Biomarkers associated with clinical manifestations in Fabry disease patients with a late-onset cardiac variant mutation

Auray‐Blais, Christiane; Lavoie, Pamela; Boutin, Michel; Ntwari, Aimé; Hsu, Ting-Rong; Huang, Chun‐Kai; Niu, Dau‐Ming

doi:10.1016/j.cca.2017.01.018

Cited by 47 publications

(48 citation statements)

References 41 publications

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“…While attempts in other studies were made to correlate Lyso-Gb 3 level with a severity indices of FD and response to treatment, many of these studies were small and not sufficiently powered to prove beyond doubt the utility of Lyso-Gb 3 in disease monitoring, but there is growing evidence linking it with FD genotype, phenotype, and treatment response (van Breemen et al 2011;Nowak et al 2017;Auray-Blais et al 2017). Recent studies have shown evidence of histological clearance of glycosphingolipids from tissue with enzyme replacement therapy and more recently with migalastat treatment (Mauer et al 2017;Najafian et al 2016).…”

Section: Discussionmentioning

confidence: 99%

Globotriaosylsphingosine (Lyso‐Gb₃) as a biomarker for cardiac variant (N215S) Fabry disease

Alharbi

Baig

Auray‐Blais

et al. 2018

J of Inher Metab Disea

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Fabry disease (FD) is a multi-systemic X-linked lysosomal disorder caused by the deficient activity of α-galactosidase-A enzyme, which leads to accumulation of glycosphingolipids in various body tissues. The N215S mutation is a known variant of FD, with a late onset cardiac phenotype. Consensus guidelines acknowledged the use of globotriaosylsphingosine (Lyso-Gb) as a diagnostic marker for classical FD but its utility for cardiac variant FD is not clear. We aim to characterize the clinical features and evaluate the diagnostic accuracy of plasma and urinary Lyso-Gb levels in N215S cardiac variant FD patients. Thirty-four FD patients with the late-onset N215S cardiac variant mutation were enrolled along with 62 classical FD patients and 109 healthy controls. Plasma and urinary Lyso-Gb and its analogues were analyzed by LC-MS/MS. Both FD males and females with N215S mutation showed Lyso-Gb levels of (mean ± SEM) 9.7 ± 1.0 and 5.4 ± 0.8 nM, respectively. These levels were significantly higher than healthy control and lower than classical FD patients (p < 0.0001). Plasma Lyso-Gb levels equal to or higher than 2.7 nM yielded a diagnostic sensitivity and specificity of 100% (AUC = 1, p < 0.0001). Cardiac involvement was frequent with 16/34 (47%) developing left ventricular hypertrophy. Three patients who underwent renal biopsy had the characteristic sphingolipid deposition in the podocytes while 6/19 (32%) had evidence of white matter changes or infarct on brain MRI. Taken together, cardiac variant N215S mutation is rather an attenuated form of classical FD. Plasma Lyso-Gb is a diagnostic hallmark to differentiate N215S variant phenotype from subjects with no FD.

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Section: Discussionmentioning

confidence: 99%

Globotriaosylsphingosine (Lyso‐Gb₃) as a biomarker for cardiac variant (N215S) Fabry disease

Alharbi

Baig

Auray‐Blais

et al. 2018

J of Inher Metab Disea

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“…17,27,28 Also, measurement of additional biomarkers, such as lyso-Gb 3 and related analogues, may improve the sensitivity of methods for identifying Fabry disease. 29 In this study, we used a general screening approach that is novel and may serve as a template for future screening studies of at-risk populations (e.g., idiopathic stroke, hypertrophic cardiomyopathy). We looked for Fabry disease at the level of the gene, the enzyme activity in blood, and the substrate in the urine in each patient, thus providing a unique opportunity to compare the different methods.…”

Section: Discussionmentioning

confidence: 99%

“…30,31 On the other hand, our study demonstrates that analysis of enzyme activity or the amount of substrate in the urine alone lacks the required specificity for large-scale screening. Urinary Gb 3 was elevated in about 15% of patients with heart disease who otherwise did not have GLA mutations, 20 and it is known to be normal in patients with mild mutations and in females, 29 or is falsely elevated for other reasons. 32 α-Galactosidase A activity was not a useful measurement either, because females often have normal enzyme levels 33 and a substantial number (15) of males screened had enzyme activity near or below 2 μmol/L/hr (data not shown), a threshold found to contain patients with Fabry disease.…”

Section: Discussionmentioning

confidence: 99%

Low frequency of Fabry disease in patients with common heart disease

Schiffmann

Swift

McNeill

et al. 2018

Genetics in Medicine

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Purpose: To test the hypothesis that undiagnosed patients with Fabry disease exist among patients affected by common heart disease.Methods: Globotriaosylceramide in random whole urine using tandem mass spectroscopy, α-galactosidase A activity in dried blood spots, and next-generation sequencing of pooled or individual genomic DNA samples supplemented by Sanger sequencing.Results: We tested 2,256 consecutive patients: 852 women (median age 65 years (19-95)) and 1,404 men (median age 65 years (21-92)). The primary diagnoses were coronary artery disease (n = 994), arrhythmia (n = 607), cardiomyopathy (n = 138), and valvular disease (n = 568). Urinary globotriaosylceramide was elevated in 15% of patients and 15 males had low α-galactosidase A activity. GLA variants found included R118C (n = 2), D83N, and D313Y (n = 7);

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“…3 The deacetylated and, therefore, soluble form of Gb3, lyso-Gb3, seems to be a reliable biomarker for both disease progression and therapy efficacy, and can be detected in blood plasma as well as urine. [4][5][6][7][8][9][10] The systemic cellular accumulation of Gb3 leads to progressive renal failure, cardiomyopathy, and recurrent cerebrovascular events, significantly limiting life expectancy in affected patients. 3 The most common cause of death is cardiovascular disease.…”

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confidence: 99%

Effects of Enzyme Replacement Therapy and Antidrug Antibodies in Patients with Fabry Disease

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2018

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FOS, Fabry outcome survey; 95% CI, 95% confidence interval; LRI, low renal impairment; HRI, high renal impairment; mGFR, measured glomerular filtration rate; OR, odds ratio. 62 95% CI, 95% confidence interval; FOS, Fabry outcome survey; LRI, low renal impairment; HRI, high renal impairment; LVMI, left ventricular mass index; LVM, left ventricular mass; MWT, mean wall thickness; LVH, left ventricular hypertrophy; IVST, interventricular septum thickness; RWT, relative wall thickness; LVWT, left ventricular wall thickness.

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Biomarkers associated with clinical manifestations in Fabry disease patients with a late-onset cardiac variant mutation

Cited by 47 publications

References 41 publications

Globotriaosylsphingosine (Lyso‐Gb₃) as a biomarker for cardiac variant (N215S) Fabry disease

Globotriaosylsphingosine (Lyso‐Gb₃) as a biomarker for cardiac variant (N215S) Fabry disease

Low frequency of Fabry disease in patients with common heart disease

Effects of Enzyme Replacement Therapy and Antidrug Antibodies in Patients with Fabry Disease

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Biomarkers associated with clinical manifestations in Fabry disease patients with a late-onset cardiac variant mutation

Cited by 47 publications

References 41 publications

Globotriaosylsphingosine (Lyso‐Gb3) as a biomarker for cardiac variant (N215S) Fabry disease

Globotriaosylsphingosine (Lyso‐Gb3) as a biomarker for cardiac variant (N215S) Fabry disease

Low frequency of Fabry disease in patients with common heart disease

Effects of Enzyme Replacement Therapy and Antidrug Antibodies in Patients with Fabry Disease

Contact Info

Product

Resources

About

Globotriaosylsphingosine (Lyso‐Gb₃) as a biomarker for cardiac variant (N215S) Fabry disease

Globotriaosylsphingosine (Lyso‐Gb₃) as a biomarker for cardiac variant (N215S) Fabry disease