Why test for globotriaosylsphingosine (lyso-Gb3)?
In patients with Fabry disease, deficient activity of the lysosomal enzyme alpha-galactosidase A (α-Gal A) leads to an accumulation of the glycosphingolipids globotriaosylceramide (Gb3) and lyso-Gb3 within almost all cell types and various organs.1-3 Alterations in the enzyme activity of α-Gal A are a result of variants in the GLA gene.4 Levels of lyso-Gb3 are markedly elevated in some patients with Fabry disease, highlighting its potential use as a diagnostic biomarker.4-6
What is the lyso-Gb3 assay?
Levels of lyso-Gb3 can be assessed in the plasma, urine or dried blood spots.7,8 Lyso-Gb3 is the deacylated form of Gb3.9 Evidence suggests that levels of lyso-Gb3 can be used for stratifying patients with either classical or late-onset Fabry disease, and as a marker of disease severity.10,11 In one study, the mean (standard deviation [SD]) plasma levels of lyso-Gb3 were elevated in patients with classical Fabry disease versus those with late-onset Fabry disease (38.7 [39.1] vs 0.8 [0.9] ng/mL; p<0.001).10 Furthermore, levels of lyso-Gb3 have been shown to correlate with the development of cerebrovascular white matter lesions in male patients and increased left ventricular mass in females, as well as decreased kidney function, renal replacement therapy, cardiomyopathy, and stroke and transient ischaemic attack.6,12 However, in female patients with late-onset Fabry disease, levels of lyso-Gb3 may overlap with levels in unaffected individuals without Fabry disease.11,13 Therefore, evaluation of lyso-Gb3 levels may be more useful in assessing disease severity in male patients with Fabry disease.12,14
How sensitive is the lyso-Gb3 assay in diagnosing Fabry disease?
The relative sensitivity of testing for plasma lyso-Gb3, α-Gal A enzyme activity in dried blood spots, and GLA gene sequencing for diagnosis of suspected Fabry disease in both males and females was assessed during a 2-year clinical diagnostics programme. The sensitivity of the assay for lyso-Gb3 for confirming a suspected diagnosis of Fabry disease was 98% in males and 97% in females. These results further suggest that plasma lyso-Gb3 is a sensitive assay for providing diagnostic information for Fabry disease. Testing for α-Gal A enzyme activity in males is considered the first step in the diagnostic work-up for Fabry disease, as the sensitivity of the enzyme assay for α-Gal A was 100% in males, but only 49% in females. Therefore, it is suggested that a diagnosis of Fabry disease in females can instead be more efficiently made using concurrent analysis of plasma lyso-Gb3 and GLA gene sequencing.15
C-ANPROM/INT/FAB/0016; Date of preparation: March 2021
- Felis A, Whitlow M, Kraus A, et al. Current and investigational therapeutics for Fabry disease. Kidney Int Rep 2019; 5: 407-413.
- Schiffmann R, Hughes DA, Linthorst GE, et al. Screening, diagnosis, and management of patients with Fabry disease: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference. Kidney Int 2017; 91: 284-293.
- Brady RO, Gal AE, Bradley RM, et al. Enzymatic defect in Fabry's disease. Ceramidetrihexosidase deficiency. N Engl J Med 1967; 276: 1163-1167.
- Vardarli I, Rischpler C, Herrmann K, et al. Diagnosis and screening of patients with Fabry disease. Ther Clin Risk Manag 2020; 16: 551-558.
- Aerts JM, Groener JE, Kuiper S, et al. Elevated globotriaosylsphingosine is a hallmark of Fabry disease. Proc Natl Acad Sci U S A 2008; 105: 2812-2817.
- Rombach SM, Dekker N, Bouwman MG, et al. Plasma globotriaosylsphingosine: diagnostic value and relation to clinical manifestations of Fabry disease. Biochim Biophys Acta 2010; 1802: 741-748.
- Ortiz A, Germain DP, Desnick RJ, et al. Fabry disease revisited: management and treatment recommendations for adult patients. Mol Genet Metab 2018; 123: 416-427.
- Nowak A, Mechtler T, Kasper DC, et al. Correlation of Lyso-Gb3 levels in dried blood spots and sera from patients with classic and later-onset Fabry disease. Mol Genet Metab 2017; 121: 320-324.
- Ferraz MJ, Kallemeijn WW, Mirzaian M, et al. Gaucher disease and Fabry disease: new markers and insights in pathophysiology for two distinct glycosphingolipidoses. Biochim Biophys Acta 2014; 1841: 811-825.
- Niemann M, Rolfs A, Störk S, et al. Gene mutations versus clinically relevant phenotypes: lyso-Gb3 defines Fabry disease. Circ Cardiovasc Genet 2014; 7: 8-16.
- Wanner C, Arad M, Baron R, et al. European expert consensus statement on therapeutic goals in Fabry disease. Mol Genet Metab 2018; 124: 189-203.
- Nowak A, Mechtler TP, Hornemann T, et al. Genotype, phenotype and disease severity reflected by serum LysoGb3 levels in patients with Fabry disease. Mol Genet Metab 2018; 123: 148-153.
- Smid BE, van der Tol L, Biegstraaten M, et al. Plasma globotriaosylsphingosine in relation to phenotypes of Fabry disease. J Med Genet 2015; 52: 262-268.
- Ouyang Y, Chen B, Pan X, et al. Clinical significance of plasma globotriaosylsphingosine levels in Chinese patients with Fabry disease. Exp Ther Med 2018; 15: 3733-3742.
- Stiles AR, Zhang H, Dai J, et al. A comprehensive testing algorithm for the diagnosis of Fabry disease in males and females. Mol Genet Metab 2020; 130: 209-214.