Elevated globotriaosylsphingosine is a hallmark of Fabry disease

Abstract

Fabry disease is an X-linked lysosomal storage disease caused by deficiency of ␣-galactosidase A that affects males and shows disease expression in heterozygotes. The characteristic progressive renal insufficiency, cardiac involvement, and neuropathology usually are ascribed to globotriaosylceramide accumulation in the endothelium. However, no direct correlation exists between lipid storage and clinical manifestations, and treatment of patients with recombinant enzymes does not reverse several key signs despite clearance of lipid from the endothelium. We therefore investigated the possibility that globotriaosylceramide metabolites are a missing link in the pathogenesis. We report that deacylated globotriaosylceramide, globotriaosylsphingosine, and a minor additional metabolite are dramatically increased in plasma of classically affected male Fabry patients and plasma and tissues of Fabry mice. Plasma globotriaosylceramide levels are reduced by therapy. We show that globotriaosylsphingosine is an inhibitor of ␣-galactosidase A activity. Furthermore, exposure of smooth muscle cells, but not fibroblasts, to globotriaosylsphingosine at concentrations observed in plasma of patients promotes proliferation. The increased intima-media thickness in Fabry patients therefore may be related to the presence of this metabolite. Our findings suggest that measurement of circulating globotriaosylsphingosine will be useful to monitor Fabry disease and may contribute to a better understanding of the disorder.

Changes in plasma and urine globotriaosylceramide levels do not predict Fabry disease progression over 1 year of agalsidase alfa

“…Finally, although some studies support globotriaosylsphingosine as a potentially useful biomarker for monitoring Fabry disease, this evidence has been generated in relatively recent years. 6,21,22 At the time of the design of the clinical trials included in the current report, globotriaosylsphingosine was not considered a potential surrogate marker of Fabry disease progression or response to treatment and, thus, was not included as a measured end point. The biological reason why changes in plasma or urine Gb 3 concentrations are not useful as biomarkers is not clear.…”

Uncertain Diagnosis of Fabry Disease in Patients with Neuropathic Pain, Angiokeratoma or Cornea Verticillata: Consensus on the Approach to Diagnosis and Follow-Up

“…Interestingly, most male patients with a GVUS demonstrate residual enzyme activity, in contrast to the absent or near absent enzyme activity in classically affected males. Also, previous studies have shown that patients with a nonclassical phenotype often only show a slight increase of lysoGb3 in plasma, while classically affected males invariably have very high levels (Aerts et al 2008;Rombach et al 2010;Gold et al 2013;Lukas et al 2013).…”

Age at First Cardiac Symptoms in Fabry Disease: Association with a Chinese Hotspot Fabry Mutation (IVS4+919G>A), Classical Fabry Mutations, and Sex in a Taiwanese Population from the Fabry Outcome Survey (FOS)

“…This hypothesis is based on increased levels of plasma lyso-Gb 3 , but not Gb 3 , found in most symptomatic female heterozygotes, which appears to be positively correlated with the severity of the clinical picture (Aerts et al 2008). This widely diffusible lyso-Gb 3 might have the capacity to induce cell damage via some mechanism that we do not yet understand well.…”