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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-galac-tosidase A (GLA) gene causing deficiency of α-galactosidase A which results in progressive glycosphingolipid ac-cumulation, 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%)) witha GLA-mutation confirmed diagnosis, we conducted a multidisciplinary clinical characterization during their routine annual examinations, and mea-sured serum LysoGb3 levels by high-sensitive electrospray ionization liquid chromatography tandem mass spec-trometry.
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. Multivar-iate 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 mu-tations (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.

Abstract

Background: Fabry disease (FD) is a rare X-linked lysosomal storage disease caused by mutations in the α-galac-tosidase A (GLA) gene causing deficiency of α-galactosidase A which results in progressive glycosphingolipid ac-cumulation, 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%)) witha GLA-mutation confirmed diagnosis, we conducted a multidisciplinary clinical characterization during their routine annual examinations, and mea-sured serum LysoGb3 levels by high-sensitive electrospray ionization liquid chromatography tandem mass spec-trometry.
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. Multivar-iate 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 mu-tations (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.

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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
Language:English
Date:2018
Deposited On:19 Oct 2017 10:11
Last Modified:20 Feb 2018 08:54
Publisher:Elsevier
ISSN:1096-7192
OA Status:Closed
Publisher DOI:https://doi.org/10.1016/j.ymgme.2017.07.002
PubMed ID:28728877

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