Genetic Screening of Anderson-Fabry Disease in Probands Referred From Multispecialty Clinics
Valentina Favalli1, Eliana Disabella1, Mariadelfina Molinaro2
1Center for Inherited Cardiovascular Diseases, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Foundation University Hospital Policlinico San Matteo, Pavia, Italy.
Insights
Expanding screening for Anderson-Fabry disease (AFD) to more specialties increased diagnosis rates. The heart is the most commonly affected organ in patients with GLA mutations, regardless of initial clinical evaluation.
Area of Science:
- Genetics
- Biochemistry
- Rare Diseases
Background:
- Anderson-Fabry disease (AFD) is a rare X-linked lysosomal storage disorder caused by alpha-galactosidase A (GLA) gene defects.
- AFD affects multiple organs including the heart, brain, kidneys, eyes, skin, nerves, and gastrointestinal tract.
- Previous screening in cardiology, neurology, and nephrology suggested a prevalence of GLA variants at 0.62%.
Purpose of the Study:
- To broaden screening for AFD beyond cardiology, neurology, and nephrology to include ophthalmology, dermatology, gastroenterology, internal medicine, pediatrics, and medical genetics.
- To enhance diagnostic yield for AFD.
- To comprehensively evaluate organ involvement in AFD patients.
Main Methods:
- A 10-year prospective, multidisciplinary, multicenter study involving expanded clinical, genetic, and biochemical screening.
- Testing of the GLA gene and alpha-galactosidase A activity in plasma and leukocytes.
- Inclusion criteria included phenotypical traits and absence of male-to-male transmission; cascade family screening was also performed.
Main Results:
- Out of 2,034 probands screened, 37 (1.8%) carried GLA mutations. Cascade screening identified 60 additional affected relatives.
- Alpha-galactosidase A activity was diagnostic in males but not females.
- In 86 affected patients, the heart was most commonly involved (69%), followed by peripheral nerves (46%), kidneys (45%), eyes (37%), brain (34%), skin (32%), and gastrointestinal tract (31%).
Conclusions:
- Screening probands with clinically suspected AFD significantly increased the diagnostic yield.
- The heart is the most frequently affected organ in AFD, irrespective of the initial clinical setting.
- Expanded screening protocols are effective in identifying more AFD cases and understanding organ involvement.
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.
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