Multiplex Analysis of
Novel Urinary Lyso-Gb<sub>3</sub>‑Related Biomarkers for Fabry
Disease by Tandem Mass Spectrometry
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Abstract
Fabry disease is a lysosomal storage disorder caused
by the absence
or reduction of α-galactosidase A enzyme activity. The enzymatic
deficiency results in the impaired catabolism of neutral sphingolipids
with terminal α-galactosyl residues and subsequent accumulation
in several tissues. Biomarkers reflecting disease severity and progression,
the response to therapeutic intervention, and details of molecular
pathogenesis are needed. Until now, two sphingolipids were targeted
as biomarkers in urine and plasma of Fabry patients: globotriaosylceramide
(Gb<sub>3</sub>) and globotriaosylsphingosine (lyso-Gb<sub>3</sub>). Using metabolomic approaches, our group recently discovered seven
novel urinary lyso-Gb<sub>3</sub>-related Fabry disease biomarkers
with mass-to-charge ratios (<i>m</i>/<i>z</i>)
of 758, 774, 784, 800, 802, 820, and 836. All these biomarkers exhibited
modifications of the lyso-Gb<sub>3</sub> sphingosine moiety. The aims
of the present study were to devise and validate a specific tandem
mass spectrometry multiplex methodology for the relative quantification
of these seven analogues and to evaluate their urinary excretion levels
in samples from 164 Fabry patients and 94 healthy controls. We found
no detectable analogues in healthy controls, except for trace amounts
of the analogue with <i>m</i>/<i>z</i> 836. Significant
correlations were established between lyso-Gb<sub>3</sub> analogue
levels in urine and gender (<i>p</i> < 0.001). Fabry
males had higher excretion levels compared to females with the disease.
Lyso-Gb<sub>3</sub> analogue levels correlated well with enzyme replacement
therapy (ERT) status in males (<i>p</i> < 0.05). The
urinary analogue distributions varied among Fabry patients. However,
the analogues with <i>m</i>/<i>z</i> 802, 820,
and 836 were generally more abundant in the majority of patients.
Lyso-Gb<sub>3</sub> analogues are promising urinary biomarkers for
Fabry disease