Extending the clinical spectrum of pain channelopathies.


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 painsignalling 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 Nav1.7 mutations. Silas Weir Mitchell (1878) first described what we call erythromelalgia, from the Greek words erythros (red), melos (extremity) and algos (pain). In the initial case, he described idiopathic paroxysmal vasodilation of the peripheral vasculature marked by sudden onset of burning pain in the hands and feet. The fingers and toes usually become red with thickened terminal phalanges and nail beds, and superficial veins are grossly engorged. Over the last century, many similar cases have been reported (Smith, 1932; van Genderen, 1993; Davis, 2000; Layzer, 2001). Yang and colleagues (2004) identified mutations in Nav1.7 in two families from China with primary erythromelalgia. Further families from around the world were subsequently identified with heterozygous missense mutations, most frequently in domains I and II (5’ region of the gene). In this context, Nav1.7 mutations cause a hyperpolarizing shift in activation and slow deactivation, thus both opening the channel earlier and keeping it open longer once it is activated. Contributing to the hyperexcitability of pain-signalling dorsal root ganglion neurons expressing these mutant channels (Dib-Hajj et al., 2005; Drenth et al., 2005; Han et al., 2006; Fischer et al., 2009). Paroxysmal extreme pain disorder, previously known as familial rectal pain, is an inherited condition first described by MacLennan (1917) as episodic rectal crisis or proctalgia fugax with intermittent attacks of sharp, severe, brief pain occurring in the region of the anorectal ring and the internal anal sphincter, typically occurring at defecation (Thaysen, 1935). In 1959, rectal, ocular and submaxillary pain (the full spectrum of paroxysmal extreme pain disorder) was described (Hayden and Grossman, 1959). The ocular pattern of pain is an intense burning sensation, followed by conjunctival injection and erythema of the eyelids and skin in the temporal region. There are often autonomic manifestations such as skin flushing and bradycardia (Dugan, 1972; Fertleman et al., 2006, 2007; Choi and Waxman, 2011). In 2006, a genome wide linkage analysis study was carried out in a large affected family. Genetic linkage was obtained to chromosome 2q24.3 and heterozygous missense mutations in Nav1.7 were identified mainly in domains III and IV (3’ region of the gene) (Fertleman et al., 2006). Functional analysis of a number of mutations associated with paroxysmal extreme pain disorder has shown them to impair fast-inactivation without altering channel activation, leading to persistent current, prolonged action potentials and repetitive neuron firing in response to provoking stimuli, such as stretching and exposure to cold temperatures. The different effects of mutations in primary erythromelalgia (which enhance channel activation) and paroxysmal extreme pain disorder (which impair channel inactivation) might contribute in part to the different symptomatology in these two disorders. In either case, these results are in keeping with the notion that Nav1.7 plays a critical role in modulation of the pain threshold (Dib-Hajj et al., 2008; Jarecki et al., 2008). An extreme phenotype has been described in a child with Brain 2012: 135; 313–319 | 313


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