Albina Nowak1, Thomas P Mechtler2, Thorsten Hornemann3, Joanna Gawinecka4, Eva Theswet5, Max J Hilz6, David C Kasper7. 1. Department of Internal Medicine, University Hospital Zurich and University of Zurich, Rämistrasse 100, 8091 Zürich, Switzerland. Electronic address: albina.nowak@usz.ch. 2. ARCHIMED Life Science, Leberstrasse 20, 1110 Vienna, Austria. Electronic address: t.mechtler@archimedlife.com. 3. Institute for Clinical Chemistry, University Hospital Zurich and University of Zurich, Rämistrasse 100, 8091 Zürich, Switzerland. Electronic address: thorsten.hornemann@usz.ch. 4. Institute for Clinical Chemistry, University Hospital Zurich and University of Zurich, Rämistrasse 100, 8091 Zürich, Switzerland. Electronic address: joanna.gawinecka@usz.ch. 5. Department of Internal Medicine, University Hospital Zurich and University of Zurich, Rämistrasse 100, 8091 Zürich, Switzerland. Electronic address: eva.theswet@uzh.ch. 6. University College London, Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom. Electronic address: m.hilz@ucl.ac.uk. 7. ARCHIMED Life Science, Leberstrasse 20, 1110 Vienna, Austria. Electronic address: d.kasper@archimedlife.com.
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.
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 FDpatients, we aimed to establish genotype/phenotype relations as indicated by serum LysoGb3 (deacylated Gb3). METHODS: In 69 consecutive adult FDpatients (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.
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