Contents lists available at ScienceDirect European Journal of Medical Genetics journal homepage: www.elsevier.com/locate/ejmg Fabry disease caused by the GLA p.Phe113Leu (p.F113L) variant: Natural history in males João P. Oliveira a,b,c,∗ , Albina Nowak d , Frédéric Barbey e , Márcia Torres f , José P. Nunes g , Fernando Teixeira-e-Costa h , Fernanda Carvalho i , Susana Sampaio j , Isabel Tavares j,k , Odete Pereira j , Ana L. Soares l , Cátia Carmona m , Maria-Teresa Cardoso n , Iulia E. Jurca-Simina o , Marco Spada p , Susana Ferreira b,c , Dominique P. Germain o a Service of Medical Genetics, São João University Hospital Center, 4200-319, Porto, Portugal b Unit of Genetics, Department of Pathology, Faculty of Medicine, University of Porto, 4200-319, Porto, Portugal c Institute for Research and Innovation in Health [Instituto de Investigação e Inovação em Saúde] – I3S, University of Porto, 4150-180, Porto, Portugal d Department of Endocrinology and Clinical Nutrition, University of Zurich, 8091, Zürich, Switzerland e Division of Genetic Medicine, Lausanne University Hospital, Lausanne, Switzerland f Service of Cardiology, Hospital of Santo Tirso, 4780-371, Santo Tirso, Portugal g Service of Cardiology, São João University Hospital Center, 4200-319, Porto, Portugal h Service of Nephrology, Garcia de Orta Hospital, 2805-267, Almada, Portugal i Unit of Renal Pathology, Service of Nephrology, Curry Cabral Hospital, 1069-166, Lisbon, Portugal j Service of Nephrology, São João University Hospital Center, 4200-319, Porto, Portugal k Uninefro, Santo Tirso Hemodialysis Clinic, 4780-383, Santo Tirso, Portugal l Vil’Alva Family Health Center, 4780-484, Santo Tirso, Portugal m Service of Neurology, Garcia de Orta Hospital, 2805-267, Almada, Portugal n Clinic for Adult Metabolic Diseases, Inherited Metabolic Diseases Reference Center, São João University Hospital Center, 4200-319, Porto, Portugal o Division of Medical Genetics, University of Versailles / Paris-Saclay University, 78180, Montigny, France p Clinic for Metabolic Diseases, Department of Pediatric Sciences, Regina Margherita Hospital, 10126, Turin, Italy ARTICLE INFO Keywords: Fabry disease Alpha-galactosidase gene (GLA) p.Phe113Leu (p.F113L) pathogenic variant Haplotype Microsatellite markers ABSTRACT Background, aims and methods: The α-galactosidase gene (GLA) c.337T > C/p.Phe113Leu variant was originally described in patients with late-onset cardiac forms of Fabry disease (FD), who had residual α-galactosidase activity. It has since emerged as the most commonly reported GLA variant in Portuguese subjects diagnosed with FD but is also prevalent in the Italian population, where two boys carrying the GLA Leu113 allele were identified in a large-scale newborn screening program, the variant allele segregating in both cases with the same sur- rounding haplotype. To further delineate the genotype-phenotype correlations of this GLA variant, we have reviewed the natural history and clinical phenotypes of 11 symptomatic Portuguese males, from 10 unrelated families originating from several different areas in mainland Portugal and Madeira Island, who were diagnosed with FD associated with the GLA Leu113 allele in a diversity of clinical and screening settings. Nine of the patients were the probands of their respective families. To test whether the GLA Leu113 allele inherited by the 10 Portuguese and the two Italian families resulted from independent mutational events, we have additionally performed a haplotype analysis with 5 highly polymorphic, closely linked microsatellite markers surrounding the GLA gene. Results and conclusions: Hemizygosity for the GLA Leu113 variant allele is associated with a late-onset form of FD, invariably presenting with severe cardiac involvement. Clinically relevant cerebrovascular and kidney in- volvement may also occur in some patients but the pathogenic relationship between the incomplete α-ga- lactosidase deficiency and the risks of stroke and of chronic kidney disease is not straightforward. The ob- servation that the Leu113 allele segregated within the same GLA microsatellite haplotype in both the Portuguese and Italian families suggests its inheritance from a common ancestor. https://doi.org/10.1016/j.ejmg.2019.103703 Received 21 March 2019; Received in revised form 20 May 2019; Accepted 9 June 2019 ∗ Corresponding author. Unidade de Genética, Departamento de Patologia, Faculdade de Medicina da Universidade do Porto, Alameda Hernâni Monteiro, 4200- 319, Porto, Portugal. E-mail address: jpo@med.up.pt (J.P. Oliveira). European Journal of Medical Genetics 63 (2020) 103703 Available online 11 June 2019 1769-7212/ © 2019 Elsevier Masson SAS. All rights reserved. T Downloaded for Ana Quininha (ana.quininha@chlc.min-saude.pt) at Hospital Centre of Central Lisbon from ClinicalKey.com by Elsevier on February 22, 2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.