离子通道变异与癫痫病

离子通道是神经系统和其它可兴奋组织(肌肉和腺体)产生兴奋和行使功能活动的核心基本物质之一。因编码离子通道基因的突变所导致的各类先天性疾病被称之为通道病因学。临床上常见的先天性癫痫综合征多属于通道病。先天性癫痫占癫痫人群的40％，常见的有以下几种：由N型乙酰胆碱受体CHRNA4或CHRNB亚基突变所致的常染色体显性夜间额叶癫痫：因电压门控钾通道KCNQ2和KCNQ3缺陷所致的良性家族性新生儿惊厥；因电压门控钠通道SCN1B．SCN1A和SCN2A亚基以及GABA受体GABRG2亚基突变诱发的高热抽搐全身型癫痫叠加综合征：南电压门控氯通道(C1C2突变)和GABAA受体或亚基突变所致的几种特发性全身性癫痫：此外，近来还发现了与电压门控钾通道KCNA1有关的另一种与1型共济失调伴发的局限性癫痫。研究分析先天性癫痫家系基因遗传谱及其突变通道的电生理特性，有利于更深入地认识和了解先天性癫痫的通道突变发病机制．制定新的抗癫痫策略，开发针对性抗癫痫新药。本文将对先天性癫痫的通道病因学研究进展作一简要梳理。     

Voltage-gated ion channelopathies of the nervous system

Mutations in genes coding for voltage-gated ion channels cause a diverse group of disorders affecting heart, skeletal muscle, and brain. Mutant channels alter the electrical excitability of cells, which increases the susceptibility to paroxysmal symptoms including cardiac arrhythmia, periodic paralysis, myotonia, seizures, migraine headache, and episodic ataxia. This review provides an update on the genetics and physiology of diseases of skeletal muscle and brain caused by mutations in voltage-gated in ion channel genes. The discovery of specific ion channel defects provides a rational basis for designing pharmacological intervention, as ion channels are the molecular targets of many drugs in clinical use. Moreover, the advent of a molecular genetic-based diagnosis provides an important tool for clarifying the natural history and effectiveness of intervention in these disorders.     

Physiologic mechanisms underlying the antidepressant discontinuation syndrome

The rate at which serotonin reuptake inhibitor (SRI) treatment is terminated and the duration of treatment appear to be key factors in predicting discontinuation symptoms. The development of animal models to explain the mechanisms of this clinical problem has proved challenging, because less than half of all patients experience any discontinuation symptoms, many of which are subjective in nature. One explanation is that SRI discontinuation symptoms may arise from the rapid decrease in serotonin (5-HT) availability when treatment ends abruptly. Yet, it would appear that discontinuation discomforts may not be mediated exclusively through 5-HT receptors, given the major regulatory role 5-HT exerts on a number of specific chemical receptor systems in the brain. As a result, attempts to explain the determinants of this phenomenon rely on a certain level of speculation. This article examines the possible physiologic bases for the antidepressant discontinuation syndrome and briefly describes these adaptations. It discusses the 3 systems most likely to account for at least part of the symptomatology--the 5-HT, the norepinephrine, and the cholinergic systems--and the possible interactions among them. It also attempts to explain their implications in the therapeutic actions of antidepressants in patients with affective and anxiety disorders.     

Muscle channelopathies

In recent years the term CHANNELOPATHY has been adopted to describe neurological disorders caused by mutations in different ion channel genes. Myopathic channelopathies include two main groups: nondystrophic myotonias and periodic paralyses. This article reviews the clinical features, diagnostic approach, molecular causes, and management of patients with nondystrophic myotonias and periodic paralyses.     

Autoimmune channelopathies

Autoimmune disorders of the neuromuscular junction remain a paradigm for our understanding of autoimmunity. Since the role of autoantibodies to acetylcholine receptors in the pathogenesis of myasthenia gravis was first recognized in the 1970s, a range of antibody-mediated disorders of the neuromuscular junction have been described, each associated with an autoantibody to a specific ligand-gated receptor, voltage-gated ion channel or related protein. In addition, antibodies to a ganglionic form of acetylcholine receptor have been detected in autoimmune forms of autonomic neuropathy. In the past few years, a role for antibodies in disorders of the CNS has begun to emerge, challenging our previous concepts regarding the blood-brain barrier and the role of the humoral immune system in CNS pathology. Although it has not yet been definitively shown that these CNS conditions are antibody-mediated, the detection of the specific antibody supports a trial of immunosuppressive therapy to which many patients appear to respond. In this article, we review the roles of antibodies to receptors and ion channels in the peripheral and central nervous systems, concentrating on the recently defined autonomic and CNS conditions and on the role of antibody measurement in diagnosis and management.     

Calcium channelopathies

Intracellular calcium ([Ca2+]i) is highly regulated in eukaryotic cells. The free [Ca2+]i is approximately four orders of magnitude less than that in the extracellular environment. It is, therefore, an electrochemical gradient favoring Ca2+ entry, and transient cellular activation increasing Ca2+ permeability will lead to a transient increase in [Ca2+]i. These transient rises of [Ca2+]i trigger or regulate diverse intracellular events, including metabolic processes, muscle contraction, secretion of hormones and neurotransmitters, cell differentiation, and gene expression. Hence, changes in [Ca2+]i act as a second messenger system coordinating modifications in the external environment with intracellular processes. Notably, information on the molecular genetics of the membrane channels responsible for the influx of Ca2+ ions has led to the discovery that mutations in these proteins are linked to human disease. Ca2+ channel dysfunction is now known to be the basis for several neurological and muscle disorders such as migraine, ataxia, and periodic paralysis. In contrast to other types of genetic diseases, Ca2+ channelopathies can be studied with precision by electrophysiological methods, and in some cases, the results have been highly rewarding with a biophysical phenotype that correlates with the ultimate clinical phenotype. This review outlines recent advances in genetic, molecular, and pathophysiological aspects of human Ca2+ channelopathies.     

Left mid-ventrolateral prefrontal cortex: underlying principles of function

There is a growing body of evidence indicating that the mid-ventrolateral prefrontal cortex in the left hemisphere is involved in some aspect of controlled verbal memory retrieval. Its precise role, however, remains unclear. We tested the hypothesis that when stimuli in memory are related to each other in multiple ways, and therefore familiarity, strong constant stimulus–stimulus links or contextual cues are not sufficient for successful retrieval, control processing emanating from the mid-ventrolateral prefrontal cortex is required to disambiguate and select the appropriate information among memory traces. We refer to this type of retrieval as active retrieval to distinguish it from automatic retrieval which depends on the simple reactivation of memory traces. Normal human subjects were scanned with functional magnetic resonance imaging while they performed three memory tasks that varied in their demands on active retrieval of verbal information. As the demands on active retrieval increased, there was an increase in the activity within the mid-ventrolateral prefrontal cortex, bilaterally, but with more prominent activity in the left hemisphere. These activity increases correlated with activity in the posterior temporal region which, in the left hemisphere, is involved in language processing. No significant activity increases were observed in any other prefrontal region. Furthermore, for the retrieval of well-learned verbally cued conditional motor associations, there were no activity increases in the mid-ventrolateral prefrontal cortex. The present findings provide strong support for the hypothesis that the mid-ventrolateral prefrontal cortex, particularly in the left hemisphere, plays a major role in the active retrieval of information from verbal memory.     

Skeletal muscle channelopathies

Ion channelopathies have common clinical features, recurrent patterns of mutations, and almost predictable mechanisms of pathogenesis. In skeletal muscle, disorders are associated with mutations in voltage-gated Na⁺, K⁺, Ca²⁺, and Cl⁻ channels leading to hypoexcitability, causing periodic paralysis and to hyperexcitabilty, resulting in myotonia or susceptibility to malignant hyperthermia. Received: 30 April 2002, Accepted: 21 May 2002 Correspondence to F. Lehmann-Horn     

Genetic neurological channelopathies

Ion channels are crucial for the normal function of excitable tissues such as neurons and skeletal muscle. Since the discovery that the paroxysmal muscle disorder periodic paralysis is caused by mutations in genes that encode voltage-gated ion channels, many genetic neurological channelopathies have been defined. These channelopathies include epilepsy syndromes that show a mendelian pattern of inheritance, certain forms of migraine and disorders of cerebellar function, as well as periodic paralysis. The clinical diversity of these disorders relates in part to the tissue-specific expression of the dysfunctional channel, but is probably influenced by other, as yet unidentified, genetic and non-genetic factors. The complementary disciplines of molecular genetics and cellular and in vitro electrophysiology have resulted in significant advances in understanding of the basic molecular pathophysiology of some of these disorders. The single-gene neurological channelopathies are generally regarded as a paradigm for understanding common human paroxysmal disorders, such as epilepsy and migraine. This article reviews the clinical and molecular features of some of the single-gene channelopathies that affect muscle and brain. The possible role of ion-channel functional and genetic variation in predisposing individuals to common forms of human epilepsy and migraine are also considered. The implications for accurate genetic diagnosis and therapeutic intervention are highlighted.     

Autoimmune and paraneoplastic channelopathies

Thirty years ago, antibodies against the muscle acetylcholine receptor (AChR) were recognized as the cause of myasthenia gravis. Since then, there has been great interest in identifying other neurological disorders associated with auto-antibodies. Several other antibody-mediated neuromuscular disorders have been identified, each associated with an antibody against a ligand- or voltage-gated ion channel. The Lambert-Eaton syndrome is caused by antibodies against voltage-gated calcium channels and often occurs in patients with small cell lung cancer. Acquired neuromyotonia is caused by voltage-gated potassium channel antibodies, and autoimmune autonomic ganglionopathy is caused by antibodies against the neuronal AChR in autonomic ganglia. There is good evidence that antibodies in these disorders cause changes in synaptic function r neuronal excitability by directly inhibiting ion channel function. More recently, studies have identified ion channel antibodies in patients with certain CNS disorders, such as steroid-responsive encephalitis and paraneoplastic cerebellar ataxia. It remains unclear if antibodies can gain access to the CNS and directly cause ion channel dysfunction. Treatment of autoimmune channelopathies includes drugs that help restore normal neuronal function and treatments to remove pathogenic antibodies (plasma exchange) or modulate the immune response (steroids or immunosuppressants). These disabling neurological disorders may be dramatically responsive to immunomodulatory therapy. Future studies will likely lead to identification of other ion channel antibodies and other autoimmune channelopathies.     

Episodic ataxia and channelopathies

Clinical details are given of different types of episodic ataxia: type 1, with myokymia, and attacks which usually last a few minutes, and may occur several times a day, and treatment with acetazolamide can reduce the number of attacks; type 2, with interictal nystagmus, and attacks which last for several hours to a day or more, and treatment with acetazolamide is very effective; paroxysmal choreoathetosis with episodic ataxia, with attacks lasting for about 20 min and occurring at varying intervals; and familial hemiplegic migraine, with transient hemiplegia presenting during the aura of a migraine headache, the symptoms improving on treatment with acetazolamide. Their inheritance is of dominant type; and the gene for type 1 is mapped to chromosome 12p near to a cluster of potassium channel genes, and that for type 2 and for familial hemiplegic migraine to chromosome l9p near to calcium channel genes. The differential diagnosis from other conditions with a periodic symptomatology is discussed, especially from a number of metabolic disorders. Treatment is effective for many of these, and the treatment of the episodic ataxias with acetazolamide can sometimes have a dramatic effect. The possible role of the channelopathies in the causation of some periodic neurological disorders is considered; with the expectation that further research will improve the identification of specific diseases, and lead to more effective treatment.     

Periodic paralysis: Understanding channelopathies

Familial periodic paralyses are typical channelopathies (ie, caused by functional disturbances of ion channel proteins). The episodes of flaccid muscle weakness observed in these disorders are due to underexcitability of sarcolemma leading to a silent electromyogram and the lack of action potentials even upon electrical stimulation. Interictally, ion channel malfunction is well compensated, so that special exogenous or endogenous triggers are required to produce symptoms in the patients. An especially obvious trigger is the level of serum potassium (K⁺), the ion responsible for resting membrane potential and degree of excitability. The clinical symptoms can be caused by mutations in genes coding for ion channels that mediate different functions for maintaining the resting potential or propagating the action potential, the basis of excitability. The phenotype is determined by the type of functional defect brought about by the mutations, rather than the channel effected, because the contrary phenotypes hyperkalemic periodic paralysis (HyperPP) and hypokalemic periodic paralysis (HypoPP) may be caused by point mutations in the same gene. Still, the common mechanism for inexcitability in all known episodic-weakness phenotypes is a long-lasting depolarization that inactivates sodium ion (Na⁺) channels, initiating the action potential.     

Muscle channelopathies and electrophysiological approach

Myotonic syndromes and periodic paralyses are rare disorders of skeletal muscle characterized mainly by muscle stiffness or episodic attacks of weakness. Familial forms are caused by mutation in genes coding for skeletal muscle voltage ionic channels. Familial periodic paralysis and nondystrophic myotonias are disorders of skeletal muscle excitability caused by mutations in genes coding for voltage-gated ion channels. These diseases are characterized by episodic failure of motor activity due to muscle weakness (paralysis) or stiffness (myotonia). Clinical studies have identified two forms of periodic paralyses: hypokalemic periodic paralysis (hypoKPP) and hyperkalemic periodic paralysis (hyperKPP), based on changes in serum potassium levels during the attacks, and three distinct forms of myotonias: paramyotonia congenita (PC), potassium-aggravated myotonia (PAM), and myotonia congenita (MC). PC and PAM have been linked to missense mutations in the SCN4A gene, which encodes α subunit of the voltage-gated sodium channel, whereas MC is caused by mutations in the chloride channel gene (CLCN1). Exercise is known to trigger, aggravate, or relieve symptoms. Therefore, exercise can be used as a functional test in electromyography to improve the diagnosis of these muscle disorders. Abnormal changes in the compound muscle action potential can be disclosed using different exercise tests. Five electromyographic (EMG) patterns (I-V) that may be used in clinical practice as guides for molecular diagnosis are discussed.     

Human skeletal muscle sodium channelopathies

Abstract Ion channels are transmembrane proteins that allow ions to flow in or out of the cell. Sodium and potassium channel activation and inactivation are the basis of action potential’s production and conduction. During the past 15 years, ion channels have been implicated in diseases that have come to be known as the channelopathies. Over 30 mutations of the muscle channel gene SCN4A, which encodes the muscle voltage-gated sodium channel, have been described and associated with neuromuscular disorders like hypo- and hyper-kalaemic periodic paralyses (hypoPP and hyperPP), paramyotonia congenita, sodium channel myotonias and congenital myasthenic syndrome. Different mutations within the same gene (SCN4A) cause distinct clinical disorders, while mutations in different channel genes may result in similar phenotypes. In addition, identical sodium channel mutations can result in different clinical phenotypes (hyperPP or paramyotonia) in different members of the same family, suggesting that the genetic background and perhaps other epigenetic factors may influence the clinical expression of a particular mutation. This article reviews the clinical features of the skeletal muscle sodium channel diseases and highlights the phenotypic or genetic overlap in these disorders.