Erythermalgia: molecular basis for an inherited pain syndrome.
ABSTRACT Inherited erythermalgia (also termed erythromelalgia) is characterized by severe pain in the limbs in response to mild thermal stimuli or exercise. Its molecular basis has, until recently, been enigmatic. Studies of families with autosomal dominant erythermalgia have now demonstrated mutations in sodium channel Na(v)1.7, which is selectively expressed within nociceptive dorsal root ganglion and sympathetic ganglion neurons. Shifts in activation and deactivation, and enhanced responses to small stimuli in mutant channels, decrease the threshold for single impulses and high-frequency trains of impulses in pain-sensing neurons. Erythermalgia, the first inherited painful neuropathy to be understood at a molecular level, is a model disease that could hold lessons for other painful conditions and for the development of rational, mechanism-based treatments for pain.
- SourceAvailable from: onlinelibrary.wiley.comAngewandte Chemie International Edition 05/2004; 42(15):1717-9. DOI:10.1002/anie.200250700 · 11.34 Impact Factor
Article: Two Cases of Precocious Puberty.*BJOG An International Journal of Obstetrics & Gynaecology 08/2005; 33(4):653 - 656. DOI:10.1111/j.1471-0528.1926.tb12137.x · 3.86 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Disease-producing mutations of ion channels are usually characterized as producing hyperexcitability or hypoexcitability. We show here that a single mutation can produce hyperexcitability in one neuronal cell type and hypoexcitability in another neuronal cell type. We studied the functional effects of a mutation of sodium channel Nav1.7 associated with a neuropathic pain syndrome, erythermalgia, within sensory and sympathetic ganglion neurons, two cell types where Nav1.7 is normally expressed. Although this mutation depolarizes resting membrane potential in both types of neurons, it renders sensory neurons hyperexcitable and sympathetic neurons hypoexcitable. The selective presence, in sensory but not sympathetic neurons, of the Nav1.8 channel, which remains available for activation at depolarized membrane potentials, is a major determinant of these opposing effects. These results provide a molecular basis for the sympathetic dysfunction that has been observed in erythermalgia. Moreover, these findings show that a single ion channel mutation can produce opposing phenotypes (hyperexcitability or hypoexcitability) in the different cell types in which the channel is expressed.Proceedings of the National Academy of Sciences 06/2006; 103(21):8245-50. DOI:10.1073/pnas.0602813103 · 9.81 Impact Factor