RESUMEN

BACKGROUND: Chronic low back pain (CLBP) is a complex condition in which genetic factors play a role in its susceptibility. Catechol-O-methyltransferase (COMT) and sodium channel NaV1.7 (SCN9A) genes are implicated in pain perception. The aim is to analyze the association of COMT and SCN9A with CLBP and their interaction, in a Mexican-Mestizo population. METHODS: A case-control study was conducted. Cases corresponded to adults of both sexes with CLBP. Controls were adults with no CLBP. Variants of SCN9A and COMT were genotyped. Allelic and genotypic frequencies and Hardy-Weinberg equilibrium (HWE) were calculated. Association was tested under codominant, dominant, and recessive models. Multifactor dimensionality reduction was developed to detect epistasis. RESULTS: Gene variants were in HWE, and there was no association under different inheritance models in the whole sample. In women, in codominant and dominant models, a trend to a high risk was observed for AA of rs4680 of COMT (OR = 1.7 [0.5-5.3] and 1.6 [0.7-3.4]) and for TT of rs4633 (OR = 1.6 [0.7-3.7] and 1.6 [0.7-3.4]). In men, a trend to low risk was observed for AG genotype of rs4680 in the same models (OR = 0.6 [0.2-1.7] and 0.7 [0.3-1.7]), and for TC genotype of rs4633 in the codominant model (OR = 0.6 [0.2-1.7]). In the interaction analysis, a model of the SCN9A and COMT variants showed a CVC of 10/10; however, the TA was 0.4141. CONCLUSION: COMT and SCN9A variants are not associated with CLBP in the analyzed Mexican-Mestizo population.

Asunto(s)

Catecol O-Metiltransferasa , Dolor de la Región Lumbar , Canal de Sodio Activado por Voltaje NAV1.7 , Adulto , Femenino , Humanos , Masculino , Estudios de Casos y Controles , Catecol O-Metiltransferasa/genética , Dolor de la Región Lumbar/genética , Canal de Sodio Activado por Voltaje NAV1.7/genética

RESUMEN

OBJECTIVE: Childhood epilepsy is a common neurological disorder with a prevalence of 300-600 cases per 100,000 people. It is associated with refractory epilepsies, global developmental delay, and epileptic encephalopathies, causing epileptic syndromes characterized by cognitive and behavioral disorders. METHODS: In this retrospective cohort study, patients with refractory epilepsy and global developmental delay, defined as epileptic encephalopathy, who applied to the Aydin 7Maternity and Children's Hospital Genetic Diagnosis Center and were followed in the pediatric neurology clinic of our hospital, between July 2018 and July 2021, were included. RESULTS: Targeted next-generation sequencing molecular genetics results were reviewed, and 3 ALDH7A1, 1 AARS, 3 CACNA1A, 1 CTNNB1, 1 DCX, 2 DBH, 2 DOCK7, 1 FOLR1, 2 GABRB3, 2 GCH1, 1 VGRIN2B, 1 GUF1, 3 KCNQ2, 2 KCNT1, 1 NECAP1, 1 PCDH19, 1 PNPO, 1 SCN8A, 1 SCN9A, 4 SCN1A, 2 SLC25A22, 1 SLC2A1, 2 SPTAN1, 2 SZT2, 4 TBC1D24, 2 TH, and 1 PCDH19 (X chromosome) mutations were detected in three of the patients using the next-generation sequencing method. CONCLUSION: Although the development of gene panels aids in diagnosis, there are still unidentified disorders in this illness category, which is highly variable in genotype and phenotype. Understanding the genetic etiology is vital for genetic counseling and, maybe, the future development of remedies for the etiology.

Asunto(s)

Epilepsia , Niño , Humanos , Estudios Retrospectivos , Epilepsia/genética , Genotipo , Fenotipo , Mutación , Secuenciación de Nucleótidos de Alto Rendimiento , Receptor 1 de Folato/genética , Proteínas de Transporte de Membrana Mitocondrial/genética , Canal de Sodio Activado por Voltaje NAV1.7/genética , Protocadherinas

RESUMEN

Pain is an experience of a subjective nature, interpreted in a personal way and according to an extensive palette of factors unique to each individual. Orofacial pain can be acute or chronic and it is usually the main reason for the patient to seek dental care. Pain perception varies widely among individuals. This variability is considered a mosaic of factors, which include biopsychosocial factors and genetic factors. Understanding these differences can be extremely beneficial for pain management in a personalized and more efficient way. We performed association studies to investigate phenotypes associated with genetic markers in pain-related genes in two groups of patients who received more or less anesthesia during dental treatment. The study group was comprised of 1289 individuals participating in the Dental Registry and DNA Repository Project (DRDR) of the University of Pittsburgh, with 900 participants in the group that received the most anesthesia and 389 constituting the comparison group that received less anesthesia. We tested 58 phenotypes and genotypic data of seven SNPs in genes that are associated with pain perception, pain modulation and response to drugs used in pain treatment: COMT (rs4818 and rs6269), GCH1 (rs3783641), DRD2 (rs6276), OPRM1 (rs1799971), SCN9A (rs6746030) and SCN10A (rs6795970). The analysis revealed a protective effect of rs1799971 on asthma in the total sample. rs3783641 was associated with salivary secretion disorders in females who received more anesthesia. rs1799971 was also associated with periodontitis in Whites who received less anesthesia. rs4818 was associated with disease and other tongue conditions in the group composed of Blacks who received less anesthesia. In conclusion, our study implicated variants in pain-related genes in asthma and oral phenotypes.

Asunto(s)

Asma , Catecol O-Metiltransferasa , Femenino , Humanos , Catecol O-Metiltransferasa/genética , Salud Bucal , Genética Inversa , Percepción del Dolor , Dolor/genética , Asma/genética , Canal de Sodio Activado por Voltaje NAV1.7/genética

RESUMEN

Increased collagen-derived advanced glycation end-products (AGEs) are consistently related to painful diseases, including osteoarthritis, diabetic neuropathy, and neurodegenerative disorders. We have recently developed a model combining a two-dimensional glycated extracellular matrix (ECM-GC) and primary dorsal root ganglion (DRG) that mimicked a pro-nociceptive microenvironment. However, culturing primary cells is still a challenge for large-scale screening studies. Here, we characterized a new model using ECM-GC as a stimulus for human sensory-like neurons differentiated from SH-SY5Y cell lines to screen for analgesic compounds. First, we confirmed that the differentiation process induces the expression of neuron markers (MAP2, RBFOX3 (NeuN), and TUBB3 (ß-III tubulin), as well as sensory neuron markers critical for pain sensation (TRPV1, SCN9A (Nav1.7), SCN10A (Nav1.8), and SCN11A (Nav1.9). Next, we showed that ECM-GC increased c-Fos expression in human sensory-like neurons, which is suggestive of neuronal activation. In addition, ECM-GC upregulated the expression of critical genes involved in pain, including SCN9A and TACR1. Of interest, ECM-GC induced substance P release, a neuropeptide widely involved in neuroinflammation and pain. Finally, morphine, the prototype opiate, decreased ECM-GC-induced substance P release. Together, our results suggest that we established a functional model that can be useful as a platform for screening candidates for the management of painful conditions.

Asunto(s)

Analgésicos/análisis , Analgésicos/farmacología , Colágeno/farmacología , Evaluación Preclínica de Medicamentos , Modelos Biológicos , Células Receptoras Sensoriales/citología , Animales , Antígenos de Neoplasias/metabolismo , Biomarcadores/metabolismo , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Matriz Extracelular/metabolismo , Galectina 3/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Glicosilación/efectos de los fármacos , Humanos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Canal de Sodio Activado por Voltaje NAV1.7/genética , Canal de Sodio Activado por Voltaje NAV1.7/metabolismo , Neuritas/efectos de los fármacos , Neuritas/metabolismo , Neuronas/citología , Neuronas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Receptores de Neuroquinina-1/genética , Receptores de Neuroquinina-1/metabolismo , Células Receptoras Sensoriales/efectos de los fármacos , Células Receptoras Sensoriales/metabolismo , Sustancia P/metabolismo , betaendorfina/metabolismo

RESUMEN

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.

Asunto(s)

Neuropatías Hereditarias Sensoriales y Autónomas , Insensibilidad Congénita al Dolor , Brasil , GTP Fosfohidrolasas/genética , Neuropatías Hereditarias Sensoriales y Autónomas/genética , Heterocigoto , Humanos , Mutación/genética , Canal de Sodio Activado por Voltaje NAV1.7/genética , Insensibilidad Congénita al Dolor/genética , Serina C-Palmitoiltransferasa

RESUMEN

BACKGROUND: Experimental studies suggest that testosterone reduces the nociceptive response after inflammatory and neuropathic stimuli, however the underlying mechanisms have not been fully elucidated. The aims of this study were to evaluate the effect of peripheral blockade of testosterone on pain behaviour and on expression levels of the genes that encode the NaV1.7 and NaV1.8 channels, in dorsal root ganglia in an acute postoperative pain model, as well as the influence of androgen blockade on the expression of these genes. METHODS: Postoperative pain was induced by a plantar incision and the study group received flutamide to block testosterone receptor. The animals were submitted to behavioural evaluation preoperatively, 2 h after incision, and on the 1st, 2nd, 3rd and 7th postoperative days. Von Frey test was used to evaluate paw withdrawal threshold after mechanical stimuli and the guarding pain test to assess spontaneous pain. The expression of the genes encoding the sodium channels at the dorsal root ganglia was determined by real time quantitative polymerase chain reaction. RESULTS: Animals treated with flutamide presented lower paw withdrawal threshold at the 1st, 2nd, 3rd, and 7th postoperative days. The guarding pain test showed significant decrease in the flutamide group at 2 h and on the 3rd and 7th postoperative days. No difference was detected between the study and control groups for the gene expression. CONCLUSIONS: Our data suggest an antinociceptive effect of androgens following plantar incision. The expression of genes that encode voltage-gated sodium channels was not influenced by androgen blockade.

Asunto(s)

Andrógenos/farmacología , Conducta Animal , Flutamida/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Canal de Sodio Activado por Voltaje NAV1.7/genética , Canal de Sodio Activado por Voltaje NAV1.8/genética , Dolor Postoperatorio/genética , Animales , Modelos Animales de Enfermedad , Canal de Sodio Activado por Voltaje NAV1.7/metabolismo , Canal de Sodio Activado por Voltaje NAV1.8/metabolismo

RESUMEN

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.

Asunto(s)

Anomalías Múltiples/genética , Enfermedades del Desarrollo Óseo/genética , Epilepsia Generalizada/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Discapacidad Intelectual/genética , Mutación , Fenotipo , Proteínas Represoras/genética , Convulsiones Febriles/genética , Anomalías Dentarias/genética , Anomalías Múltiples/diagnóstico por imagen , Anomalías Múltiples/etiología , Anomalías Múltiples/fisiopatología , Adolescente , Alelos , Enfermedades del Desarrollo Óseo/diagnóstico por imagen , Enfermedades del Desarrollo Óseo/etiología , Enfermedades del Desarrollo Óseo/fisiopatología , Brasil , Electroencefalografía , Epilepsia Generalizada/fisiopatología , Facies , Femenino , Sitios Genéticos , Heterocigoto , Humanos , Discapacidad Intelectual/diagnóstico por imagen , Discapacidad Intelectual/etiología , Discapacidad Intelectual/fisiopatología , Canal de Sodio Activado por Voltaje NAV1.7/genética , Linaje , Convulsiones Febriles/fisiopatología , Anomalías Dentarias/diagnóstico por imagen , Anomalías Dentarias/etiología , Anomalías Dentarias/fisiopatología , Secuenciación del Exoma

RESUMEN

OBJECTIVE: Trigeminal 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. METHODS: Ninety-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. RESULTS: No 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. CONCLUSIONS: Although 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.

Asunto(s)

Canal de Sodio Activado por Voltaje NAV1.7/genética , Receptor trkA/genética , Neuralgia del Trigémino/genética , Adulto , Anciano , Brasil , Femenino , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético/genética

RESUMEN

OBJECTIVES: To evaluate the clinical features of erythromelalgia in childhood associated with gain-of-function SCN9A mutations that increase activity of the Nav1.7 voltage-gated sodium channel, we conducted a systematic review of pediatric presentations of erythromelalgia related to SCN9A mutations, and compared pediatric clinical presentations of symptomatic erythromelalgia, with or without SCN9A mutations. STUDY DESIGN: PubMed, Embase, and PsycINFO Databases were searched for reports of inherited erythromelalgia in childhood. Clinical features, management, and genotype were extracted. Case notes of pediatric patients with erythromelalgia from the Great Ormond Street Hospital Pain Service were reviewed for clinical features, patient-reported outcomes, and treatments. Children aged over 10 years were recruited for quantitative sensory testing. RESULTS: Twenty-eight publications described erythromelalgia associated with 15 different SCN9A gene variants in 25 children. Pain was severe and often refractory to multiple treatments, including nonspecific sodium channel blockers. Skin damage or other complications of cold immersion for symptomatic relief were common (60%). SCN9A mutations resulting in greater hyperpolarizing shifts in Nav1.7 sodium channels correlated with symptom onset at younger ages (P = .016). Variability in reporting, and potential publication bias toward severe cases, limit any estimations of overall prevalence. In our case series, symptoms were similar but comorbidities were more common in children with SCN9A mutations. Quantitative sensory testing revealed marked dynamic warm allodynia. CONCLUSIONS: Inherited erythromelalgia in children is associated with difficult-to-manage pain and significant morbidity. Standardized reporting of outcome and management in larger series will strengthen identification of genotype-phenotype relationships. More effective long-term therapies are a significant unmet clinical need.

Asunto(s)

Eritromelalgia/complicaciones , Eritromelalgia/genética , Mutación/genética , Canal de Sodio Activado por Voltaje NAV1.7/genética , Dolor/etiología , Adolescente , Niño , Femenino , Humanos , Masculino , Estudios Retrospectivos , Evaluación de Síntomas

RESUMEN

OBJECTIVE: The objective was to evaluate the safety and efficacy of TV-45070 ointment, as a treatment for postherpetic neuralgia, and to explore the response in patients with the Nav1.7 R1150W gain-of-function polymorphism. MATERIALS AND METHODS: This was a randomized, placebo-controlled, 2-period, 2-treatment crossover trial. Patients with postherpetic neuralgia with moderate or greater pain received TV-45070 and placebo ointments, each applied twice daily for 3 weeks. The primary efficacy measure was the difference in change in mean daily pain score from baseline compared with the last week of placebo and active treatment. Secondary endpoints included responder rate analyses and a further exploratory analysis of response in carriers of the Nav1.7 R1150W polymorphism was conducted. RESULTS: Seventy patients were enrolled and 54 completed the study. TV-45070 was safe and well tolerated. No statistical difference was observed between treatments for the primary endpoint. However, the proportion of patients with ≥50% reduction in mean pain scores at week 3 was greater on TV-45070 than on placebo (26.8% vs. 10.7%, P=0.0039). Similarly, a greater proportion of patients on TV-45070 had a ≥30% reduction in mean pain scores at week 3 (39.3% on TV-45070 vs. 23.2% on placebo, P=0.0784). Of note, 63% of patients with the R1150W polymorphism versus 35% of wild-type carriers had a ≥30% reduction in mean pain score on TV-45070 at week 3 (no inferential analysis performed). CONCLUSIONS: The 50% responder analysis suggests a subpopulation may exist with a more marked analgesic response to TV-45070.The trend toward a larger proportion of responders within Nav1.7 R1150W carriers warrants further investigation.

Asunto(s)

Indoles/uso terapéutico , Canal de Sodio Activado por Voltaje NAV1.7/genética , Neuralgia Posherpética/tratamiento farmacológico , Neuralgia Posherpética/genética , Bloqueadores de los Canales de Sodio/uso terapéutico , Compuestos de Espiro/uso terapéutico , Administración Tópica , Estudios Cruzados , Femenino , Genotipo , Humanos , Indoles/efectos adversos , Indoles/sangre , Masculino , Persona de Mediana Edad , Prueba de Estudio Conceptual , Bloqueadores de los Canales de Sodio/efectos adversos , Bloqueadores de los Canales de Sodio/sangre , Compuestos de Espiro/efectos adversos , Compuestos de Espiro/sangre , Resultado del Tratamiento

RESUMEN

OBJECTIVES: Previous studies have established the role of SCN9A in various pain conditions, including idiopathic small fiber neuropathy. In the present study, we interrogate the relationship between common and rare variants in SCN9A gene and chronic neuropathic pain associated with diabetic peripheral neuropathy. DESIGN: Using a cohort of 938 patients of European ancestry with chronic neuropathic pain associated with diabetic peripheral neuropathy enrolled in 6 clinical studies and 2 controls (POPRES, n=2624 and Coriell, n=1029), we examined the relationship between SCN9A variants and neuropathic pain in a case-control study using a 2-stage design. The exonic regions of SCN9A were sequenced in a subset of 244 patients with neuropathic pain, and the variants discovered were compared with POPRES control (stage 1). The top associated variants were followed up by genotyping in the entire case collection and Coriell controls restricting the analysis to the matching patients from the United States and Canada only (stage 2). RESULTS: Seven variants were found to be associated with neuropathic pain at the sequencing stage. Four variants (Asp1908Gly, Val991Leu/Met932Leu, and an intronic variant rs74449889) were confirmed by genotyping to occur at a higher frequency in cases than controls (odds ratios ∼2.1 to 2.6, P=0.05 to 0.009). Val991Leu/Met932Leu was also associated with the severity of pain as measured by pain score Numeric Rating Scale (NRS-11, P=0.047). Val991Leu/Met932Leu variants were in complete linkage disequilibrium and previously shown to cause hyperexcitability in dorsal root ganglia neurons. CONCLUSIONS: The association of SCN9A variants with neuropathic pain and pain severity suggests a role of SCN9A in the disease etiology of neuropathic pain.

Asunto(s)

Dolor Crónico/genética , Neuropatías Diabéticas/genética , Predisposición Genética a la Enfermedad , Variación Genética , Canal de Sodio Activado por Voltaje NAV1.7/genética , Neuralgia/genética , Canadá , Dolor Crónico/fisiopatología , Estudios de Cohortes , Neuropatías Diabéticas/fisiopatología , Exones , Femenino , Técnicas de Genotipaje , Humanos , Intrones , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Neuralgia/fisiopatología , Dimensión del Dolor , Índice de Severidad de la Enfermedad , Estados Unidos , Población Blanca/genética