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

Olga Azevedo; Miguel F Gago; Gabriel Miltenberger-Miltenyi; Ana Raquel Robles; Maria Antónia Costa; Olga Pereira; Ana Teresa Vide; Gonçalo Castelo Branco; Sónia Simões; Maria José Guimarães; Ana Salgado; Nuno Sousa; Damião Cunha

doi:10.1016/j.ymgmr.2020.100565

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

Mol Genet Metab Rep. 2020 Feb 15:22:100565. doi: 10.1016/j.ymgmr.2020.100565. eCollection 2020 Mar.

Authors

Olga Azevedo^{1

2

3}, Miguel F Gago^{2

3

4}, Gabriel Miltenberger-Miltenyi^{2

3

5}, Ana Raquel Robles⁶, Maria Antónia Costa⁷, Olga Pereira⁸, Ana Teresa Vide⁹, Gonçalo Castelo Branco¹⁰, Sónia Simões¹¹, Maria José Guimarães¹², Ana Salgado¹³, Nuno Sousa^{2

3}, Damião Cunha^{2

3}

Affiliations

¹ Cardiology Department, Reference Center on Lysosomal Storage Disorders, Hospital Senhora da Oliveira, Guimarães, Portugal, member of the European Reference Network on Hereditary Metabolic Disorders (MetabERN).
² Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.
³ ICVS/3Bs PT Government Associate Laboratory, Braga/Guimarães, Portugal.
⁴ Neurology Department, Reference Center on Lysosomal Storage Disorders, Hospital Senhora da Oliveira, Guimarães, Portugal, member of the European Reference Network on Hereditary Metabolic Disorders (MetabERN).
⁵ Genetics Department, Reference Center on Lysosomal Storage Disorders, Hospital Senhora da Oliveira, Guimarães, Portugal, member of the European Reference Network on Hereditary Metabolic Disorders (MetabERN).
⁶ Otorhinolaryngology Department, Reference Center on Lysosomal Storage Disorders, Hospital Senhora da Oliveira, Guimarães, Portugal, member of the European Reference Network on Hereditary Metabolic Disorders (MetabERN).
⁷ Ophthalmology Department, Reference Center on Lysosomal Storage Disorders, Hospital Senhora da Oliveira, Guimarães, Portugal, member of the European Reference Network on Hereditary Metabolic Disorders (MetabERN).
⁸ Dermatology Department, Reference Center on Lysosomal Storage Disorders, Hospital Senhora da Oliveira, Guimarães, Portugal, member of the European Reference Network on Hereditary Metabolic Disorders (MetabERN).
⁹ Neurorradiology Department, Reference Center on Lysosomal Storage Disorders, Hospital Senhora da Oliveira, Guimarães, Portugal, member of the European Reference Network on Hereditary Metabolic Disorders (MetabERN).
¹⁰ Internal Medicine Department, Reference Center on Lysosomal Storage Disorders, Hospital Senhora da Oliveira, Guimarães, Portugal, member of the European Reference Network on Hereditary Metabolic Disorders (MetabERN).
¹¹ Psychiatry Department, Reference Center on Lysosomal Storage Disorders, Hospital Senhora da Oliveira, Guimarães, Portugal, member of the European Reference Network on Hereditary Metabolic Disorders (MetabERN).
¹² Pneumology Department, Reference Center on Lysosomal Storage Disorders, Hospital Senhora da Oliveira, Guimarães, Portugal, member of the European Reference Network on Hereditary Metabolic Disorders (MetabERN).
¹³ Radiology Department, Reference Center on Lysosomal Storage Disorders, Hospital Senhora da Oliveira, Guimarães, Portugal, member of the European Reference Network on Hereditary Metabolic Disorders (MetabERN).

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.