Brain Advance Access published online on April 15, 2009
Brain, doi:10.1093/brain/awp078
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Early- and late-onset inherited erythromelalgia: genotype–phenotype correlation
1 Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT 06510, USA 2 Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, CT 06516, USA 3 Department of Dermatology, Peking University First Hospital, Beijing 100034, China 4 Department of Dermatology, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 33006, China
Correspondence to:
Stephen G. Waxman, MD, PhD, Department of Neurology, LCI 707, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8018, USA E-mail: Stephen.Waxman{at}yale.edu Yong Yang, MD, PhD Department of Dermatology, Peking University First Hospital, No 8 Xishiku Street, Xicheng District, Beijing 100034, China E-mail: dryongyang{at}bjmu.edu.cn
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.
Key Words: channelopathy; erythromelalgia; pain; sodium channel
Abbreviations: AL, adult-long; DRG, dorsal root ganglion; HEK 293, human embryonic kidney cells; IEM, Inherited erythromelalgia; NS, neonatal-short; WT, wild-type
Received January 9, 2009. Revised February 20, 2009. Accepted February 23, 2009.