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Congenital Insensitivity to Pain (CIP) is a rare disorder that is characterized by the inability to perceive pain. It is caused by bi-allelic inactivating mutations in the SCN9A gene, which encodes the pore-forming α-subunit of the nerve voltage-gated sodium channel (Nav1.7). Patients with CIP are unable to feel pain from noxious stimuli, including heat, but all other peripheral somatosensory modalities function normally. Often anosmia is present as an additional feature. We reported a patient with CIP caused by compound heterozygous SCN9A mutations: a novel in-frame deletion of exon 7 and a novel frameshift mutation. The identification of these mutations expands the spectrum of mutations associated with CIP.

Purpose: To explore disease-causing gene mutations of epilepsy with febrile seizures plus (EFS+) in Southern Chinese Han population. Methods: Blood samples and clinical data were collected from 49 Southern Han Chinese patients with EFS+. Gene screening was performed using whole-exome sequencing and panel sequencing for 485 epilepsy-related genes. The pathogenicity of variants was evaluated based on ACMG scoring and assessment of clinical concordance. Results: We identified 10 putatively causative sodium channel gene variants in 49 patients with EFS+, including 8 variants in SCN1A (R500Q appeared twice), one in SCN3A and one in SCN9A. All these missense mutations were inherited from maternal or paternal and were evaluated to be of uncertain significance according to ACMG. The clinical features of patients were in concordance with the EFS+ phenotype of the mutated SCN1A, SCN3A and SCN9A gene. The clinical phenotypes of 11 probands with these gene variants included febrile seizures plus (FS+, n=7), Dravet Syndrome (n=3), FS+ with focal seizures (n=1). Three probands with SCN1A variants (R500Q located in the non-voltage areas, or G1711D in the pore-forming domain) developed severe Dravet syndrome. The affected individuals with the other 6 SCN1A variants located outside the pore-forming domain showed mild phenotypes. Novel SCN3A variant ((D1688Y) and SCN9A variant (R185H) were identified in two probands respectively and both of the probands had FS+. Conclusion: The SCN1A, SCN3A, and SCN9A gene mutations might be a pathogenic cause of EFS+ in Southern Chinese Han population.

The SCN9A gene encodes a voltage gated sodium channel Nav1.7 in which mutations can result in a wide variety of phenotypes ranging from congenital insensitivity to pain to small fiber neuropathy. We report the genotype phenotype analysis in a family carrying a specific mutation, I1739V, in the SCN9A gene. Neurophysiological studies have documented the gain of function impact of this mutation on this sodium channel. Interestingly, there is significant interfamilial phenotypic variability in individuals carrying this mutation. In our family, a father daughter combination had identical genotypes analyzing the SCN9A gene and multiple other genes known to cause neuropathy. Both of them carry the I1739V mutation but exhibit significant phenotypic variability with complaints of decreased sensitivity to discomfort in the father while the daughter has the clinical and laboratory features consistent with a small fiber neuropathy. We hypothesize that there are modifiers of the I1739V mutation that could involve intronic or exonic gene variants which contribute to this intrafamilial phenotypic variability. Our study has implications for genetic counseling, personalized medicine and the development of drugs to treat neuropathic pain.

Congenital insensitivity to pain (CIP) is a rare autosomal recessive genetic disease, the main clinical manifestations are loss of pain or dullness, accompanied by a series of complications. We followed up a patient with CIP for 9 years, and a total of 4 fractures in 6 parts of the lower limbs were found. The patient presented with typical pain retardation, accompanied by osteomyelitis, multiple fractures, self-harm behavior (biting the tip of the tongue and fingers), and not being afraid of heat. A mutation was found on the sodium channel type IX a subunit (SCN9A) gene (chr2: 167056320 (EX27E), NM_002977. 3: c. 4796G>T (p. Arg1599Leu)). There is currently no effective treatment for this disease. We have adopted a combination of conservative and surgical treatment for this child's orthopedic disease (osteomyelitis and fracture). During the 4th fracture hospitalization, with the informed consent of the family, we used zoledronic acid to prevent fractures caused by low energy. Follow-up for 3 years found that zoledronic acid not only promoted fracture healing, but also avoided new fracture formation. Through reviewing the literature, we observe that this is the first report of using zoledronic acid to successfully avert new fractures in this type of patient. Now we summarize the treatment experience and review the literature in order to provide reference for the clinical treatment of this disease and enrich the SCN9A gene mutation spectrum.

Hereditary sensory and autonomic neuropathy is a rare syndrome characterized by congenital insensitivity to pain, temperature changes, and an autonomic nerve formation disorder. We report an 8-year-old boy who presented with late-onset of self-mutilating behavior, insensitivity to pain, temperature, and anhidrosis with compensatory hyperhidrosis. Exome sequencing revealed a mutation of the SCN9A gene at chromosome 2 with nucleotide change c. G554A/p. Arg185His at exon 5 along with HSPB1 mutation at chromosome 5.

Background Single nucleotide polymorphisms (SNPs) of the voltage-gated sodium channel alpha subunit gene (SCN9A) have been associated with pain in various settings. The aim of this study was to investigate the association of the SNPs to evaluate the influence of common gene variants on chronic postoperative pain (CPSP) and other related pain variables in a cohort of patients who underwent a scheduled hysterectomy. Methods DNA samples from a cohort of 1,075 patients who underwent a scheduled total hysterectomy in our hospital were genotyped for three common SCN9A SNPs using TaqMan assays. Multivariate logistic regression models were used to quantify the association between independent covariates such as pain threshold, pain endurance, pain scores, morphine use, and the presence of chronic pain. Results Frequencies of the minor alleles were different between the different ethnic groups. There was a statistically significant association of rs16851799 with morphine consumption and self-reported postoperative pain for the 1,038 subjects genotyped, with the TT genotype reporting higher pain and using more morphine. For the subpopulation of 446 subjects with chronic pain data, there was a similar association with self-reported postoperative pain and tolerance of pressure pain. Univariate analysis also showed a statistically significant association of rs16851799 with CPSP, whereas multivariable analysis revealed a similar association of rs4387806 with this outcome. There were three haplotypes with different relative frequencies for the CPSP and non-CPSP groups. Conclusions Our results showed that SCN9A polymorphisms could play a role in acute pain perception and the susceptibility to chronic pain.

Background To describe the clinical phenotype of paroxysmal extreme pain disorder, an autosomal dominant condition in four members in one family with the mutation NM_002977.3:c.3892G > T (p.Val1298Phe) in the SCN9A gene. Clinical examinations and details from members of one Polish family were collected, including age at onset, features of attacks, problems between attacks, investigational results, treatments tried, and evolution over time. Case presentation Twenty two individuals from this family with paroxysmal extreme pain disorder were identified. Seven of them presented clinical manifestation of paroxysmal extreme pain disorder, of which and in four were identified missens mutations in the SCN9A gene (NM_002977.3:c.3892G > T). The onset of the disorder took place in the neonatal period or infancy and persists throughout life. Autonomic manifestations predominate with extreme pain, skin flushing and harlequin colour change were observed in all. Attacks of excruciating deep burning pain often appear in the rectal, or jaw areas, but also diffuse in the body. Attacks are triggered by factors such as: defecation, eating, pressure and emotion. Carbamazepine and other antiepileptic drugs were only partly effective in almost all, but the response was incomplete. Conclusions Paroxysmal extreme pain disorder is a hereditary sodium channelopathy with pain and an autonomic nervous system dysfunction. Paroxysmal extreme pain disorder is rare, so far only 500 cases of both women and men have been described in world literature.

Introduction or background Congenital insensitivity to pain (CIP) is caused by extremely rare Mendelian genetic disorders. CIP individuals demonstrate the unexpectedly severe consequences of painlessness. Although only a small number of causative conditions and genes are known, most have led to profound insights into human nociception. CIP gene discovery is catalyzing the manufacture of completely new classes of analgesics, and these are needed as alternatives to synthetic highly potent opioids. Sources of data Pubmed.gov peer-reviewed journal articles and reviews. Areas of agreement The importance of nerve growth factor-tropomyosin receptor kinase A (NGF-TRKA) signalling for nociceptor genesis and subsequent pain sensing. New analgesics can be generated from knowledge of the NGF-TRKA nociceptor pathway. Increased susceptibility to Staphylococcus aureus infection is a consequence of deficient NGF-TRKA signalling. Mutations in the voltage-gated sodium channels SCN9A and SCN11A can cause congenital painlessness, and in contradistinction, other mutations can cause episodic neuropathic pain. SCN9A/Nav1.7 is an analgesic target. SCN11A/Nav1.9 is unlikely to be an analgesic target. There are further Mendelian causes of painlessness to be discovered. Areas of controversy Which NGF-TRKA intracellular signalling pathways operate in nociceptor development and which in post-natal pain sensing? Why have no clinically effective Nav1.7 antagonist been generated? SCN9A-CIP causes analgesia, at least in part, through endogenous opioids. Why do all CIP phenotypes involve a complete loss of all types of nociception? Areas timely for developing research PRDM12 as an analgesic target. Discovery of the function and analgesic potential of new CIP genes. Can NGF-TRKA be used in the treatment of S. aureus?

Mutations in the alpha subunit of voltage-gated sodium channel 1.7 (NaV1.7), encoded by SCN9A gene, play an important role in the regulation of nociception and can lead to a wide range of clinical outcomes, ranging from extreme pain syndromes to congenital inability to experience pain. To expand the phenotypic and genotypic spectrum of SCN9A-related channelopathies, we describe the proband, a daughter born from consanguineous parents, who had pain insensitivity, diminished temperature sensation, foot burns, and severe loss of nociceptive nerve fibers in the epidermis. Next-generation sequencing of SCN9A (NM_002977.3) revealed a novel homozygous substitution (c.377+7TG) in the donor splice site of intron 3. As the RNA functional testing is challenging, the in silico analysis is the first approach to predict possible alterations. In this case, the computational analysis was unable to identify the splicing consensus and could not provide any prediction for splicing defects. The affected intron indeed belongs to the U12 type, a family of introns characterised by noncanonical consensus at the splice sites, accounting only for 0.35% of all human introns, and is not included in most of the training sets for splicing prediction. A functional study on proband RNA showed different aberrant transcripts, where exon 3 was missing and an intron fragment was included. A quantification study using real-time polymerase chain reaction showed a significant reduction of the NaV1.7 canonical transcript. Collectively, these data widen the spectrum of SCN9A-related insensitivity to pain by describing a mutation causing NaV1.7 deficiency, underlying the nociceptor dysfunction, and highlight the importance of molecular investigation of U12 introns' mutations despite the silent prediction.

Background KBG syndrome is a very rare autosomal dominant disorder, characterized by macrodontia, distinctive craniofacial findings, skeletal findings, post-natal short stature, and developmental delays, sometimes associated with seizures and EEG abnormalities. So far, there have been over 100 cases of KBG syndrome reported. Case presentation Here, we describe two sisters of a non-consanguineous family, both presenting generalized epilepsy with febrile seizures (GEFS+), and one with a more complex phenotype associated with mild intellectual disability, skeletal and dental anomalies. Whole exome sequencing (WES) analysis in all the family members revealed a heterozygous SCN9A mutation, p.(Lys655Arg), shared among the father and the two probands, and a novel de novo loss of function mutation in the ANKRD11 gene, p.(Tyr1715*), in the proband with the more complex phenotype. The reassessment of the phenotypic features confirmed that the patient fulfilled the proposed diagnostic criteria for KBG syndrome, although complicated by early-onset isolated febrile seizures. EEG abnormalities with or without seizures have been reported previously in some KBG cases. The shared variant, occurring in SCN9A, has been previously found in several individuals with GEFS+ and Dravet syndrome. Conclusions This report describe a novel de novo variant in ANKRD11 causing a mild phenotype of KGB syndrome and further supports the association of monogenic pattern of SCN9A mutations with GEFS+. Our data expand the allelic spectrum of ANKRD11 mutations, providing the first Brazilian case of KBG syndrome. Furthermore, this study offers an example of how WES has been instrumental allowing us to better dissect the clinical phenotype under study, which is a multilocus variation aggregating in one proband, rather than a phenotypic expansion associated with a single genomic locus, underscoring the role of multiple rare variants at different loci in the etiology of clinical phenotypes making problematic the diagnostic path. The successful identification of the causal variant in a gene may not be sufficient, making it necessary to identify other variants that fully explain the clinical picture. The prevalence of blended phenotypes from multiple monogenic disorders is currently unknown and will require a systematic re-analysis of large WES datasets for proper diagnosis in daily practice.

Objective Erythromelalgia is highly disabling and treatment is often very challenging. There have been solitary case reports that it might benefit from sympathectomy. This study sought to evaluate the short-term and long-term efficacy of chemical lumbar sympathectomy (CLS) for treatment of recalcitrant erythromelalgia and try to identify a CLS-responsive subset. Methods Patients with recalcitrant erythromelalgia were recruited from a tertiary hospital over a 10-year period. L3 to L4 CLS was performed using 5% phenol. The pain intensity score (visual analog scale [VAS] 0-10) was assessed before CLS and at 1 day, 1 week, 3 months, 6 months, 1 year, and 2 years after CLS. A VAS decrease of 90%-100% is defined as complete response, 60%-89% as major partial response. Relapse was defined by a return of a VAS score of 5 or higher. SCN9A gene mutations were screened. Results Thirteen patients were enrolled, with a median age of 15 years. The mean follow-up was 6.2 ± 3.8 years. SCN9A gene mutation was identified in five patients having family histories. The VAS was 8.2 ± 2.0 at baseline; it decreased to 4.9 ± 2.7 at 1 day and 1.9 ± 3.0 at 1 week after CLS. Nine patients (69.2%) achieved complete response at 1 week after CLS, including three patients with SCN9A gene mutation. Among the three complete response patients having the gene mutation, two reverted to major partial response and one relapsed at 2 years after CLS. Among the six complete response patients without mutation, five maintained complete response and one relapsed. Among the four patients who did not achieve complete response, one patient died at 3.5 months and one patient had an amputation performed at 4 months after CLS. Conclusions CLS provides a valid option for the treatment of recalcitrant erythromelalgia. It takes about 1 week to achieve full efficacy. Relapse may occur, especially in patients with an SCN9A gene mutation.

Fatigue is a cardinal symptom in fibromyalgia. Fatigue is assumed to be the result of genetic susceptibility and environmental factors. We aimed at examining the role of genetic susceptibility for fatigue in southern Spanish women with fibromyalgia, by looking at single nucleotide polymorphisms in 34 fibromyalgia candidate-genes, at the interactions between genes, and at the gene-physical activity interactions. We extracted DNA from saliva of 276 fibromyalgia women to analyze genepolymorphisms. Accelerometers registered physical activity and sedentary behavior. Fatigue was assessed with the Multidimensional Fatigue Inventory. Based on the Bonferroni’s and False Discovery Rate values, we found that the genotype of the rs4453709 polymorphism (sodium channel protein type 9 subunit alpha, SCN9A, gene) was related to reduced motivation (AT carriers showed the highest reduced motivation) and reduced activity (AA carriers showed the lowest reduced activity). Carriers of the heterozygous genotype of the rs1801133 (methylene tetrahydrofolate reductase, MTHFR, gene) or rs4597545 (SCN9A gene) polymorphisms who were physically active reported lower scores on fatigue compared to their inactive counterparts. Highly sedentary carriers of the homozygous genotype of the rs7607967 polymorphism (AA/GG genotype; SCN9A gene) presented more reduced activity (a dimension of fatigue) than those with lower levels of sedentary behavior. Collectively findings from the present study suggest that the contribution of genetics and gene-physical activity interaction to fatigue in fibromyalgia is modest., Spanish Ministry of Economy and Competitiveness [I + D + i DEP2010-15639, I + D + i DEP2013-40908-R to M.D.-F.; BES-2014-067612 to F.E.-L.], Spanish Ministry of Education [FPU13/03410 to D.S.-T.; FPU 15/00002 to B.G.-C.], Consejería de Turismo, Comercio y Deporte, Junta de Andalucía [CTCD-201000019242-TRA to M.D.-F.], University of Granada, Plan Propio de Investigación 2016, Excellence actions: Units of Excellence; Unit of Excellence on Exercise and Health (UCEES)

Erythromelalgia is a rare pain syndrome caused by gain-of-function mutations of the SCN9A gene. The gene encodes Nav1.7 channels, preferentially located in the sympathetic ganglia and nociceptive sensory neurons of the dorsal root ganglia (DRG),1 that play a key role in pain modulation.2 DRG hyperexcitability leads to decreased pain threshold and increased firing frequency of pain signaling neurons.3 Clinically, this presents as recurrent, severe burning pain, redness, warmth, and often swelling of the distal extremities. Exposure to cold may provide relief but can lead to skin ulcerations.4 There is anecdotal evidence of partial relief from NSAIDS, antihistamines, and sodium channel blockers.5,6 Carbamazepine and oxcarbazepine inactivate sodium channels but have been ineffective in most patients. Only 1 family with erythromelalgia and V400M mutation in the SCN9A gene that responded to carbamazepine was reported so far.3

Many studies have demonstrated the clinical utility and importance of epilepsy gene panel testing to confirm the specific aetiology of disease, enable appropriate therapeutic interventions, and inform accurate family counselling. Previously, SCN9A gene variants, in particular a c.1921A>T p.(Asn641Tyr) substitution, have been identified as a likely autosomal dominant cause of febrile seizures/febrile seizures plus and other monogenic seizure phenotypes indistinguishable from those associated with SCN1A, leading to inclusion of SCN9A on epilepsy gene testing panels. Here we present serendipitous findings of genetic studies that identify the SCN9A c.1921A>T p.(Asn641Tyr) variant at high frequency in the Amish community in the absence of such seizure phenotypes. Together with findings in UK Biobank these data refute an association of SCN9A with epilepsy, which has important clinical diagnostic implications., Author summary Epilepsy is defined as a tendency to have seizures, affecting around 1:100 people worldwide. Some genetic types of epilepsy can be diagnosed using a test that examines genes that have previously been shown to cause epilepsy when affected by genetic alterations. Identifying the genetic cause of a patient’s epilepsy can help determine which treatments are likely to be helpful, provide prognostic information and inform accurate family counselling. The genes that are included in diagnostic epilepsy gene testing panels are decided by reviewing published scientific studies. Previous publications have described an association between the SCN9A gene and forms of epilepsy, leading to inclusion of the SCN9A gene in diagnostic testing panels. In this paper we present the results of our genetic findings and follow-up studies of SCN9A gene alterations in the Amish community and UK Biobank, alongside a fresh appraisal of previous studies investigating the role of SCN9A in epilepsy. Together our findings strongly refute an association between SCN9A and epilepsy. This work has important clinical implications and should lead to the re-evaluation of SCN9A by expert groups and its removal from genetic testing panels, preventing future genetic misdiagnosis which may have devastating and sometimes lethal consequences.

ObjectiveTrigeminal neuralgia is defined as a sudden severe shock-like pain within the distribution of the trigeminal nerve. Pain is a subjective experience that is influenced by gender, culture, environment, psychological traits, and genes. Sodium channels and nerve growth factor play important roles in the transmission of nociceptive signals and pain. The aim of this study was to investigate the occurrence of Nav1.7 sodium channel and nerve growth factor receptor TrkA gene polymorphisms (SCN9A/rs6746030 and NTRK1/rs633, respectively) in trigeminal neuralgia patients.MethodsNinety-six subjects from pain specialty centers in the southeastern region of Brazil were divided into 2 groups: 48 with classical trigeminal neuralgia diagnosis and 48 controls. Pain was evaluated using the visual analog scale and multidimensional McGill Pain Questionnaire. Genomic DNA was obtained from oral swabs in all individuals and was analyzed by real-time polymerase chain reaction.ResultsNo association was observed between evaluated polymorphisms and trigeminal neuralgia. For allele analyses, patients and controls had similar frequencies for both genes. Genotype distribution or allele frequencies of polymorphisms analyzed here did not correlate to pain scores.ConclusionsAlthough no association of evaluated polymorphisms and trigeminal neuralgia diagnosis or pain severity was observed, our data do not exclude the possibility that other genotypes affecting the expression of Nav1.7 or TrkA are associated with the disease. Further studies should investigate distinct genetic polymorphisms and epigenetic factors that may be important in expression of these molecules.

Mutations in the sodium-channel Nav 1.7, encoded by the gene SCN9A, are known to cause pain disorders. In particular, gain-of-function missense mutations in Nav 1.7 have been shown to be causal in primary erythromelalgia. We present a patient with erythromelalgia, pain attacks and hyperosmia with a mutation within the sodium-channel gene SCN9A. A 50-year-old woman presented with burning pain in both feet and abdominal pain attacks developed over the course of 10 years. Furthermore, this patient experienced a hypersensitivity for odours. Clinical investigation as well as serum/cerebrospinal fluid laboratory findings and electrophysiological testing were unremarkable. Olfactory testing showed high olfactory acuity for all screened modalities and good intranasal sensitivity. Furthermore, quantitative sensory testing within the trigeminal area revealed very low thresholds for thermal, tactile and pain detection. In addition, quantitative sensory testing at the lower legs showed hyperalgesia and, as the disease progresses, thermal sensory function loss. Skin biopsies of the proximal and distal lower limbs revealed reduced epidermal nerve fibre density indicating small fibre neuropathy. Genetic analysis of the SCN9A gene demonstrated a heterozygous mutation in Exon 20 - c.3734A>G (p.N1245S). Treatment with clinically available sodium-channel inhibitors did not result in significant pain relief. Local application of the sodium-channel blocker ambroxol however, reduced pain intensity. Continuous odour exposure stabilised mood and induced a short-term pain relief. This clinical note illustrates the course of middle-age onset erythromelalgia and points to clinical findings related to a likely pathogenic missense mutation affecting the sodium-channel Nav 1.7. SIGNIFICANCE: This case report illustrates the course of middle-age onset erythromelalgia with presumed gain-of-function in olfactory and pain sensation associated with a Nav1.7 channel mutation.

A 41-year-old woman presented with burning and erythema in her extremities triggered by warmth and activity, which was relieved by applying ice. Extensive workup was consistent with adult-onset primary erythromelalgia (EM). Several pharmacological treatments were tried including local anesthetics, capsaicin, ziconotide, and dantrolene, all providing 24-48 hours of relief followed by symptom flare. Interventional therapies, including peripheral and sympathetic ganglion blocks, also failed. Thus far, clonidine and ketamine have been the only effective agents for our patient. Genetic testing was negative for an EM-associated mutation in the SCN9A gene, encoding the NaV1.7 sodium channel, suggesting a mutation in an alternate gene.

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.

Background People with fibromyalgia identify fatigue as one of the main symptoms of the disease [1]. It is hypothesised that the pathogenesis of fibromyalgia involves a genetic susceptibility that is modulated by environmental factors [2] Objectives To examine the possible role of genetic susceptibility for fatigue in southern Spanish women with fibromyalgia, by looking at the possible associations of fatigue and single nucleotide polymorphisms in 34 fibromyalgia candidate-genes, at the interactions between genes, and at the associations between gene-physical activity. Methods In this cross-sectional study participated 276 women with fibromyalgia. We extracted DNA from saliva in order to analyse gene-polymorphisms related to fibromyalgia susceptibility, symptoms, or potential mechanisms. Accelerometers registered the participants’ physical activity and sedentary time. Five dimensions of fatigue were assessed with the Multidimensional Fatigue Inventory. Age, body fat (%), and analgesics and antidepressants consumption were considered as confounders in all analyses. Based on the Bonferroni’s and False Discovery Rate (FDR) values, the statistical significance was interpreted. Results AT carriers of the rs4453709 polymorphism (sodium channel protein type 9 subunit alpha, SCN9A, gene) showed the highest scores on fatigue. Carriers of the heterozygous genotype of the rs1801133 (methylene tetrahydrofolate reductase, MTHFR, gene) or rs4597545 (SCN9A gene) polymorphisms who were physically active reported lower fatigue compared to their inactive counterparts. Highly sedentary carriers of the homozygous genotype of the rs7607967 polymorphism (AA/GG genotype; SCN9A gene) presented higher fatigue than those with lower levels of sedentary time. Conclusion Physical (in)activity behaviours and the SCN9A and MTHFR genes were jointly related to fatigue. Thereby, the potential benefits of following an active lifestyle might be observed more clearly in women with fibromyalgia genetically predispose to higher levels of fatigue. References [1] Bennett RM, et al. BMC Musculoskelet Disord 2010;11:134. doi:10.1186/1471-2474-11-134 [2] McBeth J, Mulvey MR. Nat Rev Rheumatol 2012;8:108–16. doi:10.1038/nrrheum.2011.216 Acknowledgement This work was supported by the Spanish Ministry of Economy and Competitiveness [I+D+i DEP2010-15639, I+D+i DEP2013-40908-R to M.D.-F.; BES-2014-067612 to F.E.-L.]; the Spanish Ministry of Education [FPU13/03410 to D.S.-T.; FPU 15/00002 to B.G.C]; the Consejeria de Turismo, Comercio y Deporte, Junta de Andalucia [CTCD-201000019242-TRA to MD-F]; and the University of Granada, Plan Propio de Investigacion 2016, Excellence actions: Units of Excellence; Unit of Excellence on Exercise and Health (UCEES). Disclosure of Interests None declared

A 68-year-old female with a history of sporadic type and presumably secondary erythromelalgia with chronic intractable pain presented for foot surgery. The procedure was performed with combined general anesthesia and regional anesthesia consisting of the placement of a popliteal pain catheter for postoperative pain management. Subsequent whole-genome sequencing revealed that the patient was a homozygous carrier of the common missense mutation in the SCN9A gene coding for voltage-gated sodium channel (NaV1.7) - dbSNP rs6746030 (R1150W). The occurrence of this single nucleotide polymorphism (SNP) was previously suggested not to be associated with erythromelalgia but rather thought to be part of quantitative changes in the pain threshold in different cohorts of patients. The placement of the pain catheter, although controversial in patients with erythromelalgia, provided effective postoperative pain relief without any side effects.

Introduction: Paroxysmal Extreme Pain Disorder (PEPD) is a rare autosomal dominant disease, caused by mutations in the SCN9A gene, which encodes the NaV1.7 voltage-gated sodium channel alpha subunit. Symptoms generally begin in early infancy with episodes of excruciating, burning and spreading pain in the lower part of the body, typically in the anorectal area, which can last from seconds to hours. Case description: We describe the case of a 5-year-old male with PEPD and a novel heterozygous mutation c.5825c>T (p. Thr1942ile) in the SCN9A gene. This is a novel mutation that has not previously been reported. Discussion: According to the available information, the clinical significance of the variant c.5825c>T (p. Thr1942ile) is unknown. However, its presence in the patient and in others affected family members, reinforces its possible pathogenicity and is suggestive of mutation segregation with the disease in this family. Conclusion: We consider that it is a family case of interest to the pediatrician, for allowing: 1) To be able to intuit it by the clinic early and 2) To be able to confirm it by means of the corresponding genetic study.

Genetic neuropathies comprise a range of conditions which can include neuropathy as a predominant feature of the disease or as part of a multisystem disease. Small fiber sensory neuropathy and symptoms have been described in association with sodium channel mutations such as in the SCN9A, SCN10A, and SCN11A genes, which encode Nav1.7, Nav1.8, and Nav1.9 sodium channels, respectively. Erythromelalgia is an autosomal dominant painful condition characterized by redness of the skin and intermittent burning sensation of extremities, triggered by heat or exercise, and was shown to be related to mutations of Nav1.7. Paroxysmal extreme pain disorder (PEPD, first described as familial rectal pain) is an inherited syndrome with paroxysms of rectal, ocular, or submandibular pain with flushing, also linked to gain-of-function mutations of Nav1.7. In addition, SCN9A gene variants have been found in subjects of an idiopathic small fiber neuropathy (SFN) cohort. Predominant involvement of small nerve fibers has been documented in patients with Fabry disease, familial amyloid polyneuropathy (FAP), and Tangier’s disease. This chapter focuses on small fiber neuropathies and channelopathies with sensory symptoms, particularly pain, as the sole or primary feature.

Small fiber neuropathy is a disorder of the small nerve fibers, in which patients experience severe pain and complaints of dysfunction of the autonomic nervous system (such as dizziness when standing or intestinal complaints). This dissertation describes the occurrence of underlying disorders in small fiber neuropathy, in which diabetes mellitus, immunological disorders, a vitamin B12 deficiency and certain abnormalities in the hereditary material (sodium channel mutations) were found to occur more frequently than in the general Dutch population. In addition, this thesis shows the current and new treatment options for pain in small fiber neuropathy, such as the medication lacosamide. The dissertation shows that lacosamide is a safe and complication-delaying treatment that can reduce pain in patients with small fiber neuropathy based on a sodium channel mutation in the SCN9A gene.

The sodium channel 1.7 (Nav1.7), which is encoded by SCN9A gene, is involved in neuropathic pain. As crucial regulators of gene expression, many miRNAs have already gained importance in neuropathic pain, including miR-182, which is predicted to regulate the SCN9A gene. Nav1.7 expression in L4-L6 dorsal root ganglions (DRGs) can be up regulated by spared nerve injury (SNI), while miR-182 expression was down regulated following SNI model. Exploring the connection between Nav1.7 and miR-182 may facilitate the development of a better-targeted therapy. In the current study, direct pairing of miR-182 with the SCN9A gene was verified using a luciferase assay in vitro. Over-expression of miR-182 via microinjection of miR-182 agomir reversed the abnormal increase of Nav1.7 at both mRNA and protein level in L4-6 DRGs of SNI rats, and significantly attenuated the hypersensitivity to mechanical stimulus in the rats. In contrast, administration of miR-182 antagomir enhanced the Nav1.7 expression at both mRNA and protein level in L4-6 DRGs, companied with the generation of mechanical hypersensitivity in naïve rats. Collectively, we concluded that miR-182 can alleviate SNI- induced neuropathic pain through regulating Nav1.7 in rats.

Strong human genetic evidence points to an essential contribution of the voltage-gated sodium channel Nav1.7 to pain sensation: loss of Nav1.7 function leads to congenital insensitivity to pain, whereas gain-of-function mutations in theSCN9Agene that encodes Nav1.7 cause painful neuropathies, such as inherited erythromelalgia, a syndrome characterized by episodic spontaneous pain. Selective Nav1.7 channel blockers thus hold promise as potential painkillers with improved safety and reduced unwanted side effects compared with existing therapeutics. To determine the maximum effect of a theoretically perfectly selective Nav1.7 inhibitor, we generated a tamoxifen-inducible KO mouse model enabling genetic deletion of Nav1.7 from adult mice. Electrophysiological recordings of sensory neurons from these mice following tamoxifen injection demonstrated the loss of Nav1.7 channel current and the resulting decrease in neuronal excitability of small-diameter neurons. We found that behavioral responses to most, but surprisingly not all, modalities of noxious stimulus are abolished following adult deletion of Nav1.7, pointing toward indications where Nav1.7 blockade should be efficacious. Furthermore, we demonstrate that isoform-selective acylsulfonamide Nav1.7 inhibitors show robust analgesic and antinociceptive activity acutely after a single dose in mouse pain models shown to be Nav1.7-dependent. All experiments were done with both male and female mice. Collectively, these data expand the depth of knowledge surrounding Nav1.7 biology as it relates to pain, and provide preclinical proof of efficacy that lays a clear path toward translation for the therapeutic use of Nav1.7-selective inhibitors in humans.SIGNIFICANCE STATEMENTLoss-of-function mutations in the sodium channel Nav1.7 cause congenital insensitivity to pain in humans, making Nav1.7 a top target for novel pain drugs. Targeting Nav1.7 selectively has been challenging, however, in part due to uncertainties in which rodent pain models are dependent on Nav1.7. We have developed and characterized an adult-onset Nav1.7 KO mouse model that allows us to determine the expected effects of a theoretically perfect Nav1.7 blocker. Importantly, many commonly used pain models, such as mechanical allodynia after nerve injury, appear to not be dependent on Nav1.7 in the adult. By defining which models are Nav1.7 dependent, we demonstrate that selective Nav1.7 inhibitors can approximate the effects of genetic loss of function, which previously has not been directly established.

Voltage-gated sodium channels (NaV) play a crucial role in development and propagation of action potentials in neurons and muscle cells. NaV1.7 channels take a special place in modern science since it is believed that they contribute to nerve hyperexcitability. Mutations of the gene SCN9A, which codes the α subunit of NaV1.7 channels, are associated with pain perception disorders (primary erythermalgia, congenital analgesia, and paroxysmal pain disorder). It is considered that the SCN9A gene mutations may cause variations in sensitivity to pain, from complete insensitivity to extreme sensitivity. Further research of the SCN9A gene polymorphism influence on pain sensitivity is essential for the understanding of the pathophysiology of pain and the development of the appropriate targeted pain treatment.

The aim of the present study was to identify whether the sodium voltage-gated channel alpha subunit 9 (SCN9A) gene modification is a potential treatment for diarrhea‑predominant irritable bowel syndrome (D‑IBS), via regulating the Na+ channel and the expression of nerve growth factor (NGF). The recombinant adenovirus vector of the SCN9A gene was established, and rat colon cells were isolated for SCN9A gene modification. All subjects were divided into four groups: i) The SCN9A‑modified (D‑IBS rat model implanted with SCN9A‑modified colon cells), ii) negative control (NC; D‑IBS rat model implanted with colon cells without SCN9A gene modification), iii) blank (D‑IBS rat model without any treatment) and iv) normal (normal rats without any treatment). Western blotting and reverse transcription‑quantitative polymerase chain reaction were used to detect the protein and mRNA expression levels of SCN9A, NGF and voltage gated sodium channels (Nav)1.8 and Nav1.9 in rat colon tissues. Compared with the normal group, the rats in the SCN9A, NC and blank groups had significantly elevated mRNA and protein expression levels of NGF, SCN9A, Nav1.8 and Nav1.9. The rats in the SCN9A group demonstrated significantly increased mRNA and protein expression levels of NGF, SCN9A, Nav1.8 and Nav1.9 compared with the NC group and the blank group (all P

Paroxysmal extreme pain disorder is an autosomal dominant disorder caused by mutation of the SCN9A gene. In most cases, the pain is relieved by carbamazepine. We report on a novel SCN9A mutation associated with carbamazepine-resistant. The proband was a 7-month-old child who suffered from typical attacks from birth onwards. Sequencing of SCN9A revealed a heterozygous c.4880T>G substitution. Identification of this novel mutation and characterization of the associated carbamazepine-resistant phenotype may facilitate diagnosis and drug development.