Autonomic dysfunction in Fabry disease

Abstract

In Fabry disease, progressive accumulation of glycosphingolipids (GL-3) in various tissues and body fluids such as the cornea, sweat glands, myocardium, kidneys, and blood vessel walls accounts for failure of multiple organs. At the level of the nervous system, primarily small fibers are susceptible to lipid infiltration resulting in impaired cold and heat perception, altered pain perception, as well as neuropathic pain with constant or episodic burning or tingling pain in hands and feet triggered by hot weather, fever, exercise, stress or alcohol. In addition, GL-3 accumulation results in autonomic nervous system (ANS) dysfunction. GL-3 storage in the widespread central as well as the peripheral ANS accounts for reduced sweating, impaired pupillary constriction, diminished saliva and tear formation, disordered intestinal motility and diminished cutaneous flare with scratch or intradermal histamine. Many patients suffer from postprandial cramping, episodic or chronic diarrhea, recurrent abdominal pain and feeling of fullness. Young adults frequently experience strokes due to cerebrovascular and autonomic dysfunction compromising cerebral autoregulation. Small fiber dysfunction and GL-3 storage in central autonomic neurons may compromise the arterial baroreflex function. Overall, symptoms of autonomic dysfunction are rather debilitating and reduce the patients’ quality of life. Enzyme replacement therapy (ERT) is essential to improve autonomic Fabry neuropathy. In a homogeneous group of 22 Fabry patients, we showed improved small fiber neuropathy, normalization of cerebral perfusion, cerebral autoregulation and of baroreflex function after 18 or 23 months of consequent ERT. Still, further studies are needed to assess autonomic control or peripheral organ perfusion and skin blood flow.