title: Genetic Screening of Anderson-Fabry Disease in Probands Referred From Multispecialty Clinics.
abstract: 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%.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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: Center for Inherited Cardiovascular Diseases, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Foundation University Hospital Policlinico San Matteo, Pavia, Italy.
authors: Valentina
authors: V
authors: Favalli
authors: Center for Inherited Cardiovascular Diseases, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Foundation University Hospital Policlinico San Matteo, Pavia, Italy.
authors: Eliana
authors: E
authors: Disabella
authors: Pharmacokinetics, IRCCS Foundation University Hospital Policlinico San Matteo, Pavia, Italy.
authors: Mariadelfina
authors: M
authors: Molinaro
authors: Center for Inherited Cardiovascular Diseases, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Foundation University Hospital Policlinico San Matteo, Pavia, Italy.
authors: Marilena
authors: M
authors: Tagliani
authors: Center for Inherited Cardiovascular Diseases, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Foundation University Hospital Policlinico San Matteo, Pavia, Italy.
authors: Anna
authors: A
authors: Scarabotto
authors: Center for Inherited Cardiovascular Diseases, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Foundation University Hospital Policlinico San Matteo, Pavia, Italy.
authors: Alessandra
authors: A
authors: Serio
authors: Center for Inherited Cardiovascular Diseases, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Foundation University Hospital Policlinico San Matteo, Pavia, Italy.
authors: Maurizia
authors: M
authors: Grasso
authors: 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.
authors: Nupoor
authors: N
authors: Narula
authors: Center for Inherited Cardiovascular Diseases, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Foundation University Hospital Policlinico San Matteo, Pavia, Italy.
authors: Carmela
authors: C
authors: Giorgianni
authors: Center for Inherited Cardiovascular Diseases, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Foundation University Hospital Policlinico San Matteo, Pavia, Italy.
authors: Clelia
authors: C
authors: Caspani
authors: Center for Inherited Cardiovascular Diseases, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Foundation University Hospital Policlinico San Matteo, Pavia, Italy.
authors: Monica
authors: M
authors: Concardi
authors: Center for Inherited Cardiovascular Diseases, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Foundation University Hospital Policlinico San Matteo, Pavia, Italy.
authors: Manuela
authors: M
authors: Agozzino
authors: Center for Inherited Cardiovascular Diseases, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Foundation University Hospital Policlinico San Matteo, Pavia, Italy.
authors: Calogero
authors: C
authors: Giordano
authors: Center for Inherited Cardiovascular Diseases, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Foundation University Hospital Policlinico San Matteo, Pavia, Italy.
authors: Alexandra
authors: A
authors: Smirnova
authors: 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.
authors: Takahide
authors: T
authors: Kodama
authors: Center for Inherited Cardiovascular Diseases, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Foundation University Hospital Policlinico San Matteo, Pavia, Italy.
authors: Lorenzo
authors: L
authors: Giuliani
authors: Ophthalmology, IRCCS Foundation University Hospital Policlinico San Matteo, Pavia, Italy.
authors: Elena
authors: E
authors: Antoniazzi
authors: 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.
authors: Riccardo G
authors: RG
authors: Borroni
authors: Dermatology, IRCCS Foundation University Hospital Policlinico San Matteo, Pavia, Italy.
authors: Camilla
authors: C
authors: Vassallo
authors: Nephrology, IRCCS Foundation University Hospital Policlinico San Matteo, Pavia, Italy.
authors: Filippo
authors: F
authors: Mangione
authors: Cardiology, IRCCS Foundation University Hospital Policlinico San Matteo, Pavia, Italy.
authors: Laura
authors: L
authors: Scelsi
authors: Cardiology, IRCCS Foundation University Hospital Policlinico San Matteo, Pavia, Italy.
authors: Stefano
authors: S
authors: Ghio
authors: Cardiac Surgery, IRCCS Foundation University Hospital Policlinico San Matteo, Pavia, Italy.
authors: Carlo
authors: C
authors: Pellegrini
authors: Neurology Unit, IRCCS-Arcispedale Santa Maria Nuova, Reggio Emilia, Italy.
authors: Marialuisa
authors: M
authors: Zedde
authors: Neurosciences, Neurological Clinic, University of Sassari, Sassari, Italy.
authors: Laura
authors: L
authors: Fancellu
authors: Neurosciences, Neurological Clinic, University of Sassari, Sassari, Italy.
authors: GianPietro
authors: G
authors: Sechi
authors: Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
authors: Antonello
authors: A
authors: Ganau
authors: Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
authors: Stefania
authors: S
authors: Piga
authors: Medical Genetics, Azienda Ospedaliera di Rilievo Nazionale San G. Moscati, Avellino, Italy.
authors: Annarita
authors: A
authors: Colucci
authors: Pediatrics, University Magna Graecia, Catanzaro, Italy.
authors: Daniela
authors: D
authors: Concolino
authors: Neurology and Psychiatry, Sapienza University, Roma, Italy.
authors: Maria Teresa
authors: MT
authors: Di Mascio
authors: Neurology and Psychiatry, Sapienza University, Roma, Italy.
authors: Danilo
authors: D
authors: Toni
authors: Stroke Unit, Policlinico Tor Vergata, Roma, Italy.
authors: Marina
authors: M
authors: Diomedi
authors: Cardiology, Dipartimento di Medicina Diagnostica e Sperimentale, University of Bologna, Italy.
authors: Claudio
authors: C
authors: Rapezzi
authors: Cardiology, Dipartimento di Medicina Diagnostica e Sperimentale, University of Bologna, Italy.
authors: Elena
authors: E
authors: Biagini
authors: Cardiology, Santa Chiara Hospital, Trento, Italy.
authors: Massimiliano
authors: M
authors: Marini
authors: Stroke Unit, Azienda Ospedaliera Sant'Andrea, Roma, Italy.
authors: Maurizia
authors: M
authors: Rasura
authors: Stroke Unit, Azienda Ospedaliera G. Brotzu, Cagliari, Italy.
authors: Maurizio
authors: M
authors: Melis
authors: Stroke Unit, Neurology, Saint Andrea Hospital, La Spezia, Italy; Department of Clinical Neurological Sciences, Western University, London, Ontario, Canada.
authors: Antonia
authors: A
authors: Nucera
authors: Neurology, Guglielmo da Saliceto Hospital, Piacenza, Italy.
authors: Donata
authors: D
authors: Guidetti
authors: Neurological Institute, University of Pisa, Pisa, Italy.
authors: Michelangelo
authors: M
authors: Mancuso
authors: Neurological Institute, University of Parma, Parma, Italy.
authors: Umberto
authors: U
authors: Scoditti
authors: Center for Inherited Cardiovascular Diseases, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Foundation University Hospital Policlinico San Matteo, Pavia, Italy.
authors: Pamela
authors: P
authors: Cassini
authors: Icahn School of Medicine at Mount Sinai, New York, New York.
authors: Jagat
authors: J
authors: Narula
authors: Scientific Directorate, Maria Cecilia Hospital, Gruppo Villa Maria Care and Research, Ettore Sansavini Health Science Foundation, Cotignola, Italy.
authors: Luigi
authors: L
authors: Tavazzi
authors: 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.
authors: Eloisa
authors: E
authors: Arbustini
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D000795:Fabry Disease / Q000175:diagnosis* / Q000235:genetics*; D005260:Female; D005820:Genetic Testing; D006761:Hospitals; D006801:Humans; D008297:Male; D008511:Medicine; D008875:Middle Aged; D009154:Mutation; D011446:Prospective Studies; D000519:alpha-Galactosidase / Q000235:genetics
chemical_list: D000519:alpha-Galactosidase
keywords: GLA; MOGE(S) classification; biochemical; family screening; multidisciplinary evaluation; α-Gal