Olga Azevedo1, Andreas Gal2, Rui Faria3, Paulo Gaspar4, Gabriel Miltenberger-Miltenyi5, Miguel F Gago6, Fátima Dias7, Alice Martins7, Jorge Rodrigues8, Pedro Reimão9, Olga Pereira10, Sónia Simões11, Emilia Lopes12, Maria José Guimarães13, Nuno Sousa14, Damião Cunha14. 1. Cardiology Department, Reference Center on Lysosomal Storage Disorders, Hospital Senhora da Oliveira, Guimarães, Portugal; Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; ICVS/3Bs PT Government Associate Laboratory, Braga/Guimarães, Portugal. Electronic address: olgaazevedo@hospitaldeguimaraes.min-saude.pt. 2. Labor Dr. Heidrich & Kollegen MVZ GmbH, Hamburg, Germany. 3. Communication and Society Research Centre, University of Minho, Braga, Portugal. 4. Organelle Biogenesis & Function (OBF) Group, Institute of Molecular and Cell Biology (IBMC), Instituto de Investigação e Inovação em Saúde (I3S), Porto, Portugal. 5. Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; ICVS/3Bs PT Government Associate Laboratory, Braga/Guimarães, Portugal; Genetics Department, Reference Center on Lysosomal Storage Disorders, Hospital Senhora da Oliveira, Guimarães, Portugal. 6. Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; ICVS/3Bs PT Government Associate Laboratory, Braga/Guimarães, Portugal; Neurology Department, Reference Center on Lysosomal Storage Disorders, Hospital Senhora da Oliveira, Guimarães, Portugal. 7. Transdisciplinary Culture, Space and Memory Research Centre - History of Populations Group, University of Minho, Braga, Portugal. 8. Otorhinolaryngology Department, Reference Center on Lysosomal Storage Disorders, Hospital Senhora da Oliveira, Guimarães, Portugal. 9. Ophthalmology Department, Reference Center on Lysosomal Storage Disorders, Hospital Senhora da Oliveira, Guimarães, Portugal. 10. Dermatology Department, Reference Center on Lysosomal Storage Disorders, Hospital Senhora da Oliveira, Guimarães, Portugal. 11. Psychiatry Department, Reference Center on Lysosomal Storage Disorders, Hospital Senhora da Oliveira, Guimarães, Portugal. 12. Internal Medicine Department, Reference Center on Lysosomal Storage Disorders, Hospital Senhora da Oliveira, Guimarães, Portugal. 13. Pneumology Department, Reference Center on Lysosomal Storage Disorders, Hospital Senhora da Oliveira, Guimarães, Portugal. 14. Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; ICVS/3Bs PT Government Associate Laboratory, Braga/Guimarães, Portugal.
Abstract
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.
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.F113Lpatients. Genealogy research revealed a 12-generation family tree with a common ancestor to p.F113Lpatients, suggesting a founder effect that was supported by haplotype findings. Pedigree analysis was performed and 120 consecutive p.F113Lpatients 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.
Authors: Chelsea Bender; Elizabeth Geena Woo; Bin Guan; Ehsan Ullah; Eric Feng; Amy Turriff; Santa J Tumminia; Paul A Sieving; Catherine A Cukras; Robert B Hufnagel Journal: Genes (Basel) Date: 2022-04-12 Impact factor: 4.141
Authors: 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 Journal: Mol Genet Metab Rep Date: 2020-02-15
Authors: Diego A Ávila-Sánchez; Esther Cambronero-Cortinas; Manuel Barreiro-Pérez; Juan L Rodríguez-Hernández; Brais Díaz-Fernández; Pedro L Sánchez Journal: Am J Case Rep Date: 2020-10-29