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

• Tipo: Artigo em Revista Científica Internacional
• Data: 2020

Autores

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

Revista

Título: Molecular Genetics and Metabolism

Vol. 129

Páginas: 150-160

ISSN: 1096-7192

Editora: Elsevier

Indexação

ISI Web of Knowledge - 19 Citações

Scopus - 18 Citações

Outras Informações

ID Authenticus: 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.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 11