The use of globotriaosylsphingosine to detect and monitor Fabry Disease

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Alharbi, Fahad Jazza (2016). The use of globotriaosylsphingosine to detect and monitor Fabry Disease. University of Birmingham. Ph.D.

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Abstract

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by a deficiency of the α-galactosidase-A (α-gal-A) enzyme. The lack of enzymatic activity results in the accumulation of glycosphingolipids (GSLs) in the lysosomes of various tissues and organs. Globotriaosylceramide (Gb3) and Globotriaosylsphingosine (Lyso-Gb3) and their isoforms/analogues have been identified and quantified as potential biomarkers.
This study aimed to develop an HPLC-MS based method for the quantitation of plasma and urinary Lyso-Gb3 and its analogues in Fabry patients to evaluate its utility in diagnosis and monitoring FD.
The results showed that plasma Lyso-Gb3 as a reliable diagnostic biomarker for FD, as plasma Lyso-Gb3 levels could easily discern classical Fabry patients from controls. Moreover, plasma Lyso-Gb3 could also distinguish male cardiac variant Fabry patients from control males. Nevertheless, cardiac variant Fabry females showed an overlap of Lyso-Gb3 levels with controls, hence a positive value in this group would be considered diagnostic but a negative value could not exclude FD.
In a small cohort of our patients on ERT there was a trend towards falling Lyso-Gb3 levels with time suggesting that Lyso-Gb3 has a potential value in monitoring these patients.
Urinary Lyso-Gb3 levels were substantially different between classical and cardiac variant Fabry patients, and the lack of detectable urinary Lyso-Gb3 and analogues in controls allowed us to differentiate between these patients and healthy controls. The total levels of urinary Lyso-Gb3 and its analogues proved particularly useful in differentiating between classical and atypical Fabry patients of both genders.
In the course of the study, a novel rapid MALDI-TOF-MS based Method for measuring urinary Gb3 in Fabry patients has been established. Collectively, the final findings demonstrate that urinary Lyso-Gb3 is superior to urinary Gb3 as a diagnostic biomarker for FD, where the later has been shown to be found in healthy subjects.
Our study subsequently led to development of regional laboratory service for testing Lyso-Gb3 in Queen Elizabeth Hospital, Birmingham, UK. This service is now open to Fabry patients across England.
In conclusion both plasma and urinary Lyso-Gb3 levels are useful diagnostic and monitoring biomarker in classical and cardiac variant males patients, but have questionable utility in cardiac variant females due to overlap with healthy controls. Although we studied the role of Lyso-Gb3 in diagnosing FD further studies are needed to establish its role in disease severity assessment and a larger study required to test our initial finding related to monitoring disease in patients on treatment.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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