Key result
In 120 adult patients with the p.F113L mutation for Fabry disease, left ventricular hypertrophy (40.8%) and brain white matter lesions (54.4%) were common manifestations of this late-onset phenotype.
Why the study?
Knowledge regarding clinical profiles of late-onset Fabry disease phenotypes is essential to better define their natural history.
Observational (n=120)
No
The p.F113L mutation in Fabry disease exhibits a founder effect in Portugal and presents as a late-onset phenotype with significant cardiac and common extracardiac involvement.
Answers are grounded in this paper and cite their sources.
Characterizes cardiac and neurologic features of a Portuguese founder mutation in Fabry disease; extends late-onset phenotype data while leaving management questions open.
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 GLA gene mutation c.337T>C (p.F113L) in the Portuguese region of Guimarães; 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 predefined 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.
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Azevedo et al. (2019) conducted an observational in Fabry disease (n=120). p.F113L mutation was evaluated on Multiorgan involvement (cardiac and extracardiac manifestations). In 120 adult patients with the p.F113L mutation for Fabry disease, left ventricular hypertrophy (40.8%) and brain white matter lesions (54.4%) were common manifestations of this late-onset phenotype.
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