Hirose Masanori, Okada Sho, Kobayashi Yoshio
Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
Mol Genet Metab Rep. 2023 Jun 10;36:100982. doi: 10.1016/j.ymgmr.2023.100982. eCollection 2023 Sep.
Fabry disease (FD) is an X-linked lysosomal storage disorder caused by insufficient activity of α-galactosidase A (α-Gal A) encoded by . The enzymatic defect causes the progressive accumulation of sphingolipids in various tissues and body fluids, causing systemic disorders. We report a rare familial case of inherited cardiac FD associated with a novel double mutation in the gene: W24R and N419D. A young man with severe obesity was admitted for heart failure (HF) with the diagnosis of dilated cardiomyopathy. Left ventricular hypertrophy was suspected during HF treatment after discharge, and in association with his mother's family history of cardiac diseases and sudden death, the etiology of the hypertrophy was re-examined. Very low α-Gal A activity confirmed the diagnosis of FD. Gene mutation analysis of demonstrated a double mutation: W24R and N419D. Proband analysis revealed the same double mutation in his mother. Although she had no signs or symptoms of FD, we detected mild accumulation of globotriaosylsphingosine. The good laboratory practice-validated assay using HEK293 cells showed that the double mutation was amenable to migalastat, a pharmacological chaperone stabilizing α-Gal A. This case highlights a novel double gene mutation in (W24R and N419D) identified in a family with FD. Although clinical significance of each mutation remains unknown, its combination might work synergistically to attain or augment pathogenicity.
法布里病（FD）是一种X连锁溶酶体贮积症，由编码α-半乳糖苷酶A（α-Gal A）的活性不足引起。酶缺陷导致鞘脂在各种组织和体液中进行性蓄积，从而引发全身性疾病。我们报告了一例罕见的遗传性心脏FD家族病例，该病例与 基因中的一种新型双突变相关：W24R和N419D。一名严重肥胖的年轻男性因心力衰竭（HF）入院，诊断为扩张型心肌病。出院后在HF治疗期间怀疑有左心室肥厚，鉴于其母亲有心脏病家族史和猝死情况，对肥厚的病因进行了重新检查。极低的α-Gal A活性证实了FD的诊断。 基因的突变分析显示存在双突变：W24R和N419D。先证者分析显示其母亲也有相同的双突变。尽管她没有FD的体征或症状，但我们检测到了微量的球三糖基鞘氨醇蓄积。使用HEK-293细胞经良好实验室规范验证的检测表明，这种双突变对米加司他有效，米加司他是一种稳定α-Gal A的药理伴侣。该病例突出了在一个FD家族中鉴定出的 基因中的一种新型双基因突变（W24R和N419D）。尽管每个突变的临床意义尚不清楚，但其组合可能会协同作用以达到或增强致病性。
