Familial Episodic Pain Type 3 (FEPS3) Syndrome, Hereditary Sensory and Autonomic Neuropathy Type VII (HSAN7), and other Pain-Related Disorders via the SCN11A Gene

Familial episodic pain syndrome type 3 (FEPS3) pertains to sporadic hypersensitivity to inflammatory pain that mainly involves distal lower extremities, with occasional occurrence in the upper extremities such as the joints of the fingers and arms. Episodic pain generally occurs late in the day and relapses once every 2-5 days for a total of 9-19 recurrences for each cycle (Zhang et al. 2013). The condition is exacerbated by fatigue, particularly when an individual contracts a viral infection such as a cold or has undergone profuse sweating after engaging in intense physical activities (Lolignier et al. 2011). The affected region is extremely cold, and pain is often alleviated by the application of a hot compress and the administration of ant-inflammatory drugs. Most cases of FEPS3 subside with aging. Neurologic assessment of individuals with FEPS3 generally shows normal sensitivities involving joints to light touch, as well as to pin pricks.

Hereditary sensory and autonomic neuropathy type VII (HSAN7) is a congenital, neurologic disorder that is characterized by an inability to perceive pain. Because this condition does not allow an individual to experience the unique sensation of pain, this often results in self-mutilations, as well as the occurrence of slow-healing injuries, lacerations, and multiple fractures. Individuals with HSAN7 generally present a mild degree of muscular weakness and slow motor development, as well as gastrointestinal disturbances. Muscle assessments such biopsies and electromyography usually show normal findings. A slight reduction in motor and sensory nerve conduction velocities is often observed in individuals diagnosed with HSAN7. Patients also present normal magnetic resonance imaging (MRI) findings and no signs of intellectual disability (Leipold et al. 2013).

FEPS3 and HSAN7 are autosomal dominant neurologic disorders caused by heterozygous variants in the voltage-gated sodium channel type XI, alpha subunit (SCN11A) gene, which has been mapped to 3p22.2 (Dib-Hajj et al. 1998). The SCN11A gene consists of 26 exons and encodes a tetrodotoxin (TTX)-resistant protein channel, Nav1.9, initially termed NaN, which is highly expressed in the neurons of the dorsal root ganglion and is stimulated by the occurrence of a negative action potential (Dib-Hajj et al. 1999). Nav1.9 is structurally similar to another sodium channel, Nav1.8, which is encoded by an adjacent gene, SCN10A (Faber et al. 2012). The protein channel Nav1.9 mediates the activity of brain-derived neurotrophic factor (BDNF)-evoked depolarization of membrane potentials (Cummins et al. 2000; Wilson-Gerwing et al. 2008; Vanoye et al. 2013) through the action of tyrosine kinases (Benn et al. 2001; Fang et al. 2005). Reports have shown that variants involving the SCN11A gene may cause either hypersensitivity or insensitivity to pain, which may be due to elevated electrical activities that induce the opening of sodium channels or the depolarization of the sodium channels that block an individual's perception of pain, respectively (Zhang et al. 2013; Leipold et al. 2013; Huang et al. 2014).

About 10 causative sequence variants have been reported in the SCN11A gene, which include mostly missense variants (Huang et al. 2014; Leipold et al. 2013; Zhang et al. 2013). To date, there is no distinction between mutations that cause FEPS3 or HSAN7, and both neurologic disorders are caused by gain-of-function sequence variants within the SCN11A gene. Other previous names of the SCN11A gene include SCN12A, peripheral nerve sodium channel 5 (PN5), and sensory neuron sodium channel 2 (SNS-2). Sequence variants in other types of voltage-gated cation channels such as TRPA1 (Kremeyer et al. 2010) and Nav1.8 (Faber et al. 2012) may also cause FEPS3, and sequence variants of enzymes such as DNMT1 (Klein et al. 2011, 2013), WNK1 (Davidson et al. 2012; Potulska-Chromik et al. 2012), and SPTLC2 (Rotthier et al. 2010; Murphy et al. 2013) may also result in HSAN.

Two unrelated Chinese families spanning five generations (consisting of 43 and 26 members, respectively) were diagnosed with FEPS3 and harbored missense substitutions in the SCN11A gene (Zhang et al. 2013). Electrophysiologic examination of the affected family members showed that the mutant proteins presented higher electrical activities, which in turn induces the opening of other ion channels, resulting in a hyperexcitable state that contributes to the development of FEPS3.

Two unrelated patients with HSAN7 have been reported with de novo heterozygous missense substitutions involving the SCN11A gene (Leipold et al. 2013). It has been suggested that the excessive influx of sodium ions into cells might have caused depolarization, which in turn resulted in the blockage of other ion channels that play essential roles in the generation of an action potential in neurons of the dorsal root ganglia (Persson et al. 2009; Bosmans et al. 2011).

In a study involving 58 unrelated individuals with early-onset severe sensory loss, one patient was determined to have a pathogenic sequence variant within the SCN11A gene (Leipold et al. 2013). In another study involving 393 patients diagnosed with painful peripheral neuropathy, 12 patients were determined to harbor causative variants within the SCN11A gene (Huang et al. 2014). It should be noted that in this particular study, screening for sequence variants in the SCN11A gene was only performed on patients who tested negative for variants involving the other more commonly involved sodium channel genes, namely SCN9A and SCN10A.

This test provides full coverage of all coding exons of the SCN11A gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).