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

详细信息    查看全文

• 作者：Valentina Favalli ; PhD^a ; Eliana Disabella ; BD^a ; Mariadelfina Molinaro ; BD^b ; Marilena Tagliani ; BD^a ; Anna Scarabotto ; BD^a ; Alessandra Serio ; MD^a ; Maurizia Grasso ; PhD^a ; Nupoor Narula ; MD^a ; ^c ; Carmela Giorgianni ; BS^a ; Clelia Caspani ; BD^a ; Monica Concardi ; BS^a ; Manuela Agozzino ; MD^a ; Calogero Giordano ; BD^a ; Alexandra Smirnova ; BD^a ; Takahide Kodama ; MD^a ; ^d ; Lorenzo Giuliani ; BS^a ; Elena Antoniazzi ; MD^e ; Riccardo G. Borroni ; MD^a ; ^f ; Camilla Vassallo ; MD^f ; Filippo Mangione ; MD^g ; Laura Scelsi ; MD^h ; Stefano Ghio ; MD^h ; Carlo Pellegrini ; MDⁱ ; Marialuisa Zedde ; MD^j ; Laura Fancellu ; MD^k ; GianPietro Sechi ; MD^k ; Antonello Ganau ; MD^l ; Stefania Piga ; MD^l ; Annarita Colucci ; MD^m ; Daniela Concolino ; MDⁿ ; Maria Teresa Di Mascio ; MD^o ; Danilo Toni ; MD^o ; Marina Diomedi ; MD^p ; Claudio Rapezzi ; MD^q ; Elena Biagini ; MD^q ; Massimiliano Marini ; MD^r ; Maurizia Rasura ; MD^s ; Maurizio Melis ; MD^t ; Antonia Nucera ; MD^u ; ^v ; Donata Guidetti ; MD^w ; Michelangelo Mancuso ; MD^x ; Umberto Scoditti ; MD^y ; Pamela Cassini ; BD^a ; Jagat Narula ; MD^z ; Luigi Tavazzi ; MD^aa ; Eloisa Arbustini ; MD^a ; ^{e.arbustini@smatteo.pv.it" class="auth_mail" title="E-mail the corresponding author}
• 关键词：α-Gal ; biochemical ; family screening ; GLA ; MOGE(S) classification ; multidisciplinary evaluation
• 刊名：Journal of the American College of Cardiology
• 出版年：2016
• 出版时间：6 September 2016
• 年：2016
• 卷：68
• 期：10
• 页码：1037-1050
• 全文大小：4481 K

文摘

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.