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

Authors :
Nowak A
Mechtler TP
Hornemann T
Gawinecka J
Theswet E
Hilz MJ
Kasper DC
Source :
Molecular genetics and metabolism [Mol Genet Metab] 2018 Feb; Vol. 123 (2), pp. 148-153. Date of Electronic Publication: 2017 Jul 05.
Publication Year :
2018

Abstract

Background: Fabry 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).<br />Methods: In 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 high-sensitive electrospray ionization liquid chromatography tandem mass spectrometry.<br />Results: Serum levels of LysoGb3 were significantly higher in Classic compared with Later-Onset phenotype and higher in the latter compared with controls, both in males (52 [40-83] vs 9.5 [4.5-20] vs 0.47 [0.41-0.61] ng/ml, P<0.001) and in females (9.9 [7.9-14] vs 4.9 [1.6-4.9] vs 0.41 [0.33-0.48] ng/ml, P<0.001), respectively. Multivariate linear regression analysis showed that LysoGb3 levels were independently associated with, serum creatinine (β=0.09, 95%CI 0.04-0.13, P<0.001) and the presence of cardiomyopathy (β=25, 95%CI 9.8-41, P=0.002). LysoGb3 levels were higher in males with frame-shift and nonsense mutations than in males with missense mutations (84 [72-109] vs 41 [37-52] ng/ml, P=0.002).<br />Conclusion: LysoGb3 relates to disease severity, enzyme replacement response, and to the genotype severity in males. LysoGb3 supports identifying patients at risk who require intensive monitoring and treatment. LysoGb3 appears to be one marker of metabolic phenotyping of FD.<br /> (Copyright © 2017 Elsevier Inc. All rights reserved.)

Details

Language :
English
ISSN :
1096-7206
Volume :
123
Issue :
2
Database :
MEDLINE
Journal :
Molecular genetics and metabolism
Publication Type :
Academic Journal
Accession number :
28728877
Full Text :
https://doi.org/10.1016/j.ymgme.2017.07.002