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Extending the clinical spectrum of pain channelopathies

Henry Houlden
DOI: http://dx.doi.org/10.1093/brain/aws007 313-316 First published online: 17 February 2012

The discovery of mutations in the SCN9A gene, encoding the sodium channel Nav1.7 have revealed a wide spectrum of clinical phenotypes and determined the aetiology of a number of clinical syndromes. This includes primary erythromelalgia, congenital insensitivity to pain, paroxysmal extreme pain disorder and small fibre neuropathy (Fischer and Waxman, 2010; Liu and Wood, 2011). Genetic analysis of the SCN9A gene has become an important diagnostic test in the characterization of pain syndromes. The study reported by Hoeijmakers and colleagues in this issue of Brain extends the Nav1.7 associated phenotype with the description of a family with pain, dysautonomia and small limbs (acromesomelia) (Hoeijmakers, 2012).

A number of sodium channels have been identified, but only seven (Nav1.1, Nav1.2, Nav1.3, Nav1.6, Nav1.7, Nav1.8 and Nav1.9) have been found to be expressed in the nervous system (Dib-Hajj et al., 2010). Nav1.7 channels are preferentially expressed in nociceptive dorsal root ganglion and sympathetic neurons (Catterall and Yu, 2006). Nav1.7 appears to be important in early phases of neuronal electrogenesis and is characterized by slow transition of the channel into an inactive state when depolarized, allowing it to amplify small depolarizations such as generator potentials at the nerve endings of nociceptors. Nav1.7 therefore acts as a ‘gatekeeper’ within the peripheral pain-signalling pathway. The identification of mutations in the Nav1.7 gene has been a pivotal step in our understanding of pain and the role of the sodium channels (Cummins et al., 1998; Renganathan et al., 2001). With the addition of the pain, dysautonomia and acromesomelia syndrome described in this issue, the past 5 years have seen five human pain syndromes associated with Na …

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