scholarly journals Novel SCN9A missense mutations contribute to congenital insensitivity to pain: Unexpected correlation between electrophysiological characterization and clinical phenotype

2020 ◽  
Vol 16 ◽  
pp. 174480692092388
Author(s):  
Jiaoli Sun ◽  
Lulu Li ◽  
Luyao Yang ◽  
Guangyou Duan ◽  
Tingbin Ma ◽  
...  
Keyword(s):  
Sodium Current ◽  
Hek293 Cells ◽  
Pain Patient ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Protein Levels ◽  
Congenital Insensitivity ◽  
Congenital Insensitivity To Pain ◽  
Electrophysiological Characterization ◽  
Insensitivity To Pain

Congenital insensitivity to pain (OMIM 243000) is an extremely rare disorder caused by loss-of-function mutations in SCN9A encoding Nav1.7. Although the SCN9A mutations and phenotypes of painlessness and anosmia/hyposmia in patients are previously well documented, the complex relationship between genotype and phenotype of congenital insensitivity to pain remains unclear. Here, we report a congenital insensitivity to pain patient with novel SCN9A mutations. Functional significance of novel SCN9A mutations was assessed in HEK293 cells expressing Nav1.7, the results showed that p.Arg99His significantly decreased current density and reduced total Nav1.7 protein levels, whereas p.Trp917Gly almost abolished Nav1.7 sodium current without affecting its protein expression. These revealed that mutations in Nav1.7 in this congenital insensitivity to pain patient still retained partial channel function, but the patient showed completely painlessness, the unexpected genotypic-phenotypic relationship of SCN9A mutations in our patient may challenge the previous findings “Nav1.7 total loss-of-function leads to painlessness.” Additionally, these findings are helpful for understanding the critical amino acid for maintaining function of Nav1.7, thus contributing to the development of Nav1.7-targeted analgesics.

scholarly journals Case Report: Mutant SCN9A Susceptible to Charcot Neuroarthropathy in a Patient With Congenital Insensitivity to Pain

2021 ◽  
Vol 15 ◽  
Author(s):  
Xiao-hui Xie ◽  
Jian-guang Tang ◽  
Zhong-hua Liu ◽  
Shui-jiao Peng ◽  
Zhuang-zhuang Yuan ◽  
...  
Keyword(s):  
Sodium Current ◽  
Systemic Disease ◽  
Joint Destruction ◽  
Hek293 Cells ◽  
Loss Of Function ◽  
Charcot Neuroarthropathy ◽  
Congenital Insensitivity ◽  
Congenital Insensitivity To Pain ◽  
Tissue Trauma ◽  
Insensitivity To Pain

Charcot neuroarthropathy is a systemic disease with pathological changes in the musculoskeletal system, which leads to fractures, dislocations, and deformities involving multiple bones and joints, particularly those of the feet. While the common underlying cause of Charcot neuroarthropathy is diabetes mellitus, it is also associated with congenital insensitivity to pain (CIP). CIP is a rare disorder caused by loss-of-function mutations in SCN9A encoding Nav1.7. In this study, we report a patient with CIP from a consanguineous family susceptible to Charcot neuroarthropathy with a novel SCN9A mutation. This report involves the case of a middle-aged man who suffered from CIP, had repeated painless fractures, and developed bone and joint destruction. The physical and radiological examinations revealed that multiple joints were swollen and deformed, and soft-tissue trauma was evident. We identified a novel homozygous SCN9A mutation (p.Cys1339Arg) by whole-exome sequencing (WES), which was verified using Sanger sequencing. In addition, the wild-type (WT) and mutated p. Cys1339Arg were assessed in HEK293 cells expressing Nav1.7, and the results showed that p. Cys1339Arg almost abolished the Nav1.7 sodium current. In conclusion, Charcot neuroarthropathy associated with CIP demonstrated a wider spectrum of Charcot neuroarthropathy than was previously recognized or documented. In addition, this finding is conducive to understanding the critical amino acids for maintaining the function of Nav1.7, thus contributing to the development of Nav1.7-targeted analgesics.

Congenital insensitivity to pain

2018 ◽  
Author(s):  
Bhagat Singh ◽  
Alban Latremoliere ◽  
Michael Costigan
Keyword(s):  
Sensory Processing ◽  
Molecular Mechanisms ◽  
Familial Dysautonomia ◽  
Loss Of Function ◽  
Clinical Genetic ◽  
Gene Encoding ◽  
Congenital Insensitivity ◽  
Ngf Receptor ◽  
Congenital Insensitivity To Pain ◽  
Insensitivity To Pain

The landmark paper discussed in this chapter is ‘Congenital insensitivity to pain. A clinical, genetic and neurophysiological study of four children from the same family’, published by D. C. Thrush in 1973. The study of patients with congenital conditions that result in pain insensitivity has been invaluable in helping define the molecular mechanisms of sensory processing. These patients share a major defining phenotype (they feel little or no pain from birth), although they often have differing subtle symptoms which belie a host of separate conditions that we have now started to recognize with the advent of molecular genetics (e.g. loss-of-function mutations in the gene encoding Nav1.7, and mutations related to nerve growth factor (NGF)); these include congenital insensitivity to pain with anhydrosis (CIPA; thought to be due to mutations in the gene encoding the NGF receptor NTRK1) and hereditary sensory and autonomic neuropathies (HSANs) such as familial dysautonomia.

scholarly journals Guided growth in the correction of knee deformity in patients with congenital insensitivity to pain

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Soroush Baghdadi ◽  
Sadegh Saberi ◽  
Taghi Baghdadi
Keyword(s):  
Demographic Data ◽  
Joint Destruction ◽  
Walking Ability ◽  
Guided Growth ◽  
Tertiary Referral Hospital ◽  
Common Procedure ◽  
Correction Rate ◽  
Congenital Insensitivity ◽  
Congenital Insensitivity To Pain ◽  
Insensitivity To Pain

Abstract Background Orthopedic manifestations of congenital insensitivity to pain (CIP) can be devastating if left untreated. Knee deformities are common in patients with CIP and might lead to joint destruction and loss of walking ability. The purpose of the present study was to report the results and complications of guided growth procedures around the knee in patients with CIP. Methods In a retrospective review, all patients with CIP who underwent guided growth procedures around the knee from 2009 to 2017 at a tertiary referral hospital were evaluated. Patients with secondary insensitivity to pain (e.g., syringomyelia), as well as patients with incomplete records, were excluded. Demographic data, clinical findings, correction rate, and complications were recorded. Results Ten knees in six patients fulfilled the inclusion criteria. The median age was 10 (range, 5–12), with a mean follow-up of 31 months (range, 16–56). Distal femoral tension-band hemiepiphysiodesis was the most common procedure, followed by proximal tibial hemiepiphysiodesis. The mean correction rate was 0.28°/month for femoral deformity. Staples were removed prematurely in one patient due to extrusion. No cases of infection or skin dehiscence were observed. None of the patients needed a reconstructive knee procedure during the study period. Conclusions The findings of this study suggest that guided growth procedures might have a role in the correction of knee deformities in patients with CIP. However, the correction rate is lower than that of typically developing children, patients should be closely followed to prevent complications, and stringent patient selection criteria should be followed to ensure success.

scholarly journals Identification of a novel nonsense mutation of the neurotrophic tyrosine kinase receptor type 1 gene in two siblings with congenital insensitivity to pain with anhidrosis

2017 ◽  
Vol 45 (2) ◽  
pp. 549-555 ◽  
Author(s):  
Ting Wang ◽  
Haibo Li ◽  
Jingjing Xiang ◽  
Bin Wei ◽  
Qin Zhang ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Nonsense Mutation ◽  
Mutation Screening ◽  
Receptor Type ◽  
Tyrosine Kinase Receptor ◽  
Site Mutation ◽  
Congenital Insensitivity ◽  
Congenital Insensitivity To Pain ◽  
Insensitivity To Pain

Objective To explore the aetiology of congenital insensitivity to pain with anhidrosis (CIPA) in two Chinese siblings with typical CIPA symptoms including insensitivity to pain, inability to sweat, and self-mutilating behaviours. Methods Clinical examination and genetic testing were conducted of all available family members, and the findings were used to create a pedigree. Mutation screening using PCR amplification and DNA Sanger sequencing of the entire neurotrophic tyrosine kinase receptor type 1 gene ( NTRK1) including intron–exon boundaries was used to identify mutations associated with CIPA. Results A novel nonsense mutation (c.7C > T, p. Arg3Ter) and a known splice-site mutation (c.851-33 T > A) were detected in NTRK1 and shown to be associated with CIPA. Conclusion Our findings expand the known mutation spectrum of NTRK1 and provide insights into the aetiology of CIPA.

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