Introduction: Fabry disease is an X-linked genetic disorder caused by Pathogenic variants in the GLA gene, leading to deficiency of α- galactosidase A, generating accumulation of globotriaosylceramide in key organs, including heart, kidneys and nervous system. Therapeutic options include intravenous enzyme replacement therapy (ERT) and in cases with susceptible genetic variants, oral pharmacological chaperone therapy.
Methods: All probands referred to the Inherited Cardiomyopathy Unit, from 2021 to date, for genetic testing due to hypertrophic cardiomyopathy were reviewed. Only patients with Fabry disease were included in this study. Clinical and genetic data of all new identified probands and their relatives were evaluated.
Results: A pathogenic variant in GLA gene was identified in 1 proband (III.1, Figure 1), a 40-year-old male with clinical data diagnostic of Fabry disease whose ECG showed Wolf-Parkinson pattern and Cardiac MRI showed suggestive findings (inferobasal enhancement and decreased T1 signal). Blood test showed deficient α-galactosidase A, diagnostic for Fabry disease in males. Genetic testing showed he was carrier of the Pathogenic variant GLA p.Gln279Glu. Family screening identified several carriers: 1 sister (III.2), 1 brother (III.3) and her mother (II.2). His daughters (IV.2 and IV.3) were obligated carriers, confirmed by sanger sequencing. His uncle (II.1) tested negative. Both his siblings (II.2 and III.3) showed subclinical data of Fabry heart disease (III.3 only by CRM). No extracardiac involvement was identified as described in this genetic variant. Therapeutic options considering cardiac phenotype, genetic susceptibility, and professional limitations to ERT planification, were discussed. They were all offered oral pharmacological chaperone therapy. The proband (III.1) and his brother (III.3) are successfully ongoing with the therapy. Due to pregnancy desire, the treatment was temporarily interrupted in her sister (III.2)
Conclusion: Oral chaperone therapy provides a non-intravenous, antibody-free alternative for Fabry patients with amenable pathogenic variants and specific phenotypes, such as the subclinical cardiac phenotype observed in this family. Clinical suspicion is crucial for identifying Fabry disease during its subclinical stages, as in this case, to enable early intervention. ERT remains the standard of care for patients with non-amenable pathogenic variants, and are also important for other phenotypes or advanced disease.