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

Nowak, Albina; Mechtler, Thomas P; Hornemann, Thorsten; Gawinecka, Joanna; Theswet, Eva; Hilz, Max J; Kasper, David C (2018). Genotype, phenotype and disease severity reflected by serum LysoGb3 levels in patients with Fabry disease. Molecular Genetics and Metabolism, 123(2):148-153.

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 b 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 b 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 b 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.

Additional indexing

Contributors:ARCHIMED Life Science, Leberstrasse 20, 1110 Vienna, Austria, University College London, Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom
Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic and Policlinic for Internal Medicine
04 Faculty of Medicine > University Hospital Zurich > Institute of Clinical Chemistry
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Health Sciences > Endocrinology, Diabetes and Metabolism
Life Sciences > Biochemistry
Life Sciences > Molecular Biology
Life Sciences > Genetics
Life Sciences > Endocrinology
Uncontrolled Keywords:Genetics, Biochemistry, Molecular Biology, Endocrinology, Diabetes and Metabolism, Endocrinology
Language:English
Date:2018
Deposited On:19 Oct 2017 10:11
Last Modified:17 Oct 2024 01:39
Publisher:Elsevier
ISSN:1096-7192
OA Status:Green
Publisher DOI:https://doi.org/10.1016/j.ymgme.2017.07.002
PubMed ID:28728877

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