Genetic variants associated with Fabry disease progression despite enzyme replacement therapy

// Francesca Scionti 1, * , Maria Teresa Di Martino 1, * , Simona Sestito 2 , Angela Nicoletti 2 , Francesca Falvo 2 , Katia Roppa 2 , Mariamena Arbitrio 3 , Pietro Hiram Guzzi 4 , Giuseppe Agapito 4 , Antonio Pisani 5 , Eleonora Riccio 5 , Daniela Concolino 2, # and Licia Pensabene 2, # 1 Department of Experimental and Clinical Medicine, Magna Graecia University, Salvatore Venuta University Campus, Catanzaro, Italy 2 Department of Medical and Surgical Sciences Pediatric Unit, Magna Graecia University, Catanzaro, Italy 3 ISN-CNR, Roccelletta di Borgia, Catanzaro, Italy 4 Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy 5 Department of Nephrology, University Federico II, Naples, Italy * These authors contributed equally to the work # These authors contributed equally to this work and share senior authorship Correspondence to: Maria Teresa Di Martino, email: teresadm@unicz.it Licia Pensabene, email: pensabene@unicz.it Keywords: Fabry disease; enzyme replacement therapy; DMET; ADH genes; oxidative stress Received: August 24, 2017 Accepted: October 29, 2017 Published: November 18, 2017 ABSTRACT Enzyme replacement therapy (ERT) has been widely used for the treatment of Fabry disease, a rare X-linked recessive disorder due to absent or reduced activity of lysosomal enzyme α-galactosidase A. It is still unclear why some patients under ERT show disease progression typically with renal, cardiovascular and cerebrovascular dysfunctions. Here, we investigated the involvement of drug absorption, distribution, metabolism, and excretion gene variants in response variability to ERT, genotyping 37 patients with the Affymetrix Drug Metabolizing Enzyme and Transporters (DMET) Plus microarray. We found three single nucleotide polymorphisms in human alcohol dehydrogenase (ADH)4 gene (rs1126670, rs1126671, rs2032349) and one in ADH5 gene (rs2602836) associated with disease progression ( p < 0.05). Our data provide a basic tool for identification of patient with ERT non-response risk that may represent a framework for personalized treatment of this rare disease.