Structural analysis of TrkA mutations in patients with congenital insensitivity to pain reveals PLCγ as an analgesic drug target.

Chronic pain is a major health issue, and the search for new analgesics has become increasingly important because of the addictive properties and unwanted side effects of opioids. To explore potentially new drug targets, we investigated mutations in the NTRK1 gene found in individuals with congenital insensitivity to pain with anhidrosis (CIPA). NTRK1 encodes tropomyosin receptor kinase A (TrkA), the receptor for nerve growth factor (NGF) and that contributes to nociception. Molecular modeling and biochemical analysis identified mutations that decreased the interaction between TrkA and one of its substrates and signaling effectors, phospholipase Cγ (PLCγ). We developed a cell-permeable phosphopeptide derived from TrkA (TAT-pQYP) that bound the Src homology domain 2 (SH2) of PLCγ. In HEK-293T cells, TAT-pQYP inhibited the binding of heterologously expressed TrkA to PLCγ and decreased NGF-induced, TrkA-mediated PLCγ activation and signaling. In mice, intraplantar administration of TAT-pQYP decreased mechanical sensitivity in an inflammatory pain model, suggesting that targeting this interaction may be analgesic. The findings demonstrate a strategy to identify new targets for pain relief by analyzing the signaling pathways that are perturbed in CIPA.

Rare mutations in ATL3, SPTLC2 and SCN9A explaining hereditary sensory neuropathy and congenital insensitivity to pain in a Brazilian cohort.

Hereditary sensory neuropathies (HSN) are a group of rare neurological disorders with heterogeneous clinical and genetic characteristics. Although at least 17 different genes have already been associated with HSN, the epidemiology of the disorder in Brazil is still unknown. Performing whole genome sequencing (WGS) in 23 unrelated Brazilian families diagnosed with HSN, we detected pathogenic variants in ATL3, SPTLC2, and SCN9A in 12 patients belonging to five unrelated families. Clinical features associated with heterozygous mutations in ATL3 (c.575A > G; p.(Tyr192Cys)) and SPTLC2 (c.529A > G; p.(Asn177Asp)) were sensory deficits, neuropathic pain, and recurrent ulcerations. Presenting as congenital insensitivity to pain, three unrelated probands carried biallelic loss-of-function mutations in SCN9A. The so far undescribed stop mutation c.2106G > A (p.(Trp702Ter)) and the likewise novel splicing variant c.3319-1G > A were found in compound-heterozygosity with, respectively, the known pathogenic variants c.2908G > T (p.Trp970Ter) and c.2690G > A (p.Glu897Ter). In total, we identified pathogenic mutations in 21.7% of our families, which suggests that most of the cases could be explained by yet to be discovered genes or unusual alleles. Our study represents the first mutational screen in a Brazilian HSN cohort, enabling additional insights for genotype-phenotype correlations, reducing misdiagnoses, and providing early treatment considerations.

Clinical, genomics and networking analyses of a high-altitude native American Ecuadorian patient with congenital insensitivity to pain with anhidrosis: a case report.

BACKGROUND: Congenital insensitivity to pain with anhidrosis (CIPA) is an extremely rare autosomal recessive disorder characterized by insensitivity to pain, inability to sweat and intellectual disability. CIPA is caused by mutations in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1) that encodes the high-affinity receptor of nerve growth factor (NGF). CASE PRESENTATION: Here, we present clinical and molecular findings in a 9-year-old girl with CIPA. The high-altitude indigenous Ecuadorian patient presented several health problems such as anhidrosis, bone fractures, self-mutilation, osteochondroma, intellectual disability and Riga-Fede disease. After the mutational analysis of NTRK1, the patient showed a clearly autosomal recessive inheritance pattern with the pathogenic mutation rs763758904 (Arg602*) and the second missense mutation rs80356677 (Asp674Tyr). Additionally, the genomic analysis showed 69 pathogenic and/or likely pathogenic variants in 46 genes possibly related to phenotypic heterogeneity, including the rs324420 variant in the FAAH gene. The gene ontology enrichment analysis showed 28 mutated genes involved in several biological processes. As a novel contribution, the protein-protein interaction network analysis showed that NTRK1, SPTBN2 and GRM6 interact with several proteins of the pain matrix involved in the response to stimulus and nervous system development. CONCLUSIONS: This is the first study that associates clinical, genomics and networking analyses in a Native American patient with consanguinity background in order to better understand CIPA pathogenesis.

[Congenital Analgesia: report of 2 cases]. / Analgesia congénita: reporte de dos casos.

Congenital analgesia is a rare condition, reporting in the international literature in rare cases since 1932, when it was first described. Its cause has been the subject of development of multiple theories and studies through the years. Currently various studies and experiments as its origin point mutation in the gene encoding SC9NA sodium channels, which have an important role in nociceptive transmission signals in the human body. The purpose of this study is to present two cases that were valued in the department of pediatric orthopedics at UMAE HTYOLV, patients whose insensitivity to pain has produced significant injuries that were once cause for valuation of the hospital.

La analgesia congénita es un padecimiento poco frecuente, en la literatura internacional se ha reportado en contados casos desde 1932, año en el que fue descrita por primera vez. Su causa ha sido motivo del desarrollo de múltiples teorías y numerosos estudios a través de los años. Actualmente diversos estudios y experimentos apuntan como origen la mutación en el gen SCN9A que codifica para los canales de sodio, los cuales tienen un papel muy importante en la transmisión de señales nociceptivas en el cuerpo humano. El motivo del presente estudio es dar a conocer dos casos que fueron valorados en el servicio de ortopedia pediátrica de la UMAE HTYOLV, pacientes en quienes la falta de sensibilidad al dolor ha producido lesiones importantes que fueron en su momento motivo de valoración por parte del hospital.

Analgesia congénita: reporte de dos casos / Congenital Analgesia: report of 2 cases

Resumen: La analgesia congénita es un padecimiento poco frecuente, en la literatura internacional se ha reportado en contados casos desde 1932, año en el que fue descrita por primera vez. Su causa ha sido motivo del desarrollo de múltiples teorías y numerosos estudios a través de los años. Actualmente diversos estudios y experimentos apuntan como origen la mutación en el gen SCN9A que codifica para los canales de sodio, los cuales tienen un papel muy importante en la transmisión de señales nociceptivas en el cuerpo humano. El motivo del presente estudio es dar a conocer dos casos que fueron valorados en el servicio de ortopedia pediátrica de la UMAE HTYOLV, pacientes en quienes la falta de sensibilidad al dolor ha producido lesiones importantes que fueron en su momento motivo de valoración por parte del hospital.

Abstract: Congenital analgesia is a rare condition, reporting in the international literature in rare cases since 1932, when it was first described. Its cause has been the subject of development of multiple theories and studies through the years. Currently various studies and experiments as its origin point mutation in the gene encoding SC9NA sodium channels, which have an important role in nociceptive transmission signals in the human body. The purpose of this study is to present two cases that were valued in the department of pediatric orthopedics at UMAE HTYOLV, patients whose insensitivity to pain has produced significant injuries that were once cause for valuation of the hospital.

Pain insensitivity in a child with a de novo interstitial deletion of the long arm of the chromosome 4: Case report.

Terminal and interstitial deletions of the distal segment of the long arm of chromosome 4 (Cr4q del) are not common genetic disorders. The severity of the phenotype is correlated with the size of the deletion because small deletions have little clinical impact, whereas large deletions are usually associated with multiple congenital anomalies, postnatal growth failure, and moderate to severe intellectual disability. Alteration in pain tolerance has not been included among these features, also in case of large deletions. The purpose of this report is to document a case of a child affected by interstitial Cr4q del, expressing pain insensitivity as clinical feature not previously described. We also offer a discussion on genetic disorders featuring pain insensitivity/indifference. CASE REPORT: A Caucasian girl aged 12 came to our observation for a developmental delay with multiple congenital abnormalities and moderate intellectual disability (IQ 47). A de novo interstitial Cr4 del between band q31.3 and q32.2 (Cr4 del q31.3 to q32.2) was found. The child also expresses no evidence of pain perception to injures which normally evoke pain. Consequently, she is affected by severe disability caused by painless injuries and self-injurious behaviours, such as excessive self-rubbing and scratching. The neurological examination manifested high pain threshold with preserved tactile sensitivity. CONCLUSIONS: This is the first report of pain insensitivity in a patient with a specific genetic deletion involving the interstitial region of the distal long arm of Cr4. Moreover, this report could serve as a useful model to better understand mechanisms of pain perception and its modulation.

Pain insensitivity in a child with a de novo interstitial deletion of the long arm of the chromosome 4: Case report / Insensibilidad al dolor en un niño con una deleción intersticial de novo del brazo largo del cromosoma 4

Terminal and interstitial deletions of the distal segment of the long arm of chromosome 4 (Cr4q del) are not common genetic disorders. The severity of the phenotype is correlated with the size of the deletion because small deletions have little clinical impact, whereas large deletions are usually associated with multiple congenital anomalies, postnatal growth failure, and moderate to severe intellectual disability. Alteration in pain tolerance has not been included among these features, also in case of large deletions. The purpose of this report is to document a case of a child affected by interstitial Cr4q del, expressing pain insensitivity as clinical feature not previously described. We also offer a discussion on genetic disorders featuring pain insensitivity/indifference. Case report. A Caucasian girl aged 12 came to our observation for a developmental delay with multiple congenital abnormalities and moderate intellectual disability (IQ 47). A de novo interstitial Cr4 del between band q31.3 and q32.2 (Cr4 del q31.3 to q32.2) was found. The child also expresses no evidence of pain perception to injures which normally evoke pain. Consequently, she is affected by severe disability caused by painless injuries and self-injurious behaviours, such as excessive self-rubbing and scratching. The neurological examination manifested high pain threshold with preserved tactile sensitivity. Conclusions. This is the first report of pain insensitivity in a patient with a specific genetic deletion involving the interstitial region of the distal long arm of Cr4. Moreover, this report could serve as a useful model to better understand mechanisms of pain perception and its modulation.

[Congenital corneal anesthesia: case reports]. / Anestesia congênita de córnea: relatos de casos.

Case series of nine patients with congenital corneal anesthesia, six of them showed systemic changes in association with the ocular status. Three patients were submitted to electromyography, two showed isolated bilateral ophthalmic ramus alteration. Two patients had initial visual acuity better than 20/60 and six had final best corrected visual acuity better than 20/60 at the last visit. All of them were treated surgically and developed cornea opacities of variable sizes. Treatment of corneal congenital anesthesia must be performed as soon as possible to avoid corneal opacification. Systemic investigation, close follow-up and preparing the family for longterm and multidisciplinary approach are crucial to maintain the ocular health.

Novel nonsense and frameshift NTRK1 gene mutations in Chinese patients with congenital insensitivity to pain with anhidrosis.

Congenital insensitivity to pain with anhidrosis (CIPA; MIM 256800) is a rare autosomal recessive disorder characterized by absence of reaction to noxious stimuli, recurrent episodes of fever, anhidrosis, and mental retardation. It is caused by mutations in the gene coding for neurotrophic tyrosine kinase receptor type 1 (NTRK1; MIM# 191315). We screened two Chinese CIPA cases for mutations in the NTRK1 gene and examined their phenotype. Two novel mutations of the NTRK1 gene and two known mutations were identified. Including our two novel mutations, there are now 62 different NTRK1 gene mutations reported in patients with CIPA. We find that a combination of two null alleles usually leads to the severe phenotype, while the mild form of the CIPA disease is associated with at least one mild allele. Thirty-four among the 62 mutations (55%) are located within the tyrosine kinase domain of the NTRK1 protein. We concluded that the tyrosine kinase domain is a hot spot for mutations.

Anestesia congênita de córnea: relatos de casos / Congenital corneal anesthesia: case reports

Descrição de nove casos de anestesia congênita de córnea, sendo que desses, seis apresentavam alterações sistêmicas associadas ao quadro ocular. Três pacientes realizaram eletroneuromiografia, um sem alteração ao exame e dois com alteração isolada do ramo oftálmico do nervo trigêmeo bilateralmente. Dois pacientes tinham acuidade visual inicial melhor que 20/60 no início da avaliação e seis tinham acuidade visual final melhor que 20/60 na última visita. Todos foram submetidos a algum tipo de tratamento cirúrgico e evoluíram com opacidades corneana de tamanho variável. O tratamento dos pacientes com anestesia congênita de córnea deve ser realizado o mais precoce possível e de forma rigorosa a fim de evitar danos à transparência corneana. Investigação sistêmica, acompanhamento de perto e preparação familiar para tratamento a longo prazo e multidisciplinar são necessários para preservar a saúde ocular.

Case series of nine patients with congenital corneal anesthesia, six of them showed systemic changes in association with the ocular status. Three patients were submitted to electromyography, two showed isolated bilateral ophthalmic ramus alteration. Two patients had initial visual acuity better than 20/60 and six had final best corrected visual acuity better than 20/60 at the last visit. All of them were treated surgically and developed cornea opacities of variable sizes. Treatment of corneal congenital anesthesia must be performed as soon as possible to avoid corneal opacification. Systemic investigation, close follow-up and preparing the family for longterm and multidisciplinary approach are crucial to maintain the ocular health.

Indiferencia congénita al dolor / Congenital indifference to pain

Introducción. En la fase aguda, el dolor ejerce un mecanismo natural de protección. No obstante, existen dos trastornos congénitos cuya característica principal es una baja o nula reactividad al trauma: la insensibilidad congénita al dolor y la indiferencia congénita al dolor. Esta última es una condición poco común en la que a pesar de no existir anormalidades neurológicas en las vías del dolor, el individuo carece de una respuesta emocional a la lesión tisular. Objetivos. Presentar el caso de una niña con indiferencia congénita al dolor y hacer revisión de la fisiopatología y una aproximación diagnóstica. Metodología y resultados. Presentación de caso clínico. Conclusiones. El diagnóstico de indiferencia congénita al dolor es básicamente un diagnóstico de exclusión y dado que aún no se conoce cura para este trastorno, la prevención, la educación y el tratamiento interdisciplinario son lo primordial en estas entidades.

Introduction. In the acute phase, pain exerts a natural protective mechanism, However, there are two congenital disorders, in which the main characteristic is a low or nule reactivity to trauma: congenital insensitivity to pain and congenital indifference to pain. The last one is an uncommon condition in which, while not having neurological abnormalities in the pain pathways, the individual lacks of an emotional response to tissue injury.Objectives. To show the case of a girl with congenital indifference to pain and to make a review of the pathophysiology and diagnostic approach. Methodology and results. Presentation of a clinical case. Conclusions. The diagnosis of congenital indifference to pain is basically a diagnosis by exclusión and since a cure for this disorder is not yet known, prevention, education and interdisciplinary treatment are the priority aspects in this entities.

Complicações osteoarticulares da analgesia congênita / Osteoarticular complications of congenital analgesia

Os autores apresentam dois irmãos com diagnóstico de analgesia congênita, com suas características clínicas e evolução. Essa doença é rara, apresenta alta morbidade e gera complicações osteoarticulares de difícil solução. O objetivo dos autores foi ressaltar a importância do diagnóstico tanto para o tratamento de suas afecções secundárias, quanto para seu aspecto jurídico.

The authors present two brothers with congenital pain insensitivity, with their clinical characteristics and evolution. This disease is rare, has high morbidity and originates complex osteoarticular complications. The aim of the authors was to emphasize the value of the diagnosis for a better treatment and to avoid legal problems to the parents.

Anestesia em paciente com insensibilidade congênita a dor e anidrose / Anestesia en paciente con insensibilidad congénita al dolor y anhidrosis / Anesthesia in a patient with congenital insensitivity to pain and anhidrosis

JUSTIFICATIVA E OBJETIVOS: A insensibilidade congênita a dor e anidrose (ICDA) ou neuropatia hereditária sensorial e autonômica tipo IV (NHSA tipo IV) é neuropatia autossômica recessiva rara do grupo das neuropatias hereditárias sensoriais e autonômicas (NHSA), caracterizada por insensibilidade ao estímulo doloroso, anidrose e retardo mental. Existem poucos relatos sobre a conduta anestésica em pacientes com ICDA devido sua extrema raridade. O objetivo deste relato foi apresentar a conduta anestésica em paciente com ICDA submetida à artrodese de tornozelo esquerdo com colocação de haste e discutir as características de interesse para a anestesia nestes pacientes. RELATO DO CASO: Paciente com história de ICDA foi admitida para artrodese de tornozelo esquerdo devido à artropatia de Charcot. Na sala de operação foi monitorizada com eletrocardiógrafo, índice bispectral, SEF 95 por cento, pressão arterial não invasiva e saturação periférica da hemoglobina, medicada com midazolam como pré-anestésico e submetida à anestesia venosa com propofol e cisatracúrio. Não houve a necessidade de administração de analgésicos. Após intubação traqueal, foi acrescentada monitorização da pressão expiratória final do gás carbônico e da temperatura esofágica. Não apresentou complicações no período perioperatório. Teve alta hospitalar no segundo dia de pós-operatório. CONCLUSÕES: Embora apresentem insensibilidade à dor, alguns pacientes apresentam hiperestesia tátil, o que poderia causar sensações desagradáveis durante a manipulação cirúrgica. Apesar de relatos na literatura de pacientes submetidos a bloqueios no neuroeixo e até mesmo a procedimentos sem anestesia, neste caso utilizou-se a anestesia venosa que proporcionou condições adequadas para o procedimento anestésico-cirúrgico.

ACKGROUND AND OBJECTIVES: Congenital insensitivity to pain and Anhidrosis (CIPA) or hereditary sensory and autonomic neuropathy type IV (HSAN IV) is a rare autosomal recessive neuropathy of the group of hereditary sensory and autonomic neuropathies (HSAN) characterized by insensitivity to pain, anhidrosis, and mental retardation. Since it is a rare condition, reports on the anesthetic conduct in patients with CIPA are not easily found in the literature. The objective of this report was to present the anesthetic conduct in a patient with CIPA undergoing left ankle arthrodesis with placement of an implant, and to discuss the characteristics of this disorder that concern anesthesiologists the most. CASE REPORT: A female patient with a history of CIPA was admitted for left ankle arthrodesis due to Charcot arthropathy. In the operating room, the patient was monitored with an electrocardiograph, bispectral index, 95 percent SEF, non-invasive blood pressure, and peripheral hemoglobin saturation; she was pre-medicated with midazolam and underwent intravenous anesthesia with propofol and cisatracurium. The administration of analgesics was not necessary. After tracheal intubation, monitoring of end-expiratory pressure of carbon dioxide and esophageal temperature were added. The patient did not develop postoperative complications. She was discharged from the hospital on the second postoperative day. CONCLUSIONS: Although there is insensitivity to pain, some patients present tactile hyperesthesia that can cause unpleasant feelings during surgical manipulation. Despite reports in the literature of patients undergoing neuroaxis blocks, and even procedures without anesthesia, intravenous anesthesia, which provided adequate conditions for the anesthetic-surgical procedure was used in this case.

JUSTIFICATIVA Y OBJETIVOS: La falta de sensibilidad congénita al dolor y la anhidrosis (ICDA) o neuropatía hereditaria sensorial y autonómica tipo IV (NHSA tipo IV), es una neuropatía autosómica recesiva rara del grupo de las neuropatías hereditarias sensoriales y autonómicas (NHSA), caracterizada por la insensibilidad al estímulo doloroso, anhidrosis y retraso mental. Existen pocos relatos sobre la conducta anestésica en pacientes con ICDA, debido a su extrema raridad. El objetivo de este relato, fue presentar la conducta anestésica en paciente con ICDA sometida a la artrodesis de tobillo izquierdo con colocación de vástago y discutir las características de interés para la anestesia en esos pacientes. RELATO DEL CASO: Paciente con historial de ICDA que fue admitida para artrodesis de tobillo izquierdo debido a la artropatía de Charcot. En la sala de operación, fue monitorizada con electrocardiógrafo, índice bispectral, SEF 95 por ciento, presión arterial no invasiva y saturación periférica de la hemoglobina, y medicada con midazolam como preanestésico. Posteriormente fue sometida a anestesia venosa con propofol y cisatracurio. No hubo necesidad de administrar analgésicos. Después de la intubación traqueal, se le monitoreó la presión expiratoria final del gas carbónico y de la temperatura esofágica. No presentó complicaciones en el período perioperatorio. Obtuvo su alta al segundo día del postoperatorio. CONCLUSIONES: Aunque presenten insensibilidad al dolor, algunos pacientes debutan con hiperestesia táctil, lo que podría causar sensaciones desagradables durante la manipulación quirúrgica. A pesar de los relatos en la literatura de pacientes sometidos a bloqueos en el neuro eje, e incluso a procedimientos sin anestesia, en ese caso se usó la anestesia venosa, proporcionando condiciones adecuadas para el procedimiento anestésico-quirúrgico.

Traumatic lesions from congenital insensitivity to pain with anhidrosis in a pediatric patient: dental management.

Congenital insensitivity to pain with anhidrosis is a rare autosomal-recessive disorder characterized by unexplained fever episodes, anhidrosis, pain insensitivity, self-mutilating behavior, and mental retardation. The lack of sensitivity to pain results in traumatic lesions, such as ulcers, fractures, burns, bites, scars, and digital amputations. Several methods have been suggested to treat these patients; however, appropriate management is difficult, especially when the mutilation is particularly severe. This report describes the case of a 2-year-old female patient who had severe self-mutilating injuries to her tongue, hands, lips, and oral mucosa caused by biting. The patient presented digital amputation and also a premature loss of a permanent tooth germ during the treatment. The dental management is described and discussed. It is important to include the dentist on the multidisciplinary team to reduce the frequency and severity of the self-inflicted lesions in these patients, also to prevent complications.

[Anesthesia in a patient with congenital insensitivity to pain and anhidrosis]. / Anestesia em paciente com insensibilidade congênita a dor e anidrose.

BACKGROUND AND OBJECTIVES: Congenital insensitivity to pain and Anhidrosis (CIPA) or hereditary sensory and autonomic neuropathy type IV (HSAN IV) is a rare autosomal recessive neuropathy of the group of hereditary sensory and autonomic neuropathies (HSAN) characterized by insensitivity to pain, anhidrosis, and mental retardation. Since it is a rare condition, reports on the anesthetic conduct in patients with CIPA are not easily found in the literature. The objective of this report was to present the anesthetic conduct in a patient with CIPA undergoing left ankle arthrodesis with placement of an implant, and to discuss the characteristics of this disorder that concern anesthesiologists the most. CASE REPORT: A female patient with a history of CIPA was admitted for left ankle arthrodesis due to Charcot arthropathy. In the operating room, the patient was monitored with an electrocardiograph, bispectral index, 95% SEF, non-invasive blood pressure, and peripheral hemoglobin saturation; she was pre-medicated with midazolam and underwent intravenous anesthesia with propofol and cisatracurium. The administration of analgesics was not necessary. After tracheal intubation, monitoring of end-expiratory pressure of carbon dioxide and esophageal temperature were added. The patient did not develop postoperative complications. She was discharged from the hospital on the second postoperative day. CONCLUSIONS: Although there is insensitivity to pain, some patients present tactile hyperesthesia that can cause unpleasant feelings during surgical manipulation. Despite reports in the literature of patients undergoing neuroaxis blocks, and even procedures without anesthesia, intravenous anesthesia, which provided adequate conditions for the anesthetic-surgical procedure was used in this case.

Spinal anesthesia in a patient with congenital insensitivity to pain with anhidrosis.

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare, hereditary, autonomic recessive disorder. The inability to perceive pain results from loss of nociceptive afferents, while anhidrosis is caused by loss of innervation to the sweat glands. Insensitivity to pain and mental retardation lead to self-inflicted injuries, corneal lacerations, painless bony fractures, joint deformities with consequent chronic osteomyelitis, and septic arthritis. There are only a few reports on the anesthetic management for patients with CIPA. We describe the anesthetic management of a young woman with CIPA receiving bilateral arthrodesis of the ankle.