sangamo. BV has received honoraria, travel and accommodation funding from Greenovation Biotech GmbH, Sanofi, Takeda, Amicus, Chiesi and Swixx, and is a member of the EU Advisory Board of Fabry Registry, sponsored by Sanofi. AN received lecturing honoraria and research support from Takeda, Amicus and Sanofi/Genzyme. AP received travel expenses and grants from Takeda, Sanofi, Amicus and Chiesi. DPG has received consulting honoraria from Chiesi, Idorsia Pharmaceuticals, Sanofi and Takeda, and speaker honoraria and travel support from Sanofi and Takeda. IK has received lecture, travel and consulting fees from Amicus, Chiesi, Bayer, Boehringer-Ingelheim, Sanofi-Genzyme and Takeda-Shire. AM has received non-financial support from Chiesi Pharmaceuticals, during the conduct of the study; personal fees from AstraZeneca, Bayer Pharmaceuticals and Janssen Pharmaceuticals, outside the submitted work. AK has received honoraria, travel support and/or participated as an investigator in clinical studies supported by Protalix, Sanofi and Idorsia and on advisory meetings for Protalix, Sanofi, Takeda, Amicus and Chiesi. SW has been a paid consultant to Protalix. ML is involved in premarketing studies with Sanofi-Genzyme, Protalix/Chiesi and Idorsia. Financial arrangements were made through AMC Research BV. No fees, travel support or grants were obtained from the pharmaceutical industry. EBA and RC were full-time employees of Protalix Biotherapeutics at the time of study conduct and analysis and are now consultants to Protalix Biotherapeutics. SA is a full-time employee of Protalix Biotherapeutics. RR is a full-time employee of Chiesi Farmaceutici S.p.A. AS was a paid consultant to Protalix at the time of study conduct and analysis and is currently a paid consultant to Chiesi USA, Inc. DGW is involved in clinical trials/registries/consulting with Amicus, Chiesi, Idorsia and Protalix., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2024
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18. Pegunigalsidase alfa: a novel, pegylated recombinant alpha-galactosidase enzyme for the treatment of Fabry disease.
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Germain DP and Linhart A
- Abstract
Fabry disease, a rare X-linked genetic disorder, results from pathogenic variants in GLA , leading to deficient lysosomal α-galactosidase A enzyme activity and multi-organ manifestations. Since 2001, enzyme replacement therapy (ERT), using agalsidase alfa or agalsidase beta, has been the mainstay treatment, albeit with limitations such as rapid clearance and immunogenicity. Pegunigalsidase alfa, a novel PEGylated recombinant alpha-galactosidase, offers promise as an alternative. Produced in plant cells, pegunigalsidase alfa exhibits enhanced stability, prolonged half-life, and reduced immunogenicity due to pegylation. A phase 1/2 clinical trial demonstrated Gb3 clearance from renal capillary endothelial cells and its 48-month extension study revealed notable outcomes in renal function preservation. Three phase 3 clinical trials (BRIDGE, BRIGHT, and BALANCE) have shown favorable efficacy and safety profile, although caution is warranted in interpreting the results of BRIDGE and BRIGHT which lacked control groups. In BALANCE, the pivotal phase 3 trial comparing pegunigalsidase alfa with agalsidase beta, an intention-to-treat analysis of the eGFR decline over 2 years showed that the intergroup difference [95%confidence interval] in the median slope was -0.36 mL/min/1.73 m
2 /year [-2.44; 1.73]. The confidence interval had a lower limit above the prespecified value of -3 mL/min/1.73 m2 /year and included zero. Despite challenges such as occasional hypersensitivity reactions and immune-complex-mediated glomerulonephritis, pegunigalsidase alfa approval by the European Medicines Agency and the Food and Drug Administration represents a significant addition to Fabry disease therapeutic landscape providing an option for patients in whom enzyme replacement therapy with current formulations is poorly tolerated or poorly effective., Competing Interests: DG has received speaker’s fees and honoraria from Chiesi, Idorsia, Sanofi, and Takeda. AL has received speaker’s fees and honoraria from Amicus Therapeutics, Chiesi, Sanofi, and Takeda., (Copyright © 2024 Germain and Linhart.)- Published
- 2024
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19. Reconceptualizing podocyte damage in Fabry disease: new findings identify α-synuclein as a putative therapeutic target.
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Germain DP
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- Humans, alpha-Synuclein therapeutic use, alpha-Galactosidase genetics, alpha-Galactosidase therapeutic use, Trihexosylceramides, Fabry Disease diagnosis, Fabry Disease drug therapy, Podocytes
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- 2024
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20. Use of T1 mapping in cardiac MRI for the follow-up of Fabry disease in a pediatric population.
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Werner O, Ichay L, Djouadi N, Vetromile F, Vincenti M, Guillaumont S, Germain DP, and Fila M
- Abstract
Background: Fabry disease (FD) is a rare X-linked lysosomal disorder caused by pathogenic variants in the alpha-galactosidase-A gene ( GLA ). Life threatening complications in adulthood include chronic kidney failure, strokes and the cardiac involvement which is the leading cause of mortality. Usually, it presents with hypertrophic cardiomyopathy, together with arrhythmia and conduction abnormalities. An early indicator is decreased T1 value on cardiac magnetic resonance (CMR). Enzyme replacement therapy (ERT) is effective on some extra-cardiac symptoms but its effect on cardiac lesions depends on the level of initial myocardial lesions. CMR is routinely used to monitor cardiac involvement in FD due to its capacity for tissular characterization. However, there is a lack of data on the pediatric population to understand how to integrate CMR into early therapeutic decisions., Method: Monocentric longitudinal study carried out at Montpellier University Hospital from 2016 to 2022. All pediatric patients with FD were evaluated over time with clinical, biological, and cardiac imaging (CMR, echocardiography)., Results: Out of the six patients included, (3 males), five were treated with ERT during the study. Low T1 values were observed in 4 patients. The normalization of T1 values was observed after 4 years of ERT in 3 patients., Conclusion: Due to the lack of strong clinical and biological markers of FD in pediatric patients, initiation and follow-up of ERT efficacy remain challenging. CMR with T1-mapping, a noninvasive method, could play a role in the evaluation of early cardiac impairment in young patients at diagnosis and during follow-up with or without ERT., Competing Interests: D.P.G. is a consultant for Amicus, Sanofi-Genzyme and Shire. He has received speaker's honoraria from Amicus, Sanofi-Genzyme and Shire., (© 2023 The Authors.)
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- 2023
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21. Impact of GLA Variant Classification on the Estimated Prevalence of Fabry Disease: A Systematic Review and Meta-Analysis of Screening Studies.
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Monda E, Diana G, Graziani F, Rubino M, Bakalakos A, Linhart A, Germain DP, Scarpa M, Biagini E, Pieroni M, Elliott PM, and Limongelli G
- Subjects
- Humans, Infant, Newborn, alpha-Galactosidase genetics, Prevalence, Hypertrophy, Left Ventricular, Fabry Disease diagnosis, Fabry Disease epidemiology, Fabry Disease genetics, Stroke
- Abstract
Background: The diagnosis of Fabry disease (FD) has relevant implications related to the management. Thus, a clear assignment of GLA variant pathogenicity is crucial. This systematic review and meta-analysis aimed to investigate the prevalence of FD in high-risk populations and newborns and evaluate the impact of different GLA variant classifications on the estimated prevalence of FD., Methods: We searched the EMBASE and PubMed databases on February 21, 2023. Observational studies evaluating the prevalence of FD and reporting the identified GLA variants were included. GLA variants were re-evaluated for their pathogenicity significance using the American College of Medical Genetics and Genomics criteria and the ClinVar database. The pooled prevalence of FD among different settings was calculated. The study was registered on PROSPERO (CRD42023401663) and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines., Results: Of the 3941 studies identified, 110 met the inclusion criteria. The pooled prevalence of FD was significantly different according to the clinical setting and criteria used for the pathogenicity assessment. Using the American College of Medical Genetics and Genomics criteria, the pooled prevalence was 1.2% in patients with left ventricular hypertrophy/hypertrophic cardiomyopathy (26 studies; 10 080 patients screened), 0.3% in end-stage renal disease/chronic kidney disease (38 studies; 62 050 patients screened), 0.7% in stroke (25 studies; 15 295 patients screened), 0.7% in cardiac conduction disturbance requiring pacemaker (3 studies; 1033 patients screened), 1.0% in small-fiber neuropathy (3 studies; 904 patients screened), and 0.01% in newborns (15 studies; 11 108 793 newborns screened). The pooled prevalence was different if the GLA variants were assessed using the ClinVar database, and most patients with a discrepancy in the pathogenicity assignment carried 1 of the following variants: p.A143T, p.D313Y, and p.E66Q., Conclusions: This systematic review and meta-analysis describe the prevalence of FD among newborns and high-risk populations, highlighting the need for a periodic reassessment of the GLA variants in the context of recent clinical, biochemical, and histological data., Registration: URL: https://crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42023401663., Competing Interests: Disclosures None.
- Published
- 2023
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22. Global reach of over 20 years of experience in the patient-centered Fabry Registry: Advancement of Fabry disease expertise and dissemination of real-world evidence to the Fabry community.
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Wanner C, Ortiz A, Wilcox WR, Hopkin RJ, Johnson J, Ponce E, Ebels JT, Batista JL, Maski M, Politei JM, Martins AM, Banikazemi M, Linhart A, Mauer M, Oliveira JP, Weidemann F, and Germain DP
- Subjects
- Female, Humans, alpha-Galactosidase genetics, alpha-Galactosidase therapeutic use, Enzyme Replacement Therapy methods, Registries, Phenotype, Patient-Centered Care, Observational Studies as Topic, Fabry Disease drug therapy, Fabry Disease epidemiology, Fabry Disease genetics
- Abstract
Fabry disease (FD, α-galactosidase A deficiency) is a rare, progressive, complex lysosomal storage disorder affecting multiple organ systems with a diverse spectrum of clinical phenotypes, particularly among female patients. Knowledge of its clinical course was still limited in 2001 when FD-specific therapies first became available and the Fabry Registry (NCT00196742; sponsor: Sanofi) was initiated as a global observational study. The Fabry Registry has now been operational for over 20 years, overseen by expert Boards of Advisors, and has collected real-world demographic and longitudinal clinical data from more than 8000 individuals with FD. Leveraging the accumulating evidence base, multidisciplinary collaborations have resulted in the creation of 32 peer-reviewed scientific publications, which have contributed to the greatly expanded knowledge on the onset and progression of FD, its clinical management, the role of sex and genetics, the outcomes of enzyme replacement therapy with agalsidase beta, and prognostic factors. We review how the Fabry Registry has evolved from its inception to become the largest global source of real-world FD patient data, and how the generated scientific evidence has helped to better inform the medical community, individuals living with FD, patient organizations, and other stakeholders. The patient-centered Fabry Registry fosters collaborative research partnerships with the overarching goal of optimizing the clinical management of patients with FD and is well positioned to add to its past achievements., Competing Interests: Declaration of Competing Interest C.W. has received honoraria for board meetings and lecturing from Amicus Therapeutics, Chiesi Pharmaceuticals, Idorsia Pharmaceuticals, Sanofi, and Takeda. A.O. has received grants from Sanofi and consultancy, speaker fees or travel support from Advicenne, Alexion, Amgen, Amicus Therapeutics, Astellas, AstraZeneca, Bayer, Chiesi Pharmaceuticals, Fresenius Medical Care, GlaxoSmithKline, Idorsia Pharmaceuticals, Kyowa Kirin, Menarini, Novo-Nordisk, Otsuka, and Vifor Fresenius Medical Care Renal Pharma, and is Director of the Cátedra Mundipharma-UAM of diabetic kidney disease and the Cátedra AstraZeneca-UAM of chronic kidney disease and electrolytes. W.R.W. is a member of the Fabry Registry Board of Advisors, has consulted for Amicus Therapeutics, Sanofi, Spark, Takeda, and UniQure, and has been an investigator in clinical studies for Fabry disease sponsored by Amicus Therapeutics, Chiesi Pharmaceuticals, Freeline Therapeutics, Idorsia Pharmaceuticals, 4D Molecular Therapeutics, Protalix Biotherapeutics, Sangamo Therapeutics, and Sanofi. These activities are monitored and are in compliance with the conflict-of-interest policies at Emory University School of Medicine. R.J.H. is a member of the Fabry Registry Advisory Board, consults with Amicus Therapeutics and Sanofi, and has been an investigator in clinical trials sponsored by Amicus Therapeutics, Idorsia Pharmaceuticals, Protalix Biotherapeutics, Sangamo Therapeutics, Sanofi, and Takeda. These activities have been monitored and found to be in compliance with the conflict-of-interest policies at Cincinnati Children's Hospital Medical Center. J.J. has received honoraria from Sanofi, and travel support from Amicus Therapeutics and Sanofi. E.P., J.T.E., J.L.B., and Ma.M. are full-time employees of Sanofi and may hold/have held stock and/or stock options in that company. J.M.P. has received honoraria from Amicus Therapeutics, Sanofi, and Takeda, and consulting fees from Sanofi and Takeda. A.M.M. has received Advisory Board honoraria from Astra Zeneca-Alexion Pharmaceuticals, BioMarin Pharmaceutical, JCR Pharmaceuticals, and Sanofi, and speaker honoraria and travel support from Astra Zeneca-Alexion Pharmaceuticals, BioMarin Pharmaceutical, Chiesi Pharmaceuticals, JCR Pharmaceuticals, and Sanofi. M.B. is a member of the Fabry Registry Advisory Board and has received honoraria for consultancies, honoraria for disease registry advisory board meetngs, honoraria for lecturing and support for research from Sanofi. She also has received consulting and/or lecturing honoraria from Amicus Therapeutics and Chiesi Pharmaceuticals. A.L. has received consulting honoraria from Amicus Therapeutics, Sanofi Genzyme, and Takeda, and speaker honoraria and travel support from Sanofi Genzyme and Takeda. Mi.M. is a member of the Fabry Registry Board, has an investigator-initiated research grant from Sanofi, performs laboratory work and is a consultant to Sanofi for clinical trial design, received speaker fees and travel support from Sanofi for non-promotional presentations (these interests have been reviewed and managed by the University of Minnesota in accordance with its conflict-of-interest policies), is a consultant and performs laboratory work for Amicus Therapeutics, and is a consultant to Acelink Therapeutics, Avrobio, Freeline Therapeutics, and Sangamo Therapeutics. J.P.O. is member of the European Advisory Board of the Fabry Registry and has received honoraria for consultancies, honoraria for disease registry advisory board, honoraria for lecturing and support for research from Sanofi. He also has received consulting and/or lecturing honoraria from Amicus Therapeutics, Chiesi Pharmaceuticals and Takeda, and support for travel and accommodation from Amicus Therapeutics, Sanofi, and Takeda. F.W. has received research grants from Sanofi and Takeda and speaker honoraria from Amicus Therapeutics, Sanofi, and Takeda. D.P.G. has received grants and consultancy fees from Chiesi Pharmaceuticals, Idorsia Pharmaceuticals, Sanofi, and Takeda, and travel support from Sanofi., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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23. Diagnostic work-up and phenotypic characteristics of a family with variable severity of distal arthrogryposis type 2B (Sheldon-Hall syndrome) and TNNT3 pathogenic variant.
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Dabaj I, Carlier RY, Dieterich K, Desguerre I, Faure J, Romero NB, Trang W, Quijano-Roy S, and Germain DP
- Abstract
Background: Sheldon-Hall syndrome (SHS) or distal arthrogryposis 2B (DA2B) is a rare clinically and genetically heterogeneous multiple congenital contracture syndrome characterized by contractures of the distal joints of the limbs and mild facial involvement, due to pathogenic variants in genes encoding the fast-twitch skeletal muscle contractile myofiber complex (TNNT3, TNNI2, TMP2, and MYH3 genes). Patients and methods: A 16-year-old boy with a history of congenital distal arthrogryposis developed severe kyphoscoliosis and respiratory insufficiency. His mother and younger sister had phenotypes compatible with SHS but to a much lesser extent. Diagnostic work-up included physical examination and whole-body muscular MRI (WBMRI) in all three patients and electroneuromyography (ENMG) and paravertebral muscle biopsy in the proband. DNA sequencing was used to confirm the diagnosis. Results: Physical examination suggested the diagnosis of SHS. No muscle signal abnormalities were found in WBMRI. Large motor unit potentials and reduced recruitment suggestive of neurogenic changes were observed on needle EMG in distal and paravertebral muscles in the proband. DNA sequencing revealed a pathogenic variant in TNNT3 (c.187C>T), which segregated as a dominant trait with the phenotype. Discussion: This is the first report on neurogenic features in a patient with DA2B and a pathogenic variant in TNNT3 encoding the fast-twitch skeletal muscle contractile myofiber complex. A superimposed length-dependent motor nerve involvement was unexpected. Whether developmental disarrangements in number, distribution, or innervation of the motor unit in fetal life might lead to pseudo-neurogenic EMG features warrants further studies, as well as the role of genetic modifiers in SHS variability., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Dabaj, Carlier, Dieterich, Desguerre, Faure, Romero, Trang, Quijano-Roy and Germain.)
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- 2023
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24. Clinical outcomes among young patients with Fabry disease who initiated agalsidase beta treatment before 30 years of age: An analysis from the Fabry Registry.
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Hopkin RJ, Cabrera GH, Jefferies JL, Yang M, Ponce E, Brand E, Feldt-Rasmussen U, Germain DP, Guffon N, Jovanovic A, Kantola I, Karaa A, Martins AM, Tøndel C, Wilcox WR, Yoo HW, Burlina AP, and Mauer M
- Subjects
- Male, Female, Humans, alpha-Galactosidase genetics, alpha-Galactosidase adverse effects, Abdominal Pain chemically induced, Abdominal Pain drug therapy, Registries, Enzyme Replacement Therapy adverse effects, Fabry Disease complications, Fabry Disease drug therapy, Acute Pain chemically induced, Acute Pain drug therapy
- Abstract
Background: Clinical manifestations of classic Fabry disease (α-galactosidase A deficiency) usually occur in childhood, while complications involving major organs typically develop in adulthood. Outcomes of Fabry-specific treatment among young patients have not been extensively reported. Our aim was to analyze clinical outcomes among patients aged 5-30 years at initiation of treatment with agalsidase beta using data from the Fabry Registry (NCT00196742, sponsor: Sanofi)., Methods: Reported GLA variants were predicted to be associated with the classic phenotype or not classified in fabry-database.org. Linear mixed models were conducted to assess changes over ≥2-year follow-up in the estimated glomerular filtration rate (eGFR) stratified by low (LRI) and high (HRI) renal involvement (defined by proteinuria/albuminuria levels), and changes in interventricular septal thickness (IVST) and left ventricular posterior wall thickness (LVPWT) Z-scores stratified by median age at first treatment. Self-reports ('yes'/'no') of abdominal pain, diarrhea, chronic peripheral pain (denoting neuropathic pain), and acute pain crises at baseline were compared with reports after ≥0.5-year and ≥2.5-year follow-up using McNemar's test., Results: Male (n = 117) and female patients (n = 59) with LRI initiated treatment at a median age of 19.9 and 23.6 years, respectively, and were followed for a median of 6.3 and 5.0 years, respectively. The eGFR slopes were -1.18 (P
from 0 <0.001) and -0.92 mL/min/1.73 m2 /year (Pfrom 0 = 0.040), respectively. Males with HRI (n = 23, median UPCR 1.0 g/g), who started treatment at a median age of 26.7 years, had an eGFR slope of -2.39 mL/min/1.73 m2 /year (Pfrom 0 <0.001; Pdifference = 0.055, as compared with the slope of -1.18 mL/min/1.73 m2 /year for LRI males) during a median follow-up of 5.6 years. Echocardiographic variables were stable among males, regardless of age, and among young females (median follow-up >5.5 years and ≥4.5 years, respectively). Older females (treatment initiation at median age 27.5 years) had a slope of LVPWT Z-scores of 0.18/year (n = 12, Pfrom 0 = 0.028), whereas IVST Z-scores remained stable (n = 13, 0.10/year, Pfrom 0 = 0.304) during a median follow-up of ≥3.7 years. These slopes did not significantly differ from slopes of younger females. Reports of chronic peripheral pain and acute pain crises by males, and of diarrhea and acute pain crises by females, significantly reduced after a median follow-up of ≥4.0 years. After a median follow-up of ≥5.4 years, reports of all four symptoms significantly decreased among males, whereas among females only reports of abdominal pain significantly decreased., Conclusions: During sustained treatment with agalsidase beta in young Fabry patients with a predicted classic phenotype or with unclassified GLA variants with similar characteristics, the decline in eGFR was modest among male and female patients with LRI. The greater decline in eGFR among older, proteinuric (i.e., HRI) males may suggest a benefit of earlier treatment. Overall, echocardiographic variables remained stable, particularly among males and younger females. Significant reductions in symptom reports occurred primarily among males after longer follow-up and were less noticeable among females. These observed trends are suggestive of an overall improvement after treatment in young patients, but warrant larger longitudinal studies., Competing Interests: Declaration of Competing Interest R.J.H. is a member of the Fabry Registry Advisory Board, consults with Amicus Therapeutics and Sanofi, and has been an investigator in clinical trials sponsored by Amicus Therapeutics, Idorsia Pharmaceuticals, Protalix Biotherapeutics, Sangamo Therapeutics, Sanofi, and Takeda. These activities have been monitored and found to be in compliance with the conflict-of-interest policies at Cincinnati Children's Hospital Medical Center. G.H.C. has consulting arrangements with and received speaking fees from Sanofi, and has received travel support from Sanofi and Takeda. J.L.J. has received Advisory Board honoraria from Sanofi. M.Y. is a former employee of Sanofi. E.P. is a full-time employee of Sanofi. Both may hold/have held stock and/or stock options in that company. E.B. has received Advisory Board honoraria from Amicus Therapeutics, Chiesi Pharmaceuticals, Greenovation Biotech, Sanofi, and Takeda, speaker honoraria and research grants from Amicus Therapeutics, Chiesi Pharmaceuticals, Sanofi, and Takeda, and travel support from Amicus Therapeutics. U.F.R. has received Advisory Board honoraria from Amicus Therapeutics, Freeline Therapeutics, Sanofi, and Takeda, speaker honoraria from Amicus Therapeutics, Sanofi, and Takeda, grant support from Sanofi and Takeda, and is a member of the European Advisory Board of the Fabry Registry. D.P.G. has received consulting honoraria from Idorsia Pharmaceuticals, Sanofi, and Takeda, and speaker honoraria and travel support from Amicus Therapeutics, Sanofi, and Takeda. N.G. has received travel support from Sanofi and Takeda. A.J. has received Advisory Board honoraria from Amicus Therapeutics, Sanofi, and Takeda, speaker honoraria from Amicus Therapeutics, BioMarin Pharmaceutical, and Sanofi, and travel support from Amicus Therapeutics and Sanofi. I.K. has received speaker honoraria and travel support from Sanofi and Takeda. A.K. has received research grants, reimbursement for travel, and consulting payments from Sanofi, Stealth BioTherapeutics, and Takeda, received research grants and reimbursement for travel from Protalix Biotherapeutics and Reata Pharmaceuticals, received research grants from Astellas Pharma, Cyclerion Therapeutics, Idorsia Pharmaceuticals, Mitobridge, and PTC Therapeutics, and received consulting payments from Akros Pharma, Alexion Pharmaceuticals, Astellas Pharma, Homology Medicines, Lumleian, Mitobridge, NeuroVive Pharmaceutical, Reneo Pharmaceuticals, and Zogenix. A.M.M. has received Advisory Board honoraria from BioMarin Pharmaceutical and Sanofi, and speaker honoraria and travel support from Alexion Pharmaceuticals, BioMarin Pharmaceutical, and Sanofi. C.T. is a member of the European Fabry Registry Board of Advisors, has received consultancy honoraria from Acelink Therapeutics, Amicus Therapeutics, Chiesi Pharmaceuticals, Freeline Therapeutics, and Sanofi, and is investigator in studies supported by Freeline Therapeutics, Idorsia Pharmaceuticals, Protalix Biotherapeutics, Sanofi, and Takeda. W.R.W. consults for Amicus Therapeutics, Sanofi, and Takeda, and is an investigator in clinical studies for Fabry disease sponsored by Amicus Therapeutics, Freeline Therapeutics, Idorsia Pharmaceuticals, 4D Molecular Therapeutics, Protalix Biotherapeutics, Sangamo Therapeutics, and Sanofi. These activities are monitored and are in compliance with the conflict-of-interest policies at Emory University School of Medicine. H.W.Y. has received honoraria from Sanofi. A.P.B. has received speaker honoraria and travel support from Amicus Therapeutics, Freeline Therapeutics, Sanofi, and Takeda, and is a member of the European Advisory Board of the Fabry Registry. M.M. is a member of the Fabry Registry Board, has an investigator-initiated research grant from Sanofi, performs laboratory work and is a consultant to Sanofi for clinical trial design, received speaker fees and travel support from Sanofi for non-promotional presentations (these interests have been reviewed and managed by the University of Minnesota in accordance with its conflict-of-interest policies), is a consultant and performs laboratory work for Amicus Therapeutics, and is a consultant to Acelink Therapeutics, Avrobio, Freeline Therapeutics, and Sangamo Therapeutics., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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25. Screening of Fabry disease in patients with an implanted permanent pacemaker.
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Fingrova Z, Havranek S, Sknouril L, Bulava A, Vancura V, Chovanec M, Dedek V, Curila K, Skala T, Jäger J, Kluh T, Dostalova G, Germain DP, and Linhart A
- Subjects
- Adult, Humans, Male, Middle Aged, Aged, Bradycardia complications, Bradycardia therapy, Sick Sinus Syndrome diagnosis, Sick Sinus Syndrome epidemiology, Sick Sinus Syndrome therapy, Prospective Studies, Fabry Disease diagnosis, Fabry Disease epidemiology, Fabry Disease genetics, Atrioventricular Block diagnosis, Atrioventricular Block epidemiology, Atrioventricular Block therapy, Pacemaker, Artificial adverse effects
- Abstract
Background: Anderson-Fabry disease (AFD) is an X-linked inherited lysosomal disease caused by a defect in the gene encoding lysosomal enzyme α-galactosidase A (GLA). Atrio-ventricular (AV) nodal conduction defects and sinus node dysfunction are common complications of the disease. It is not fully elucidated how frequently AFD is responsible for acquired AV block or sinus node dysfunction and if some AFD patients could manifest primarily with spontaneous bradycardia in general population. The purpose of study was to evaluate the prevalence of AFD in male patients with implanted permanent pacemaker (PM)., Methods: The prospective multicentric screening in consecutive male patients between 35 and 65 years with implanted PM for acquired third- or second- degree type 2 AV block or symptomatic second- degree type 1 AV block or sinus node dysfunction was performed., Results: A total of 484 patients (mean age 54 ± 12 years at time of PM implantation) were enrolled to the screening in 12 local sites in Czech Republic. Out of all patients, negative result was found in 481 (99%) subjects. In 3 cases, a GLA variant was found, classified as benign: p.Asp313Tyr, p.D313Y). Pathogenic GLA variants (classical or non-classical form) or variants of unclear significance were not detected., Conclusion: The prevalence of pathogenic variants causing AFD in a general population sample with implanted permanent PM for AV conduction defects or sinus node dysfunction seems to be low. Our findings do not advocate a routine screening for AFD in all adult males with clinically significant bradycardia., Competing Interests: Declaration of Competing Interest ZF and SH received the travel grants and speaker's honoraria from Takeda. GD received honoraria and travel funding from Sanofi Genzyme, Takeda, Protalix, and Greenovation Biotech GmbH. DG is a consultant for Amicus Therapeutics, Sanofi Genzyme, and Shire; has received research support from Sanofi Genzyme and Shire; and has received speaker honoraria and travel support from Amicus Therapeutics, Sanofi Genzyme, and Shire. AL received consultancy honoraria from Amicus Therapeutics, Sanofi Genzyme, Takeda, and speaker's honoraria from Sanofi Genzyme and Takeda., (Copyright © 2022 Elsevier B.V. All rights reserved.)
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- 2023
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26. Venglustat, an orally administered glucosylceramide synthase inhibitor: Assessment over 3 years in adult males with classic Fabry disease in an open-label phase 2 study and its extension study.
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Deegan PB, Goker-Alpan O, Geberhiwot T, Hopkin RJ, Lukina E, Tylki-Szymanska A, Zaher A, Sensinger C, Gaemers SJM, Modur V, Thurberg BL, Sharma J, Najafian B, Mauer M, DasMahapatra P, Wilcox WR, and Germain DP
- Subjects
- Humans, Male, Adult, Adolescent, Young Adult, alpha-Galactosidase therapeutic use, Glucosyltransferases, Fabry Disease pathology
- Abstract
Venglustat inhibits the enzymatic conversion of ceramide to glucosylceramide, reducing available substrate for the synthesis of more complex glycosphingolipids. It offers a potential new approach to the treatment of patients with Fabry disease (α-Gal A deficiency), in whom progressive accumulation of such glycosphingolipids, including globotriaosylceramide (GL-3), in the lysosomes of a wide range of cell types often leads to vital organ complications in adulthood. An international, open-label, single-arm, Phase 2a uncontrolled 26-week clinical study (NCT02228460) and a 130-week extension study (NCT02489344) were conducted to assess the safety, pharmacodynamics, pharmacokinetics, and exploratory efficacy of 15 mg once daily oral venglustat in treatment-naïve adult male patients with classic Fabry disease. Of 11 patients (18-37 years old) who initially enrolled, nine completed the 26-week study and seven completed the extension study. A total of 169 treatment-emergent adverse events (TEAEs) were reported by nine patients, the majority being mild (73%) and unrelated to the study drug (70%). Nine serious TEAEs (serious adverse events) and 11 severe TEAEs, including a self-harm event, were reported. No deaths or treatment-related life-threatening adverse events were reported. Skin GL-3 scores in superficial skin capillary endothelium (SSCE), estimated by light microscopy, were unchanged from baseline at Week 26 in five patients, decreased in three patients, and increased in one patient. There was no significant change in GL-3 scores or significant shift in grouped GL-3 scores. Five of six patients had reductions from baseline in GL-3 score at the end of the extension study. At Weeks 26 and 156 the mean (standard deviation) changes from baseline in the fraction of the volume of SSCE cytoplasm occupied by GL-3 inclusions, measured by electron microscopy unbiased stereology, were - 0.06 (0.03) (p = 0.0010) and - 0.12 (0.04) (p = 0.0008), respectively. Venglustat treatment reduced markers in the synthetic and degradative pathway of major glycosphingolipids; proximal markers reduced rapidly and more distal markers (plasma GL-3 and globotriaosylsphingosine) reduced progressively. There were no biochemical or histological indications of progression of Fabry disease over 3 years of follow-up. These findings confirm target engagement and the pharmacodynamic effects of venglustat in adult males with classic Fabry disease. However, further clinical evaluation in larger studies is needed to determine efficacy and safety., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2023
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27. The Benefits of Family Screening in Rare Diseases: Genetic Testing Reveals 165 New Cases of Fabry Disease among At-Risk Family Members of 83 Index Patients.
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Moiseev S, Tao E, Moiseev A, Bulanov N, Filatova E, Fomin V, and Germain DP
- Subjects
- Family, Genetic Testing, Glycosphingolipids, Humans, Mutation, Quality of Life, Rare Diseases genetics, alpha-Galactosidase genetics, Fabry Disease diagnosis, Fabry Disease genetics, Fabry Disease metabolism, Renal Insufficiency, Chronic diagnosis, Renal Insufficiency, Chronic genetics
- Abstract
Background: Fabry disease (FD, OMIM #301500) is a rare, progressive, X-linked, inherited genetic disease caused by a functional deficiency of lysosomal α-galactosidase, leading to the accumulation of glycosphingolipids in virtually all of the body's cell types and fluids. Patients with rare genetic diseases and non-specific symptoms often experience substantial diagnostic delays, which can negatively impact the prompt initiation of treatment. If FD is not treated specifically, end organ damage (such as chronic renal failure, hypertrophic cardiomyopathy with arrhythmia, and strokes) impairs quality of life and reduces life expectancy., Patients and Methods: For 83 consecutive patients with FD referred to the Russian reference center for lysosomal storage diseases, family trees were built and genetic testing (cascade genotyping) was offered to family members., Results: The pathogenic GLA variant associated with FD was identified for all 83 probands. Family testing using cascade genotyping enabled the identification of 165 additional cases of FD among the tested 331 at-risk family members., Discussion: This is the first study to have described family screening in a large Russian cohort of patients with FD and chronic kidney disease. Raising awareness of FD among clinicians is important for earlier diagnosis and specific treatment.
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- 2022
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28. An expert consensus on practical clinical recommendations and guidance for patients with classic Fabry disease.
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Germain DP, Altarescu G, Barriales-Villa R, Mignani R, Pawlaczyk K, Pieruzzi F, Terryn W, Vujkovac B, and Ortiz A
- Subjects
- Male, Female, Humans, alpha-Galactosidase genetics, alpha-Galactosidase therapeutic use, Enzyme Replacement Therapy, Consensus, Quality of Life, Glycosphingolipids, Biomarkers, Fabry Disease diagnosis, Fabry Disease genetics, Fabry Disease therapy
- Abstract
Fabry disease is an X-linked inherited lysosomal disorder that causes accumulation of glycosphingolipids in body fluids and tissues, leading to progressive organ damage and reduced life expectancy. It can affect both males and females and can be classified into classic or later-onset phenotypes. In classic Fabry disease, α-galactosidase A (α-Gal A) activity is absent or severely reduced and disease manifestations have an early onset that can affect multiple organs. In contrast, in later-onset Fabry disease, patients have residual α-Gal A activity and clinical features are primarily confined to the heart. Individualized therapeutic goals in Fabry disease are required due to varying phenotypes and patient characteristics, and the wide spectrum of disease severity. An international group of expert physicians convened to discuss and develop practical clinical recommendations for disease- and organ-specific therapeutic goals in Fabry disease, based on expert consensus and evidence identified through a structured literature review. Biomarkers reflecting involvement of various organs in adult patients with classic Fabry disease are discussed and consensus recommendations for disease- and organ-specific therapeutic goals are provided. These consensus recommendations should support the establishment of individualized approaches to the management of patients with classic Fabry disease by considering identification, diagnosis, and initiation of disease-specific therapies before significant organ involvement, as well as routine monitoring, to reduce morbidity, optimize patient care, and improve patient health-related quality of life., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2022
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29. Challenging the traditional approach for interpreting genetic variants: Lessons from Fabry disease.
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Germain DP, Levade T, Hachulla E, Knebelmann B, Lacombe D, Seguin VL, Nguyen K, Noël E, and Rabès JP
- Subjects
- Female, Gene Frequency, Humans, Mutation, Phenotype, alpha-Galactosidase genetics, Fabry Disease diagnosis, Fabry Disease genetics, Fabry Disease pathology
- Abstract
Fabry disease (FD) is an X-linked genetic disease due to pathogenic variants in GLA. The phenotype varies depending on the GLA variant, alpha-galactosidase residual activity, patient's age and gender and, for females, X chromosome inactivation. Over 1000 variants have been identified, many through screening protocols more susceptible to disclose non-pathogenic variants or variants of unknown significance (VUS). This, together with the non-specificity of some FD symptoms, challenges physicians attempting to interpret GLA variants. The traditional way to interpreting pathogenicity is based on a combined approach using allele frequencies, genomic databases, global and disease-specific clinical databases, and in silico tools proposed by the American College of Medical Genetics and Genomics. Here, a panel of FD specialists convened to study how expertise may compare with the traditional approach. Several GLA VUS, highly controversial in the literature (p.Ser126Gly, p.Ala143Thr, p.Asp313Tyr), were re-analyzed through reviews of patients' charts. The same was done for pathogenic GLA variants with some specificities. Our data suggest that input of geneticists and physicians with wide expertise in disease phenotypes, prevalence, inheritance, biomarkers, alleles frequencies, disease-specific databases, and literature greatly contribute to a more accurate interpretation of the pathogenicity of variants, bringing a significant additional value over the traditional approach., (© 2021 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)
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- 2022
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30. Diagnosis and Management of Cardiovascular Involvement in Fabry Disease.
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Rubino M, Monda E, Lioncino M, Caiazza M, Palmiero G, Dongiglio F, Fusco A, Cirillo A, Cesaro A, Capodicasa L, Mazzella M, Chiosi F, Orabona P, Bossone E, Calabrò P, Pisani A, Germain DP, Biagini E, Pieroni M, and Limongelli G
- Subjects
- Enzyme Replacement Therapy, Humans, Hypertrophy, Left Ventricular, Quality of Life, Cardiomyopathy, Hypertrophic, Fabry Disease complications, Fabry Disease diagnosis, Fabry Disease genetics
- Abstract
Fabry disease (FD, OMIM 301500) is an X-linked lysosomal storage disease caused by pathogenic variants in the GLA gene. Cardiac involvement is common in FD and is responsible for impaired quality of life and premature death. The classic cardiac involvement is a nonobstructive form of hypertrophic cardiomyopathy, usually manifesting as concentric left ventricular hypertrophy, with subsequent arrhythmogenic intramural fibrosis. Treatment of patients with FD should be directed to prevent the disease progression to irreversible organ damage and organ failure. The aim of this review is to describe the current state of knowledge regarding cardiovascular involvement in FD, focusing on clinical and instrumental features, cardiovascular management, and targeted therapy., Competing Interests: Disclosure The authors have nothing to disclose. D.P. Germain is a consultant for Sanofi Genzyme and Takeda., (Copyright © 2021 Elsevier Inc. All rights reserved.)
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- 2022
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31. Humoral Immune Response to SARS-CoV-2 Vaccination after a Booster Vaccine Dose in Two Kidney Transplant Recipients with Fabry Disease and Variable Secondary Immunosuppressive Regimens.
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Bernea L, Ailioaie OR, Benhamouda N, Tartour E, and Germain DP
- Abstract
The urgent need to fight the COVID-19 pandemic has accelerated the development of vaccines against SARS-CoV-2 and approval processes. Initial analysis of two-dose regimens with mRNA vaccines reported up to 95% efficacy against the original strain of the SARS-CoV-2 virus. Challenges arose with the appearance of new strains of the virus, and reports that solid organ transplant recipients may have reduced vaccination success rates after a two-dose mRNA vaccination regimen encouraged health authorities to recommend a booster in immunocompromised patients. Fabry disease is an X-linked inherited lysosomal disorder, which may lead to chronic end-stage renal disease. We report on two patients with advanced Fabry disease, renal graft and adjunctive immunosuppressive therapies who exhibited variable humoral vaccination-related immune responses against SARS-CoV-2 after three vaccine doses. The first patient developed mild COVID-19 infection, while the second patient did not seroconvert after three shots of an mRNA vaccine. Both cases emphasize that patients with Fabry disease and renal graft are susceptible to develop a weak response to COVID-19 vaccination and highlight the importance of maintaining barrier protection measures. Vaccination of family members should be encouraged to lower the risk of viral transmission to immunocompromised, transplanted patients, including vaccinated ones.
- Published
- 2021
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32. Newborn Screening for Fabry Disease in Northeastern Italy: Results of Five Years of Experience.
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Gragnaniello V, Burlina AP, Polo G, Giuliani A, Salviati L, Duro G, Cazzorla C, Rubert L, Maines E, Germain DP, and Burlina AB
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- Dried Blood Spot Testing trends, Fabry Disease epidemiology, Female, Follow-Up Studies, Glycolipids blood, Humans, Infant, Newborn, Italy epidemiology, Male, Neonatal Screening trends, Sphingolipids blood, Time Factors, Dried Blood Spot Testing methods, Fabry Disease blood, Fabry Disease diagnosis, Neonatal Screening methods, alpha-Galactosidase blood
- Abstract
Fabry disease (FD) is a progressive multisystemic lysosomal storage disease. Early diagnosis by newborn screening (NBS) may allow for timely treatment, thus preventing future irreversible organ damage. We present the results of 5.5 years of NBS for FD by α-galactosidase A activity and globotriaosylsphingosine (lyso-Gb
3 ) assays in dried blood spot through a multiplexed MS/MS assay. Furthermore, we report our experience with long-term follow-up of positive subjects. We screened more than 170,000 newborns and 22 males were confirmed to have a GLA gene variant, with an incidence of 1:7879 newborns. All patients were diagnosed with a variant previously associated with the later-onset phenotype of FD or carried an unclassified variant (four patients) or the likely benign p.Ala143Thr variant. All were asymptomatic at the last visit. Although lyso-Gb3 is not considered a reliable second tier test for newborn screening, it can simplify the screening algorithm when its levels are elevated at birth. After birth, plasma lyso-Gb3 is a useful marker for non-invasive monitoring of all positive patients. Our study is the largest reported to date in Europe, and presents data from long-term NBS for FD that reveals the current incidence of FD in northeastern Italy. Our follow-up data describe the early disease course and the trend of plasma lyso-Gb3 during early childhood.- Published
- 2021
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33. Screening for Fabry disease in male patients with end-stage renal disease in western France.
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Vigneau C, Germain DP, Larmet D, Jabbour F, and Hourmant M
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- Humans, Male, Prospective Studies, Renal Dialysis, alpha-Galactosidase genetics, Fabry Disease complications, Fabry Disease diagnosis, Fabry Disease epidemiology, Kidney Failure, Chronic diagnosis, Kidney Failure, Chronic epidemiology, Kidney Failure, Chronic etiology
- Abstract
Context: Fabry disease is a rare X-linked genetic disease due to pathogenic variants in the GLA gene. Classic Fabry disease is characterized by glycosphingolipids accumulation in all organs including the kidney, resulting in end-stage renal disease in a subset of male patients. Fabry disease should therefore be considered in the differential diagnosis of patients with unexplained end-stage renal disease., Objective: We performed a prospective screening study in Western France to determine the prevalence of Fabry disease in a large population of dialyzed and transplanted patients., Patients and Methods: Patients meeting the inclusion criteria (males, 18-70 years with end-stage renal disease of unknown or vascular origin) were selected from the REIN® registry and the CRISTAL® database. Screening on filter papers was performed after patient consent was obtained during either a dialysis session or a transplantation follow-up visit., Results: One thousand five hundred and sixty-one end-stage renal disease male patients were screened and 819 consented (dialysis: n=242; transplant: n=577). One single patient was found with decreased alpha-galactosidase levels <25%. GLA sequencing identified the p.Phe113Leu variant in favor of an unknown superimposed kidney disease responsible for end-stage renal disease since this GLA pathogenic variant is associated with a later-onset cardiac form of Fabry disease with minimal kidney involvement. Family cascade genotyping revealed a previously undiagnosed affected brother., Conclusion: The prevalence of Fabry disease in end-stage renal disease patients was 0.12%, questioning the efficacy of this screening strategy with respect to the low prevalence. However, beside the benefit for the patient and his family, the increased awareness of Fabry disease among participating nephrologists may be of interest for future patients., (Copyright © 2021 Société francophone de néphrologie, dialyse et transplantation. Published by Elsevier Masson SAS. All rights reserved.)
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- 2021
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34. The benefits and challenges of family genetic testing in rare genetic diseases-lessons from Fabry disease.
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Germain DP, Moiseev S, Suárez-Obando F, Al Ismaili F, Al Khawaja H, Altarescu G, Barreto FC, Haddoum F, Hadipour F, Maksimova I, Kramis M, Nampoothiri S, Nguyen KN, Niu DM, Politei J, Ro LS, Vu Chi D, Chen N, and Kutsev S
- Subjects
- Fabry Disease diagnosis, Genetic Testing standards, Humans, Pedigree, Fabry Disease genetics, Genetic Testing methods
- Abstract
Background: Family genetic testing of patients newly diagnosed with a rare genetic disease can improve early diagnosis of family members, allowing patients to receive disease-specific therapies when available. Fabry disease, an X-linked lysosomal storage disorder caused by pathogenic variants in GLA, can lead to end-stage renal disease, cardiac arrhythmias, and stroke. Diagnostic delays are common due to the rarity of the disease and non-specificity of early symptoms. Newborn screening and screening of at-risk populations, (e.g., patients with hypertrophic cardiomyopathy or undiagnosed nephropathies) can identify individuals with Fabry disease. Subsequent cascade genotyping of family members may disclose a greater number of affected individuals, often at younger age than they would have been diagnosed otherwise., Methods: We conducted a literature search to identify all published data on family genetic testing for Fabry disease, and discussed these data, experts' own experiences with family genetic testing, and the barriers to this type of screening that are present in their respective countries., Results: There are potential barriers that make implementation of family genetic testing challenging in some countries. These include associated costs and low awareness of its importance, and cultural and societal issues. Regionally, there are barriers associated with population educational levels, national geography and infrastructures, and a lack of medical geneticists., Conclusion: In this review, the worldwide experience of an international group of experts of Fabry disease highlights the issues faced in the family genetic testing of patients affected with rare genetic diseases., (© 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)
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- 2021
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35. Case Report: First Two Identified Cases of Fabry Disease in Central Asia.
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Cainelli F, Argandykov D, Kaldarbekov D, Mukarov M, Tran Thi Phuong L, and Germain DP
- Abstract
Background: Fabry disease (FD, OMIM #301500) is a rare, progressive, X-linked inherited, genetic disease due to the functional deficiency of lysosomal α-galactosidase (α-GAL) that leads to the accumulation of glycosphingolipids (mainly globotriaosylceramide or Gb
3 ) and its derivative globotriaosylsphingosine or lyso-Gb3 . Classic FD is a multisystem disorder which initially presents in childhood with neuropathic pain and dermatological, gastrointestinal, ocular, and cochleo-vestibular manifestations. Over time, end-organ damage such as renal failure, cardiac arrhythmia and early stroke may develop leading to reduced life expectancy in the absence of specific treatment. Case presentation: We describe two Kazakh patients who presented in adulthood with a delayed diagnosis. We conducted also a family screening through cascade genotyping. Conclusion: This is the first description of cases of Fabry disease in Central Asia. An extensive family pedigree enabled the identification of ten additional family members. Patients with rare genetic diseases often experience substantial delays in diagnosis due to their rarity and non-specific symptoms, which can negatively impact their management and delay treatment. FD may be difficult to diagnose because of the non-specificity of its early and later-onset symptoms and its X-linked inheritance. Raising awareness of clinicians is important for earlier diagnosis and optimal outcome of specific therapies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cainelli, Argandykov, Kaldarbekov, Mukarov, Tran Thi Phuong and Germain.)- Published
- 2021
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36. Fabry disease and COVID-19: international expert recommendations for management based on real-world experience.
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Laney DA, Germain DP, Oliveira JP, Burlina AP, Cabrera GH, Hong GR, Hopkin RJ, Niu DM, Thomas M, Trimarchi H, Wilcox WR, Politei JM, and Ortiz A
- Abstract
The rapid spread of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 has raised questions about Fabry disease (FD) as an independent risk factor for severe COVID-19 symptoms. Available real-world data on 22 patients from an international group of healthcare providers reveals that most patients with FD experience mild-to-moderate COVID-19 symptoms with an additional complication of Fabry pain crises and transient worsening of kidney function in some cases; however, two patients over the age of 55 years with renal or cardiac disease experienced critical COVID-19 complications. These outcomes support the theory that pre-existent tissue injury and inflammation may predispose patients with more advanced FD to a more severe course of COVID-19, while less advanced FD patients do not appear to be more susceptible than the general population. Given these observed risk factors, it is best to reinforce all recommended safety precautions for individuals with advanced FD. Diagnosis of FD should not preclude providing full therapeutic and organ support as needed for patients with FD and severe or critical COVID-19, although a FD-specific safety profile review should always be conducted prior to initiating COVID-19-specific therapies. Continued specific FD therapy with enzyme replacement therapy, chaperone therapy, dialysis, renin-angiotensin blockers or participation to clinical trials during the pandemic is recommended as FD progression will only increase susceptibility to infection. In order to compile outcome data and inform best practices, an international registry for patients affected by Fabry and infected by COVID-19 should be established., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA.)
- Published
- 2020
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37. Improvement of gastrointestinal symptoms in a significant proportion of male patients with classic Fabry disease treated with agalsidase beta: A Fabry Registry analysis stratified by phenotype.
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Hopkin RJ, Feldt-Rasmussen U, Germain DP, Jovanovic A, Martins AM, Nicholls K, Ortiz A, Politei J, Ponce E, Varas C, Weidemann F, Yang M, and Wilcox WR
- Abstract
Background: Fabry disease is an inherited disorder of glycolipid metabolism with progressive involvement of multiple organs, including the gastrointestinal tract, in classically affected male patients. Clinical presentations in males with later-onset Fabry phenotypes are more heterogeneous and largely dependent on the level of residual α-galactosidase A activity., Methods: We assessed agalsidase beta treatment outcomes of gastrointestinal symptoms in adult males with classic or later-onset Fabry disease. Self-reports of abdominal pain and diarrhea ('present'/'not present' since previous assessment) at last clinical visit (≥0.5 year of follow-up) were compared with treatment-baseline., Results: Classic male patients were considerably younger at first treatment than the fewer males with later-onset phenotypes (36 vs. ~47 years) and reported gastrointestinal symptoms more frequently at baseline (abdominal pain: 56% vs. 13%; diarrhea: 57% vs. 23%). As compared with baseline, significantly fewer classic patients reported abdominal pain after a median of 4.7 years of treatment ( N = 171, 56% vs. 41%, P < 0.001). Moreover, significantly fewer patients reported diarrhea after 5.5 years of follow-up ( N = 169, 57% vs. 47%, P < 0.05). Among the males with later-onset phenotypes, albeit statistically non-significant, abdominal pain reports reduced after a median of 4.2 years ( N = 48, 13% vs. 4%) and diarrhea reports reduced after a median of 4.4 years of treatment ( N = 47, 23% vs. 13%)., Conclusions: Sustained treatment with agalsidase beta was associated with improvement in abdominal pain and diarrhea in a significant proportion of classic male Fabry patients. Males with later-onset phenotypes reported gastrointestinal symptoms much less frequently at baseline as compared with classic patients, and non-significant reductions were observed., Competing Interests: RJH has received consulting honoraria from Amicus Therapeutics, Protalix Corporation, Sanofi Genzyme and Takeda, was an investigator in clinical trials sponsored by Amicus Therapeutics, Protalix Corporation, Sanofi Genzyme and Takeda, and received research funding from Amicus Therapeutics, Protalix Corporation and Sanofi Genzyme; these activities have been monitored and found to be in compliance with the conflict of interest policies at Cincinnati Children's Hospital Medical Center. UFR has received Advisory Board honoraria from Amicus Therapeutics, Freeline, Sanofi Genzyme and Takeda, and speaker honoraria from Amicus Therapeutics, Sanofi Genzyme and Takeda. DPG has received consulting honoraria from Sanofi Genzyme and Takeda, and speaker honoraria and travel support from Amicus Therapeutics, Sanofi Genzyme and Takeda. AJ has received a research grant from Amicus Therapeutics, Advisory Board honoraria from Amicus Therapeutics, Sanofi Genzyme and Takeda, speaker honoraria from Amicus Therapeutics, BioMarin and Sanofi Genzyme, and travel support from Amicus Therapeutics and Sanofi Genzyme. AMM has received Advisory Board honoraria from BioMarin and Sanofi Genzyme, and speaker honoraria and travel support from Alexion, BioMarin and Sanofi Genzyme. AO has received consulting honoraria and travel support from Sanofi Genzyme, and speaker honoraria from Amicus Therapeutics, Freeline, Sanofi Genzyme and Takeda. KN has served as an advisor for Amicus Therapeutics, Sanofi Genzyme and Takeda, has received research support from Amicus Therapeutics and Takeda, and has received travel support from Sanofi Genzyme. JP has received honoraria and travel support from Amicus Therapeutics, Protalix Corporation, Sanofi Genzyme and Takeda. EP and MY are full-time employees of Sanofi Genzyme. CV is a member of the Fabry Registry Board of Advisors. FW has received speaker honoraria and travel support from Amicus Therapeutics, Sanofi Genzyme and Takeda. WRW consults for Sanofi Genzyme and was an investigator in clinical studies and trials sponsored by Amicus Therapeutics, Protalix Corporation, Sanofi Genzyme and Takeda, and has received research funding from Amicus Therapeutics, Sanofi Genzyme, and Takeda; these activities are monitored and are in compliance with the conflict of interest policies at Emory University School of Medicine., (© 2020 Published by Elsevier Inc.)
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- 2020
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38. Use of a rare disease registry for establishing phenotypic classification of previously unassigned GLA variants: a consensus classification system by a multispecialty Fabry disease genotype-phenotype workgroup.
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Germain DP, Oliveira JP, Bichet DG, Yoo HW, Hopkin RJ, Lemay R, Politei J, Wanner C, Wilcox WR, and Warnock DG
- Subjects
- Aged, Alleles, Fabry Disease pathology, Female, Genetic Association Studies, Genotype, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Mutation genetics, Phenotype, Polymorphism, Single Nucleotide genetics, Rare Diseases pathology, Registries, Fabry Disease genetics, Rare Diseases genetics, alpha-Galactosidase genetics
- Abstract
Background: Fabry disease (α-galactosidase deficiency) is an X-linked genetic disease caused by a variety of pathogenic GLA variants. The phenotypic heterogeneity is considerable, with two major forms, classic and later-onset disease, but adjudication of clinical phenotype is currently lacking for many variants. We aimed to determine consensus phenotypic classification for previously unclassified GLA variants from the GLA -specific fabry-database.org database., Methods: A Fabry disease genotype-phenotype workgroup developed a five-stage iterative system based on expert clinical assessment, published literature and clinical evidence of pathogenicity using a 2-point scoring system based on clinical hallmarks of classic disease. Kaplan-Meier (KM) analysis of severe clinical event-free survival was used as final validation. Results were compared with those from web-based disease databases and in silico pathogenicity prediction programmes., Results: Final consensus on classifications of 'pathogenic' was achieved for 32 of 33 GLA variants (26 'classic' phenotype, 171 males; 6 'later-onset' phenotype, 57 males). One variant remained of uncertain significance. KM curves were similar for the known fabry-database.org database phenotypes and when workgroup consensus classifications were added, and the curves retained the same separation between 'classic' and 'later-onset' phenotypes., Conclusion: The iterative system implemented by a Fabry disease genotype-phenotype workgroup achieved phenotypic classifications for variants that were previously unclassified. Clinical pathogenicity associated with a particular GLA variant defined in affected males appears to have predictive value and also generally correlates with risk for affected females. The newly established classifications can be of benefit to the clinical care of Fabry patients harbouring these variants., Competing Interests: Competing interests: DPG is a consultant for Sanofi Genzyme and Takeda/Shire, was an investigator in clinical trials sponsored by Amicus Therapeutics and Sanofi Genzyme and has received speaker honoraria and travel support from Amicus Therapeutics, Sanofi Genzyme and Takeda/Shire. JPO has received consulting honoraria and unrestricted research grants and funding for research projects from Sanofi Genzyme, has received speaker honoraria from Sanofi Genzyme and Takeda/Shire and has received conference and travel support from Amicus Therapeutics, Sanofi Genzyme and Takeda/Shire. DGB has received speaker honoraria from Amicus Therapeutics, Sanofi Genzyme and Takeda/Shire. HWY has received honoraria from Sanofi Genzyme. RJH has received consulting honoraria from Sanofi Genzyme, Amicus Therapeutics, Protalix Corporation and Takeda/Shire, was an investigator in clinical trials sponsored by Amicus Therapeutics, Sanofi Genzyme and Takeda/Shire and received research funding from Sanofi Genzyme, Protalix Corporation and Amicus Therapeutics; these activities have been monitored and found to be in compliance with the conflict of interest policies at Cincinnati Children’s Hospital Medical Center. RL is an employee of Sanofi Genzyme. JP has received honoraria and travel support from Amicus Therapeutics, Protalix Corporation, Sanofi Genzyme and Takeda/Shire. CW has received research support from Sanofi Genzyme and is a consultant for Actelion Pharmaceuticals, Protalix Corporation, Boehringer Ingelheim GmbH and Sanofi Genzyme. WRW consults for Sanofi Genzyme and was an investigator in clinical studies and trials sponsored by Amicus Therapeutics, Protalix Corporation, Sanofi Genzyme and Takeda/Shire and has received research funding from Sanofi Genzyme, Amicus Therapeutics and Takeda/Shire; these activities are monitored and are in compliance with the conflict of interest policies at Emory University School of Medicine. DGW received consulting honoraria from Amicus Therapeutics, Sanofi Genzyme, Actelion Pharmaceuticals, AVROBIO, Freeline Therapeutics and Protalix Biotherapeutics and has received research funding from Amicus Therapeutics and Sanofi Genzyme. DPG, JPO, DGB, HWY, RJH, JP and CW are Regional or International Fabry Registry Board members and have received Fabry Registry Board honoraria., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2020
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39. IN VIVO OBSERVATION OF RETINAL VASCULAR DEPOSITS USING ADAPTIVE OPTICS IMAGING IN FABRY DISEASE.
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Sodi A, Germain DP, Bacherini D, Finocchio L, Pacini B, Marziali E, Lenzetti C, Tanini I, Koraichi F, Coriat C, Nencini P, Olivotto I, Virgili G, Rizzo S, and Paques M
- Subjects
- Adult, Aged, Arterioles diagnostic imaging, Fabry Disease diagnostic imaging, Female, Humans, Male, Middle Aged, Muscle, Smooth, Vascular diagnostic imaging, Optics and Photonics, Retinal Artery diagnostic imaging, Young Adult, Arterioles pathology, Fabry Disease physiopathology, Muscle, Smooth, Vascular metabolism, Ophthalmoscopy methods, Retinal Artery pathology, Sphingolipids metabolism
- Abstract
Purpose: To report a novel finding in patients with Fabry disease, that is, the observation by adaptive optics ophthalmoscopy of intracellular lipidic deposits in retinal vessels., Methods: Observational two-center case series. Eighteen patients with genetically proven Fabry disease underwent flood-illumination adaptive optics ophthalmoscopy imaging (rtx1; Imagine Eyes, Orsay, France) of retinal vessels., Results: Fourteen patients (78% of all patients; 7 of the 10 women and 7 of the 8 men) showed paravascular punctuate or linear opacities in both eyes. In the least-affected patients, these were seen only in the wall of precapillary arterioles as discrete spots of 5 µm to 10 µm large, whereas in those more severely affected, capillaries and first-order vessels were also involved with diffuse opacification of the wall. These deposits sometime showed a striated pattern, suggesting colocalization with vascular smooth muscle cells., Conclusion: Adaptive optics ophthalmoscopy of retinal vessels may be of interest for patients with Fabry disease, providing noninvasive, gradable evaluation of microvascular involvement.
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- 2020
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40. An expert consensus document on the management of cardiovascular manifestations of Fabry disease.
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Linhart A, Germain DP, Olivotto I, Akhtar MM, Anastasakis A, Hughes D, Namdar M, Pieroni M, Hagège A, Cecchi F, Gimeno JR, Limongelli G, and Elliott P
- Subjects
- Consensus, Enzyme Replacement Therapy, Humans, alpha-Galactosidase genetics, Fabry Disease complications, Fabry Disease genetics, Fabry Disease therapy, Heart Failure
- Abstract
Fabry disease (FD) is an X-linked lysosomal storage disorder caused by pathogenic variants in the α-galactosidase A (GLA) gene that leads to reduced or undetectable α-galactosidase A enzyme activity and progressive accumulation of globotriaosylceramide and its deacylated form globotriaosylsphingosine in cells throughout the body. FD can be multisystemic with neurological, renal, cutaneous and cardiac involvement or be limited to the heart. Cardiac involvement is characterized by progressive cardiac hypertrophy, fibrosis, arrhythmias, heart failure and sudden cardiac death. The cardiac management of FD requires specific measures including enzyme replacement therapy or small pharmacological chaperones in patients carrying amenable pathogenic GLA gene variants and more general management of cardiac symptoms and complications. In this paper, we summarize current knowledge of FD-related heart disease and expert consensus recommendations for its management., (© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)
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- 2020
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41. Cardiomyopathy and kidney function in agalsidase beta-treated female Fabry patients: a pre-treatment vs. post-treatment analysis.
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Wanner C, Feldt-Rasmussen U, Jovanovic A, Linhart A, Yang M, Ponce E, Brand E, Germain DP, Hughes DA, Jefferies JL, Martins AM, Nowak A, Vujkovac B, Weidemann F, West ML, and Ortiz A
- Subjects
- Enzyme Replacement Therapy, Female, Humans, Isoenzymes, Kidney, alpha-Galactosidase, Cardiomyopathies, Fabry Disease complications, Fabry Disease diagnosis, Fabry Disease drug therapy
- Abstract
Aims: Long-term treatment effect studies in large female Fabry patient groups are challenging to design because of phenotype heterogeneity and lack of appropriate comparison groups, and have not been reported. We compared long-term cardiomyopathy and kidney function outcomes after agalsidase beta treatment with preceding treatment-naive outcomes., Methods and Results: Self-controlled pretreatment and post-treatment comparison (piecewise mixed linear modelling) included Fabry female patients ≥18 years at treatment initiation who received agalsidase beta (0.9-1.1 mg/kg every other week) for ≥2 years, with ≥2 pretreatment and ≥2 post-treatment outcome measurements during 10-year follow-up. Left ventricular posterior wall thickness (LVPWT)/interventricular septal thickness (IVST) and estimated glomerular filtration rate (eGFR, Chronic Kidney Disease Epidemiology Collaboration creatinine equation) analyses included 42 and 86 patients, respectively, aged 50.0 and 46.3 years at treatment initiation, respectively. LVPWT and IVST increased pretreatment (follow-up 3.5 years) but stabilized during 3.6 years of treatment (LVPWT: n = 38, slope difference [95% confidence interval (CI)] = -0.41 [-0.68, -0.15] mm/year, P
pre-post difference <0.01; IVST: n = 38, slope difference = -0.32 [-0.67, 0.02] mm/year, Ppre-post difference = 0.07). These findings were not modified by renal involvement or antiproteinuric agent use. Compared with the treatment-naive period (follow-up 3.6 years), eGFR decline remained modest and stabilized within normal ranges during 4.1 years of treatment (slope difference, 95% CI: -0.13 [-1.15, 0.89] mL/min/1.73m2 /year, Ppre-post difference = 0.80)., Conclusions: Cardiac hypertrophy, progressing during pretreatment follow-up, appeared to stabilize during sustained agalsidase beta treatment. eGFR decline remained within normal ranges. This suggests that treatment may prevent further Fabry-related progression of cardiomyopathy in female patients and maintain normal kidney function., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)- Published
- 2020
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42. Fabry disease caused by the GLA p.Phe113Leu (p.F113L) variant: Natural history in males.
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Oliveira JP, Nowak A, Barbey F, Torres M, Nunes JP, Teixeira-E-Costa F, Carvalho F, Sampaio S, Tavares I, Pereira O, Soares AL, Carmona C, Cardoso MT, Jurca-Simina IE, Spada M, Ferreira S, and Germain DP
- Subjects
- Adult, Aged, Alleles, Cardiovascular Diseases complications, Cardiovascular Diseases genetics, Cardiovascular Diseases metabolism, Cerebrovascular Disorders complications, Cerebrovascular Disorders genetics, Cerebrovascular Disorders metabolism, Fabry Disease complications, Fabry Disease diagnostic imaging, Genetic Association Studies, Genotype, Haplotypes, Humans, Italy epidemiology, Male, Microsatellite Repeats genetics, Middle Aged, Mutation, Myocytes, Cardiac pathology, Myocytes, Cardiac ultrastructure, Phenotype, Portugal epidemiology, Renal Insufficiency, Chronic complications, Renal Insufficiency, Chronic genetics, Renal Insufficiency, Chronic metabolism, Risk Factors, Fabry Disease diagnosis, Fabry Disease genetics, alpha-Galactosidase genetics, alpha-Galactosidase metabolism
- Abstract
Background, Aims and Methods: The α-galactosidase gene (GLA) c.337T>C/p.Phe113Leu variant was originally described in patients with late-onset cardiac forms of Fabry disease (FD), who had residual α-galactosidase activity. It has since emerged as the most commonly reported GLA variant in Portuguese subjects diagnosed with FD but is also prevalent in the Italian population, where two boys carrying the GLA Leu113 allele were identified in a large-scale newborn screening program, the variant allele segregating in both cases with the same surrounding haplotype. To further delineate the genotype-phenotype correlations of this GLA variant, we have reviewed the natural history and clinical phenotypes of 11 symptomatic Portuguese males, from 10 unrelated families originating from several different areas in mainland Portugal and Madeira Island, who were diagnosed with FD associated with the GLA Leu113 allele in a diversity of clinical and screening settings. Nine of the patients were the probands of their respective families. To test whether the GLA Leu113 allele inherited by the 10 Portuguese and the two Italian families resulted from independent mutational events, we have additionally performed a haplotype analysis with 5 highly polymorphic, closely linked microsatellite markers surrounding the GLA gene., Results and Conclusions: Hemizygosity for the GLA Leu113 variant allele is associated with a late-onset form of FD, invariably presenting with severe cardiac involvement. Clinically relevant cerebrovascular and kidney involvement may also occur in some patients but the pathogenic relationship between the incomplete α-galactosidase deficiency and the risks of stroke and of chronic kidney disease is not straightforward. The observation that the Leu113 allele segregated within the same GLA microsatellite haplotype in both the Portuguese and Italian families suggests its inheritance from a common ancestor., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)
- Published
- 2020
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43. Treatment needs and expectations for Fabry disease in France: development of a new Patient Needs Questionnaire.
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Noël E, Dussol B, Lacombe D, Bedreddine N, Fouilhoux A, Ronco P, Genevaz D, Bekri S, Hagège A, Dupuis-Siméon F, Derrien Ansquer V, Germain DP, and Lidove O
- Subjects
- France, Humans, Psychometrics methods, Quality of Life, Surveys and Questionnaires, Fabry Disease physiopathology
- Abstract
Background: Fabry disease (FD) is a rare, X-linked, inherited lysosomal disease caused by absent or reduced α-galactosidase A activity. Due to the heterogeneity of disease presentation and progression, generic patient-reported outcome (PRO) tools do not provide accurate insight into patients' daily lives and impact of disease specific treatments. Also, the French National Health Authority, (HAS) actively encourages a patient-centric approach to improve the quality of care throughout the patient journey. In response to this initiative, we aimed to develop and validate a specific, self-reported, Patient Needs Questionnaire for people living with Fabry disease to appraise patient needs and expectations towards their treatment (PNQ Fabry). This endeavour was led with the help of French patient associations (APMF & VML) and dedicated expert centres. PNQ Fabry was developed according to the FDA/EMA methodologies and best practices for the development of PRO tools in rare diseases. Our approach comprised of three steps, as follows: concept elicitation and item generation, item reduction, and final validation of the questionnaire through a two-stage survey., Results: Intrinsic and extrinsic reliability was established, using a validated benchmark questionnaire. With the invaluable help of patient associations, we recruited a satisfactory population in this rare disease setting, to ensure robust participation to validate our PNQ (final number of questionnaires: 76). At the end of the process, a 26-item patient-reported questionnaire was obtained with excellent psychometric properties, exhibiting very satisfactory measurement outcomes for reliability and validity. The results of this initiative demonstrate that the PNQ Fabry is accurate, suitable and tailored to FD patients, as it addresses themes identified during patient interviews, that were further validated through statistical analyses of quantitative surveys. An ongoing phase IV study is using this tool., Conclusion: We believe the PNQ Fabry will be a reliable and insightful tool in clinical practice, to improve patient management in FD.
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- 2019
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44. Why systematic literature reviews in Fabry disease should include all published evidence.
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Elliott PM, Germain DP, Hilz MJ, Spada M, Wanner C, and Falissard B
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- Evidence-Based Medicine methods, Evidence-Based Medicine standards, Fabry Disease epidemiology, Fabry Disease etiology, Humans, Publication Bias, Publications, Fabry Disease diagnosis, Fabry Disease therapy, Medicine in Literature, Review Literature as Topic
- Abstract
Fabry disease is an X-linked inherited, progressive disorder of lipid metabolism resulting from the deficient activity of the enzyme α-galactosidase. Enzyme replacement therapy (ERT) with recombinant agalsidase, with intravenous infusions of either agalsidase beta or agalsidase alfa, is available and clinical experience now exceeds 15 years. There are very few randomised, placebo-controlled clinical trials evaluating the outcomes of ERT. Data are often derived from observational, registry-based studies and case reports. Pooled analysis of data from different sources may be limited by the heterogeneity of the patient populations, outcomes and treatment. Therefore, comprehensive systematic literature reviews of unpooled data are needed to determine the effects of ERT on disease outcomes. A systematic literature search was conducted in the Embase and PubMed (MEDLINE) databases to retrieve original articles that evaluated outcomes of ERT in patients with Fabry disease; the outcome data were analysed unpooled. The literature analysis included the full range of published literature including observational studies and case series/case reports. Considerable heterogeneity was found among the studies, with differences in sample size, statistical methods, ERT regimens and patient demographic and clinical characteristics. We have demonstrated the value of performing an unpooled systematic literature review of all published evidence of ERT outcomes in Fabry disease, highlighting that in a rare genetic disorder like Fabry disease, which is phenotypically diverse, different patient populations can require different disease management and therapeutic goals depending on age, genotype, and disease severity/level of organ involvement. In addition, these findings are valuable to guide the design and reporting of new clinical studies., (Copyright © 2019. Published by Elsevier Masson SAS.)
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- 2019
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45. Efficacy of the pharmacologic chaperone migalastat in a subset of male patients with the classic phenotype of Fabry disease and migalastat-amenable variants: data from the phase 3 randomized, multicenter, double-blind clinical trial and extension study.
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Germain DP, Nicholls K, Giugliani R, Bichet DG, Hughes DA, Barisoni LM, Colvin RB, Jennette JC, Skuban N, Castelli JP, Benjamin E, Barth JA, and Viereck C
- Subjects
- 1-Deoxynojirimycin administration & dosage, 1-Deoxynojirimycin adverse effects, Adolescent, Adult, Double-Blind Method, Fabry Disease genetics, Fabry Disease pathology, Female, Genetic Variation genetics, Glomerular Filtration Rate genetics, Humans, Kidney pathology, Leukocytes, Mononuclear, Male, Middle Aged, Mutation, Pharmacogenetics, Young Adult, 1-Deoxynojirimycin analogs & derivatives, Fabry Disease drug therapy, Precision Medicine, alpha-Galactosidase genetics
- Abstract
Purpose: Outcomes in patients with Fabry disease receiving migalastat during the phase 3 FACETS trial (NCT00925301) were evaluated by phenotype., Methods: Data were evaluated in two subgroups of patients with migalastat-amenable GLA variants: "classic phenotype" (n = 14; males with residual peripheral blood mononuclear cell α-galactosidase A <3% normal and multiorgan system involvement) and "other patients" (n = 36; males not meeting classic phenotype criteria and all females). Endpoints included estimated glomerular filtration rate (eGFR), left ventricular mass index (LVMi), Gastrointestinal Symptoms Rating Scale diarrhea subscale (GSRS-D), renal peritubular capillary (PTC) globotriaosylceramide (GL-3) inclusions, and plasma globotriaosylsphingosine (lyso-Gb
3 )., Results: Baseline measures in the classic phenotype patients suggested a more severe phenotype. At month 24, mean (SD) annualized change in eGFRCKD-EPI with migalastat was -0.3 (3.76) mL/min/1.73 m2 in the classic phenotype subgroup; changes in LVMi, GSRS-D, and lyso-Gb3 were -16.7 (18.64) g/m2 , -0.9 (1.66), and -36.8 (35.78) nmol/L, respectively. At month 6, mean PTC GL-3 inclusions decreased with migalastat (-0.8) and increased with placebo (0.3); switching from placebo to migalastat, PTC inclusions decreased by -0.7. Numerically smaller changes in these endpoints were observed in the other patients., Conclusion: Migalastat provided clinical benefit to patients with Fabry disease and amenable variants, regardless of disease severity.- Published
- 2019
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46. Atypical COL3A1 variants (glutamic acid to lysine) cause vascular Ehlers-Danlos syndrome with a consistent phenotype of tissue fragility and skin hyperextensibility.
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Ghali N, Baker D, Brady AF, Burrows N, Cervi E, Cilliers D, Frank M, Germain DP, Hulmes DJS, Jacquemont ML, Kannu P, Lefroy H, Legrand A, Pope FM, Robertson L, Vandersteen A, von Klemperer K, Warburton R, Whiteford M, and van Dijk FS
- Subjects
- Adult, Aged, Ehlers-Danlos Syndrome classification, Ehlers-Danlos Syndrome pathology, Female, Glutamic Acid genetics, Glycine genetics, High-Throughput Nucleotide Sequencing, Humans, Lysine genetics, Male, Middle Aged, Mutation, Pedigree, Phenotype, Skin Abnormalities pathology, Collagen Type III genetics, Ehlers-Danlos Syndrome genetics, Skin Abnormalities genetics
- Abstract
Purpose: The Ehlers-Danlos syndromes (EDS) are a group of rare inherited connective tissue disorders. Vascular EDS (vEDS) is caused by pathogenic variants in COL3A1, most frequently glycine substitutions. We describe the phenotype of the largest series of vEDS patients with glutamic acid to lysine substitutions (Glu>Lys) in COL3A1, which were all previously considered to be variants of unknown significance., Methods: Clinical and molecular data for seven families with three different Glu>Lys substitutions in COL3A1 were analyzed., Results: These Glu>Lys variants were reclassified from variants of unknown significance to either pathogenic or likely pathogenic in accordance with American College of Medical Genetics and Genomics guidelines. All individuals with these atypical variants exhibited skin hyperextensibility as seen in individuals with classical EDS and classical-like EDS and evidence of tissue fragility as seen in individuals with vEDS., Conclusion: The clinical data demonstrate the overlap between the different EDS subtypes and underline the importance of next-generation sequencing gene panel analysis. The three different Glu>Lys variants point toward a new variant type in COL3A1 causative of vEDS, which has consistent clinical features. This is important knowledge for COL3A1 variant interpretation. Further follow-up data are required to establish the severity of tissue fragility complications compared with patients with other recognized molecular causes of vEDS.
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- 2019
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47. Consensus recommendations for diagnosis, management and treatment of Fabry disease in paediatric patients.
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Germain DP, Fouilhoux A, Decramer S, Tardieu M, Pillet P, Fila M, Rivera S, Deschênes G, and Lacombe D
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- Age Factors, Age of Onset, Child, Child, Preschool, Clinical Decision-Making, Combined Modality Therapy, Disease Management, Enzyme Replacement Therapy, Fabry Disease epidemiology, Humans, Monitoring, Physiologic, Phenotype, Symptom Assessment, Consensus, Fabry Disease diagnosis, Fabry Disease therapy, Practice Guidelines as Topic
- Abstract
Fabry disease (FD), a rare X-linked disease, can be treated with bi-monthly infusion of enzyme replacement therapy (ERT) to replace deficient α-galactosidase A (AGAL-A). ERT reduces symptoms, improves quality of life (QoL), and improves clinical signs and biochemical markers. ERT initiation in childhood could slow or stop progressive organ damage. Preventative treatment of FD from childhood is thought to avoid organ damage in later life, prompting a French expert working group to collaborate and produce recommendations for treating and monitoring children with FD. Organ involvement should be assessed by age 5 for asymptomatic boys (age 12-15 for asymptomatic girls), and immediately for children diagnosed via symptoms. The renal, cardiac, nervous and gastrointestinal systems should be assessed, as well as bone, skin, eyes, hearing, and QoL. The plasma biomarker globotriaosylsphingosine is also useful. ERT should be considered for symptomatic boys and girls with neuropathic pain, pathological albuminuria (≥3 mg/mmol creatinine), severe GI involvement and abdominal pain or cardiac involvement. ERT should be considered for asymptomatic boys from the age of 7. Organ involvement should be treated as needed. Early diagnosis and management of FD represents a promising strategy to reduce organ damage, morbidity and premature mortality in adulthood., (© 2019 The Authors. Clinical Genetics published by John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2019
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48. Response to Gurevich and colleagues: The effect of enzyme replacement therapy on clinical outcomes in male patients with Fabry disease: a systematic literature review by a European panel of experts.
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Germain DP, Falissard B, Hilz MJ, Spada M, Wanner C, and Elliott PM
- Abstract
Competing Interests: D.P. Germain is a consultant for Amicus Therapeutics, Sanofi Genzyme and Takeda, and has received speaker honoraria from Amicus Therapeutics, Sanofi Genzyme and Takeda. B. Falissard has been a consultant for Actelion, Allergan, Almirall, Astellas, AstraZeneca, Bayer, Biotronik, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly and Company, Gilead Sciences, GlaxoSmithKline, Grünenthal, HRA Pharma, Janssen, Lundbeck, MSD, Novartis, Otsuka, Pierre Fabre, Roche, Sanofi, Sanofi Genzyme, Servier, Stallergene, UCB Pharmaceuticals and ViiV Healthcare. M.J. Hilz has received research/grant support from Bayer Health Care and Novartis Pharma, and has received speaker honoraria and travel support from Sanofi Genzyme. M. Spada has received speaker and advisory board honoraria and travel support from Sanofi Genzyme and Takeda. C. Wanner has received research support from Sanofi Genzyme, is a consultant for Actelion Pharmaceuticals, Protalix, Boehringer Ingelheim and Sanofi Genzyme, and is a member of the European Advisory Board of the Fabry Registry. P.M. Elliott has received speaker honoraria from Takeda, and has received consultancy and speaker honoraria from Gilead Sciences, MyoKardia, Pfizer and Sanofi Genzyme.
- Published
- 2019
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49. Semen and male genital tract characteristics of patients with Fabry disease: the FERTIFABRY multicentre observational study.
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Papaxanthos-Roche A, Maillard A, Chansel-Debordeaux L, Albert M, Patrat C, Lidove O, Germain DP, Perez P, and Lacombe D
- Abstract
Background: Fabry disease (FD) is a rare disorder caused by the deficient activity of α-galactosidase A (α-Gal A). This enzymatic deficit results in the cellular accumulation of globotriaosylceramide (GL-3 or Gb
3 ) and related glycosphingolipids in practically all organs and tissues in the body. The identification of deposits of Gb3 at the reproductive tract level suggests that this part of the body might be involved. We undertook this study to assess the impact of Fabry disease in male gonadal function., Materials and Methods: This was a multicentre cross-sectional, prospective study that included patients aged 18 to 65 years with Fabry disease, receiving care in a specialized institution. The prevalence of at least one abnormal category in the semen analysis was presented with 95% confidence intervals (CI). The association between infertility and semen analysis abnormality was assessed by Fisher's exact test. The association of factors associated with fertility or semen analysis abnormality were analysed by a multivariable logistic regression model and expressed by an odds ratio (OR) and its bilateral 95% CI., Results: Overall, 14 (82.4% [95% CI, 56.6-96.2]) of the patients had at least one abnormal category in the semen analysis based on WHO criteria. Sixteen patients responded to the questionnaire on fertility, 11 of whom were classified as fertile. Nine of the 11 fertile patients presented at least one abnormal category in the semen analysis. No association was found between infertility and semen analysis abnormality ( p = 1.0000). Age of patient at inclusion (OR, 1.19; 95% CI, 0.98 to 1.45; p = 0.0854) and duration of replacement therapy (OR, 1.28; 95% CI, 0.96 to 1.65; p = 0.1263) were associated with sperm abnormalities. Eleven of the 16 patients had a normal hormonal profile. An ultrasound anomaly of the genital tract was observed in 12 patients., Conclusions: These results suggest that, while FD might have a detrimental effect on the semen characteristics, the reproductive function diminished only slightly. Further studies are warranted to assess the impact of the disease and of sperm abnormalities in the fertility of male patients with FD., Competing Interests: The study was approved by the Interregional ethics committee SOOM III (N° 2008- AO1307–48). Before enrolment, all patients gave informed consent.Not applicable.OL: Travel fees and speaker honorarium from Amicus, Sanofi-Genzyme and Shire HGT. DPG: Research grants, travel fees and speaker honoraria from Amicus, Sanofi-Genzyme and Shire HGT.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.- Published
- 2019
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50. Fabry disease in cardiology practice: Literature review and expert point of view.
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Hagège A, Réant P, Habib G, Damy T, Barone-Rochette G, Soulat G, Donal E, and Germain DP
- Subjects
- Adult, Aged, Cardiomyopathy, Hypertrophic diagnosis, Diagnosis, Differential, Echocardiography, Electrocardiography, Enzyme Replacement Therapy, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Predictive Value of Tests, Prognosis, Risk Factors, Ventricular Function, Left, Ventricular Remodeling, Cardiology, Fabry Disease diagnosis, Fabry Disease mortality, Fabry Disease physiopathology, Fabry Disease therapy, Hypertrophy, Left Ventricular diagnosis, Hypertrophy, Left Ventricular mortality, Hypertrophy, Left Ventricular physiopathology, Hypertrophy, Left Ventricular therapy
- Abstract
Fabry disease is an X-linked progressive multisystemic genetic sphingolipidosis caused by deficient activity of lysosomal α-galactosidase A. Men aged>30 years and women aged>40 years most often present with unexplained left ventricular hypertrophy, usually concentric and non-obstructive, but sometimes mimicking sarcomeric hypertrophic cardiomyopathy, particularly when isolated, as in the cardiac or late-onset variant of the disease. In hypertrophic cardiomyopathy cohorts, up to 1% of patients have been diagnosed with Fabry disease. Frequent cardiac symptoms include chronotropic incompetence, severe conduction disturbances and arrhythmias, heart failure and sudden death, and cardiovascular complications are currently the leading cause of death at a mean age of 55 years in men and 66 years in women. Complementary to screening for extracardiac manifestations, the initial cardiac evaluation should include long-duration electrocardiogram recordings, echocardiography and late gadolinium and T1 mapping magnetic resonance imaging. Abnormalities of a non-hypertrophied inferolateral wall at the base of the left ventricle (thinning, decreased strain, midwall fibrosis) and low native T1 signal on magnetic resonance imaging are evocative. Aggressive cardiac management may include the control of cardiovascular risk factors, anticoagulation, permanent cardiac pacing and/or an implantable cardioverter defibrillator device, while antiarrhythmics and beta-blockers should be used with caution. Specific therapy should be initiated at the earliest stage, when the first structural or functional cardiac abnormalities are detected, and should include enzyme replacement therapy (available since 2001) or chaperone therapy (available since 2016) (the use of which is limited to patients with Fabry disease and an amenable α-galactosidase A [GLA] gene mutation)., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)
- Published
- 2019
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