Background Fabry disease (FD), a lysosomal storage disorder caused by α-galactosidase A (GLA) gene variants, has a heterogeneous phenotype. GLA variants can lead to classical FD, an attenuated non-classical phenotype, or no disease at all. This study investigates the value of plasma globotriaosylsphingosine (lysoGb3) to distinguish between these groups. This is of particular importance in the diagnosis of individuals with a GLA variant and an uncertain diagnosis of FD, lacking characteristic features of classical FD.

Methods Subjects with GLA variants were grouped as classical, non-classical, uncertain or no FD, using strict phenotypical, biochemical and histological criteria. Plasma lysoGb3 was assessed by LC/MS/MS (normal ≤0.6 nmol/L).

Results 154 subjects were grouped into classical (38 males (M), 66 females (F)), non-classical (13M, 14F), uncertain (5M, 9F) or no FD (6M, 3F). All subjects with a classical phenotype had elevated lysoGb3 values (M: range 45–150, F: 1.5–41.5). LysoGb3 values in patients with a non-classical phenotype (M: 1.3–35.7, F: 0.5–2.0) were different from healthy controls (M: p<0.01, F: p<0.05), but females overlapped with controls. In the no-FD group, lysoGb3 was normal.

Conclusions LysoGb3 is a reliable diagnostic tool to discern classical FD from subjects without FD. This study suggests that the same applies to patients with a non-classical phenotype. LysoGb3 values of female patients overlap with controls. Consequently, in uncertain cases, increased lysoGb3 values are very suggestive for FD, but normal values cannot exclude FD. Confirmation in larger cohorts and data on the specificity of small lysoGb3 increases are necessary.