Genetic Screening of Anderson-Fabry Disease in Probands Referred From Multispecialty Clinics

Valentina Favalli, Eliana Disabella, Mariadelfina Molinaro, Marilena Tagliani, Anna Scarabotto, Alessandra Serio, Maurizia Grasso, Nupoor Narula, Carmela Giorgianni, Clelia Caspani, Monica Concardi, Manuela Agozzino, Calogero Giordano, Alexandra Smirnova, Takahide Kodama, Lorenzo Giuliani, Elena Antoniazzi, Riccardo G. Borroni, Camilla Vassallo, Filippo MangioneLaura Scelsi, Stefano Ghio, Carlo Pellegrini, Marialuisa Zedde, Laura Fancellu, Gian Pietro Sechi, Antonello Ganau, Stefania Piga, Annarita Colucci, Daniela Concolino, Maria Teresa Di Mascio, Danilo Toni, Marina Diomedi, Claudio Rapezzi, Elena Biagini, Massimiliano Marini, Maurizia Rasura, Maurizio Melis, Antonia Nucera, Donata Guidetti, Michelangelo Mancuso, Umberto Scoditti, Pamela Cassini, Jagat Narula, Luigi Tavazzi, Eloisa Arbustini

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1037-1050
Number of pages14
JournalJournal of the American College of Cardiology
Volume68
Issue number10
DOIs
Publication statusPublished - Sep 6 2016

Fingerprint

Galactosidases
Fabry Disease
Genetic Testing
Peripheral Nerves
Mutation
Gastrointestinal Tract
Leukocytes
Lysosomal Storage Diseases
alpha-Galactosidase
Kidney
Skin
Nephrology
Hypertrophic Cardiomyopathy
Medical Genetics
Brain
Gastroenterology
Ophthalmology
Neurology
Internal Medicine
Dermatology

Keywords

  • biochemical
  • family screening
  • GLA
  • MOGE(S) classification
  • multidisciplinary evaluation
  • α-Gal

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Genetic Screening of Anderson-Fabry Disease in Probands Referred From Multispecialty Clinics. / Favalli, Valentina; Disabella, Eliana; Molinaro, Mariadelfina; Tagliani, Marilena; Scarabotto, Anna; Serio, Alessandra; Grasso, Maurizia; Narula, Nupoor; Giorgianni, Carmela; Caspani, Clelia; Concardi, Monica; Agozzino, Manuela; Giordano, Calogero; Smirnova, Alexandra; Kodama, Takahide; Giuliani, Lorenzo; Antoniazzi, Elena; Borroni, Riccardo G.; Vassallo, Camilla; Mangione, Filippo; Scelsi, Laura; Ghio, Stefano; Pellegrini, Carlo; Zedde, Marialuisa; Fancellu, Laura; Sechi, Gian Pietro; Ganau, Antonello; Piga, Stefania; Colucci, Annarita; Concolino, Daniela; Di Mascio, Maria Teresa; Toni, Danilo; Diomedi, Marina; Rapezzi, Claudio; Biagini, Elena; Marini, Massimiliano; Rasura, Maurizia; Melis, Maurizio; Nucera, Antonia; Guidetti, Donata; Mancuso, Michelangelo; Scoditti, Umberto; Cassini, Pamela; Narula, Jagat; Tavazzi, Luigi; Arbustini, Eloisa.

In: Journal of the American College of Cardiology, Vol. 68, No. 10, 06.09.2016, p. 1037-1050.

Research output: Contribution to journalArticle

Favalli, V, Disabella, E, Molinaro, M, Tagliani, M, Scarabotto, A, Serio, A, Grasso, M, Narula, N, Giorgianni, C, Caspani, C, Concardi, M, Agozzino, M, Giordano, C, Smirnova, A, Kodama, T, Giuliani, L, Antoniazzi, E, Borroni, RG, Vassallo, C, Mangione, F, Scelsi, L, Ghio, S, Pellegrini, C, Zedde, M, Fancellu, L, Sechi, GP, Ganau, A, Piga, S, Colucci, A, Concolino, D, Di Mascio, MT, Toni, D, Diomedi, M, Rapezzi, C, Biagini, E, Marini, M, Rasura, M, Melis, M, Nucera, A, Guidetti, D, Mancuso, M, Scoditti, U, Cassini, P, Narula, J, Tavazzi, L & Arbustini, E 2016, 'Genetic Screening of Anderson-Fabry Disease in Probands Referred From Multispecialty Clinics', Journal of the American College of Cardiology, vol. 68, no. 10, pp. 1037-1050. https://doi.org/10.1016/j.jacc.2016.05.090
Favalli, Valentina ; Disabella, Eliana ; Molinaro, Mariadelfina ; Tagliani, Marilena ; Scarabotto, Anna ; Serio, Alessandra ; Grasso, Maurizia ; Narula, Nupoor ; Giorgianni, Carmela ; Caspani, Clelia ; Concardi, Monica ; Agozzino, Manuela ; Giordano, Calogero ; Smirnova, Alexandra ; Kodama, Takahide ; Giuliani, Lorenzo ; Antoniazzi, Elena ; Borroni, Riccardo G. ; Vassallo, Camilla ; Mangione, Filippo ; Scelsi, Laura ; Ghio, Stefano ; Pellegrini, Carlo ; Zedde, Marialuisa ; Fancellu, Laura ; Sechi, Gian Pietro ; Ganau, Antonello ; Piga, Stefania ; Colucci, Annarita ; Concolino, Daniela ; Di Mascio, Maria Teresa ; Toni, Danilo ; Diomedi, Marina ; Rapezzi, Claudio ; Biagini, Elena ; Marini, Massimiliano ; Rasura, Maurizia ; Melis, Maurizio ; Nucera, Antonia ; Guidetti, Donata ; Mancuso, Michelangelo ; Scoditti, Umberto ; Cassini, Pamela ; Narula, Jagat ; Tavazzi, Luigi ; Arbustini, Eloisa. / Genetic Screening of Anderson-Fabry Disease in Probands Referred From Multispecialty Clinics. In: Journal of the American College of Cardiology. 2016 ; Vol. 68, No. 10. pp. 1037-1050.
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TY - JOUR

T1 - Genetic Screening of Anderson-Fabry Disease in Probands Referred From Multispecialty Clinics

AU - Favalli, Valentina

AU - Disabella, Eliana

AU - Molinaro, Mariadelfina

AU - Tagliani, Marilena

AU - Scarabotto, Anna

AU - Serio, Alessandra

AU - Grasso, Maurizia

AU - Narula, Nupoor

AU - Giorgianni, Carmela

AU - Caspani, Clelia

AU - Concardi, Monica

AU - Agozzino, Manuela

AU - Giordano, Calogero

AU - Smirnova, Alexandra

AU - Kodama, Takahide

AU - Giuliani, Lorenzo

AU - Antoniazzi, Elena

AU - Borroni, Riccardo G.

AU - Vassallo, Camilla

AU - Mangione, Filippo

AU - Scelsi, Laura

AU - Ghio, Stefano

AU - Pellegrini, Carlo

AU - Zedde, Marialuisa

AU - Fancellu, Laura

AU - Sechi, Gian Pietro

AU - Ganau, Antonello

AU - Piga, Stefania

AU - Colucci, Annarita

AU - Concolino, Daniela

AU - Di Mascio, Maria Teresa

AU - Toni, Danilo

AU - Diomedi, Marina

AU - Rapezzi, Claudio

AU - Biagini, Elena

AU - Marini, Massimiliano

AU - Rasura, Maurizia

AU - Melis, Maurizio

AU - Nucera, Antonia

AU - Guidetti, Donata

AU - Mancuso, Michelangelo

AU - Scoditti, Umberto

AU - Cassini, Pamela

AU - Narula, Jagat

AU - Tavazzi, Luigi

AU - Arbustini, Eloisa

PY - 2016/9/6

Y1 - 2016/9/6

N2 - 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.

AB - 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.

KW - biochemical

KW - family screening

KW - GLA

KW - MOGE(S) classification

KW - multidisciplinary evaluation

KW - α-Gal

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