Fabry disease screening in high-risk populations in Japan: A nationwide study [post]

2020 unpublished
Fabry disease (FD) is a rare, X-linked inherited disorder caused by mutations in the GLA gene, which results in deficiency of α-galactosidase A (α-Gal A). This leads to the progressive accumulation of metabolites, which can cause malfunctions in systemic organs. A recent screening study in newborns demonstrated that the incidence of FD was more frequent than previously estimated and that there are still many undiagnosed or misdiagnosed Fabry patients. Therefore, the purpose of this study was to
more » ... identify Fabry patients by performing high-risk screening in 18,171 individuals, enrolled from October 2006 to March 2019, with renal, cardiac, or neurological manifestations from all of the prefectures in Japan. A total of 601 hospitals from all the prefectures in Japan participated in this study. Results: From October 2006 to March 2019, 18,171 individuals with renal, cardiac, or neurological manifestations were enrolled. Low α-Gal A activity was detected in 846 individuals, with 224 of them diagnosed with FD by GLA sequencing. Cases with a family history of FD (n = 64) were also subjected to sequencing, without α-Gal A assay, as per individual request and 12 of them were diagnosed with a variant of FD. A total of 236 Fabry patients (97 males and 139 females) were detected from the 18,235 participants. There were 101 GLA variants, including 26 novel variants, detected in the 236 Fabry patients from 143 families, with 39 amenable variants (39%) and 79 of the 236 patients (33%) suitable for migalastat treatment. Conclusions: From the 18,235 participants, 101 GLA variants, including 26 novel variants, were identified in the 236 Fabry patients from 143 families. Migalastat was identified as a suitable treatment option in 33% of the Fabry patients and 39% of the GLA variants were detected as amenable. Therefore, the simple screening protocol, using dried blood spots, that was performed in this study could be useful for early diagnosis and selection of 3 appropriate treatments for FD in high-risk and underdiagnosed patients suffering from various renal, cardiac, or neurological manifestations. Background Fabry disease (FD; OMIM 301500) is an inherited X-linked disorder caused by mutations in the GLA gene, which encodes the lysosomal enzyme α-galactosidase A (α-Gal A; EC 3.2.1.22). To date, 516 GLA variants have been incorporated into the Fabry-database (Fabry-database.org, ver.3.2.2, last updated on February 15, 2019) [1] . The functional deficiency of α-Gal A results in the progressive accumulation of metabolites, such as globotriaosylceramide in lysosomes, biological fluids, and the vascular endothelium, which can cause the escalation of malfunctions in systemic organs, such as the skin, eyes, kidneys, ears, lungs, heart, and brain [2] [3] [4] . Fabry patients who have less, or very low, α-Gal A activity exhibit the classic phenotype and are generally asymptomatic in early childhood [5, 6] . In contrast, Fabry patients with residual α-Gal A activity exhibit milder clinical manifestations and onset occurs later than in those with the classic phenotype. Heterozygous females with pathogenic GLA variants are not only carriers but also express wide manifestation spectra, ranging from asymptomatic to as severe as those of the classic phenotype, depending on random X-chromosomal inactivation [7] . Clinical manifestations are multisystemic, including limb pain, acroparesthesia, angiokeratoma, anhidrosis, and corneal opacity in childhood, with a progression to major organ involvement in adulthood, such as proteinuria, impaired renal function, cardiomyopathy, and stroke. Because these manifestations are frequently observed in individuals with diabetes, hypertension, and arteriosclerosis, which are nonspecific, this might lead to delayed or mistaken diagnosis [8, 9] . Recent newborn screening (NBS) studies, including our previous study [10] , demonstrated that the incidence of FD was as high as 1:1,600 to 1:8,485 [11, 12] . Therefore, the prevalence of FD had been
doi:10.21203/rs.3.rs-16566/v1 fatcat:ifublzhwxrdrdbdcwkzfnxftd4