Newborn screening for Fabry disease in the western region of Japan

Takaaki Sawada,Jun Kido,Shinichiro Yoshida,Keishin Sugawara,Ken Momosaki,Takahito Inoue,Go Tajima,Hirotake Sawada,Shirou Mastumoto,Fumio Endo,Shinichi Hirose,Kimitoshi Nakamura

doi:10.1016/j.ymgmr.2019.100562

Abstract

Newborn screening (NBS) for Fabry disease (FD) is the best way to detect FD early prior to presentation of symptoms and is currently implemented in Taiwan and several states such as Illinois, Missouri, and Tennessee in the United States of America. In this report, we provide data from the first large-scale NBS program for FD in Japan. From August 2006 to December 2018, 599,711 newborns were screened; 26 variants, including 15 pathogenic variants and 11 variants of uncertain significance (VOUS; including eight novel variants), were detected in 57 newborns. Twenty-six male and 11 female newborns with pathogenic variants were diagnosed as hemizygous and heterozygous patients, respectively. Thirteen male and seven female newborns with VOUS were diagnosed as potential hemizygous and potential heterozygous patients, respectively. At the most recent follow up, three of 26 hemizygous patients had manifested symptoms and were receiving enzyme replacement therapy. The other patients were being followed up by clinicians. The frequency of FD (pathogenic variants + VOUS) in this study was estimated to be 1:7683, whereas that of patients with pathogenic variants was 1:11,854. In the future, the NBS system for FD may contribute to the detection of newborns not presenting manifestations related to FD and adults who have or have not developed manifestations related to FD.

Highlights

Fabry disease (FD; OMIM 301500) is an inherited X-linked glycosphingolipid storage disorder caused by mutations in the GLA gene, which encodes the lysosomal enzyme α-galactosidase A (α-Gal A, EC 3.2.1.22)
We present the results of this Newborn screening (NBS) and discuss this NBS system and the genetic backgrounds of newborns with mutations or pathogenic variants
The frequency of male FD was estimated to be 1:6212 (0.016%). These findings were comparable to the results of our previous pilot study [14] and other NBS studies performed in WA [26], IL [27], and NY in the USA [28]; the prevalence rates of FD with pathogenic variants were 1:10,585 (2/21,170), 1:18,151 (6/108,905), 1:21,973 (10/ 219,730), and 1:9373 (7/65,605) live births, respectively

Summary

Introduction

Fabry disease (FD; OMIM 301500) is an inherited X-linked glycosphingolipid storage disorder caused by mutations in the GLA gene, which encodes the lysosomal enzyme α-galactosidase A (α-Gal A, EC 3.2.1.22). Male patients who have very low α-Gal A activity exhibit the classic phenotype and are generally asymptomatic until early childhood (the mean age of onset is reported to be 9 years) [4,5]. Patients with FD having residual α-Gal A activity present milder clinical manifestations, and their onset time is later than that of patients with the classic type. Females with heterozygous mutations have a wide clinical manifestation spectra, ranging from asymptomatic to symptoms as severe as those in patients with the classic type, depending on random X-chromosomal inactivation [6,7]. 516 variants have been incorporated into the public database (Fabry-database.org, last updated at February 15, 2019, ver.3.2.2) [8], and 349 of 516 variants were reported as a classic or severe type mutations

Methods

Results

Conclusion