Wladimir Mauhin1,2, Olivier Benveniste2,3, Damien Amelin2, Clémence Montagner1, Foudil Lamari4,5, Catherine Caillaud6,7, Claire Douillard8, Bertrand Dussol9,10, Vanessa Leguy-Seguin11, Pauline D'Halluin12, Esther Noel13, Thierry Zenone14, Marie Matignon15,16, François Maillot17,18, Kim-Heang Ly19, Gérard Besson20, Marjolaine Willems21, Fabien Labombarda22, Agathe Masseau23, Christian Lavigne24, Didier Lacombe25,26, Hélène Maillard27, Olivier Lidove1,2. 1. Internal Medicine Department, Reference Center for Lysosomal Storage Disorders, Groupe Hospitalier Diaconesses Croix Saint-Simon, Paris, France. 2. UMRS 974, INSERM, Sorbonne Université, Paris, France. 3. Internal Medicine Department, Pitié Salpêtrière University Hospital, Assistance Publique Hôpitaux de Paris, Paris, France. 4. Metabolic Biochemistry Department, Pitié Salpêtrière University Hospital, Assistance Publique Hôpitaux de Paris, Paris, France. 5. Groupe de Recherche Clinique 13 Neurométabolisme, Sorbonne Université, Paris, France. 6. Biochemistry, Metabolomic and Proteomic Department, Necker Enfants Malades University Hospital, Assistance Publique Hôpitaux de Paris, Paris, France. 7. UMRS 1151, INSERM, Institute Necker Enfants Malades, Paris Descartes University, Paris, France. 8. Reference Center for Inborn Metabolic Diseases, Jeanne de Flandres Hospital, Lille, France. 9. Nephrology Department, Assistance Publique Hôpitaux de Marseille, Marseille, France. 10. Centre d'Investigation Clinique 1409, INSERM, Aix Marseille Université, Marseille, France. 11. Internal Medicine and Clinical Immunology Department, Francois Mitterrand Hospital, Dijon, France. 12. Nephrology and Haemodialysis Department, Centre Hospitalier Côte Basque, Bayonne, France. 13. Internal Medicine Department, Strasbourg University Hospital, Strasbourg, France. 14. Internal Medicine Department, Valence Hospital, Valence, France. 15. Nephrology and Renal Transplantation Department, Institut Francilien de Recherche en Néphrologie et Transplantation (IFRNT), Henri-Mondor/Albert-Chenevier University Hospital, Assistance Publique Hôpitaux de Paris, Créteil, France. 16. UMRS 955, Institut Mondor de Recherche Biomédicale, INSERM, University of Paris-Est-Créteil, Créteil, France. 17. Internal Medicine Department, Tours University Hospital, Tours, France. 18. UMRS 1253, University of Tours, Tours, France. 19. Internal Medicine Department, Dupuytren University Hospital, Limoges, France. 20. Neurology Department, Grenoble University Hospital, Grenoble, France. 21. Medical Genetics and Rare Diseases Department, Montpellier University Hospital, Montpellier, France. 22. Cardiology Department, Caen University Hospital, Caen, France. 23. Internal Medicine Department, Hôtel-Dieu University Hospital, Nantes, France. 24. Internal Medicine and Vascular Diseases Department, Angers University Hospital, Angers, France. 25. Medical Genetics Department, Bordeaux University Hospital, Bordeaux, France. 26. INSERM U1211, Bordeaux University, Bordeaux, France. 27. Internal Medicine Department, Huriez Hospital, University of Lille, Lille, France.
Abstract
BACKGROUD: Fabry disease (OMIM #301 500), the most prevalent lysosomal storage disease, is caused by enzymatic defects in alpha-galactosidase A (GLA gene; Xq22.1). Fabry disease has historically been characterized by progressive renal failure, early stroke and hypertrophic cardiomyopathy, with a diminished life expectancy. A nonclassical phenotype has been described with an almost exclusive cardiac involvement. Specific therapies with enzyme substitution or chaperone molecules are now available depending on the mutation carried. Numerous clinical and fundamental studies have been conducted without stratifying patients by phenotype or severity, despite different prognoses and possible different pathophysiologies. We aimed to identify a simple and clinically relevant way to classify and stratify patients according to their disease severity. METHODS: Based on data from the French Fabry Biobank and Registry (FFABRY; n = 104; 54 males), we applied unsupervised multivariate statistics to determine clusters of patients and identify clinical criteria that would allow an effective classification of adult patients. Thanks to these criteria and empirical clinical considerations we secondly elaborate a new score that allow the severity stratification of patients. RESULTS: We observed that the absence of acroparesthesia or cornea verticillata is sufficient to classify males as having the nonclassical phenotype. We did not identify criteria that significantly cluster female patients. The classical phenotype was associated with a higher risk of severe renal (HR = 35.1; p <10-3) and cardiac events (HR = 4.8; p = 0.008) and a trend toward a higher risk of severe neurological events (HR = 7.7; p = 0.08) compared to nonclassical males. Our simple, rapid and clinically-relevant FFABRY score gave concordant results with the validated MSSI. CONCLUSION: Acroparesthesia and cornea verticillata are simple clinical criteria that efficiently stratify Fabry patients, defining 3 different groups: females and males with nonclassical and classical phenotypes of significantly different severity. The FFABRY score allows severity stratification of Fabry patients.
BACKGROUD: Fabry disease (OMIM #301 500), the most prevalent lysosomal storage disease, is caused by enzymatic defects in alpha-galactosidase A (GLA gene; Xq22.1). Fabry disease has historically been characterized by progressive renal failure, early stroke and hypertrophic cardiomyopathy, with a diminished life expectancy. A nonclassical phenotype has been described with an almost exclusive cardiac involvement. Specific therapies with enzyme substitution or chaperone molecules are now available depending on the mutation carried. Numerous clinical and fundamental studies have been conducted without stratifying patients by phenotype or severity, despite different prognoses and possible different pathophysiologies. We aimed to identify a simple and clinically relevant way to classify and stratify patients according to their disease severity. METHODS: Based on data from the French Fabry Biobank and Registry (FFABRY; n = 104; 54 males), we applied unsupervised multivariate statistics to determine clusters of patients and identify clinical criteria that would allow an effective classification of adult patients. Thanks to these criteria and empirical clinical considerations we secondly elaborate a new score that allow the severity stratification of patients. RESULTS: We observed that the absence of acroparesthesia or cornea verticillata is sufficient to classify males as having the nonclassical phenotype. We did not identify criteria that significantly cluster female patients. The classical phenotype was associated with a higher risk of severe renal (HR = 35.1; p <10-3) and cardiac events (HR = 4.8; p = 0.008) and a trend toward a higher risk of severe neurological events (HR = 7.7; p = 0.08) compared to nonclassical males. Our simple, rapid and clinically-relevant FFABRY score gave concordant results with the validated MSSI. CONCLUSION:Acroparesthesia and cornea verticillata are simple clinical criteria that efficiently stratify Fabry patients, defining 3 different groups: females and males with nonclassical and classical phenotypes of significantly different severity. The FFABRY score allows severity stratification of Fabry patients.
Authors: Michael Beck; Uma Ramaswami; Elizabeth Hernberg-Ståhl; Derralynn A Hughes; Christoph Kampmann; Atul B Mehta; Kathleen Nicholls; Dau-Ming Niu; Guillem Pintos-Morell; Ricardo Reisin; Michael L West; Jörn Schenk; Christina Anagnostopoulou; Jaco Botha; Roberto Giugliani Journal: Orphanet J Rare Dis Date: 2022-06-20 Impact factor: 4.303