RESUMEN

Variants in KCNMA1, encoding the voltage- and calcium-activated K+ (BK) channel, are associated with human neurological disease. The effects of gain-of-function (GOF) and loss-of-function (LOF) variants have been predominantly studied on BK channel currents evoked under steady-state voltage and Ca2+ conditions. However, in their physiological context, BK channels exist in partnership with voltage-gated Ca2+ channels and respond to dynamic changes in intracellular Ca2+ (Ca2+i). In this study, an L-type voltage-gated Ca2+ channel present in the brain, CaV1.2, was co-expressed with wild type and mutant BK channels containing GOF (D434G, N999S) and LOF (H444Q, D965V) patient-associated variants in HEK-293T cells. Whole-cell BK currents were recorded under CaV1.2 activation using buffering conditions that restrict Ca2+i to nano- or micro-domains. Both conditions permitted wild type BK current activation in response to CaV1.2 Ca2+ influx, but differences in behavior between wild type and mutant BK channels were reduced compared to prior studies in clamped Ca2+i. Only the N999S mutation produced an increase in BK current in both micro- and nano-domains using square voltage commands and was also detectable in BK current evoked by a neuronal action potential within a microdomain. These data corroborate the GOF effect of N999S on BK channel activity under dynamic voltage and Ca2+ stimuli, consistent with its pathogenicity in neurological disease. However, the patient-associated mutations D434G, H444Q, and D965V did not exhibit significant effects on BK current under CaV1.2-mediated Ca2+ influx, in contrast with prior steady-state protocols. These results demonstrate a differential potential for KCNMA1 variant pathogenicity compared under diverse voltage and Ca2+ conditions.

Asunto(s)

Canales de Calcio Tipo L , Subunidades alfa de los Canales de Potasio de Gran Conductancia Activados por Calcio , Humanos , Subunidades alfa de los Canales de Potasio de Gran Conductancia Activados por Calcio/genética , Subunidades alfa de los Canales de Potasio de Gran Conductancia Activados por Calcio/metabolismo , Células HEK293 , Canales de Calcio Tipo L/metabolismo , Canales de Calcio Tipo L/genética , Canalopatías/genética , Canalopatías/metabolismo , Calcio/metabolismo , Canales de Potasio de Gran Conductancia Activados por el Calcio/metabolismo , Canales de Potasio de Gran Conductancia Activados por el Calcio/genética , Mutación

RESUMEN

Ion channels are membrane proteins that allow the passage of ions across the membrane. They characteristically contain a pore where the selectivity of certain ion species is determined and gates that open and close the pore are found. The pore is often connected to additional domains or subunits that regulate its function. Channels are grouped into families based on their selectivity for specific ions and the stimuli that control channel opening and closing, such as voltage or ligands. Ion channels are fundamental to the electrical properties of excitable tissues. Dysfunction of channels can lead to abnormal electrical signaling of neurons and muscle cells, accompanied by clinical manifestations, known as channelopathies. Many naturally occurring toxins target ion channels and affect excitable cells where the channels are expressed. Furthermore, ion channels, as membrane proteins and key regulators of a number of physiologic functions, are an important target for drugs in clinical use. In this chapter, we give a general overview of the classification, genetics and structure-function features of the main ion channel families, and address some pharmacologic aspects relevant to neurologic channelopathies.

Asunto(s)

Canalopatías , Canales Iónicos , Humanos , Canalopatías/metabolismo , Canalopatías/genética , Canales Iónicos/metabolismo , Animales , Relación Estructura-Actividad

RESUMEN

Pediatric skeletal muscle channelopathies include a spectrum of conditions including nondystrophic myotonias and periodic paralyses. They are rare inherited conditions that can cause significant morbidity. They are characterized by episodic stiffness and weakness. While there is significant phenotypic variability, there are distinct diagnostic features. The nondystrophic myotonias encompass myotonia congenita, paramyotonia congenita, and sodium channel myotonia caused by mutations in chloride and sodium channels. The clinical manifestations vary across age groups and a small subset with sodium channel mutations may have severe presentation with fetal akinesia, laryngospasm, or congenital myopathy. The periodic paralyses include hypokalemic periodic paralysis, hyperkalemic periodic paralysis, and Andersen-Tawil syndrome. The phenotypic differences between the groups can be helpful in diagnosis. It is important to review the cardiac phenotype in Andersen-Tawil syndrome due to a risk of life-threatening cardiac arrhythmias. Early and accurate diagnosis utilizing clinical features aided by investigations is important across all the pediatric channelopathies, as effective symptomatic treatment is available and can substantially improve quality of life.

Asunto(s)

Canalopatías , Humanos , Canalopatías/genética , Canalopatías/diagnóstico , Niño , Enfermedades Neuromusculares/diagnóstico , Enfermedades Neuromusculares/genética , Pediatría/métodos , Miotonía/genética , Miotonía/diagnóstico , Mutación/genética

RESUMEN

The autoimmune channelopathies represent a rapidly evolving scientific and clinical domain. The description of channels, expressed on neurons and glia, as targets of autoantibodies in neuromyelitis optica, autoimmune encephalitis, and related syndromes have revolutionized many areas of neurologic practice. To date, tens of surface antibody specificities have been described, a number that is likely to continue to increase. A central paradigm for all these disorders is that of pathogenic autoantibodies which target extracellular epitopes accessible for binding in vivo. Hence, in these disorders, the autoantibodies are causative diagnostic tools, and provide valuable reagents to model the diseases. Their production by B-lineage cells provides opportunities to study and modulate their production. Across these syndromes, early recognition and treatment are critical since most respond to immunotherapies. Yet, several unmet medical needs persist within treated patient populations, and widespread clinical under-recognition remains a challenge. In this review, we summarize the neuroscience and immunologic basis of autoantibody-mediated central nervous system channelopathies, the molecular effects of the autoantibodies, clinical phenotypes, and treatment approaches. We describe progress since the inauguration of the field through to open questions and potential future directions.

Asunto(s)

Autoanticuerpos , Canalopatías , Humanos , Autoanticuerpos/inmunología , Canalopatías/inmunología , Animales

RESUMEN

Recent advances in genetic diagnosis have revealed the underlying etiology of many epilepsies and have identified pathogenic, causative variants in numerous ion and ligand-gated channel genes. This chapter describes the clinical presentations of epilepsy associated with different channelopathies including classic electroclinical syndromes and emerging gene-specific phenotypes. Also discussed are the archetypal epilepsy channelopathy, SCN1A-Dravet syndrome, considering the expanding phenotype. Clinical presentations where a channelopathy is suspected, such as sleep-related hypermotor epilepsy and epilepsy in association with movement disorders, are reviewed. Channelopathies pose an intriguing problem for the development of gene therapies. Design of targeted therapies requires physiologic insights into the often multifaceted impact of a pathogenic variant, coupled with an understanding of the phenotypic spectrum of a gene. As gene-specific novel therapies come online for the channelopathies, it is essential that clinicians are able to recognize epilepsy phenotypes likely to be due to channelopathy and institute early genetic testing in both children and adults. These findings are likely to have immediate management implications and to inform prognostic and reproductive counseling.

Asunto(s)

Epilepsia , Humanos , Epilepsia/genética , Epilepsia/diagnóstico , Epilepsia/terapia , Canalopatías/genética , Canalopatías/terapia , Canalopatías/diagnóstico

RESUMEN

There has been significant progress in our understanding of the molecular basis by which nociceptors transduce and transmit noxious (tissue damaging) stimuli. This is dependent on ion channels, many of which are selectively expressed in nociceptors. Mutations in such proteins have recently been linked to inherited pain disorders in humans. An exemplar is the voltage-gated sodium channel (VGSC) NaV1.7. Loss of function mutations in NaV1.7 result in congenital inability to experience pain while gain-of-function mutations can cause a number of distinct neuropathic pain disorders, including erythromelalgia, paroxysmal extreme pain disorder, and small-fiber neuropathy. Furthermore, variants in the VGSCs 1.8 and 1.9 have also been linked to human pain disorders. There is a correlation between the impact of mutations on the biophysical properties of the ion channel and the severity of the clinical phenotype. Pain channelopathies are not restricted to VGSCs: a mutation in the ligand-gated ion channel TRPA1, (which responds to environmental irritants) causes a familial episodic pain disorder. Ion channel variants have also been linked to more common neuropathic pain disorders such as painful diabetic neuropathy. Not only do these ion channels present targets for novel analgesics, but stratification based on genotype may improve treatment selection of existing analgesics.

Asunto(s)

Canalopatías , Humanos , Canalopatías/genética , Mutación/genética , Canal de Sodio Activado por Voltaje NAV1.7/genética , Dolor/genética , Neuralgia/genética

Asunto(s)

Fibrilación Atrial , Canalopatías , Humanos , Canalopatías/genética , Canalopatías/diagnóstico , Medición de Riesgo

RESUMEN

INTRODUCTION: In tauopathies, altered tau processing correlates with impairments in synaptic density and function. Changes in hyperpolarization-activated cyclic nucleotide-gated (HCN) channels contribute to disease-associated abnormalities in multiple neurodegenerative diseases. METHODS: To investigate the link between tau and HCN channels, we performed histological, biochemical, ultrastructural, and functional analyses of hippocampal tissues from Alzheimer's disease (AD), age-matched controls, Tau35 mice, and/or Tau35 primary hippocampal neurons. RESULTS: Expression of specific HCN channels is elevated in post mortem AD hippocampus. Tau35 mice develop progressive abnormalities including increased phosphorylated tau, enhanced HCN channel expression, decreased dendritic branching, reduced synapse density, and vesicle clustering defects. Tau35 primary neurons show increased HCN channel expression enhanced hyperpolarization-induced membrane voltage "sag" and changes in the frequency and kinetics of spontaneous excitatory postsynaptic currents. DISCUSSION: Our findings are consistent with a model in which pathological changes in tauopathies impact HCN channels to drive network-wide structural and functional synaptic deficits. HIGHLIGHTS: Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are functionally linked to the development of tauopathy. Expression of specific HCN channels is elevated in the hippocampus in Alzheimer's disease and the Tau35 mouse model of tauopathy. Increased expression of HCN channels in Tau35 mice is accompanied by hyperpolarization-induced membrane voltage "sag" demonstrating a detrimental effect of tau abnormalities on HCN channel function. Tau35 expression alters synaptic organization, causing a loosened vesicle clustering phenotype in Tau35 mice.

Asunto(s)

Enfermedad de Alzheimer , Hipocampo , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización , Ratones Transgénicos , Sinapsis , Proteínas tau , Animales , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización/metabolismo , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Ratones , Proteínas tau/metabolismo , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/genética , Sinapsis/patología , Sinapsis/metabolismo , Neuronas/metabolismo , Neuronas/patología , Canalopatías/genética , Canalopatías/patología , Masculino , Femenino , Anciano , Modelos Animales de Enfermedad , Tauopatías/patología , Tauopatías/metabolismo

RESUMEN

Genetic arrhythmia disorders are rare diseases; however, they are a common cause of sudden cardiac death in children, adolescents, and young adults. In principle, a distinction can be made between channelopathies and cardiomyopathies in the context of genetic diseases. This paper focuses on the channelopathies long and short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia (CPVT). Early diagnosis of these diseases is essential, as drug therapy, behavioral measures, and if necessary, implantation of a cardioverter defibrillator can significantly improve the prognosis and quality of life of patients. This paper highlights the pathophysiological and genetic basis of these channelopathies, describes their clinical manifestations, and comments on the principles of diagnosis, risk stratification and therapy.

Asunto(s)

Arritmias Cardíacas , Síndrome de Brugada , Canalopatías , Humanos , Arritmias Cardíacas/genética , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/terapia , Arritmias Cardíacas/fisiopatología , Canalopatías/genética , Canalopatías/diagnóstico , Canalopatías/terapia , Síndrome de Brugada/genética , Síndrome de Brugada/diagnóstico , Síndrome de Brugada/fisiopatología , Síndrome de Brugada/terapia , Taquicardia Ventricular/genética , Taquicardia Ventricular/terapia , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/fisiopatología , Adolescente , Niño , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/diagnóstico , Síndrome de QT Prolongado/terapia , Síndrome de QT Prolongado/fisiopatología , Muerte Súbita Cardíaca/prevención & control , Muerte Súbita Cardíaca/etiología , Adulto , Desfibriladores Implantables , Electrocardiografía

RESUMEN

Store-operated calcium entry (SOCE) plays a crucial role in maintaining cellular calcium homeostasis. This mechanism involves proteins, such as stromal interaction molecule 1 (STIM1) and ORAI1. Mutations in the genes encoding these proteins, especially STIM1, can lead to various diseases, including CRAC channelopathies associated with severe combined immunodeficiency. Herein, we describe a novel homozygous mutation, NM_003156 c.792-3C > G, in STIM1 in a patient with a clinical profile of CRAC channelopathy, including immune system deficiencies and muscle weakness. Functional analyses revealed three distinct spliced forms in the patient cells: wild-type, exon 7 skipping, and intronic retention. Calcium influx analysis revealed impaired SOCE in the patient cells, indicating a loss of STIM1 function. We developed an antisense oligonucleotide treatment that improves STIM1 splicing and highlighted its potential as a therapeutic approach. Our findings provide insights into the complex effects of STIM1 mutations and shed light on the multifaceted clinical presentation of the patient.

Asunto(s)

Calcio , Mutación , Proteínas de Neoplasias , Molécula de Interacción Estromal 1 , Humanos , Molécula de Interacción Estromal 1/genética , Molécula de Interacción Estromal 1/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Calcio/metabolismo , Canalopatías/genética , Masculino , Canales de Calcio Activados por la Liberación de Calcio/genética , Canales de Calcio Activados por la Liberación de Calcio/metabolismo , Femenino , Inmunodeficiencia Combinada Grave/genética , Proteína ORAI1/genética , Proteína ORAI1/metabolismo

RESUMEN

Cardiac channelopathies are a group of heritable disorders that affect the heart's electrical activity due to genetic variations present in genes coding for ion channels. With the advent of new sequencing technologies, molecular diagnosis of these disorders in patients has paved the way for early identification, therapeutic management and family screening. The objective of this retrospective study was to understand the efficacy of whole-genome sequencing in diagnosing patients with suspected cardiac channelopathies who were reported negative after whole exome sequencing and analysis. We employed a 3-tier analysis approach to identify nonsynonymous variations and loss-of-function variations missed by exome sequencing, and structural variations that are better resolved only by sequencing whole genomes. By performing whole genome sequencing and analyzing 25 exome-negative cardiac channelopathy patients, we identified 3 pathogenic variations. These include a heterozygous likely pathogenic nonsynonymous variation, CACNA1C:NM_000719:exon19:c.C2570G:p. P857R, which causes autosomal dominant long QT syndrome in the absence of Timothy syndrome, a heterozygous loss-of-function variation CASQ2:NM_001232.4:c.420+2T>C classified as pathogenic, and a 9.2 kb structural variation that spans exon 2 of the KCNQ1 gene, which is likely to cause Jervell-Lange-Nielssen syndrome. In addition, we also identified a loss-of-function variation and 16 structural variations of unknown significance (VUS). Further studies are required to elucidate the role of these identified VUS in gene regulation and decipher the underlying genetic and molecular mechanisms of these disorders. Our present study serves as a pilot for understanding the utility of WGS over clinical exomes in diagnosing cardiac channelopathy disorders.

Asunto(s)

Canalopatías , Secuenciación del Exoma , Linaje , Secuenciación Completa del Genoma , Humanos , Canalopatías/genética , Canalopatías/diagnóstico , Femenino , Masculino , Canal de Potasio KCNQ1/genética , Canales de Calcio Tipo L/genética , Adulto , Estudios Retrospectivos , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/diagnóstico , Niño , Mutación , Exoma/genética , Predisposición Genética a la Enfermedad

RESUMEN

OBJECTIVE: To explore genetic variation including whole genome copy number variation and sequence analysis of 98 genes associated with pediatric or adult cardiomyopathies, cardiac channelopathies, and sudden death in an unexplained intrauterine fetal death cohort. METHODS: The study population included 55 stillbirth cases that remained unexplained after thorough postmortem examination, excluding maternal, fetal, and placental causes of stillbirth. Molecular karyotyping was performed in 55 cases and the trio exome sequencing approach was applied in 19 cases. RESULTS: The analysis revealed six rare variants with predicted effects on protein function in six genes (CASQ2, DSC2, KCNE1, LDB3, MYH6, and SCN5A) previously reported in cases of stillbirth or severe early onset pediatric cardiac related phenotypes. When applying strict American College of Genetics and Genomics classification guidelines, these are still variants of uncertain significance. CONCLUSIONS: Several potentially stillbirth-related genetic variants were detected in our cohort, adding to the growing literature on cardiac phenotype gene variation in stillbirth. However, the mechanisms of action, gene-gene interaction, and contribution of the uterine environment are still to be deciphered. In order to advance our knowledge of the genetics of unexplained fetal death, there is an evident need for international collaboration and field standardization.

Asunto(s)

Cardiomiopatías , Canalopatías , Mortinato , Humanos , Femenino , Cardiomiopatías/genética , Mortinato/genética , Mortinato/epidemiología , Embarazo , Canalopatías/genética , Adulto , Canal de Sodio Activado por Voltaje NAV1.5/genética , Canales de Potasio con Entrada de Voltaje/genética , Cadenas Pesadas de Miosina/genética , Masculino , Variaciones en el Número de Copia de ADN , Estudios de Cohortes , Secuenciación del Exoma , Miosinas Cardíacas

RESUMEN

Inherited cardiovascular diseases are rare diseases that are difficult to diagnose by non-expert professionals. Genetic analyses play a key role in the diagnosis of these diseases, in which the identification of a pathogenic genetic variant is often a diagnostic criterion. Therefore, genetic variant classification and routine reinterpretation as data become available represent one of the main challenges associated with genetic analyses. Using the genetic variants identified in an inherited cardiovascular diseases unit during a 10-year period, the objectives of this study were: 1) to evaluate the impact of genetic variant reinterpretation, 2) to compare the reclassification rates between different cohorts of cardiac channelopathies and cardiomyopathies, and 3) to establish the most appropriate periodicity for genetic variant reinterpretation. All the evaluated cohorts (full cohort of inherited cardiovascular diseases, cardiomyopathies, cardiac channelopathies, hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic cardiomyopathy, Brugada syndrome, long QT syndrome and catecholaminergic polymorphic ventricular tachycardia) showed reclassification rates above 25%, showing even higher reclassification rates when there is definitive evidence of the association between the gene and the disease in the cardiac channelopathies. Evaluation of genetic variant reclassification rates based on the year of the initial classification showed that the most appropriate frequency for the reinterpretation would be 2 years, with the possibility of a more frequent reinterpretation if deemed convenient. To keep genetic variant classifications up to date, genetic counsellors play a critical role in the reinterpretation process, providing clinical evidence that genetic diagnostic laboratories often do not have at their disposal and communicating changes in classification and the potential implications of these reclassifications to patients and relatives.

Asunto(s)

Enfermedades Cardiovasculares , Humanos , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/diagnóstico , Canalopatías/genética , Canalopatías/diagnóstico , Pruebas Genéticas/métodos , Variación Genética , Cardiomiopatías/genética , Cardiomiopatías/diagnóstico , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/diagnóstico , Síndrome de Brugada/genética , Síndrome de Brugada/diagnóstico

RESUMEN

As obesity has raised heightening awareness, researchers have attempted to identify potential targets that can be treated for therapeutic intervention. Focusing on the central nervous system (CNS), the key organ in maintaining energy balance, a plethora of ion channels that are expressed in the CNS have been inspected and determined through manipulation in different hypothalamic neural subpopulations for their roles in fine-tuning neuronal activity on energy state alterations, possibly acting as metabolic sensors. However, a remaining gap persists between human clinical investigations and mouse studies. Despite having delineated the pathways and mechanisms of how the mouse study-identified ion channels modulate energy homeostasis, only a few targets overlap with the obesity-related risk genes extracted from human genome-wide association studies. Here, we present the most recently discovered CNS-specific metabolism-correlated ion channels using reverse and forward genetics approaches in mice and humans, respectively, in the hope of illuminating the prospects for future therapeutic development.

Asunto(s)

Canalopatías , Obesidad , Humanos , Animales , Obesidad/genética , Obesidad/metabolismo , Canalopatías/genética , Canalopatías/metabolismo , Canales Iónicos/genética , Canales Iónicos/metabolismo , Metabolismo Energético/genética , Ratones , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/fisiopatología

RESUMEN

The aim of this special issue was to showcase recent advanced in understanding ion channel function and dysfunction associated with disease [...].

Asunto(s)

Canalopatías , Humanos , Canalopatías/genética , Canales Iónicos/genética

RESUMEN

The limited literature and increasing interest in studies on cardiac electrophysiology, explicitly focusing on cardiac ion channelopathies and sudden cardiac death in diverse populations, has prompted a comprehensive examination of existing research. Our review specifically targets Hispanic/Latino and Indigenous populations, which are often underrepresented in healthcare studies. This review encompasses investigations into genetic variants, epidemiology, etiologies, and clinical risk factors associated with arrhythmias in these demographic groups. The review explores the Hispanic paradox, a phenomenon linking healthcare outcomes to socioeconomic factors within Hispanic communities in the United States. Furthermore, it discusses studies exemplifying this observation in the context of arrhythmias and ion channelopathies in Hispanic populations. Current research also sheds light on disparities in overall healthcare quality in Indigenous populations. The available yet limited literature underscores the pressing need for more extensive and comprehensive research on cardiac ion channelopathies in Hispanic/Latino and Indigenous populations. Specifically, additional studies are essential to fully characterize pathogenic genetic variants, identify population-specific risk factors, and address health disparities to enhance the detection, prevention, and management of arrhythmias and sudden cardiac death in these demographic groups.

Asunto(s)

Arritmias Cardíacas , Canalopatías , Muerte Súbita Cardíaca , Predisposición Genética a la Enfermedad , Hispánicos o Latinos , Humanos , Muerte Súbita Cardíaca/etnología , Muerte Súbita Cardíaca/etiología , Canalopatías/genética , Canalopatías/etnología , Canalopatías/mortalidad , Canalopatías/diagnóstico , Arritmias Cardíacas/etnología , Arritmias Cardíacas/fisiopatología , Arritmias Cardíacas/genética , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/mortalidad , Factores de Riesgo , Medición de Riesgo , Disparidades en el Estado de Salud , Masculino , Disparidades en Atención de Salud/etnología , Femenino , Estados Unidos/epidemiología , Fenotipo , Pronóstico , Adulto , Factores Raciales , Potenciales de Acción , Persona de Mediana Edad

RESUMEN

Pathogenic variants in genes encoding ion channels are causal for various pediatric and adult neurological conditions. In particular, several epilepsy syndromes have been identified to be caused by specific channelopathies. These encompass a spectrum from self-limited epilepsies to developmental and epileptic encephalopathies spanning genetic and acquired causes. Several of these channelopathies have exquisite responses to specific antiseizure medications (ASMs), while others ASMs may prove ineffective or even worsen seizures. Some channelopathies demonstrate phenotypic pleiotropy and can cause other neurological conditions outside of epilepsy. This review aims to provide a comprehensive exploration of the pathophysiology of seizure generation, ion channels implicated in epilepsy, and several genetic epilepsies due to ion channel dysfunction. We outline the clinical presentation, pathogenesis, and the current state of basic science and clinical research for these channelopathies. In addition, we briefly look at potential precision therapy approaches emerging for these disorders.

Asunto(s)

Canalopatías , Epilepsia , Humanos , Canalopatías/genética , Canalopatías/terapia , Canalopatías/complicaciones , Epilepsia/genética , Epilepsia/etiología , Epilepsia/tratamiento farmacológico , Epilepsia/fisiopatología , Epilepsia/terapia , Canales Iónicos/genética , Anticonvulsivantes/uso terapéutico

RESUMEN

Thalamocortical (TC) circuits are essential for sensory information processing. Clinical and preclinical studies of autism spectrum disorders (ASDs) have highlighted abnormal thalamic development and TC circuit dysfunction. However, mechanistic understanding of how TC dysfunction contributes to behavioral abnormalities in ASDs is limited. Here, our study on a Shank3 mouse model of ASD reveals TC neuron hyperexcitability with excessive burst firing and a temporal mismatch relationship with slow cortical rhythms during sleep. These TC electrophysiological alterations and the consequent sensory hypersensitivity and sleep fragmentation in Shank3 mutant mice are causally linked to HCN2 channelopathy. Restoring HCN2 function early in postnatal development via a viral approach or lamotrigine (LTG) ameliorates sensory and sleep problems. A retrospective case series also supports beneficial effects of LTG treatment on sensory behavior in ASD patients. Our study identifies a clinically relevant circuit mechanism and proposes a targeted molecular intervention for ASD-related behavioral impairments.

Asunto(s)

Trastorno del Espectro Autista , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización , Proteínas del Tejido Nervioso , Tálamo , Animales , Tálamo/metabolismo , Tálamo/patología , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización/metabolismo , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización/genética , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Ratones , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/fisiopatología , Trastorno del Espectro Autista/patología , Lamotrigina/farmacología , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Proteínas de Microfilamentos/genética , Proteínas de Microfilamentos/metabolismo , Canalopatías/genética , Canalopatías/metabolismo , Canalopatías/patología , Humanos , Modelos Animales de Enfermedad , Masculino , Neuronas/metabolismo , Femenino , Ratones Endogámicos C57BL , Mutación/genética , Sueño/fisiología , Sueño/efectos de los fármacos , Sueño/genética , Canales de Potasio

RESUMEN

BACKGROUND: Congenital insensitivity to pain with anhidrosis (CIPA) is an extremely rare autosomal recessive disorder caused by loss-of-function mutations of the NTRK1 gene, affecting the autonomic and sensory nervous system. Clinical manifestation is varied and includes recurrent fever, pain insensitivity, anhidrosis, self-mutilating behavior, and intellectual disability. METHODS: Clinical and genetic features were assessed in two males and one female with genetically confirmed CIPA using exome or genome sequencing. RESULTS: CIPA symptoms including recurrent fever, pain insensitivity, and anhidrosis manifested at the age of 1 year (age range: 0.3-8 years). Two patients exhibited self-mutilation tendencies, intellectual disability, and developmental delay. Four NTRK1 (NM_002529.3) mutations, c.851-33T>A (p.?), c.2020G>T (p.Asp674Tyr), c.2303C>T (p.Pro768Leu), and c.574-156_850+1113del (exons 5-7 del) were identified. Two patients exhibited early onset and severe phenotype, being homozygous for c.851-33T>A (p.?) mutations and compound heterozygous for c.851-33T>A (p.?) and c.2020G>T (p.Asp674Tyr) mutation of NTRK1. The third patient with compound heterozygous mutations of c.2303C>T (p.Pro768Leu) and c.574-156_850+1113del (exons 5-7 del) displayed a late onset and milder clinical manifestation. CONCLUSION: All three patients exhibited variable phenotypes and disease severity. This research enriches our understanding of clinical and genetic aspects of CIPA, highlighting variable phenotypes and disease severity.

Asunto(s)

Canalopatías , Neuropatías Hereditarias Sensoriales y Autónomas , Hipohidrosis , Indoles , Discapacidad Intelectual , Insensibilidad Congénita al Dolor , Propionatos , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Neuropatías Hereditarias Sensoriales y Autónomas/genética , Hipohidrosis/genética , Dolor

RESUMEN

CASE: A 38-year-old man with congenital pain insensitivity underwent bilateral below-knee amputations. After his subsequent bilateral osseointegration (OI) limb replacements, he rapidly developed severe bilateral knee arthritis and varus deformity. In lieu of performing bilateral above-knee amputations, he underwent bilateral staged total knee arthroplasties (TKA) with excellent clinical and radiographic evaluation at 1-year follow-up. CONCLUSION: To address both the limited bone stock and OI implant stem location, TKA after OI limb replacement in congenital pain insensitivity patients can be successfully achieved with a nonkeeled cementless tibial component and augmentation with a tibial cone.

Asunto(s)

Artroplastia de Reemplazo de Rodilla , Canalopatías , Insensibilidad Congénita al Dolor , Masculino , Humanos , Adulto , Oseointegración , Amputación Quirúrgica