Founder effect of Fabry disease due to p.F113L mutation: Clinical profile of a late-onset phenotype

• Type: Article in International Scientific Journal
• Date: 2020

Authors

Azevedo, O (Author) Other; Gal, A (Author) Other; Faria, R (Author) Other; Gaspar, P (Author) Other; Miltenberger Miltenyi, G (Author) Other; Gago, MF (Author) Other; Dias, F (Author) Other; Martins, A (Author) Other; Rodrigues, J (Author) FMUP; Reimao, P (Author) Other; Pereira, O (Author) Other; Simoes, S (Author) Other; Lopes, E (Author) Other; Guimaraes, MJ (Author) Other; Sousa, N (Author) Other; Cunha, D (Author) Other

Journal

Title: Molecular Genetics and Metabolism

Vol. 129

Pages: 150-160

ISSN: 1096-7192

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 19 Citations

Scopus - 18 Citations

Other information

Authenticus ID: P-00R-1GC

DOI: 10.1016/j.ymgme.2019.07.012

Abstract (EN): Background: Knowledge on clinical profiles of late-onset phenotypes of Fabry disease (FD) is essential to better define their natural history. Our study aims to demonstrate a founder effect of FD due to the GM gene mutation c.337T > C (p.F113L) in the Portuguese region of Guimaraes; and to characterize the clinical profile of this late-onset phenotype in a large cohort of genetically related adult patients, living in the same region. Methods and Results: FD screening was performed in 150 adult patients with hypertrophic cardiomyopathy (HCM) and found 25 Fabry patients (16.6%). The p.F113L mutation was found in 21 of them, leading to a genealogy study and haplotype analysis of the p.F113L patients. Genealogy research revealed a 12-generation family tree with a common ancestor to p.F113L patients, suggesting a founder effect that was supported by haplotype findings. Pedigree analysis was performed and 120 consecutive p.F113L patients underwent a pre-defined diagnostic evaluation of FD multiorgan involvement. This late-onset phenotype was characterized by common and/or potentially severe cardiac manifestations (left ventricular hypertrophy 40.8%, atrial fibrillation 5%, non-sustained ventricular tachycardia 12.5%, atrioventricular block 18.3%, bifascicular block 13.4%). Extracardiac manifestations included albuminuria > 30 mg/24 h 36.1%, chronic kidney disease >= G3 7.6%, brain white matter lesions 54.4%, stroke 3.3%, sensorineural deafness 44.5%, cornea verticillata 13.9%. Plasma lyso-GB3 was undetectable in females, regardless of clinical manifestations. Conclusion: A founder effect of FD due to p.F113L mutation was documented by genealogy and genetics in a Portuguese region. In this late-onset phenotype, although cardiac manifestations carry the highest prognostic impact, extracardiac involvement is common.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 11