Inherited Channelopathies Associated with Epilepsy.
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ABSTRACT:
SUBMITTER: George AL
PROVIDER: S-EPMC531663 | biostudies-literature | 2004 Mar
REPOSITORIES: biostudies-literature
Publications
Ion channels are critical for neuronal excitability and provide important targets for anticonvulsant drugs. In the past few years, several monogenetic epilepsies have been linked to mutations in genes encoding either voltage-gated or ligand-gated channels. The recognition that certain epilepsy syndromes are "channelopathies" initiates a new era in understanding the molecular pathophysiology of seizure disorders. This review summarizes recent advances related to this exciting area of investigatio ...[more]
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Project description:A proper interpretation of the pathogenicity of rare variants is crucial before clinical translation. Ongoing addition of new data may modify previous variant classifications; however, how often a reanalysis is necessary remains undefined. We aimed to extensively reanalyze rare variants associated with inherited channelopathies originally classified 5 years ago and its clinical impact. In 2016, rare variants identified through genetic analysis were classified following the American College of Medical Genetics and Genomics' recommendations. Five years later, we have reclassified the same variants following the same recommendations but including new available data. Potential clinical implications were discussed. Our cohort included 49 cases of inherited channelopathies diagnosed in 2016. Update show that 18.36% of the variants changed classification mainly due to improved global frequency data. Reclassifications mostly occurred in minority genes associated with channelopathies. Similar percentage of variants remain as deleterious nowadays, located in main known genes (SCN5A, KCNH2 and KCNQ1). In 2016, 69.38% of variants were classified as unknown significance, but now, 53.06% of variants are classified as such, remaining the most common group. No management was modified after translation of genetic data into clinics. After 5 years, nearly 20% of rare variants associated with inherited channelopathies were reclassified. This supports performing periodic reanalyses of no more than 5 years since last classification. Use of newly available data is necessary, especially concerning global frequencies and family segregation. Personalized clinical translation of rare variants can be crucial to management if a significant change in classification is identified.
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Project description:Epilepsy is a disease characterized by abnormal brain activity and a predisposition to generate epileptic seizures, leading to neurobiological, cognitive, psychological, social, and economic impacts for the patient. There are several known causes for epilepsy; one of them is the malfunction of ion channels, resulting from mutations. Voltage-gated sodium channels (NaV) play an essential role in the generation and propagation of action potential, and malfunction caused by mutations can induce irregular neuronal activity. That said, several genetic variations in NaV channels have been described and associated with epilepsy. These mutations can affect channel kinetics, modifying channel activation, inactivation, recovery from inactivation, and/or the current window. Among the NaV subtypes related to epilepsy, NaV1.1 is doubtless the most relevant, with more than 1500 mutations described. Truncation and missense mutations are the most observed alterations. In addition, several studies have already related mutated NaV channels with the electrophysiological functioning of the channel, aiming to correlate with the epilepsy phenotype. The present review provides an overview of studies on epilepsy-associated mutated human NaV1.1, NaV1.2, NaV1.3, NaV1.6, and NaV1.7.
| S-EPMC7461817 | biostudies-literature
Project description:Studies of genetic forms of epilepsy, chronic pain, and migraine caused by mutations in ion channels have given crucial insights into molecular mechanisms, pathogenesis, and therapeutic approaches to complex neurological disorders. Gain-of-function missense mutations in the brain type-I sodium channel Na(V)1.1 are a primary cause of generalized epilepsy with febrile seizures plus. Loss-of-function mutations in Na(V)1.1 channels cause severe myoclonic epilepsy of infancy, an intractable childhood epilepsy. Studies of a mouse model show that this disease is caused by selective loss of sodium current and excitability of GABAergic inhibitory interneurons, which leads to hyperexcitability, epilepsy, and ataxia. Mutations in the peripheral sodium channel Na(V)1.7 cause familial pain syndromes. Gain-of-function mutations cause erythromelalgia and paroxysmal extreme pain disorder as a result of hyperexcitability of sensory neurons, whereas loss-of-function mutations cause congenital indifference to pain because of attenuation of action potential firing. These experiments have defined correlations between genotype and phenotype in chronic pain diseases and focused attention on Na(V)1.7 as a therapeutic target. Familial hemiplegic migraine is caused by mutations in the calcium channel, Ca(V)2.1, which conducts P/Q-type calcium currents that initiate neurotransmitter release. These mutations increase activation at negative membrane potentials and increase evoked neurotransmitter release at cortical glutamatergic synapses. Studies of a mouse genetic model show that these gain-of-function effects lead to cortical spreading depression, aura, and potentially migraine. Overall, these experiments indicate that imbalance in the activity of excitatory and inhibitory neurons is an important underlying cause of these diseases.
| S-EPMC3177942 | biostudies-literature
Project description:INTRODUCTION:Cardiac channelopathies are a frequent cause of sudden cardiac death (SCD) and often manifest with convulsive syncope, leading to a misdiagnosis of epilepsy. We aim to evaluate the clinical impact of epilepsy misdiagnosis in a cohort of patients with cardiac channelopathies. METHODS:Fifty probands/families with a cardiac channelopathy were included. We retrospectively collected information from medical records to identify all patients who presented with convulsive syncope and were diagnosed with epilepsy after neurological evaluation. Clinical data and outcome were compared with those of patients without a previous epilepsy diagnosis. RESULTS:Eight patients had a previous diagnosis of epilepsy. At first episode, 3 of them presented a positive family history of SCD and 5 showed a pathological electrocardiogram; half presented with sudden cardiac arrest (SCA) and the rest with recurrent syncope despite treatment with 1 or more anti-epileptic drugs. Five patients had long QT syndrome, 2 had catecholaminergic polymorphic ventricular tachycardia, and 1 had Brugada syndrome. Epilepsy misdiagnosis was associated with an increased risk of SCA/SCD (OR 6.92, P = .04), a delay of 12 years (P = .047) in correct diagnosis, and a delay from first symptom to channelopathy diagnosis of 18.45 years (P < .0001). CONCLUSION:Cardiac channelopathy patients can be misdiagnosed with epilepsy. This involves a delayed diagnosis, a delay from the first symptom to a correct diagnosis, and an increased risk of SCA/SCD.
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Project description: Not available
| S-EPMC3073829 | biostudies-literature
Project description:Inherited mutations in voltage-gated sodium channels (VGSCs; or Nav) cause many disorders of excitability, including epilepsy, chronic pain, myotonia, and cardiac arrhythmias. Understanding the functional consequences of the disease-causing mutations is likely to provide invaluable insight into the roles that VGSCs play in normal and abnormal excitability. Here, we sought to test the hypothesis that disease-causing mutations lead to increased resurgent currents, unusual sodium currents that have not previously been implicated in disorders of excitability. We demonstrated that a paroxysmal extreme pain disorder (PEPD) mutation in the human peripheral neuronal sodium channel Nav1.7, a paramyotonia congenita (PMC) mutation in the human skeletal muscle sodium channel Nav1.4, and a long-QT3/SIDS mutation in the human cardiac sodium channel Nav1.5 all substantially increased the amplitude of resurgent sodium currents in an optimized adult rat-derived dorsal root ganglion neuronal expression system. Computer simulations indicated that resurgent currents associated with the Nav1.7 mutation could induce high-frequency action potential firing in nociceptive neurons and that resurgent currents associated with the Nav1.5 mutation could broaden the action potential in cardiac myocytes. These effects are consistent with the pathophysiology associated with the respective channelopathies. Our results indicate that resurgent currents are associated with multiple channelopathies and are likely to be important contributors to neuronal and muscle disorders of excitability.
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Project description:Advancements in genetic screening have generated massive amounts of data on genetic variation; however, a lack of clear pathogenic stratification has left most variants classified as being of unknown significance. This is a critical limitation for translating genetic data into clinical practice. Genetic screening is currently recommended in the guidelines for diagnosis and treatment of cardiac channelopathies, which are major contributors to sudden cardiac death in young people. We propose to characterize the pathogenicity of genetic variants associated with cardiac channelopathies using a stratified scoring system. The development of this system was considered by using all of the tools currently available to define pathogenicity. The use of this scoring system could help clinicians to understand the limitations of genetic associations with a disease, and help them better define the role that genetics can have in their clinical routine.
| S-EPMC4302303 | biostudies-other
Project description:Early-onset epilepsy is a neurological abnormality in childhood, and it is especially common in the first 2 years after birth. Seizures in early life mostly result from structural or metabolic disorders in the brain, and the genetic causes of idiopathic seizures have been extensively investigated. In this study, we identified four missense mutations in the SETD1A gene (SET domain-containing 1A, histone lysine methyltransferase): three de novo mutations in three individuals and one inherited mutation in a four-generation family. Whole-exome sequencing indicated that all four of these mutations were responsible for the seizures. Mutations of SETD1A have been implicated in schizophrenia and developmental disorders, so we examined the role of the four mutations (R913C, Q269R, G1369R, and R1392H) in neural development. We found that their expression in mouse primary cortical neurons affected excitatory synapse development. Moreover, expression of the R913C mutation also affected the migration of cortical neurons in the mouse brain. We further identified two common genes (Neurl4 and Usp39) affected by mutations of SETD1A. These results suggested that the mutations of SETD1A play a fundamental role in abnormal synaptic function and the development of neurons, so they may be pathogenic factors for neurodevelopmental disorders.
| S-EPMC6864154 | biostudies-literature
Project description:The CACNA1C gene encodes the pore-forming subunit of the CaV1.2 L-type Ca2+ channel, a critical component of membrane physiology in multiple tissues, including the heart, brain, and immune system. As such, mutations altering the function of these channels have the potential to impact a wide array of cellular functions. The first mutations identified within CACNA1C were shown to cause a severe, multisystem disorder known as Timothy syndrome (TS), which is characterized by neurodevelopmental deficits, long-QT syndrome, life-threatening cardiac arrhythmias, craniofacial abnormalities, and immune deficits. Since this initial description, the number and variety of disease-associated mutations identified in CACNA1C have grown tremendously, expanding the range of phenotypes observed in affected patients. CACNA1C channelopathies are now known to encompass multisystem phenotypes as described in TS, as well as more selective phenotypes where patients may exhibit predominantly cardiac or neurological symptoms. Here, we review the impact of genetic mutations on CaV1.2 function and the resultant physiological consequences.
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Project description:More than 650 inherited metabolic diseases may present with epilepsy or seizures. These diseases are often multisystem, life-long and induce complex needs of patients and families. Multidisciplinary care involves all stages of disease management: diagnostics, specific or symptomatic, acute and chronic treatments, and integrated care that takes into account not only medical, but also manifold psychosocial, educational, vocational and other needs of patients and their caregivers. Care coordination is indispensable to ensure smooth transitions of care across life and disease stages, including management of emergencies, transition from pediatric to adult services and palliative care. Care pathways are highly diverse and have to find the right balance between highly specialized and locally provided services. While multidisciplinary teams consist of many professionals, a named supervising physician in a highly specialized healthcare setting and a care coordinator are highly important. As the greatest burden of care always falls onto the shoulders of patients and/or families, patient empowerment should be a part of every care pathway and include provision of required information, involvement into common decision-making, patient's and family's education, support for self-management, liaison with peer support groups and emotional/ psychological support. Due to the rarity and complexity of these diseases, sufficient expertise may not be available in a national healthcare system and cross-border services (virtual or physical) in the recently developed European Reference Networks should be ensured through the proper organization of referral systems in each EU and EEA country. Finally, digital technologies are particularly important in the provision of services for patients with rare diseases and can significantly increase the availability of highly specialized services and expertise.
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