Journal Article

Early- and late-onset inherited erythromelalgia: genotype–phenotype correlation

Chongyang Han, Sulayman D. Dib-Hajj, Zhimiao Lin, Yan Li, Emmanuella M. Eastman, Lynda Tyrrell, Xianwei Cao, Yong Yang and Stephen G. Waxman

in Brain

Published on behalf of The Guarantors of Brain

Volume 132, issue 7, pages 1711-1722
Published in print July 2009 | ISSN: 0006-8950
Published online April 2009 | e-ISSN: 1460-2156 | DOI: http://dx.doi.org/10.1093/brain/awp078
Early- and late-onset inherited erythromelalgia: genotype–phenotype correlation

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Inherited erythromelalgia (IEM), an autosomal dominant disorder characterized by severe burning pain in response to mild warmth, has been shown to be caused by gain-of-function mutations of sodium channel Nav1.7 which is preferentially expressed within dorsal root ganglion (DRG) and sympathetic ganglion neurons. Almost all physiologically characterized cases of IEM have been associated with onset in early childhood. Here, we report the voltage-clamp and current-clamp analysis of a new Nav1.7 mutation, Q10R, in a patient with clinical onset of erythromelalgia in the second decade. We show that the mutation in this patient hyperpolarizes activation by only −5.3 mV, a smaller shift than seen with early-onset erythromelalgia mutations, but similar to that of I136V, another mutation that is linked to delayed-onset IEM. Using current-clamp, we show that the expression of Q10R induces hyperexcitability in DRG neurons, but produces an increase in excitability that is smaller than the change produced by I848T, an early-onset erythromelalgia mutation. Our analysis suggests a genotype–phenotype relationship at three levels (clinical, cellular and molecular/ion channel), with mutations that produce smaller effects on sodium channel activation being associated with a smaller degree of DRG neuron excitability and later onset of clinical signs.

Keywords: channelopathy; erythromelalgia; pain; sodium channel

Journal Article.  6429 words.  Illustrated.

Subjects: Neurology ; Neuroscience

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