The use and performance of lyso-Gb3 for the diagnosis and monitoring of Fabry disease: A systematic literature review.

Background: Fabry disease (FD) is a rare, X-linked lysosomal storage disorder in which a lack of alpha-galactosidase (α-Gal A) enzyme activity leads to intracellular accumulation of deacylated globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3), and their analogs. Lyso-Gb3, present in the blood and urine of affected patients, has been extensively investigated as a biomarker for FD. This systematic literature review (SLR) aimed to comprehensively assess the use of lyso-Gb3 as a biomarker for screening, monitoring, and diagnosis of FD in both real-world and clinical trial settings.

Methods: An SLR was performed to identify the following outcomes in adult and pediatric patients with FD: lyso-Gb3 testing patterns, lyso-Gb3 levels in subpopulations, performance and accuracy of lyso-Gb3 testing for diagnosis, and lyso-Gb3 testing for monitoring of disease progression or treatment efficacy/effectiveness. Interventional and non-interventional studies published between 1 January 2017 and 3 November 2022 were included. Searches were primarily conducted in MEDLINE and Embase; pragmatic or hand searches were also performed. The methodological quality of included full-text studies was assessed using validated appraisal tools. Extracted data were synthesized qualitatively.

Results: The SLR included 83 eligible publications, comprising 71 observational studies and 12 clinical trials. Differences in lyso-Gb3 levels were identified across subpopulations, with several studies reporting higher levels in males versus females. Lyso-Gb3 demonstrated good diagnostic performance in newborns and high-risk patients when used in combination with other markers (α-Gal A activity or GLA variants) but failed to diagnose females with late-onset FD. Reliability and stability across different methods used to measure lyso-Gb3 was high, with a coefficient of variation <10 % for inter- and intra-assay measurements. Several studies identified moderate to strong correlation between plasma lyso-Gb3 levels and cardiac measures, but association with renal measures needs further investigation.

Conclusions: Lyso-Gb3 testing demonstrated accuracy in screening, diagnosis, and monitoring of FD in certain subpopulations, particularly males, but considering its lower sensitivity in late-onset female patients, it should be used in conjunction with other tools. Given the reliability of the test, it can be considered a feasible method for monitoring disease progression in FD in individual patients. Several gaps in the literature were identified, warranting further investigation.

Registration: PROSPERO (CRD42022375141).