Genetic insights and therapeutic implications in Egyptian patients with Fabry Disease

BackgroundFabry disease (FD) is an X-linked lysosomal storage disorder resulting from pathogenic variants in the α-galactosidase (GLA) gene, leading to deficiency in “α-galactosidase A” (GLA) activity. This enzyme deficiency leads to progressive accumulation of glycosphingolipids in various tissues and organs. ObjectivesThis study aims to clinical, biochemical, and molecular diagnosis for three unrelated Egyptian families with Fabry disease.Patients and methods The GLA enzyme activity was measured in 3 males from 3 unrelated families. The GLA activity was measured by using the fluorogenic substrate “4-methylumbelliferyl-α-D-galactopyranoside” and the diagnosis of FD was established by GLA deficiency. The patients presented with variable renal, cardiac, ocular and dermatological manifestations. History and pedigree was done for 3 families. Molecular analysis of GLA gene was performed for 3 patients, the mother, two daughters and the sister of P1, the mother, wife and daughter of P2, and the mother, brother, and cousin of P3. Genetic tests by PCR of the gene-coding region followed by Sanger sequencing. Results We revealed 3 previously reported GLA variants in 3 Fabry families. Family 1, a nonsense variant c.627G>A, p.W209* was identified in patient 1 and in one of the patient’s daughters. In Family 2, a splice-site variant c.370-2A>G was detected in patient 2 and in his mother and daughter. In Family 3, a missense variant c.334C>T, p.R112C was detected in patient 3.Conclusion This study expands the molecular genetic spectrum of the GLA gene associated with Egyptian FD patients. Our findings highlighted the importance of early diagnosis, proper genetic counseling and therapy for FD patients. To the best of our knowledge, the present study is the first delineating the GLA variant profile in Egyptian FD patients. The patients are currently receiving Enzyme Replacement Therapy (ERT) at National Research Centre (NRC).