ABC | Volume 113, Nº1, July 2019

Original Article Chaves-Markman et al A novel mutation in Fabry disease Arq Bras Cardiol. 2019; 113(1):77-84 had LVH. The mean MVT was 16.7 ± 1.9 mm in the study by Takenaka et al., 28 which is closer to that shown in this study. Patients with GLA mutation were screened from an HCM sample, which may explain the tendency for the higher mean values of MVT. In our study, patients with GLA mutations had an older mean age. This finding could perhaps be attributed to the fact that the cardiac variant of FD has a later onset. Regarding the hypertrophy pattern, FD is predominantly associated with concentric hypertrophy. 29 However, some studies found a higher prevalence of the asymmetrical variety, 25 which was in accordance with our results. This variety is usually associated with severe presentations of the disease. 25,29 Atrioventricular blockwas present in the electrocardiographic (ECG) findings in two patients with GLA mutation (50%), which is in accordance with the findings from previous studies. 29 However, repolarization abnormalities were common in patients with HCM, but not in patients with FD, as expected. These abnormalities are associated with mild concentric hypertrophy. 30 In our study, only one patient showed concentric hypertrophy, which may explain the absence of repolarization abnormalities in the ECG results of our patients with GLA mutation. The mean myocardial fibrosis percentage on MRI was 12±11.6% and 10.5±13.7% in patients with GLA mutation and no mutation, respectively. However, there was no statistically significant differences between the compared groups (p = 0.85). Although the clinical presentation of FD has been well described, the physiopathological mechanism linking the intracellular accumulation of Gb3 to tissue damage and clinical manifestations is still not well established. 31 It is hypothesized that intracellular storage of Gb3 triggers important physiopathological cascades related to inflammatory processes, leading to myocardial cell changes and, over time, to fibrosis. 31–33 GLA mutation was not associated with any specific late gadolinium enhancement (LGE) pattern on MRI. Patient 2 shows LGE in the basal midventricular septum, anterior septum, lateral inferior and apical segments of the left ventricle. Patient 3 shows LGE in the interventricular septum, inferior wall and in the right ventricle insertions. Patient 4 shows LGE in the basal segments of the inferior septum and inferior wall segments of the right ventricle. Information about LGE in patient 1 was not available. One of the variants found has not been described in previous studies and in the Exome Aggregation Consortium, Exome Sequencing Project or 1000 Genomes Browser databases. The variant, c.967C>A (p.Pro323Thr), is located in exon 6 of the GLA gene. This mutation results in the substitution of a threonine amino acid by a proline amino acid at position 323 of the protein. This position shows a highly conserved nucleotide and a highly conserved amino acid, with moderated physico-chemical differences between the proline and threonine amino acids. It has characteristics of pathogenicity based on the analysis using Polyphen-2, SIFT, MutationTaster, and Align-GVGD software. Patient 1, the carrier of this mutation, had severe cardiac defects, manifested as arrhythmia and hypertrophy, with no other explainable causes. The variant 352C>T (p.Arg118Cys) in exon 2 of the GLA gene was initially described to be pathogenic by Spada et al. 34 According to Ferreira et al., 35 the moderated enzymatic deficiency related to p.Arg118Cys may not be sufficient to cause major complications of FD, suggesting low pathogenicity. 35 This mutation was found in two unrelated patients (patients 3 and 4), both with LVH. Patient 3 also showed first-degree atrioventricular block and paroxysmal atrial fibrillation on ECG, as well as proteinuria. Patient 4 had a history of ischemic stroke. Despite the controversy over the pathogenicity of this variant, the authors believe it may cause specific organ manifestations, such as cardiac and cerebral involvement. With regard to the third variant found in exon 6 of the GLA gene, GLA c.937G>T (p.Asp313Tyr) in patient 2, there are also contradictory results about its pathogenicity. Some studies showed that genotype D313Y is not responsible for severe organic lesions similar to those associated with the well‑established genotypes of classic FD. 36 Lenders et al. 36 and Niemann et al., 37 reported that the presence of this variant is potentially associated with important white matter lesions in the central nervous system. 36,37 The patient had severe cardiac hypertrophy, a history of uncontrolled systemic arterial hypertension, and complained of generalized pain with emotional lability. She has been receiving enzymatic replacement therapy for six months and has shown significant improvement of symptoms and blood pressure control. The study of variants c.937G>T (p.Asp313Tyr) and c.352C>T (p.Arg118Cys) show contradictory results in the literature, but the authors believe they are pathogenic. The variant p. Asp313Tyr, found in this group, was identified in members of the same family and all follow the X-linked inheritance, with important cardiac hypertrophy and symptoms. Regarding the p.Arg118Cys, which has also shown controversial results in the literature, it was found in two patients from different families in this group. One is a homozygous male with cardiac hypertrophy and ischemic stroke; the other one is a heterozygous female patient also with cardiac hypertrophy, arterial thrombosis and proteinuria. The authors are currently working with the objective of gathering more evidence about the pathogenicity of these variants in the other family members. The new variant found, c.967C>A (p. Pro323Thr) seems to be pathogenic according to the analysis carried out with Polyphen-2, SIFT, MutationTaster and Align-GVGD software. As stated before, the patient is a heterozygous female with cardiac hypertrophy and transitory ischemic attack and investigation of the family members suggest pathogenicity. Although the 352C> T (p.Arg118Cys) and c.937G> T (p.Asp313Tyr) variants are controversial as to pathogenicity, the families' heredogram confirms an X-linked inheritance. One of the most relevant results of the study was the identification of a new mutation in the GLA gene that seems to be pathogenic, in addition to the identification of 14 other carriers among the relatives of the four index patients. The probability of performing enzyme replacement therapy and pharmacological chaperones emphasizes the importance of an early diagnosis of FD 38–40 and the search to identify the pathogenicity of the variants found. 81