Search

Up to now, SCN9A mutations encoding Nav1.7 have been limited to inherited pain syndromes. A few of pathogenic SCN9A mutations with or without SCN1A mutations have been identified in epileptic patients. Here, we report two heterozygous SCN9A mutations with no SCN1A mutations, which are associated with variable epilepsy phenotypes and explored the possibility of SCN9A contributing to a multifactorial etiology for epilepsy. Our findings suggest that the two SCN9A mutations (c.980G>A chr2:167149868 p.G327E; c.5702_5706del chr2:167055410 p.I1901fs) should be regarded as pathogenic mutations. Two heterozygous mutations of SCN9A are associated with a wide clinical spectrum of seizure phenotypes including simple febrile seizures, afebrile seizures, generalized tonic-clonic seizure, myoclonic or tonic seizures, and focal clonic seizures. Patients with deletion mutations tend to be associated with more severe seizure type than missense mutations.

Voltage-gated sodium channels play a pivotal role in pain transmission. They are widely expressed in nociceptive neurons, and participate in the generation of action potentials. Alteration in ionic conduction of these channels causes abnormal electrical firing, thus renders neurons hyperexcitable. So far, mutations in the Na(v)1.7 sodium channel, which is expressed in the dorsal root ganglia cells and sympathetic neurons, have been described to cause perturbations in pain sensation. Until recently, gain-of-function Na(v)1.7 mutations were known to cause two neuropathic pain syndromes: inherited erythromelalgia and paroxysmal extreme pain syndrome. These syndromes are inherited in a dominant trait; they usually begin in childhood or infancy, and are characterized by attacks of severe neuropathic pain accompanied with autonomic symptoms. Recently, small fiber neuropathy and chronic nonparoxysmal pain have been described in patients harboring gain-of-function mutations in Na(v)1.7 channel. Loss-of-function mutations in Na(v)1.7 are extremely rare, and invariably cause congenital inability to perceive pain.

Small-diameter afferents do not just subserve pain and temperature sensibilities, important for protection of the body though they are: there is a system of low-threshold unmyelinated afferents that respond to light stroking (C-tactile afferents) and they are believed to subserve the affective components of touch. Patients with large-fibre sensory neuropathies exhibit skin sympathetic responses to stroking, and report the stimuli as feeling pleasant. Moreover, the posterior insula is activated. Patients with small-diameter sensory neuropathies, specifically those with congenital insensitivity to pain, suffer from cumulative injuries that can lead to joint degeneration. There is evidence that the nociceptive (and sympathetic) axons die because nerve growth factor is not being produced by the target tissues; patients with congenital insensitivity to pain have mutations in the NTRK1 gene, the gene responsible for producing the TrkA receptor, but there is also evidence for mutations in the SCN9A gene, which codes for a specific subunit of the voltage-gated sodium channel. Specific mutations, leading to clusters of cases of congenital insensitivity to pain, have been found in several geographical locations, with several genetic mutations having been documented. Interestingly, even patients with congenital insensitivity to pain, despite having never experienced pain, can still empathise with the pain in others—we do not need to feel pain in order to empathise, but we do need to feel pain in order to ensure that our body looks after itself.