Abstract
Fabry disease (FD) is an X-linked inherited disorder caused by mutations in the GLA gene, which encodes the lysosomal enzyme α-galactosidase A (α-Gal A). FD detection in patients at an early stage is essential to achieve sufficient treatment effects, and high-risk screening may be effective. Here, we performed high-risk screening for FD in Japan and showed that peripheral neurological manifestations are important in young patients with FD. Moreover, we reviewed the literature on high-risk screening in patients with renal, cardiac, and central neurological manifestations. Based on the results of this study and review of research abroad, we believe that FD can be detected more effectively by targeting individuals based on age. In recent years, the methods for high-risk screening have been ameliorated, and high-risk screening studies using GLA next-generation sequencing have been conducted. Considering the cost-effectiveness of screening, GLA sequencing should be performed in individuals with reduced α-Gal A activity and females with certain FD manifestations and/or a family history of FD. The findings suggest that family analysis would likely detect FD patients, although GLA sequencing of asymptomatic family members requires adequate genetic counseling.
Highlights
We reviewed 23 high-risk screenings for Fabry disease (FD) in individuals with cardiac manifestations (Table 2), with 20 screenings performed for individuals with either left ventricular hypertrophy (LVH) or hypertrophic cardiomyopathy (HCM) [40,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98]
There were FD patients presenting only central neurological manifestations as FD manifestations, suggesting that central neurological manifestations are important for high-risk screening of FD, even if they are less frequent than other symptoms
FD patients and some heterozygous females, α-galactosidase A (α-Gal A) activity should be measured for individuals with peripheral neurological manifestations, and GLA sequencing should be performed in individuals with impaired α-Gal A activity
Summary
Fabry disease (FD; MIM 301500) is an X-linked inherited disorder caused by mutations in the GLA gene and resulting in the impaired activity of the lysosomal enzyme αgalactosidase A (α-Gal A; EC 3.2.1.22) [1]. α-Gal A deficiency causes globotriaosylceramide (Gb3) accumulation in cells throughout the body, leading to various clinical manifestations. A pharmacological chaperone therapy (Migalastat; 1-deoxygalactonojirimycin) was recently approved for FD patients with amenable GLA variants [5]. High-risk screening is one method of FD detection via uniform screening in patients with FD-related symptoms, including renal, cardiac, and central neurological manifestations. In. Japan, we previously performed high-risk screening in patients with risk factors for FD [13], and gene and substrate-reducing therapies for FD are currently undergoing clinical trials worldwide [19]. We previously performed high-risk screening in patients with risk factors for FD [13], and gene and substrate-reducing therapies for FD are currently undergoing clinical trials worldwide [19] The approval of these new treatments will make high-risk screening for FD increasingly important because patients with FD can be treated using these new medicines. We review the outcomes of the high-risk screening performed in our study and those worldwide and discuss future methods of high-risk screening
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