Episodic Pain Syndrome Panel

The Familial Episodic Pain Syndromes (FEPSs) are small fiber neuropathies characterized by intense, episodic inflammatory pain in specific regions of the body (Faber et al. 2012; Bennett and Woods, 2014). Currently, there are three recognized subtypes of this disorder (FEPS I-III).

FEPS type I is generally confined to the upper body, including the thorax and arms (Kremeyer et al. 2010). Attacks initially present in infancy and are often triggered by fasting in combination with other physical stressors, such as illness, cold temperature, and fatigue. Other symptoms may include breathing difficulties, tachycardia, sweating, pallor, and peribuccal cyanosis.

FEPS type II typically involves the distal lower extremities, although at least two patients have also reported hand pain (Faber et al. 2012; Han et al. 2014). Individuals may also present with allodynia, hyperalgesia, and/or red discoloration of the feet. While only a few patients with FEPS II have been described to date, onset of this disorder appears to occur in adulthood, and attacks may be triggered by stimuli such as cold temperature or intense physical exercise.

Finally, the pain associated with FEPS type III is primarily concentrated in the distal lower extremities, occasionally arising in the joints of fingers and arms (Zhang et al. 2013). Other symptoms may include numbness and tingling, skin discoloration, dry eyes and mouth, hyperhidrosis, orthostatic dizziness, palpitations, and/or hot flushes (Huang et al. 2014). In contrast to FEPS types I and II, age of onset of FEPS type III appears to be highly variable, although severity of the disorder may diminish with age (Zhang et al. 2013; Huang et al. 2014).

The symptoms of FEPS also overlap with those of other episodic pain syndromes, such as SCN9A-associated paroxysmal extreme pain disorder, primary erythermalgia, and small fiber neuropathy (Emery et al. 2015).

Paroxysmal extreme pain disorder (PEPD) is characterized by episodes of extreme pain that is generally confined to proximal regions of the body, including the rectum, eye, and mandible. Additionally, individuals may present with inflammation, excess secretions from the eyes or nose, and/or tonic attacks with apnea and bradycardia (Bennett and Woods 2014). Episodes may occur at birth or shortly after, and can be triggered by certain types of provoking stimuli, such as yawning, eating, or defecation (Fertleman et al. 2006).

The predominant symptom of primary erythermalgia is an episodic burning sensation in the hands and feet, often accompanied by redness and swelling (Bennett and Woods 2014). An increase in temperature further aggravates these symptoms, while a decrease in temperature provides relief. In contrast, while SCN9A-associated small fiber neuropathy is also characterized by a painful burning sensation in the lower extremities, patients are unaffected by alterations in temperature (Faber et al. 2012).

The episodic pain syndromes are autosomal dominant diseases caused by gain-of-function variants that result in either enhanced activation of cation channels or impairment of cation channel deactivation (Bennet and Woods 2014; Emery et al. 2015). Our Episodic Pain Syndrome NextGen Panel currently includes the genes SCN9A, SCN10A, and SCN11A. Sequencing of TRPA1, which is associated with Familial Episodic Pain Syndrome (FEPS) Type I, is not available at this time.

SCN9A: The SCN9A gene encodes the alpha subunit of a type IX voltage-gated sodium channel, also referred to as Nav1.7 (Faber et al. 2012). Over 60 pathogenic variants have been reported in SCN9A to date (http://www.hgmd.cf.ac.uk/). Heterozygous gain-of-function missense variants in this gene may cause one of several pain disorders, including erythermalgia, small fiber neuropathy, and paroxysmal extreme pain disorder (Faber et al. 2012; Michiels et al. 2005; Fertleman et al. 2006). In contrast, loss-of-function variants in SCN9A may result in congenital indifference to pain, an autosomal recessive disease (Cox et al. 2006).

SCN10A: The SCN10A gene encodes the alpha subunit of the type X voltage-gated sodium channel. also referred to as Nav1.8 (Faber et al. 2012). SCN10A gain-of-function missense variants are responsible for FEPS type II. To date, four variants have been reported as causative for SCN10A-associated pain syndromes (Faber et al. 2012; Huang et al. 2013; Han et al. 2014).

SCN11A: The SCN11A gene encodes the alpha subunit of the type XI voltage-gated sodium channel, also referred to as Nav1.9 or NaN (Zhang et al. 2013). SCN11A gain-of-function missense variants are responsible for FEPS type III, and at least six pathogenic variants have been described in this gene (http://www.hgmd.cf.ac.uk/). Additionally, one gain-of-function missense change in SCN11A has been associated with hereditary sensory and autonomic neuropathy type VII (HSAN7), a congenital disorder characterized by the inability to perceive pain (Leipold et al. 2013).

In a cohort of 104 patients who presented with painful, predominantly small-fiber neuropathy, Faber et al. reported 9 individuals (~8.5%) with pathogenic variants in SCN10A (Faber et al. 2012).

In a separate study of 345 patients who presented with painful peripheral neuropathy and were negative for causative variants in SCN9A or SCN10A, 12 patients (~3.5%) harbored pathogenic variants within the SCN11A gene (Huang et al. 2014).

Clinical sensitivity for the SCN9A-related episodic pain syndromes is difficult to predict due to the absence of large cohort studies and the phenotypic heterogeneity of these disorders. Analytic sensitivity is likely high, however, as all reported pathogenic variants to date are missense changes that are expected to be identified by direct sequencing of genomic DNA.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes 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 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).