Prevalência e fatores associados a variantes do gene GLA (doença de Fabry): Screening nacional

Abstract

Introduction: Fabry disease (FD) is a genetic, chronic, progressive and multisystem pathology linked to the chromosome X. It is caused by variants in the gene GLA that causes enzyme Alpha Gal A absence or deficiency, leading to globotriaosylceramide (Gb3) accumulation. More than 1000 genetic variants causing FD have been described in the literature. Objectives: To determine the prevalence of Fabry disease in Brazilian population by a screening of dialysis patient population and their families. Characterize the variants and the study population, considering the demographic and clinical variables present in the screening questionnaire and in the clinical report of patients submitted to genotyping test. Evaluate associations between Fabry disease genotype and phenotype (demographic, clinical and diagnostic variables, and levels of Alpha Gal A activity and Lyso-Gb3). Method: This is a cross-sectional study with secondary data, from 854 dialysis centers in Brazil, collected from June 2013 to November 2019. A total of 75059 patients and DF patient’s family members were analyzed. All data collected were included into a database. An algorithm was created to classify dialysis patients in suspected of FD, non-suspected or pending analysis patients. These pending analysis patients were analyzed by an expert to decide which group they would be include in, suspect or non-suspect. The suspect group consisted of 6,369 individuals who underwent the genotyping test. The other 68,690 did not undergo genetic testing, but had data on signs, symptoms and comorbidities collected. Results: Of the 75,059 individuals screened, 408 individuals had FD variants. The screened population was 58.4% men, and the variant positive population was 64.2% women. Regarding the age group, the screened population had an average age of 59.5 years, and the positive variant an average of 42.7 years. In the evaluation of clinical data, SAH was the most frequent comorbidity both in screened individuals (79.39%) and in those with variants (17.89%). The Southeast region of Brazil was the one that most screened 51.5% and diagnosed 79.7% patients. We found 47 different variants, with c.352C>T p.Arg118Cys being the most frequent (23.3%) with predominant location in the exon. The heterozygous variant was more prevalent. Alfa Gal A activity was altered in 90% of the dosages while Lyso-Gb3 levels were altered in 27.5%. The most prevalent signs and symptoms were peripheric neurological disorders and gastrointestinal disorders. Conclusion: This is the first nationwide Brazilian screening study to include men and women and also map the exon-intron junction. The prevalence in the general population studied (75,059) was 0.54%. Considering the population that underwent genetic testing (6,369) it was 6.40%. The mean age of FD population was 42.7 years. FD was more frequent in women. Five variants were highly frequent among mutated patients, the most frequent being c.352C>T p.Arg118Cys (24.8%). There was a genotype/phenotype association in relation to cardiac and neurological symptoms. We found statistically significant difference when comparing patients whit and without the variant in terms of Alpha-Gal A, Lyso-Gb3 levels and the presence of renal symptoms. The typical signs of FD (angiokeratoma and whorled cornea) were rare in the analyzed population.