Understanding and diagnosing an inherited pain syndrome

July 14, 2005

New Haven, Conn.-Yale School of Medicine researchers report the first demonstration that a single mutation in a human sodium channel gene can trigger pain in people with an inherited pain syndrome known as primary erythromelalgia, according to a study published this month in the journal Brain.

The research provides novel insights into the molecular basis for altered firing of pain signaling neurons in primary erythromelalgia, according to Stephen Waxman, M.D., senior author of the study, chair of the Department of Neurology and director of the West Haven Veterans Administration Rehabilitation Research Center.

DNA samples were studied from a family with 36 members, of which 17 exhibit symptoms typical of erythromelalgia-attacks of intense burning pain of the hands and feet triggered most commonly by heat and moderate exercise. There is currently no effective treatment for erythromelalgia.

All 17 affected members of this family carried a mutation in the gene for sodium channel Nav1.7, one of the nine sodium channels. Nav1.7 is abundantly and preferentially present in small-diameter nerve fibers and free nerve endings within the peripheral nervous system and is associated with pain transmission.

Previous studies linked primary erythromelalgia to two mutations in the gene coding for sodium channel Nav1.7. This study describes a third mutation in Nav1.7 and is evidence that mutant Nav1.7 predisposes its pain sensing neurons to become hyperexcitable and fire rapid bursts of signals at lower than normal stimulation. Hyperexcitability has long been considered a hallmark of painful neuropathies.

Identification of mutations in a specific sodium channel in people with primary erythromelalgia suggests the possibility of rational therapies that target the affected channel. Also, because other pain syndromes, including acquired disorders, involve altered sodium channel function, erythromelalgia may emerge as a model disease that holds more general lessons about the molecular neurobiology of chronic pain.

Yale University

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