Nowak, A;
Mechtler, TP;
Hornemann, T;
Gawinecka, J;
Theswet, E;
Hilz, MJ;
Kasper, DC;
(2018)
Genotype, phenotype and disease severity reflected by serum LysoGb3 levels in patients with Fabry disease.
Molecular Genetics and Metabolism
, 123
(2)
pp. 148-153.
10.1016/j.ymgme.2017.07.002.
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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). / 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. / 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). / 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.
| Type: | Article |
|---|---|
| Title: | Genotype, phenotype and disease severity reflected by serum LysoGb3 levels in patients with Fabry disease |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.ymgme.2017.07.002 |
| Publisher version: | http://doi.org/10.1016/j.ymgme.2017.07.002 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Fabry disease; GLA-mutation; LysoGb3; Biomarker; Genotype phenotype relation; Disease severity |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1568463 |
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