From the, Department of Neurology, University of Würzburg, Würzburg, Germany.
Fabry Centre for Interdisciplinary Therapy Würzburg (FAZIT), University of Würzburg, Würzburg, Germany.
J Intern Med. 2020 Nov;288(5):593-604. doi: 10.1111/joim.13125. Epub 2020 Jun 24.
Fabry disease (FD) is an X-linked lysosomal storage and multi-system disorder due to mutations in the α-galactosidase A (α-GalA) gene. We investigated the impact of individual amino acid exchanges in the α-GalA 3D-structure on the clinical phenotype of FD patients.
We enrolled 80 adult FD patients with α-GalA missense mutations and stratified them into three groups based on the amino acid exchange location in the α-GalA 3D-structure: patients with active site mutations, buried mutations and other mutations. Patient subgroups were deep phenotyped for clinical and laboratory parameters and FD-specific treatment.
Patients with active site or buried mutations showed a severe phenotype with multi-organ involvement and early disease manifestation. Patients with other mutations had a milder phenotype with less organ impairment and later disease onset. α-GalA activity was lower in patients with active site or buried mutations than in those with other mutations (P < 0.01 in men; P < 0.05 in women) whilst lyso-Gb3 levels were higher (P < 0.01 in men; <0.05 in women).
The type of amino acid exchange location in the α-GalA 3D-structure determines disease severity and temporal course of symptom onset. Patient stratification using this parameter may become a useful tool in the management of FD patients.
法布里病（FD）是一种 X 连锁溶酶体贮积症和多系统疾病，由α-半乳糖苷酶 A（α-GalA）基因突变引起。我们研究了α-GalA 3D 结构中单个氨基酸交换对 FD 患者临床表型的影响。
我们招募了 80 名携带 α-GalA 错义突变的成年 FD 患者，并根据 α-GalA 3D 结构中的氨基酸交换位置将他们分为三组：活性部位突变组、埋藏突变组和其他突变组。对患者亚组进行了深入的临床和实验室参数及 FD 特异性治疗的表型分析。
活性部位或埋藏突变的患者表现出严重的多器官受累和早期发病的表型。其他突变的患者表现出较轻的表型，器官损害较少，发病较晚。活性部位或埋藏突变患者的 α-GalA 活性低于其他突变患者（男性 P<0.01；女性 P<0.05），而溶酶体-Gb3 水平较高（男性 P<0.01；女性 P<0.05）。
α-GalA 3D 结构中氨基酸交换位置的类型决定了疾病的严重程度和症状发作的时间进程。使用该参数对患者进行分层可能成为 FD 患者管理的有用工具。
