Abstract：
Fabry disease is a rare lysosomal storage disorder caused by mutations in the GLA gene, resulting in reduced or absent α-Gal A activity. Migalastat is an oral chaperone therapy for Fabry patients with amenable GLA variants. We previously reported a case of a 60-year-old male patient with a classic phenotype of Fabry disease, presenting with two GLA variants: p.R356Q and p.G360R. Herein, we report that, although these two missense variants are individually classified as amenable to migalastat in the validated in vitro human embryonic kidney-293 cell-based assay, their combination precludes the patient to be treated with this oral chaperone. This case illustrates how therapeutic decisions may be challenging and how a good genotypic characterization of Fabry patients is critical for the selection of the correct therapeutic strategy.
Fabry disease is a rare genetic disease that is part of a group of conditions called lysosomal storage diseases. It is characterized by an abnormal accumulation of glycosphingolipids, a subclass of glycolipids which are important components of the body’s cell membranes. This accumulation is caused by a reduction in, or absence of, enzyme α-Gal A activity, which normally breaks glycosphingolipids down into smaller units, avoiding their accumulation. The absence or reduction in the α-Gal A enzyme activity is caused by mutations (changes in the normal DNA sequence) in the GLA gene. Migalastat is an oral treatment for Fabry patients with GLA mutations that respond to this treatment. We report a case of a 60-year-old male patient with Fabry disease, presenting with two GLA mutations (p.R356Q and p.G360R). Although these mutations are individually amenable to migalastat, their combination and interaction in the same chromosome precludes response to this treatment. This case illustrates how therapeutic decisions for treating Fabry disease can be challenging depending on the mutations causing the disease and how genetic material is decisive for therapy selection.
Fabry disease is a rare genetic disease that is part of a group of conditions called lysosomal storage diseases. It is characterized by an abnormal accumulation of glycosphingolipids, a subclass of glycolipids which are important components of the body’s cell membranes. This accumulation is caused by a reduction in, or absence of, enzyme α-Gal A activity, which normally breaks glycosphingolipids down into smaller units, avoiding their accumulation. The absence or reduction in the α-Gal A enzyme activity is caused by mutations (changes in the normal DNA sequence) in the GLA gene. Migalastat is an oral treatment for Fabry patients with GLA mutations that respond to this treatment. We report a case of a 60-year-old male patient with Fabry disease, presenting with two GLA mutations (p.R356Q and p.G360R). Although these mutations are individually amenable to migalastat, their combination and interaction in the same chromosome precludes response to this treatment. This case illustrates how therapeutic decisions for treating Fabry disease can be challenging depending on the mutations causing the disease and how genetic material is decisive for therapy selection.
摘要：
Fabry病是一种罕见的由GLA基因突变引起的溶酶体贮积症，导致α-GalA活性降低或缺失。Migalastat是一种适合GLA变异的Fabry患者的口腔伴侣疗法。我们之前报道了一例60岁男性患者的典型表型为法布里病，提供两种GLA变体：p.R356Q和p.G360R。在这里，我们报告说，尽管这两个错义变体在经过验证的体外人胚肾-293细胞检测中被单独分类为适合migalastat，它们的组合使患者无法接受这种口腔伴侣的治疗。该案例说明了治疗决策可能具有挑战性，以及法布里患者的良好基因型表征对于选择正确的治疗策略至关重要。
法布里病是一种罕见的遗传病，是一组称为溶酶体贮积病的疾病的一部分。它的特征是鞘糖脂的异常积累，糖脂的一个亚类，是人体细胞膜的重要组成部分。这种积累是由减少引起的，或者没有，酶α-GalA活性，通常将鞘糖脂分解成更小的单位，避免积累。α-GalA酶活性的缺失或降低是由GLA基因的突变(正常DNA序列的变化)引起的。Migalastat是对GLA突变的Fabry患者的口服治疗，对这种治疗有反应。我们报告了一例60岁的男性患者患有法布里病，呈现两个GLA突变（p。R356Q和p.G360R）。尽管这些突变单独适用于migalastat，它们在同一染色体中的组合和相互作用排除了对这种治疗的反应。这个案例说明了治疗法布里病的治疗决策如何具有挑战性，这取决于导致疾病的突变以及遗传物质如何决定治疗选择。
法布里病是一种罕见的遗传病，是一组称为溶酶体贮积病的疾病的一部分。它的特征是鞘糖脂的异常积累，糖脂的一个亚类，是人体细胞膜的重要组成部分。这种积累是由减少引起的，或者没有，酶α-GalA活性，通常将鞘糖脂分解成更小的单位，避免积累。α-GalA酶活性的缺失或降低是由GLA基因的突变(正常DNA序列的变化)引起的。Migalastat是对GLA突变的Fabry患者的口服治疗，对这种治疗有反应。我们报告了一例60岁的男性患者患有法布里病，呈现两个GLA突变（p。R356Q和p.G360R）。尽管这些突变单独适用于migalastat，它们在同一染色体中的组合和相互作用排除了对这种治疗的反应。这个案例说明了治疗法布里病的治疗决策如何具有挑战性，这取决于导致疾病的突变以及遗传物质如何决定治疗选择。
