Genotype, phenotype and disease severity reflected by serum LysoGb3 levels in patients with Fabry disease

Abstract

BackgroundFabry disease (FD) is a rare X-linked lysosomal storage disease caused by mutations in the α-galactosidase A (GLA) gene causing deficiency of α-galactosidase A which results in progressive glycosphingolipid accumulation, especially globotriaosylceramide (Gb3), in body liquids and lysosomes. In a large cohort of FD patients, we aimed to establish genotype/phenotype relations as indicated by serum LysoGb3 (deacylated Gb3). MethodsIn 69 consecutive adult FD patients (males: n=28 (41%)) with a GLA-mutation confirmed diagnosis, we conducted a multidisciplinary clinical characterization during their routine annual examinations, and measured serum LysoGb3 levels by highsensitive electrospray ionization liquid chromatography tandem mass spectrometry. ResultsSerum levels of LysoGb3 were significantly higher in Classic compared with LaterOnset phenotype and higher in the latter compared with controls, both in males (52

Diagnostic strategy for females suspected of Fabry disease

“…As previously published, lyso‐GL‐3 values are driven by phenotype . In contrast to previous reports, no correlation between lyso‐GL‐3 levels and age was observed .…”

“…As previously published, lyso-GL-3 values are driven by phenotype. 15 In contrast to previous reports, no correlation between lyso-GL-3 levels and age was observed. 11 In general, we can conclude that cases with a high lyso-GL-3 concentration are unlikely to be explained by a benign variant.…”

“…In recent years, lyso‐GL‐3 has emerged as a useful biomarker in FD, even allowing to differentiate between classic and later‐onset FD . However, lyso‐GL‐3 is not solely specific to FD, so diagnosis cannot be based on lyso‐GL‐3 elevations alone.…”

“…In contrast, primarily genetic testing leads to the identification of variants of unknown significance (VUS), and above all, to frequent benign variants, such as p.D313Y and p.A143T. [6][7][8][9] In recent years, lyso-GL-3 has emerged as a useful biomarker in FD, [10][11][12][13][14][15][16] even allowing to differentiate between classic and later-onset FD. 17 However, lyso-GL-3 is not solely specific to FD, 18 so diagnosis cannot be based on lyso-GL-3 elevations alone.…”

Glucosylceramide synthase inhibition with lucerastat lowers globotriaosylceramide and lysosome staining in cultured fibroblasts from Fabry patients with different mutation types

“…The reduced α-GalA activity leads to accumulation of its substrates, globotriaosylceramide (Gb3) and other α-galactose linked neutral glycosphingolipids in many cell types, including podocytes and capillary endothelial cells (5). The accumulated lysosomal Gb3 can be converted to globotriaosylsphingosine (lysoGb3) (6), the plasma levels of which are a useful diagnostic marker, which also show some relationship to genotype and phenotype (7,8). Fabry patients suffer from a range of non-specific, severe symptoms, including neuropathic pain, progressive renal disease, cardiomyopathy, stroke and gastrointestinal problems (1,3,9).…”