Valentina Favalli1, Eliana Disabella1, Mariadelfina Molinaro2, Marilena Tagliani1, Anna Scarabotto1, Alessandra Serio1, Maurizia Grasso1, Nupoor Narula3, Carmela Giorgianni1, Clelia Caspani1, Monica Concardi1, Manuela Agozzino1, Calogero Giordano1, Alexandra Smirnova1, Takahide Kodama4, Lorenzo Giuliani1, Elena Antoniazzi5, Riccardo G Borroni6, Camilla Vassallo7, Filippo Mangione8, Laura Scelsi9, Stefano Ghio9, Carlo Pellegrini10, Marialuisa Zedde11, Laura Fancellu12, GianPietro Sechi12, Antonello Ganau13, Stefania Piga13, Annarita Colucci14, Daniela Concolino15, Maria Teresa Di Mascio16, Danilo Toni16, Marina Diomedi17, Claudio Rapezzi18, Elena Biagini18, Massimiliano Marini19, Maurizia Rasura20, Maurizio Melis21, Antonia Nucera22, Donata Guidetti23, Michelangelo Mancuso24, Umberto Scoditti25, Pamela Cassini1, Jagat Narula26, Luigi Tavazzi27, Eloisa Arbustini28. 1. Center for Inherited Cardiovascular Diseases, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Foundation University Hospital Policlinico San Matteo, Pavia, Italy. 2. Pharmacokinetics, IRCCS Foundation University Hospital Policlinico San Matteo, Pavia, Italy. 3. Center for Inherited Cardiovascular Diseases, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Foundation University Hospital Policlinico San Matteo, Pavia, Italy; Internal Medicine, Mayo Clinic, Rochester, Minnesota. 4. Center for Inherited Cardiovascular Diseases, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Foundation University Hospital Policlinico San Matteo, Pavia, Italy; Cardiovascular Center, Toranomon Hospital, Tokyo, Japan. 5. Ophthalmology, IRCCS Foundation University Hospital Policlinico San Matteo, Pavia, Italy. 6. Center for Inherited Cardiovascular Diseases, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Foundation University Hospital Policlinico San Matteo, Pavia, Italy; Dermatology, IRCCS Foundation University Hospital Policlinico San Matteo, Pavia, Italy. 7. Dermatology, IRCCS Foundation University Hospital Policlinico San Matteo, Pavia, Italy. 8. Nephrology, IRCCS Foundation University Hospital Policlinico San Matteo, Pavia, Italy. 9. Cardiology, IRCCS Foundation University Hospital Policlinico San Matteo, Pavia, Italy. 10. Cardiac Surgery, IRCCS Foundation University Hospital Policlinico San Matteo, Pavia, Italy. 11. Neurology Unit, IRCCS-Arcispedale Santa Maria Nuova, Reggio Emilia, Italy. 12. Neurosciences, Neurological Clinic, University of Sassari, Sassari, Italy. 13. Clinical and Experimental Medicine, University of Sassari, Sassari, Italy. 14. Medical Genetics, Azienda Ospedaliera di Rilievo Nazionale San G. Moscati, Avellino, Italy. 15. Pediatrics, University Magna Graecia, Catanzaro, Italy. 16. Neurology and Psychiatry, Sapienza University, Roma, Italy. 17. Stroke Unit, Policlinico Tor Vergata, Roma, Italy. 18. Cardiology, Dipartimento di Medicina Diagnostica e Sperimentale, University of Bologna, Italy. 19. Cardiology, Santa Chiara Hospital, Trento, Italy. 20. Stroke Unit, Azienda Ospedaliera Sant'Andrea, Roma, Italy. 21. Stroke Unit, Azienda Ospedaliera G. Brotzu, Cagliari, Italy. 22. Stroke Unit, Neurology, Saint Andrea Hospital, La Spezia, Italy; Department of Clinical Neurological Sciences, Western University, London, Ontario, Canada. 23. Neurology, Guglielmo da Saliceto Hospital, Piacenza, Italy. 24. Neurological Institute, University of Pisa, Pisa, Italy. 25. Neurological Institute, University of Parma, Parma, Italy. 26. Icahn School of Medicine at Mount Sinai, New York, New York. 27. Scientific Directorate, Maria Cecilia Hospital, Gruppo Villa Maria Care and Research, Ettore Sansavini Health Science Foundation, Cotignola, Italy. 28. Center for Inherited Cardiovascular Diseases, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Foundation University Hospital Policlinico San Matteo, Pavia, Italy. Electronic address: e.arbustini@smatteo.pv.it.
Abstract
BACKGROUND: Anderson-Fabry disease (AFD) is a rare X-linked lysosomal storage disease, caused by defects of the alpha-galactosidase A (GLA) gene. AFD can affect the heart, brain, kidney, eye, skin, peripheral nerves, and gastrointestinal tract. Cardiology (hypertrophic cardiomyopathy), neurology (cryptogenic stroke), and nephrology (end-stage renal failure) screening studies suggest the prevalence of GLA variants is 0.62%, with diagnosis confirmation in 0.12%. OBJECTIVES: This study sought to expand screening from these settings to include ophthalmology, dermatology, gastroenterology, internal medicine, pediatrics, and medical genetics to increase diagnostic yield and comprehensively evaluate organ involvement in AFD patients. METHODS: In a 10-year prospective multidisciplinary, multicenter study, we expanded clinical, genetic, and biochemical screening to consecutive patients enrolled from all aforementioned clinical settings. We tested the GLA gene and α-galactosidase A activity in plasma and leukocytes. Inclusion criteria comprised phenotypical traits and absence of male-to-male transmission. Screening was extended to relatives of probands harboring GLA mutations. RESULTS: Of 2,034 probands fulfilling inclusion criteria, 37 (1.8%) were carriers of GLA mutations. Cascade family screening identified 60 affected relatives; clinical data were available for 4 affected obligate carriers. Activity of α-galactosidase A in plasma and leukocytes was diagnostic in male subjects, but not in female subjects. Of the 101 family members harboring mutations, 86 were affected, 10 were young healthy carriers, and 5 refused clinical evaluation. In the 86 patients, involved organs or organ systems included the heart (69%), peripheral nerves (46%), kidney (45%), eye (37%), brain (34%), skin (32%), gastrointestinal tract (31%), and auditory system (19%). Globotriaosylceramide accumulated in organ-specific and non-organ-specific cells in atypical and classic variants, respectively. CONCLUSIONS: Screening probands with clinically suspected AFD significantly increased diagnostic yield. The heart was the organ most commonly involved, independent of the clinical setting in which the patient was first evaluated.
BACKGROUND:Anderson-Fabry disease (AFD) is a rare X-linked lysosomal storage disease, caused by defects of the alpha-galactosidase A (GLA) gene. AFD can affect the heart, brain, kidney, eye, skin, peripheral nerves, and gastrointestinal tract. Cardiology (hypertrophic cardiomyopathy), neurology (cryptogenic stroke), and nephrology (end-stage renal failure) screening studies suggest the prevalence of GLA variants is 0.62%, with diagnosis confirmation in 0.12%. OBJECTIVES: This study sought to expand screening from these settings to include ophthalmology, dermatology, gastroenterology, internal medicine, pediatrics, and medical genetics to increase diagnostic yield and comprehensively evaluate organ involvement in AFDpatients. METHODS: In a 10-year prospective multidisciplinary, multicenter study, we expanded clinical, genetic, and biochemical screening to consecutive patients enrolled from all aforementioned clinical settings. We tested the GLA gene and α-galactosidase A activity in plasma and leukocytes. Inclusion criteria comprised phenotypical traits and absence of male-to-male transmission. Screening was extended to relatives of probands harboring GLA mutations. RESULTS: Of 2,034 probands fulfilling inclusion criteria, 37 (1.8%) were carriers of GLA mutations. Cascade family screening identified 60 affected relatives; clinical data were available for 4 affected obligate carriers. Activity of α-galactosidase A in plasma and leukocytes was diagnostic in male subjects, but not in female subjects. Of the 101 family members harboring mutations, 86 were affected, 10 were young healthy carriers, and 5 refused clinical evaluation. In the 86 patients, involved organs or organ systems included the heart (69%), peripheral nerves (46%), kidney (45%), eye (37%), brain (34%), skin (32%), gastrointestinal tract (31%), and auditory system (19%). Globotriaosylceramide accumulated in organ-specific and non-organ-specific cells in atypical and classic variants, respectively. CONCLUSIONS: Screening probands with clinically suspected AFD significantly increased diagnostic yield. The heart was the organ most commonly involved, independent of the clinical setting in which the patient was first evaluated.
Authors: Antoine Bondue; Eloisa Arbustini; Anna Bianco; Michele Ciccarelli; Dana Dawson; Matteo De Rosa; Nazha Hamdani; Denise Hilfiker-Kleiner; Benjamin Meder; Adelino F Leite-Moreira; Thomas Thum; Carlo G Tocchetti; Gilda Varricchi; Jolanda Van der Velden; Roddy Walsh; Stephane Heymans Journal: Cardiovasc Res Date: 2018-08-01 Impact factor: 10.787
Authors: Krista L Lentine; Bertram L Kasiske; Andrew S Levey; Patricia L Adams; Josefina Alberú; Mohamed A Bakr; Lorenzo Gallon; Catherine A Garvey; Sandeep Guleria; Philip Kam-Tao Li; Dorry L Segev; Sandra J Taler; Kazunari Tanabe; Linda Wright; Martin G Zeier; Michael Cheung; Amit X Garg Journal: Transplantation Date: 2017-08 Impact factor: 4.939