Results of Fabry Disease Screening in Male Pre-End Stage Renal Disease Patients with Unknown Etiology Found Through the Platform of a Chronic Kidney Disease Education Program in a Northern Taiwan Medical Center

Abstract

Background/Aims: Fabry disease (FD), a rare x-lined genetic disorder is a cause of renal deterioration. The phenotype of FD is highly variable and nonspecific, and correct diagnosis has always been delayed. We aimed to explore the prevalence and clinical presentation of FD in this high-risk male population in a Northern Taiwan medical center. Methods: This is the first study to survey the incidence of FD in this high-risk population through the platform of a chronic kidney disease (CKD) education program in Asia. A total of 1,012 male patients with unknown CKD causes were screened using an assay of alpha-galactosidase A activity (α-Gal A) by dried blood spots (DBS). A final GLA gene analysis was also done for those with low enzyme activity. Results: We identified two new patients with classic FD and four patients with late-onset FD. One novel GLA mutation with c.413 G>A was found in one classic FD patient (index 5). The prevalence of FD is about 0.59 % (6 in 1,012) in the high-risk population group with CKD. The clinical symptoms of FD patients are nonspecific except in those with various degrees of renal failure. Those patients’ correct diagnosis was delayed, taking years and even decades. Three patients received enzyme replacement therapy and one started regular hemodialysis due to persistent renal function deterioration. Another two patients were found from family screening through a new index. In addition, a false negative result occurred in one patient who was proved to have FD by his kidney pathology as determined by this screening. Conclusion: FD is not such as rare a disease and its prevalence is greater in this high-risk male population. Clinicians need to be aware that FD should be included in the differential diagnosis in CKD with unknown etiology.

High Prevalence of Late-Onset Fabry Cardiomyopathy in a Cohort of 499 Non-Selective Patients with Left Ventricular Hypertrophy: The Asian Fabry Cardiomyopathy High-Risk Screening Study (ASIAN-FAME)

“…A dried blood spot (DBS) assay of blood samples of all patients was performed to measure alpha-galactosidase A activity using the MS/MS method [ 13 ] as previously described by the biochemical lab in the National Taiwan University hospital [ 14 ]. Alpha-L-iduronidase (IDUA) was used as the control enzyme in duplication.…”

“…Alpha-L-iduronidase (IDUA) was used as the control enzyme in duplication. For subjects with low plasma alpha-galactosidase A activity (defined as the IDUA/GLA ratio ≥ 10) [ 14 ], 3 mL of blood was collected and kept in an ethylenediaminetetraacetic acid tube for GLA gene sequencing using the Sanger method.…”

Screening for Fabry Disease in patients with unexplained left ventricular hypertrophy

“…In the Hong Kong cohort, for the DBS enzyme assay, alpha-L-iduronidase (IDUA) was used as the control enzyme. Low plasma α-Gal A activity was defined as the IDUA/GLA ratio ≥ 10 [ 23 ]. For both males and females, when their α-GAL A level was within the low range as per the above criteria, Sanger Sequencing was used to search for mutations in the GLA gene.…”

The benefits and challenges of family genetic testing in rare genetic diseases—lessons from Fabry disease

“…This literature review suggests that family genetic testing used in combination with newborn screening or screening of at-risk populations, such as patients on renal replacement therapy or those with hypertrophic cardiomyopathy (HCM), can lead to the identification of several additional family members with Fabry disease (Table 1), with one screening study among 150 patients with HCM reporting an additional 99 relatives diagnosed with the disease from 21 probands (Azevedo et al, 2020). Variable prevalence of Fabry disease was found using newborn screening or screening of at-risk populations, with additional affected relatives disclosed using family genetic testing after identification of index cases (Adalsteinsdottir et al, 2017;Azevedo et al, 2020;Barman et al, 2020;Chinen et al, 2017;De Brabander et al, 2013;Feriozzi et al, 2007;Hagège et al, 2011;Liao et al, 2018;Lin et al, 2018;Lv et al, 2009;Maron et al, 2018;Merta et al, 2007;Okur et al, 2013;Russo et al, 2018;Silva et al, 2016;Spada et al, 2006;Terryn et al, 2008;Turkmen et al, 2016;Veloso et al, 2018). Family screening for rare genetic diseases can be highly effective, but the logistics and economics of its implementation are complex.…”