Lyso-Gb3 associates with adverse long-term outcome in patients with Fabry disease.
genetics
genotype
human genetics
medical
phenotype
Journal
Journal of medical genetics
ISSN: 1468-6244
Titre abrégé: J Med Genet
Pays: England
ID NLM: 2985087R
Informations de publication
Date de publication:
03 2022
03 2022
Historique:
received:
13
07
2020
revised:
06
11
2020
accepted:
03
12
2020
pubmed:
27
1
2021
medline:
10
5
2022
entrez:
26
1
2021
Statut:
ppublish
Résumé
Fabry disease (FD) is a rare X-linked lysosomal storage disease caused by mutations in the α-galactosidase A gene ( In a cohort of 66 patients with genetically confirmed FD (26 males and 40 females), we analysed serum Lyso-Gb3 as a factor associated with adverse clinical outcomes in a long-term study. The main outcome was a composite endpoint of incident kidney replacement therapy, atrial fibrillation, pacemaker and/or implantable cardioverter defibrillator, cerebrovascular events or death, whichever occurred first. During the median follow-up time of 68 (40-80) months, events occurred in 19 (29%) of the patients. In a Cox multivariate regression analysis, Lyso-Gb3 levels (HR 4.62 (1.55 to 13.81); p=0.006) and the pretreatment exposure to Lyso-Gb3 (HR 3.41 (1.11 to 10.49); p=0.03) (both per SD increase) were significantly associated with adverse outcomes. If pretreatment Lyso-Gb3 exposure was added to multivariable logistic regression models containing age, sex, phenotype and enzyme replacement therapy as other covariates with the composite outcome as dependent variable, the area under the curve for the composite outcome significantly improved from 0.72 to 0.86 (p comparison=0.04). Lyso-Gb3 is a significant risk factor associated with important clinical events. Whether treatment-related amelioration of Lyso-Gb3 levels will be associated with improved long-term outcome needs to be established in prospective intervention trials.
Sections du résumé
BACKGROUND
Fabry disease (FD) is a rare X-linked lysosomal storage disease caused by mutations in the α-galactosidase A gene (
METHODS
In a cohort of 66 patients with genetically confirmed FD (26 males and 40 females), we analysed serum Lyso-Gb3 as a factor associated with adverse clinical outcomes in a long-term study. The main outcome was a composite endpoint of incident kidney replacement therapy, atrial fibrillation, pacemaker and/or implantable cardioverter defibrillator, cerebrovascular events or death, whichever occurred first.
RESULTS
During the median follow-up time of 68 (40-80) months, events occurred in 19 (29%) of the patients. In a Cox multivariate regression analysis, Lyso-Gb3 levels (HR 4.62 (1.55 to 13.81); p=0.006) and the pretreatment exposure to Lyso-Gb3 (HR 3.41 (1.11 to 10.49); p=0.03) (both per SD increase) were significantly associated with adverse outcomes. If pretreatment Lyso-Gb3 exposure was added to multivariable logistic regression models containing age, sex, phenotype and enzyme replacement therapy as other covariates with the composite outcome as dependent variable, the area under the curve for the composite outcome significantly improved from 0.72 to 0.86 (p comparison=0.04).
CONCLUSION
Lyso-Gb3 is a significant risk factor associated with important clinical events. Whether treatment-related amelioration of Lyso-Gb3 levels will be associated with improved long-term outcome needs to be established in prospective intervention trials.
Identifiants
pubmed: 33495303
pii: jmedgenet-2020-107338
doi: 10.1136/jmedgenet-2020-107338
pmc: PMC8867289
doi:
Substances chimiques
Glycolipids
0
Sphingolipids
0
globotriaosyl lysosphingolipid
126550-86-5
alpha-Galactosidase
EC 3.2.1.22
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
287-293Informations de copyright
© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: AN received lecturing honoraria and research support from Sanofi Genzyme, Takeda and Amicus and received financial publication support for this article from Sanofi Genzyme. DGW serves as a consultant for Amicus, Protalix, and Chiesi Pharma.
Références
Nephrol Dial Transplant. 2009 Jul;24(7):2102-11
pubmed: 19218538
Genet Med. 2019 Mar;21(3):631-640
pubmed: 30093709
Neurosci Lett. 2015 May 6;594:163-8
pubmed: 25697597
Clin Genet. 2016 Jan;89(1):44-54
pubmed: 25974833
Int J Mol Sci. 2018 Nov 23;19(12):
pubmed: 30477121
Clin Exp Nephrol. 2018 Aug;22(4):843-849
pubmed: 29288396
Mol Genet Metab. 2017 Jun;121(2):157-161
pubmed: 28495078
J Med Genet. 2001 Nov;38(11):769-75
pubmed: 11732485
J Inherit Metab Dis. 2018 Jan;41(1):141-149
pubmed: 29039131
N Engl J Med. 1991 Feb 7;324(6):395-9
pubmed: 1846223
Future Microbiol. 2020 Mar;15:227-231
pubmed: 32271110
Ital J Pediatr. 2017 Jan 3;43(1):1
pubmed: 28049500
Hum Genomics. 2006 Mar;2(5):297-309
pubmed: 16595074
Mol Genet Metab. 2017 Jan - Feb;120(1-2):57-61
pubmed: 27773586
Mol Genet Metab. 2017 Aug;121(4):320-324
pubmed: 28663131
J Med Genet. 2015 May;52(5):353-8
pubmed: 25795794
Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):2812-7
pubmed: 18287059
Clin Chim Acta. 2020 Feb;501:234-240
pubmed: 31778673
Genet Med. 2017 Apr;19(4):430-438
pubmed: 27657681
J Inherit Metab Dis. 2013 Sep;36(5):881-5
pubmed: 23109060
Biochim Biophys Acta. 2010 Sep;1802(9):741-8
pubmed: 20471476
Circ Cardiovasc Genet. 2014 Feb;7(1):8-16
pubmed: 24395922
Kidney Int. 2003 Sep;64(3):801-7
pubmed: 12911529
J Med Genet. 2018 May;55(5):351-358
pubmed: 29437868
J Inherit Metab Dis. 2006 Feb;29(1):106-11
pubmed: 16601876
J Am Soc Nephrol. 2017 May;28(5):1631-1641
pubmed: 27979989
Hum Mol Genet. 2015 Oct 15;24(20):5720-32
pubmed: 26206887
Biochim Biophys Acta. 2011 Jan;1812(1):70-6
pubmed: 20851180
Clin Chim Acta. 2020 Feb;501:27-32
pubmed: 31770509
Ann Intern Med. 2003 Feb 18;138(4):338-46
pubmed: 12585833
Mol Genet Metab. 2018 Feb;123(2):148-153
pubmed: 28728877
Int J Cardiol. 2017 Dec 15;249:261-267
pubmed: 28964554
Clin Genet. 2015 Aug;88(2):161-6
pubmed: 25040344
Am J Hum Genet. 2003 Jul;73(1):162-73
pubmed: 12796853
J Biol Chem. 1995 Feb 10;270(6):2411-4
pubmed: 7852296
N Engl J Med. 1995 Aug 3;333(5):288-93
pubmed: 7596372
J Inherit Metab Dis. 2020 Mar;43(2):326-333
pubmed: 31449323
J Inherit Metab Dis. 2018 Mar;41(2):239-247
pubmed: 29294190
J Med Genet. 2018 Apr;55(4):261-268
pubmed: 29330335
Sci Rep. 2019 Aug 19;9(1):12010
pubmed: 31427622
Eur J Med Genet. 2020 Feb;63(2):103703
pubmed: 31200018