Metabolic Fingerprinting of Fabry Disease: Diagnostic and Prognostic Aspects

Abstract

Fabry disease (FD) is an X-linked lysosomal disease due to a deficiency in the activity of the lysosomal-galactosidase A (GalA), a key enzyme in the glycosphingolipid degradation pathway. FD is a complex disease with a poor genotype-phenotype correlation. In the early stages, FD could involve the peripheral nervous system (acroparesthesias and dysautonomia) and the ski (angiokeratoma), but later kidney, heart or central nervous system impairment may significantly decrease life expectancy. The advent of omics technologies offers the possibility of a global, integrated and systemic approach well-suited for the exploration of this complex disease. In this narrative review, we will focus on the main metabolomic studies, which have underscored the importance of detecting biomarkers for a diagnostic and prognostic purpose in FD. These investigations are potentially useful to explain the wide clinical, biochemical and molecular heterogeneity found in FD patients. Moreover, the quantitative mass spectrometry methods developed to evaluate concentrations of these biomarkers in urine and plasma will be described. Finally, the complex metabolic biomarker profile depicted in FD patients will be reported, which varies according to gender, types of mutations, and therapeutic treatment.

Keywords: Fabry disease; LysoGb3; lysosomal storage diseases; metabolomics; systems biology.

Figure 1

Pathophysiology of FABRY disease. The impairment of GalA activity results in a progressive storage of glycosphingolipid derivatives such as Gb3 or Lyso-Gb3 in the lysosome.

Figure 2

Clinical manifestations and disease progression in Fabry Disease. (A) Multisystemic organ involvement in Fabry Disease. (B) Model of disease progression related to major organs’ involvement in the classic form of Fabry Disease.

Figure 3

Structure of LysoGb3 and related analogues. LysoGb3 analogues have modification at sphingosine moieties (d18:1 = 18 carbon atoms with a single double bond). The table shows LysoGb3 analogues found in plasma [67,80] (+) and urine [66,81] (*) of Fabry patients as biomarkers for diagnosis/prognosis and monitoring therapy.

Figure 4

Structure of globotriaosylceramide (Gb3) and analogues/isoforms. Gb3 with behenic acid (C22), as native Gb3 and methylated Gb3. Glu: glucose; Gal: galactose. The table shows that Gb3 isoforms/analogues, detected in plasma of Fabry patients, are statistically different from healthy controls [41]. Some of Gb3 analogues/isoforms have been found in urine of Fabry patients [68]. Gb3 Isoforms: Gb3 with varying length fatty acid chains joined by an amide linkage to an unmodified sphingosine moiety. The main sphingosine species are described as d18:1 = 18 carbon atoms with a single double bond. Gb3 Analogues: Gb3 has modified sphingosine moieties. The structure of Gb3 isoforms and analogues is expressed in the following way Gb3(dv:w)(Cx:y)Z, where d indicates the sphingosine group, v shows the number of carbons in the sphingosine moiety, w shows the number of double bonds in the sphingosine moiety, C indicates the fatty acid group, x shows the number of carbon atoms in the fatty acid moiety, y shows the number of carbon−carbon double bonds in the fatty acid moiety, and Z indicates other modifications related to the sphingosine structure (e.g., methylated (Me) or hydrated (H₂O)). +: detected in plasma; ++: abundantly detected in plasma; +++: highly abundant in plasma; *: detected in urine; **: abundantly detected in urine; ***: highly abundant in urine; nd: not detected.