Natural history of the late-onset phenotype of Fabry disease due to the p.F113L mutation

Abstract

Background: The common GLA gene mutation p.F113L causes late-onset phenotype of Fabry disease (FD) with predominant cardiac manifestations. A founder effect of FD due to this mutation was found in the Portuguese region of Guimarães. Our study aims to deepen the knowledge on the natural history of this late-onset variant.

Methods: 203 consecutive adult Fabry patients with p.F113L mutation (79 males; mean age 46 ± 18 years), from this region, were submitted at baseline to a predefined diagnostic protocol. The occurrence of FD manifestations was analyzed in each decade of age in both genders.

Results: In males, left ventricular hypertrophy (40.2%) and late gadolinium enhancement (21.4%) arose over 30 years; heart failure (HF) (21.9%), ventricular tachycardia (8.9%) and conduction disorders over 40 years; and bifascicular (13.1%) and complete atrioventricular blocks (5.9%) beyond 50 years of age. Cardiac manifestations occurred more commonly and 1-2 decades earlier in males; their frequency increased with age. Septum and posterior wall thickness, LV mass, QRS interval duration and pro-BNP levels increased with age in both genders. Mean survival free from HF (64 ± 1 vs. 76 ± 2 years) and pacemaker (71 ± 2 vs. 86 ± 1 years) was higher in females (p < .001). Albuminuria A2/A3 (33.7%), brain white matter lesions (50.3%) and sensorineural deafness (44.7%) arose before 30 years of age in both genders, increasing with age. Renal failure and stroke were rare. Lysosomal inclusions were demonstrated in podocytes of patients with proteinuria.

Conclusion: This study improves the knowledge on natural history of late-onset variants of FD, carrying major impact on clinical decisions and guidelines.

Keywords: Cardiac; F113L; Fabry disease; Late-onset; Natural history; Phenotype.

Fig. 1

Frequency of cardiac manifestations according to age category in male and female Fabry patients with the p.F113L mutation (LVH, heart failure, LGE, non-sustained VT, LAFB, RBBB, bifascicular block, complete AV block). * p < .05.

Fig. 2

Left panel: Relationship of IVS and PW thickness, LV mass and QRS interval duration with age, depicted by a quadratic model; Right panel: IVS and PW thickness and LV mass per age category in male and female patients with FD due to the p.F113L mutation. The mean line is shown and means are marked on the boxplots with an X. * p < .05.

Fig. 3

Kaplan-Meier curves of survival free from heart failure and survival free from pacemaker in male and female Fabry patients with the p.F113L mutation.

Fig. 4

(a) Brain MRI showing WML lesions in a 29-year old female with FD due to the p.F113L mutation, in the absence of cardiovascular risk factors or other morbidities; (b, c) Electronic microscopy from a kidney biopsy showing lysosomal inclusions in renal podocytes in a 42-year old female with FD due to the p.F113L mutation, who presented proteinuria >1 g/24 h, in the absence of other morbidities.

Fig. 5

Frequency of albuminuria A2/A3, brain WML, sensorineural deafness and cornea verticillata according to age category in male and female Fabry patients with the p.F113L mutation. * p < .05.

Fig. S1

Family tree provided by the historians research, demonstrating the genealogical connection of 25 of 34 FD families with the p.F113L mutation to a common ancestor who was born in 1611 in the region of Guimarães. For simplification, only FD patients are depicted and respective spouses were removed from the pedigree.

Fig. S2

Frequency of albuminuria A2/A3 per age category in normotensive nondiabetic Fabry patients with the p.F113L mutation. * p < .05