Prof. Dr. Mirko Pham
Dept. of Neuroradiology, University Hospital Würzburg
Prof. Dr. Claudia Sommer
Dept. of Neurology, University Hospital Würzburg
Prof. Dr. Nurcan Üçeyler
Dept. of Neurology, University Hospital Würzburg

Mechanisms of globotriaosylceramide induced dorsal root ganglion pathology and pain in Fabry disease



Human sensory neurons generated from skin fibroblasts via iPSC. Neurons express marker proteins such as Nav1.8, TRPV1, and CGRP. In pilot experiments, patch-clamp analysis reveals higher action potential firing frequency in sensory neurons obtained from Fabry patients (preliminary). Abbreviations: CGRP = calcitonin gene-related peptide; iPSC = induced pluripotent stem cells; Nav1.8 = voltage gated sodium channel 1.8; TRPV1 = transient receptor potential vanilloid channel 1.

Fabry disease (FD) is an X-linked lysosomal storage disorder that is caused by deficiency of α-galactosidase A (GLA) and consecutive cellular accumulation of Gb3. FD patients suffer from triggerable and episodic acral burning pain, however, the underlying pathomechanism is unknown. Advanced dorsal root ganglion (DRG) in vivo imaging provides evidence for a reduction in DRG perfusion and an increase in DRG size of FD patients. We hypothesize that endothelial and neuronal Gb3 play a central role in this process and aim at deciphering the circuitry linking Gb3 with FD pain. We will correlate human 3T DRG imaging data with extensive clinical and human-experimental data obtained from a very well-characterized patient cohort from all over Germany via the Fabry center for interdisciplinary therapy (FAZIT) of the University of Würzburg. To understand the biological basis of DRG imaging pathology observed in humans, we will investigate pathways of inflammation and hypoxia in the GLA knockout model of Fabry disease applying a capsaicin induced pain paradigm and correlating behavioral and histological findings with those of 7T murine MRI images. To find key players within cellular and neural circuits underlying FD pain, we will generate and investigate circuits in patient-derived endothelial and neuronal cells obtained from skin fibroblasts via induced pluripotent stem cells (Figure).

Finally, we will determine surrogate markers analyzing the functional and structural effects of FD-specific therapy in a longitudinal study sequentially applying experimental DRI imaging. Our long-term goal is to validate and transfer DRG-centered diagnostic and therapeutic means and to establish functional non-invasive imaging methods that are independent from tracer application.