Pain Insensitivity, Congenital
Androgen-Insensitivity Syndrome
A novel point mutation affecting the tyrosine kinase domain of the TRKA gene in a family with congenital insensitivity to pain with anhidrosis. (1/35)
A nerve growth factor receptor encoded by the TRKA gene plays an important part in the formation of autonomic neurons and small sensory neurons in dorsal root ganglia and in signal transduction through its intracytoplasmic tyrosine kinase domain. Recently, three mutations in the tyrosine kinase domain of TRKA have been reported in patients with congenital insensitivity to pain with anhidrosis, which is an autosomal recessive disorder characterized by recurrent fever due to absence of sweating, no reaction to noxious stimuli, self-mutilating behavior, and mental retardation. We examined the TRKA gene in five generations of a large Japanese family with many consanguineous marriages who live in a small remote island of the southern part of Japan. We found a novel point mutation at nucleotide 1825 (A-->G transition) resulting in Met-581-Val in the tyrosine kinase domain. Two of the three affected patients were homozygous for this mutation; however, the third affected patient was heterozygous. Further analysis revealed that the third patient was a compound heterozygote with the Met-581-Val mutation in one allele and with a single base C deletion mutation at nucleotide 1726 in exon 14 in the other allele, resulting in a frameshift and premature termination codon. (+info)Congenital insensitivity to pain with anhidrosis: novel mutations in the TRKA (NTRK1) gene encoding a high-affinity receptor for nerve growth factor. (2/35)
Congenital insensitivity to pain with anhidrosis (CIPA) is characterized by recurrent episodes of unexplained fever, anhidrosis (inability to sweat), absence of reaction to noxious stimuli, self-mutilating behavior, and mental retardation. Human TRKA encodes a high-affinity tyrosine kinase receptor for nerve growth factor (NGF), a member of the neurotrophin family that induces neurite outgrowth and promotes survival of embryonic sensory and sympathetic neurons. We have recently demonstrated that TRKA is responsible for CIPA by identifying three mutations in a region encoding the intracellular tyrosine kinase domain of TRKA in one Ecuadorian and three Japanese families. We have developed a comprehensive strategy to screen for TRKA mutations, on the basis of the gene's structure and organization. Here we report 11 novel mutations, in seven affected families. These are six missense mutations, two frameshift mutations, one nonsense mutation, and two splice-site mutations. Mendelian inheritance of the mutations is confirmed in six families for which parent samples are available. Two mutations are linked, on the same chromosome, to Arg85Ser and to His598Tyr;Gly607Val, hence, they probably represent double and triple mutations. The mutations are distributed in an extracellular domain, involved in NGF binding, as well as the intracellular signal-transduction domain. These data suggest that TRKA defects cause CIPA in various ethnic groups. (+info)Congenital insensitivity to pain with anhidrosis: a case report. (3/35)
Congenital insensitivity to pain with anhidrosis (CIPA) is a very rare genetic disorder of the peripheral nervous system characterized by recurrent episodes of unexplained fever, generalized anhidrosis, insensitivity to pain and temperature, and accompanied by self-mutilating behavior and mental retardation. We report on a 16 month-old boy with CIPA who exhibited these characteristic clinical features. A sural nerve biopsy revealed markedly reduced numbers of unmyelinated and small myelinated fibers, consistent with the characteristic features of CIPA. (+info)Altered pain responses in mice lacking alpha 1E subunit of the voltage-dependent Ca2+ channel. (4/35)
alpha(1) subunit of the voltage-dependent Ca(2+) channel is essential for channel function and determines the functional specificity of various channel types. alpha(1E) subunit was originally identified as a neuron-specific one, but the physiological function of the Ca(2+) channel containing this subunit (alpha(1E) Ca(2+) channel) was not clear compared with other types of Ca(2+) channels because of the limited availability of specific blockers. To clarify the physiological roles of the alpha(1E) Ca(2+) channel, we have generated alpha(1E) mutant (alpha(1E)-/-) mice by gene targeting. The lacZ gene was inserted in-frame and used as a marker for alpha(1E) subunit expression. alpha(1E)-/- mice showed reduced spontaneous locomotor activities and signs of timidness, but other general behaviors were apparently normal. As involvement of alpha(1E) in pain transmission was suggested by localization analyses with 5-bromo-4-chloro-3-indolyl beta-d-galactopyranoside staining, we conducted several pain-related behavioral tests using the mutant mice. Although alpha(1E)+/- and alpha(1E)-/- mice exhibited normal pain behaviors against acute mechanical, thermal, and chemical stimuli, they both showed reduced responses to somatic inflammatory pain. alpha(1E)+/- mice showed reduced response to visceral inflammatory pain, whereas alpha(1E)-/- mice showed apparently normal response compared with that of wild-type mice. Furthermore, alpha(1E)-/- mice that had been presensitized with a visceral noxious conditioning stimulus showed increased responses to a somatic inflammatory pain, in marked contrast with the wild-type mice in which long-lasting effects of descending antinociceptive pathway were predominant. These results suggest that the alpha(1E) Ca(2 +) channel controls pain behaviors by both spinal and supraspinal mechanisms. (+info)Congenital insensitivity to pain with anhidrosis (CIPA): effect of TRKA (NTRK1) missense mutations on autophosphorylation of the receptor tyrosine kinase for nerve growth factor. (5/35)
Human TRKA (NTRK1) encodes the receptor tyrosine kinases (RTKs) for nerve growth factor (NGF) and is the gene responsible for congenital insensitivity to pain with anhidrosis (CIPA), an autosomal recessive disorder characterized by a lack of pain sensation and anhidrosis. We reported 11 putative missense mutations in 31 CIPA families from various ethnic groups. Here we have introduced the corresponding mutations into the TRKA cDNA and examined NGF-stimulated autophosphorylation. We find that wild-type TRKA precursor proteins in a neuronal and a non-neuronal cell line were differentially processed and phosphorylated in an NGF-dependent and -independent manner, respectively. Two mutants (L93P and L213P) in the extracellular domain were aberrantly processed and showed diminished autophosphorylation in neuronal cells. Five mutants (G516R, G571R, R643W, R648C and G708S) in the tyrosine kinase domain were processed as wild-type TRKA but showed significantly diminished autophosphorylation in both neuronal and non-neuronal cells. In contrast, R85S and (H598Y; G607V), detected previously as double and triple mutations, are probably polymorphisms in a particular ethnic background. The other putative mutant D668Y might be a rare polymorphism or might impair the function of TRKA without compromising autophosphorylation. Mutated residues in the tyrosine kinase domain are conserved in various RTKs and probably contribute to critical function of these proteins. Thus, naturally occurring TRKA missense mutations with loss of function provide considerable insight into the structure-function relationship in the RTK family. Our data may aid in developing a drug which targets the clinically devastating 'complex regional pain syndrome'. (+info)Characterization of acute somatosensory pain transmission in P/Q-type Ca(2+) channel mutant mice, leaner. (6/35)
To study the role of the Ca(v)2.1/alpha(1A) (P/Q-type) Ca(2+) channel in somatosensory pain processing, behavioral and electrophysiological studies were conducted using the leaner (tg(la)/tg(la)) mouse. Behavioral analyses in tg(la)/tg(la) revealed reduced responses to mechanical stimuli, and enhanced responses to heat stimuli. Electrophysiological analyses showed that tg(la)/tg(la) had a significantly reduced ability to evoke dorsal root potentials, suggesting a functional deficit in the spinal dorsal horn local circuitry responsible for presynaptic inhibition of primary sensory fibers. These results suggest the critical importance of the P/Q-type channel in modulation of acute somatosensory pain transmission in spinal cord. (+info)Novel pathogenic mechanisms of congenital insensitivity to pain with anhidrosis genetic disorder unveiled by functional analysis of neurotrophic tyrosine receptor kinase type 1/nerve growth factor receptor mutations. (7/35)
Congenital insensitivity to pain with anhidrosis (CIPA) is a rare genetic disease characterized by absence of reaction to noxious stimuli and anhidrosis. The genetic bases of CIPA have remained long unknown. A few years ago, point mutations affecting both coding and noncoding regions of the neurotrophic tyrosine receptor kinase type 1 (NTRK1)/nerve growth factor receptor gene have been detected in CIPA patients, demonstrating the implication of the nerve growth factor/NTRK1 pathway in the pathogenesis of the disease. We have previously shown that two CIPA mutations, the G571R and the R774P, inactivate the NTRK1 receptor by interfering with the autophosphorylation process. We have extended our functional analysis to seven additional NTRK1 mutations associated with CIPA recently reported by others. Through a combination of biochemical and biological assays, we have identified polymorphisms and pathogenic mutations. In addition to the identification of residues important for NTRK1 activity, our analysis suggests the existence of two novel pathogenic mechanisms in CIPA: one based on the NTRK1 receptor processing and the other acting through the reduction of the receptor activity. (+info)Congenital insensitivity to pain. Orthopaedic manifestations. (8/35)
We reviewed 13 patients with congenital insensitivity to pain. A quantitative sweat test was carried out in five and an intradermal histamine test in ten. DNA examination showed specific mutations in four patients. There were three clinical presentations: type A, in which multiple infections occurred (five patients); type B, with fractures, growth disturbances and avascular necrosis (three patients); and type C, with Charcot arthropathies and joint dislocations, as well as fractures and infections (five patients, four with mental retardation). Patient education, shoeware and periods of non-weight-bearing are important in the prevention and early treatment of decubitus ulcers. The differentiation between fractures and infections should be based on aspiration and cultures to prevent unnecessary surgery. Established infections should be treated by wide surgical debridement. Deformities can be managed by corrective osteotomies, and shortening by shoe raises or epiphysiodesis. Joint dislocations are best treated conservatively. (+info)Congenital pain insensitivity, also known as congenital analgesia, is a rare genetic disorder characterized by the absence of ability to feel pain due to the malfunction or lack of functioning nociceptors - the nerve cells that transmit painful stimuli to the brain. It is typically caused by mutations in the SCN9A gene, which encodes a sodium channel necessary for the function of nociceptors.
Individuals with congenital pain insensitivity may not feel any pain from injuries or other sources of harm, and as a result, they are at risk for serious injury or even death due to lack of protective responses to painful stimuli. They may also have an increased risk of developing recurrent infections and self-mutilation behaviors.
It is important to note that while these individuals do not feel pain, they can still experience other sensory inputs such as touch, temperature, and pressure. Congenital pain insensitivity is a complex medical condition that requires careful management and monitoring by healthcare professionals.
Androgen Insensitivity Syndrome (AIS) is a genetic condition that occurs in individuals who are genetically male (have one X and one Y chromosome) but are resistant to androgens, which are hormones that play a role in male sexual development. This resistance is caused by changes (mutations) in the gene for the androgen receptor.
There are three main types of AIS: complete androgen insensitivity syndrome (CAIS), partial androgen insensitivity syndrome (PAIS), and mild androgen insensitivity syndrome (MAIS).
In CAIS, individuals are completely resistant to androgens, which results in the development of female external genitalia at birth. Despite having testes, these individuals do not have a functioning male reproductive system and typically have a female gender identity. They may be diagnosed during adolescence when they do not begin to menstruate or experience other signs of puberty.
In PAIS and MAIS, the degree of androgen insensitivity varies, resulting in a range of physical characteristics that can include both male and female features. These individuals may have ambiguous genitalia at birth, and their gender identity may not align with their genetic sex.
It's important to note that people with AIS are typically healthy and do not have an increased risk of medical conditions beyond those related to their hormonal differences. However, they may face challenges related to their gender identity, sexual development, and fertility. It is recommended that individuals with AIS receive comprehensive medical care and support from a team of healthcare professionals who specialize in this condition.
Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. It is a complex phenomenon that can result from various stimuli, such as thermal, mechanical, or chemical irritation, and it can be acute or chronic. The perception of pain involves the activation of specialized nerve cells called nociceptors, which transmit signals to the brain via the spinal cord. These signals are then processed in different regions of the brain, leading to the conscious experience of pain. It's important to note that pain is a highly individual and subjective experience, and its perception can vary widely among individuals.