Characterization of small fiber pathology in a mouse model of Fabry disease

Fabry disease is a life-threatening disorder that runs in families and affects many parts of the body. Symptoms begin in early childhood, often with episodes of burning pain in the hands and feet. As patients with Fabry disease grow older, sensory nerve fibers in their skin start to break down. As a result, affected individuals may often struggle to detect heat or cold against their skin. Mutations in a gene called alpha-galactosidase A cause Fabry disease. These mutations prevent the alpha-galactosidase A (alpha-GAL) enzyme from working properly. This enzyme breaks down fatty substances in the cells, in particular a molecule named globotriaosylceramide (Gb3). In patients with Fabry disease, Gb3 accumulates inside cells and is thought to cause pain, reduced temperature sensitivity, and loss of nerve fibers in the skin. But how it does this is still unclear. To find out more, Hofmann et al. studied mutant mice with a disrupted alpha-GAL gene, which consequently lack enzyme activity. Like patients, the mice accumulate Gb3 inside their sensory nerve cells as they age. This build-up of Gb3 damages the cells and reduces the function of ion channels (passages for charged ions to enter and leave a cell) in their membranes. This may contribute to the loss of nerve fibers and the reduced cold-warm sensitivity in Fabry patients. However, one particular ion channel is more abundant in elderly mutant mice than in normal animals. This channel, called TRPV1, responds to high temperatures and also to capsaicin, the chemical that makes chilli peppers hot. Hofmann et al. propose that the accumulation Gb3 may be linked to the excessive activation of TRPV1 in the sensory nerve cells of patients with Fabry disease. This may in turn contribute to the heat-induced pain. By providing insights into the mechanisms underlying some of the symptoms of Fabry disease, these findings will assist researchers to develop new treatments. They will also be useful for clinicians who manage patients with the disorder. Further studies should investigate the exact cellular mechanisms linking Gb3 accumulation with changes in cellular activity.