Natural history of the late-onset phenotype of Fabry disease due to the p.F113L mutation.,Molecular Genetics and Metabolism Reports

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Natural history of the late-onset phenotype of Fabry disease due to the p.F113L mutation.
Molecular Genetics and Metabolism Reports ( IF 1.9 ) Pub Date : 2020-02-15 , DOI: 10.1016/j.ymgmr.2020.100565
Olga Azevedo _{1,

2,

3} , Miguel F Gago _{2,

3,

4} , Gabriel Miltenberger-Miltenyi _{2,

3,

5} , Ana Raquel Robles ₆ , Maria Antónia Costa ₇ , Olga Pereira ₈ , Ana Teresa Vide ₉ , Gonçalo Castelo Branco ₁₀ , Sónia Simões ₁₁ , Maria José Guimarães ₁₂ , Ana Salgado ₁₃ , Nuno Sousa _{2,

3} , Damião Cunha _{2,

3}

Affiliation

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).
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, member of the European Reference Network on Hereditary Metabolic Disorders (MetabERN).
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).
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).
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).
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).
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).
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).
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).
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).
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).

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.

中文翻译：

p.F113L 突变导致法布里病迟发表型的自然史。

背景

常见的GLA基因突变 p.F113L 会导致迟发型法布里病 (FD)，以心脏表现为主。在葡萄牙吉马良斯地区发现了由于这种突变而产生的 FD 创始人效应。我们的研究旨在加深对这种晚发变异的自然史的了解。

方法

来自该地区的 203 名连续患有 p.F113L 突变的成年 Fabry 患者（79 名男性；平均年龄 46 ± 18 岁）在基线时接受了预定义的诊断方案。对两性每十岁的 FD 表现的发生情况进行分析。

结果

在男性中，左心室肥厚（40.2%）和晚期钆增强（21.4%）在30年内出现；40 岁以上患有心力衰竭 (HF) (21.9%)、室性心动过速 (8.9%) 和传导障碍；50 岁以上出现双束性房室传导阻滞 (13.1%) 和完全性房室传导阻滞 (5.9%)。心脏症状在男性中更常见，且早 1-20 年；他们的频率随着年龄的增长而增加。无论男女，隔膜和后壁厚度、左心室质量、QRS 间期持续时间和 BNP 前体水平均随着年龄的增长而增加。女性无心力衰竭（64 ± 1 与 76 ± 2 年）和起搏器（71 ± 2 与 86 ± 1 年）的平均生存期较高 ( p < .001)。A2/A3蛋白尿（33.7%）、脑白质病变（50.3%）和感音神经性耳聋（44.7%）在男女中均出现在30岁之前，且随着年龄的增长而增加。肾衰竭和中风很少见。在蛋白尿患者的足细胞中发现了溶酶体包涵体。