Congenital Insensitivity To Pain Research Articles

Genetic analysis of a child with Congenital insensitivity to pain due to compound heterozygous variants of SCN9A gene

To explore the genetic etiology of a child featuring multiple fractures and congenital insensitivity to pain (CIP). A child who had presented at the West China Hospital of Sichuan University on March 16, 2023 for recurrent fractures and CIP was selected as the study subject. Peripheral blood samples of the child and his parents was collected. Trio-whole exome sequencing was carried out. Candidate variants were verified by Sanger sequencing and bioinformatic analysis. This study has been approved by the Medical Ethics Committee of West China Hospital of Sichuan University (No. 2019-772). Trio-whole exome sequencing revealed that the child has harbored compound heterozygous variants of the SCN9A gene, namely c.560delC (p.P187Rfs*15) and c.829C>T (p.R277*), which were respectively inherited from his father and mother. Homozygous c.829C>T variant had been demonstrated as pathogenic among CIP patients, whilst the c.560delC (p.P187Rfs*15) variant was unreported previously and predicted to be pathogenic based on the guidelines of the American College of Medical Genetics and Genomics (ACMG). The child was diagnosed with CIP due to the compound heterozygous variants of the SCN9A gene. Above finding has enabled genetic counselling and reproductive guidance for this family.

Midfacial toddler excoriation syndrome (MiTES): case series, diagnostic criteria and evidence for a pathogenic mechanism.

PRDM12 polyalanine tract expansions cause two different disorders: midfacial toddler excoriation syndrome (MiTES; itch with normal pain sensation associated with 18 homozygous alanines (18A); and congenital insensitivity to pain (CIP) with normal itch associated with 19 homozygous alanines (19A). Knowledge of the phenotype, genotype and disease mechanism of MiTES is incomplete. Why 18A vs. 19A PRDM12 can cause almost opposite phenotypes is unknown; no other polyalanine or polyglutamine tract expansion disease causes two such disparate phenotypes. To assess the genotype and phenotype of nine new, nine atypical and six previously reported patients diagnosed with MiTES. Using cell lines with homozygous PR domain zinc finger protein 12 (PRDM12) containing 12 alanines (12A; normal), 18A (MiTES) and 19A (CIP), we examined PRDM12 aggregation and subcellular localization by image-separation confocal microscopy and subcellular fractionation Western blotting. MiTES presents in the first year of life; in all cases the condition regresses over the first decade, leaving scarring. The MiTES phenotype is highly distinctive. Features overlapping with PRDM12 CIP are rarely found. The genotype-phenotype study of the PRDM12 polyalanine tract shows that having 7-15 alanines is normal; 16-18 alanines is associated with MiTES; 19 alanines leads to CIP; and no clinically atypical cases of MiTES had a polyalanine tract expansion. PRDM12 aggregation and subcellular localization differed significantly between 18A and normal 12A cell lines and between 18A and 19A cell lines. MiTES is a new protein-aggregation disease. We provide diagnostic criteria for MiTES and improved longitudinal data. MiTES and CIP are distinct phenotypes, despite their genotypes varying by a single alanine in the PRDM12 polyalanine tract. We found clear distinctions between the cellular phenotypes of normal, MiTES and CIP cells. We hypothesize that the developmental environment of the trigeminal ganglion is unique and critically sensitive to pre- and postnatal levels of PRDM12.

Congenital Insensitivity to Pain: A Fatal Entity

Abstract Congenital insensitivity to pain (CIP), also known as congenital analgesia, is an autosomal recessive, extraordinarily rare condition, in which a patient cannot feel pain in any part of his or her body. These patients may experience hyperthermia due to anhidrosis and sustain multiple fatal injuries because they are unable to feel pain at all. All these contribute to the early demise of the patient at a young age. Herein, we attempt to highlight the potentially catastrophic effects of CIP in a 4-year-old girl and reevaluate the representative features that a prudent physician should be aware of.

Identification and In-Silico study of non-synonymous functional SNPs in the human SCN9A gene.

Single nucleotide polymorphisms are the most common form of DNA alterations at the level of a single nucleotide in the genomic sequence. Genome-wide association studies (GWAS) were carried to identify potential risk genes or genomic regions by screening for SNPs associated with disease. Recent studies have shown that SCN9A comprises the NaV1.7 subunit, Na+ channels have a gene encoding of 1988 amino acids arranged into 4 domains, all with 6 transmembrane regions, and are mainly found in dorsal root ganglion (DRG) neurons and sympathetic ganglion neurons. Multiple forms of acute hypersensitivity conditions, such as primary erythermalgia, congenital analgesia, and paroxysmal pain syndrome have been linked to polymorphisms in the SCN9A gene. Under this study, we utilized a variety of computational tools to explore out nsSNPs that are potentially damaging to heath by modifying the structure or activity of the SCN9A protein. Over 14 potentially damaging and disease-causing nsSNPs (E1889D, L1802P, F1782V, D1778N, C1370Y, V1311M, Y1248H, F1237L, M936V, I929T, V877E, D743Y, C710W, D623H) were identified by a variety of algorithms, including SNPnexus, SNAP-2, PANTHER, PhD-SNP, SNP & GO, I-Mutant, and ConSurf. Homology modeling, structure validation, and protein-ligand interactions also were performed to confirm 5 notable substitutions (L1802P, F1782V, D1778N, V1311M, and M936V). Such nsSNPs may become the center of further studies into a variety of disorders brought by SCN9A dysfunction. Using in-silico strategies for assessing SCN9A genetic variations will aid in organizing large-scale investigations and developing targeted therapeutics for disorders linked to these variations.

Genetic landscape of congenital insensitivity to pain and hereditary sensory and autonomic neuropathies.

Congenital insensitivity to pain (CIP) and hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders exclusively or predominantly affecting the sensory and autonomic neurons. Due to the rarity of the diseases and findings based mainly on single case reports or small case series, knowledge about these disorders is limited. Here, we describe the molecular workup of a large international cohort of CIP/HSAN patients including patients from normally under-represented countries. We identify 80 previously unreported pathogenic or likely pathogenic variants in a total of 73 families in the >20 known CIP/HSAN-associated genes. The data expand the spectrum of disease-relevant alterations in CIP/HSAN, including novel variants in previously rarely recognized entities such as ATL3-, FLVCR1- and NGF-associated neuropathies and previously under-recognized mutation types such as larger deletions. In silico predictions, heterologous expression studies, segregation analyses and metabolic tests helped to overcome limitations of current variant classification schemes that often fail to categorize a variant as disease-related or benign. The study sheds light on the genetic causes and disease-relevant changes within individual genes in CIP/HSAN. This is becoming increasingly important with emerging clinical trials investigating subtype or gene-specific treatment strategies.

Charcot arthropathy and acro-osteolysis in a 5-year-old girl with hereditary sensory and autonomic neuropathy type II: A case report

Charcot neuropathic arthropathy is a destructive process that can occur in patients with neuropathy associated with medical diseases such as diabetes. A rare cause of neuropathic arthropathy is congenital insensitivity to pain (CIP) which includes varying degrees of sensory loss and lack of pain perception contributing to absent withdrawal responses. The clinical manifestations of CIP include delayed diagnosis of fractures, joint dislocations, acro-osteolysis, avascular necrosis, osteomyelitis, heterotopic ossification, and Charcot arthropathy. We herein report a case of Charcot arthropathy of ankle joints in a 5-year-old girl with CIP due to underlying hereditary sensory and autonomic neuropathy who had recurrent upper and lower limb fractures with acro-osteolysis. She had an inability to perceive pain from the first year of her life. She also had mild developmental delay. Family history was unremarkable. Blood count, liver and thyroid function tests, erythrocyte sedimentation rate, C-reactive protein, blood electrolytes, blood sugar and other laboratory tests were normal. Charcot neuropathic arthropathy in children is rare and can be a part of congenital diseases like CIP. A high degree of suspicion may lead to early detection and can prevent joint and bone destruction and deformities.

A rare case of postoperative pain in congenital analgesia: case report

A rare case of postoperative pain in congenital analgesia: case report

Novel SCN9A variant associated with congenital insensitivity to pain.

Congenital insensitivity to pain (CIP) is a rare autosomal recessive syndrome characterized by lack of pain perception and a wide spectrum of clinical signs such as anosmia and hyposmia. Variants in SCN9A gene are associated with CIP. We here report on a Lebanese family with three CIP patients referred for genetic investigations. Whole exome sequencing analysis revealed the presence of a novel nonsense, homozygous SCN9A pathogenic variant: SCN9A (NM_001365536.1): c.4633G > T, p.(Glu1545*) in exon 26. Our three Lebanese patients had CIP, urinary incontinence and normal olfactory function while two of them also presented with osteoporosis and osteoarthritis; this association of features has not been previously reported in the literature. We hope that this report would contribute to a better delineation of the phenotypic spectrum associated with SCN9A pathogenic variants.

Novel Variants and Phenotypic Heterogeneity in Congenital Insensitivity to Pain (S23.002)

<h3>Objective:</h3> We present novel variants in the <i>SCN9A</i> gene in three cases with congenital insensitivity to pain (CIP), two of whom were siblings. <h3>Background:</h3> CIP is a rare disorder. Patients have no perception of pain against injurious stimuli but are otherwise normal. It is caused by loss-of-function mutations in the <i>SCN9A</i> gene encoding for the T voltage-gated sodium channel Nav1.7. <h3>Design/Methods:</h3> Case 1 was an 18 months old male with recurrent self-injurious behavior and insensitivity to pain and heat. Case 2 was a 15 years old male patient with insensitivity to pain, juvenile arthritis, and inability to gain weight. Case 3 (elder sister) had similar complaints. Parents reported insensitivity to pain decreased with time and that both siblings began to experience pain after age 10. All cases had a normal neurologic examination and electromyography (EMG) result, except they were unresponsive to pain. <h3>Results:</h3> Clinical exome sequencing (CES) from peripheral blood was performed for both cases. <h3>Case 1:</h3> A homozygous frameshift variant (c.2362dupG (c.2362_2363insG) (p.Asp788GlyfsTer4)) was detected in <i>SCN9A</i> which was predicted as pathogenic in <i>in silico</i> databases. <h3>Case 2:</h3> A homozygous frameshift variant (c.3143_3154delTCAGTGGTTTTGinsA (p.Ile1048LysfsTer13)) was detected in <i>SCN9A which</i> was predicted as likely pathogenic in <i>in silico</i> databases. Both variants were not reported previously. The segregation analysis was performed for both cases. Case 2 had an additional intronic SNP (rs4303728), which in one study associated this variant with severe postoperative pain. <h3>Conclusions:</h3> Homozygous and compound heterozygous mutations cause CIP. Partial regain of pain is a unique situation. The variants can be hypomorphic alleles, allowing low levels of Nav1.7- channel function. The inactivating mutation may have an attenuated effect on channel function. Further studies are required to understand the effect of the variants on Nav1.7 channel function. <b>Disclosure:</b> Ms. Ovunc has nothing to disclose. Dr. Kalayci Yigin has nothing to disclose. Dr. Kesriklioglu has nothing to disclose. Gizem Izgi has nothing to disclose. Fitnat Ulug has nothing to disclose. Sema Saltık has nothing to disclose. Prof. Seven has nothing to disclose. Dr. Agirbaslo has nothing to disclose.

Nav1.7 gain-of-function mutation I228M triggers age-dependent nociceptive insensitivity and C-LTMR dysregulation

Gain-of-function mutations in Scn9a, which encodes the peripheral sensory neuron-enriched voltage-gated sodium channel Nav1.7, cause paroxysmal extreme pain disorder (PEPD), inherited erythromelalgia (IEM), and small fiber neuropathy (SFN). Conversely, loss-of-function mutations in the gene are linked to congenital insensitivity to pain (CIP). These mutations are evidence for a link between altered sodium conductance and neuronal excitability leading to somatosensory aberrations, pain, or its loss. Our previous work in young adult mice with the Nav1.7 gain-of-function mutation, I228M, showed the expected DRG neuron hyperexcitability, but unexpectedly the mice had normal mechanical and thermal behavioral sensitivity. We now show that with aging both male and female mice with this mutation unexpectedly develop a profound insensitivity to noxious heat and cold, as well skin lesions that span the body. Electrophysiology demonstrates that, in contrast to young mice, aged I228M mouse DRGs have a profound loss of sodium conductance and changes in activation and slow inactivation dynamics, representing a loss-of-function. Through RNA sequencing we explored how these age-related changes may produce the phenotypic changes and found a striking and specific decrease in C-low threshold mechanoreceptor- (cLTMR) associated gene expression, suggesting a potential contribution of this DRG neuron subtype to Nav1.7 dysfunction phenotypes. A GOF mutation in a voltage-gated channel can therefore produce over a prolonged time, highly complex and unexpected alterations in the nervous system beyond excitability changes.

Congenital insensitivity to pain: the controversy and possible pathophysiology model in progress

Congenital insensitivity to pain (CIP) is a disorder that emphasizes the critical role of nociception in protecting against tissue damage and is characterized by repeated injuries, burns, and poor wound healing. CIP is a developmental defect caused by pathogenic genetic variants in multiple genes. Current treatment modalities for patients with CIP are primarily symptomatic, but the first targeted therapies are being tested. Interestingly, this area of research offers new ideas for slow-moving pain, one of the great challenges still unresolved by the medical community.

Congenital insensitivity to pain associated with PRDM12 mutation: Two case reports and a literature review.

Background: PRDM12 is a newly discovered gene responsible for congenital insensitivity to pain (CIP). Its clinical manifestations are various and not widely known. Methods: The clinical data of two infants diagnosed with CIP associated with PRDM12 mutation were collected. A literature review was performed, and the clinical characteristics of 20 cases diagnosed with a mutation of PRDM12 were summarized and analyzed. Results: Two patients had pain insensitivity, tongue and lip defects, and corneal ulcers. The genomic analysis results showed that variants of PRDM12 were detected in the two families. The case 1 patient carried heterozygous variations of c.682+1G > A and c.502C > T (p.R168C), which were inherited from her father and mother, respectively. We enrolled 22 patients diagnosed with CIP through a literature review together with our cases. There were 16 male (72.7%) and 6 female (27.3%) patients. The age of onset ranged from 6 months to 57years. The prevalence of clinic manifestation was 14 cases with insensitivity to pain (63.6%), 19 cases with self-mutilation behaviors (86.4%), 11 cases with tongue and lip defects (50%), 5 cases with mid-facial lesions (22.7%), 6 cases with distal phalanx injury (27.3%), 11 cases of recurrent infection (50%), 3 cases (13.6%) with anhidrosis, and 5 cases (22.7%) with global developmental delay. The prevalence of ocular symptoms was 11 cases (50%) with reduced tear secretion, 6 cases (27.3%) with decreased corneal sensitivity, 7 cases (31.8%) with disappeared corneal reflexes, 5.5 cases (25%, 0.5 indicated a single eye) with corneal opacity, 5 cases (22.7%) with corneal ulceration, and 1 case (4.5%) with a corneal scar. Conclusion: The syndrome caused by PRDM12 mutation is a clinically distinct and diagnosable disease that requires joint multidisciplinary management to control the development of the disease and minimize the occurrence of complications.

The NGF R100W Mutation, Associated with Hereditary Sensory Autonomic Neuropathy Type V, Specifically Affects the Binding Energetic Landscapes of NGF and of Its Precursor proNGF and p75NTR.

Nerve Growth Factor (NGF), the prototype of the neurotrophin family, stimulates morphological differentiation and regulates neuronal gene expression by binding to TrkA and p75NTR receptors. It plays a critical role in maintaining the function and phenotype of peripheral sensory and sympathetic neurons and in mediating pain transmission and perception during adulthood. A point mutation in the NGFB gene (leading to the amino acid substitution R100W) is responsible for Hereditary Sensory and Autonomic Neuropathy type V (HSAN V), leading to a congenital pain insensitivity with no clear cognitive impairments, but with alterations in the NGF/proNGF balance. The available crystal structures of the p75NTR/NGF and 2p75NTR/proNGF complexes offer a starting point for Molecular Dynamics (MD) simulations in order to capture the impact of the R100W mutation on their binding energetic landscapes and to unveil the molecular determinants that trigger their different physiological and pathological outcomes. The present in silico studies highlight that the stability and the binding energetic fingerprints in the 2p75NTR/proNGF complex is not affected by R100W mutation, which on the contrary, deeply affects the energetic landscape, and thus the stability in the p75NTR/NGF complex. Overall, these findings present insights into the structural basis of the molecular mechanisms beyond the clinical manifestations of HSAN V patients.

SCN9A variant in a family of mixed breed dogs with congenital insensitivity to pain.

Congenital insensitivity to pain (CIP) and hereditary sensory and autonomic neuropathies (HSANs) are a rare group of genetic disorders causing inability to feel pain. Three different associated variants have been identified in dogs: 1 in Border Collies, 1 in mixed breed dogs, and 1 in Spaniels and Pointers. To clinically and genetically characterize CIP in a family of mixed breed dogs. Two mixed breed dogs from the same litter were independently presented: 1 for evaluation of painless fractures, and the other for chronic thermal skin injuries. Physical, neurological, and histopathological evaluations were performed. Whole genome sequencing of 1 affected dog was used to identify homozygous protein-changing variants that were not present in 926 control genomes from diverse dog breeds. Physical and neurological examinations showed the absence of superficial and deep pain perception in the entire body. Histopathological evaluations of the brain, spinal cord and sensory ganglia were normal. Whole genome sequencing identified a homozygous missense variant in SCN9A, XM_038584713.1:c.2761C>T or XP_038440641.1:(p.Arg921Cys). Both affected dogs were homozygous for the mutant allele, which was not detected in 926 dogs of different breeds. We confirmed the diagnosis of CIP in a family of mixed breed dogs and identified a likely pathogenic variant in the SCN9A gene. The clinical signs observed in these dogs mimic those reported in humans with pathogenic SCN9A variants causing CIP. This report is the first of a spontaneous pathogenic SCN9A variant in domestic animals.

Isolation and transfection of myenteric neurons from mice for patch-clamp applications.

The enteric nervous system (ENS) is a complex neuronal network organized in ganglionated plexuses that extend along the entire length of the gastrointestinal tract. Largely independent of the central nervous system, the ENS coordinates motility and peristalsis of the digestive tract, regulates secretion and absorption, and is involved in immunological processes. Electrophysiological methods such as the patch-clamp technique are particularly suitable to study the function of neurons as well as the biophysical parameters of the underlying ion channels under both physiological and pathophysiological conditions. However, application of the patch-clamp method to ENS neurons remained difficult because they are embedded in substantial tissue layers that limit access to and targeted manipulation of these cells. Here, we present a robust step-by-step protocol that involves isolation of ENS neurons from adult mice, culturing of the cells, their transfection with plasmid DNA, and subsequent electrophysiological characterization of individual neurons in current-clamp and voltage-clamp recordings. With this protocol, ENS neurons can be prepared, transfected, and electrophysiologically characterized within 72 h. Using isolated ENS neurons, we demonstrate the feasibility of the approach by functional overexpression of recombinant voltage-gated NaV1.9 mutant channels associated with hereditary sensory and autonomic neuropathy type 7 (HSAN-7), a disorder characterized by congenital analgesia and severe constipation that can require parenteral nutrition. Although our focus is on the electrophysiological evaluation of isolated ENS neurons, the presented methodology is also useful to analyze molecules other than sodium channels or to apply alternative downstream assays including calcium imaging, proteomic and nucleic acid approaches, or immunochemistry.

Ocular manifestations among patients with congenital insensitivity to pain due to variants in PRDM12 and SCN9A genes.

Congenital insensitivity to pain (CIP) is a group of rare genetic disorders with a common characteristic of absent sensation to nociceptive pain. Here we present a series of six patients; three had a novel variant in the PRDM12 gene (group A), and three had a missense variant in the SCN9A gene (group B). We compared the ocular manifestations between the two groups. Records of these patients from 2009 through 2018 were reviewed. The retrieved data included demographics, genetic analysis results, ocular history and ophthalmic findings including visual acuity, corneal sensitivity, tear production, ocular surface findings, cycloplegic refraction, and fundoscopy. We found that patients with PRDM12 variant had more severe manifestations of ocular surface disease, with more prevalent corneal opacities and worse visual acuity, compared to patients with SCN9A variant.

Genetic pain loss disorders.

Genetic pain loss includes congenital insensitivity to pain (CIP), hereditary sensory neuropathies and, if autonomic nerves are involved, hereditary sensory and autonomic neuropathy (HSAN). This heterogeneous group of disorders highlights the essential role of nociception in protecting against tissue damage. Patients with genetic pain loss have recurrent injuries, burns and poorly healing wounds as disease hallmarks. CIP and HSAN are caused by pathogenic genetic variants in >20 genes that lead to developmental defects, neurodegeneration or altered neuronal excitability of peripheral damage-sensing neurons. These genetic variants lead to hyperactivity of sodium channels, disturbed haem metabolism, altered clathrin-mediated transport and impaired gene regulatory mechanisms affecting epigenetic marks, long non-coding RNAs and repetitive elements. Therapies for pain loss disorders are mainly symptomatic but the first targeted therapies are being tested. Conversely, chronic pain remains one of the greatest unresolved medical challenges, and the genes and mechanisms associated with pain loss offer new targets for analgesics. Given the progress that has been made, the coming years are promising both in terms of targeted treatments for pain loss disorders and the development of innovative pain medicines based on knowledge of these genetic diseases.

Novel compound heterozygous SCN9A variations causing congenital insensitivity to pain in a patient

To explore the genetic basis for a child featuring congenital insensitivity to pain (CIP). Targeted capture and next generation sequencing (NGS) was carried out for the proband. Suspected pathogenic variants were confirmed by Sanger sequencing of the proband and his parents. The proband was found to harbor compound heterozygous variants of SCN9A gene, namely c.1598delA (p.N533Ifs*31) and c.295_296delCGinsAT (p.R99I), which were respectively inherited from his father and mother. Both variants were predicted to be pathogenic, and neither was reported previously. The compound heterozygous variants of the SCN9A gene probably underlay the CIP in this child. Above finding has enabled genetic counseling for this family.

Nav1.7 is required for normal C-low threshold mechanoreceptor function in humans and mice.

Patients with bi-allelic loss of function mutations in the voltage-gated sodium channel Nav1.7 present with congenital insensitivity to pain (CIP), whilst low threshold mechanosensation is reportedly normal. Using psychophysics (n = 6 CIP participants and n = 86 healthy controls) and facial electromyography (n = 3 CIP participants and n = 8 healthy controls), we found that these patients also have abnormalities in the encoding of affective touch, which is mediated by the specialized afferents C-low threshold mechanoreceptors (C-LTMRs).In the mouse, we found that C-LTMRs express high levels of Nav1.7. Genetic loss or selective pharmacological inhibition of Nav1.7 in C-LTMRs resulted in a significant reduction in the total sodium current density, an increased mechanical threshold and reduced sensitivity to non-noxious cooling. The behavioural consequence of loss of Nav1.7 in C-LTMRs in mice was an elevation in the von Frey mechanical threshold and less sensitivity to cooling on a thermal gradient.Nav1.7 is therefore not only essential for normal pain perception but also for normal C-LTMR function, cool sensitivity and affective touch.

Case report of a 7-year-old CIPA child with multiple debridement's and amputations.

Background: Congenital Insensitivity to Pain (CIPA), otherwise known as Hereditary Sensory and Autonomic Neuropathy Type IV (HSAN IV), is a rarely occurring autosomal recessive disorder encompassed by a group of hereditary and sensory autonomic neuropathies, which was initially described as pure analgesia present congenitally. Its clinical manifestation includes recurrent episodes of infections with unexplained behavior, anhidrosis, mental retardation, and damage to oral structures.&#x0D; Case Presentation: In this case report, we have demonstrated the signs and symptoms of a 7-year-old boy presented to the pediatric out-patient department of Memon Medical Institute Hospital with complaints of multiple fluid-filled blisters since the age of 1 year. He had a history of multiple hospital admissions due to infections, where he was diagnosed with a case of CIPA.&#x0D; Management &amp; Results: Since the diagnosis of this medical condition, the child has undergone multiple debridements of his wound and amputations. The treatment plan was aimed to manage the blisters, prevent self-injuries, and treat orthopedic problems by regular dermal and orthopedic follow-ups.&#x0D; Conclusion: There is no cure for CIPA patients, the families that have CIPA patients must undergo prenatal testing and screening to prevent the birth of another affected child.