#4973 PATHOGENIC ROLE OF D313Y MUTATION IN FABRY DISEASE

Abstract

Abstract Background and Aims Fabry disease (FD) is a multisystem lysosomal storage disorder caused by mutations in the GLA gene. The significance of the mutation p.D313Y in the GLA gene is under debate. Our aim is to evaluated the pathogenic role of the D313Y. Method For clinical FD phenotype a 60-year-old woman (index case) with cadaveric donor renal transplantation and unknown cause of renal disease was undergoing genetic investigation. She reported D313Y as single variant in the GLA gene. A prospective analysis of clinical manifestation, genetic and biochemical (lyso-GB3 and enzyme activity) data was performed in all her brothers, sisters and sons. Data were assessed as part of routine follow-up visits. Results Genotype information of our index case was: nucleotide change c.937G>T, exon 6 involved, amino acid change p.Asp313Tyr, HGMD accession CM930335, mutation type missense. In our cohort comprising n.9 family members: n°5 (55%, n°3 females, n°3 males age range 45-60) had the p.D313Y mutation. In nobody the biomarker lyso-Gb3 was elevated. Two brothers (age range of 40-50 y) died for acute cardiovascular attack before genetic investivagation was performed. The 5 family members showed the following clinical features: 2 hypertension and cardiac hypertrophy (2M, 44/61y); our index case renal failure, LVH and bruning pains; 2F with burning pains (49/46y). Enzyme replacement therapy (ERT) was started in our index case. Annual routine visits are performed in the others. Conclusion D313Y mutation seems to correlate with clinically rilevant symptoms (mainly cardiovascular and renal) compatible with FD, also without lyso-Gb3 elevation. ERT might be considered as therapeutic option not only in patients with already organ involvement, but also in paucisymptomatic to prevent disease progression.