ABC | Volume 113, Nº1, July 2019

Original Article GLA Gene Mutation in Hypertrophic Cardiomyopathy with a New Variant Description: Is it Fabry's Disease? Ândrea Virgínia Chaves-Markman, 1,2,3,4, 5 Manuel Markman, 2 Eveline Barros Calado, 1 Ricardo Flores Pires, 6 Marcelo Antônio Oliveira Santos-Veloso, 3,4, 5 C atarina Maria Fonseca Pereira, 7 Andréa Bezerra de Melo da Silveira Lordsleem, 1,3,5 Sandro Gonçalves de Lima, 1,3,5 Brivaldo Markman Filho, 1 Dinaldo Cavalcanti de Oliveira 1,4,5 Universidade Federal de Pernambuco - Hospital das Clínicas - Área Acadêmica de Medicina Clínica – Centro de Medicina Clínica – CCM, 1 Recife, PE – Brazil Hospital Agamenon Magalhães, 2 Recife, PE – Brazil Universidade Federal de Pernambuco - Grupo de pesquisa em Epidemiologia e Cardiologia (EPICARDIO), 3 Recife, PE – Brazil Pós Graduação em Inovação Terapêutica (PPGIT) - Universidade Federal de Pernambuco, 4 Recife, PE – Brazil Centro Universitário Mauricio de Nassau - Curso de Medicina, 5 Recife, PE – Brazil Clínica de Doenças Metabólicas, 6 Porto Alegre, RS – Brazil Cetogene AG, 7 Rostock – Germany Mailing Address: Ândrea Virgínia Chaves-Markman • Rua Doutor Pedro de melo Cahú, 51/2102. Postal Code 51020-080, Boa Viagem, Recife, PE – Brazil E-mail: andreachaves.cardio@gmail.com Manuscript received June 14, 2018, revised manuscript October 31, 2018, accepted November 01, 2018 DOI: 10.5935/abc.20190112 Abstract Background: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the alpha galactosidase A gene (GLA) that lead to the enzymatic deficiency of alpha galactosidase ( α -Gal A) , resulting in the accumulation of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3), causing multiple organ dysfunctions. Objective: To perform GLA gene screening in a group of patients with echocardiographic diagnosis of hypertrophic cardiomyopathy (HCM). Methods: A cross-sectional study was conducted with HCM patients from a university hospital. Patients with coronary artery disease and valvulopathies were excluded. Mutation analysis of the GLA gene was performed. In male subjects, the analysis was performed after evidence of low α -Gal A activity. Results: 60 patients with echocardiographic diagnosis of HCM were included. Age ranged from 12 to 85 years and 60% were women. Mean myocardial fibrosis percentage on MRI was 10.7 ± 13.1% and mean ventricular thickness was18.7 ± 6.7 mm. Four patients had the following GLA gene mutations: c.967C>A (p.Pro323Thr), not yet described in the literature; c.937G>T (p.Asp313Tyr); and c.352C>T (p.Arg118Cys). All patients had normal levels of lyso-Gb3 and non-ischemic myocardial fibrosis on magnetic resonance imaging; one patient had proteinuria and one patient had ventricular tachycardia. Conclusion: In this study, the frequency of mutation in the GLA gene in patients with HCM was 6.7%. A novel mutation in exon 6 of the GLA gene, c.967C>A (p.Pro323Thr), was identified. Patients with HCM may have GLA mutations and FD should be ruled out. Plasma (lyso-Gb3) levels do not seem to be sufficient to attain a diagnosis and organ biopsy should be considered. (Arq Bras Cardiol. 2019; 113(1):77-84) Keywords: Fabry Disease/genetic; Cardiomyopathy, Hypertrophic; Hypertrophy, Left Ventricular; Glycosphingolipids. Introduction Hypertrophic cardiomyopathy (HCM) is the most prevalent cardiopathy of genetic origin, caused by >1400 mutations in genes encoding proteins that are components of cardiac sarcomeres and other proteins of related structures, such as Z-discs and intercalated discs. 1–3 Due to advances in molecular biology techniques, the differential diagnosis of HCM has been extended, and other genetic disorders that present with ventricular hypertrophy have been reported. 4 Fabry disease (FD) is a rare X-linked genetic condition. It is caused by inborn errors in glycosphingolipidmetabolismdue to mutations in the gene encoding the enzyme α -galactosidase A ( α -Gal A). Total or partial deficiency of this enzyme results in progressive accumulation of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) in some tissues, particularly in the blood vessels, kidneys, and myocardium. 5–7 More than 900 mutations with different effects on α -Gal A enzyme activity have been described. 8,9 The incidence of FD is estimated at 1:40,000 to 117,000 individuals, and both male homozygous and female heterozygous may be affected. 5,6,8,9 Two phenotypes are recognized: a classic form that is characterized by an early‑onset with manifestations during childhood, and a late‑onset form that frequently affects only one organ. 5,6,8 Cardiac changes 77