Neurological disorders caused by inherited ion-channel mutations

Several neurological diseases-including neuromuscular disorders, movement disorders, migraine, and epilepsy-are caused by inherited mutations of ion channels. The list of these "channelopathies" is expanding rapidly, as is the phenotypic range associated with each channel. At present the best understood channelopathies are those that affect muscle-fibre excitability. These channelopathies produce a range of disorders which include: periodic paralysis, myotonias, malignant hyperthermia, and congenital myasthenic syndromes. By contrast, the mechanisms of diseases caused by mutations of ion channels that are expressed in neurons are less well understood. However, as for the muscle channelopathies, a striking feature is that many neuronal channelopathies cause paroxysmal symptoms. This review summarises the clinical features of the known neurological channelopathies, within the context of the functions of the individual ion channels.     

Autonomic ganglia, acetylcholine receptor antibodies, and autoimmune ganglionopathy

Nicotinic acetylcholine receptors (AChR) are ligand-gated cation channels that are present throughout the nervous system. The ganglionic (alpha3-type) neuronal AChR mediates fast synaptic transmission in sympathetic, parasympathetic and enteric autonomic ganglia. Autonomic ganglia are an important site of neural integration and regulation of autonomic reflexes. Impaired cholinergic ganglionic synaptic transmission is one important cause of autonomic failure. Ganglionic AChR antibodies are found in many patients with autoimmune autonomic ganglionopathy (AAG). These antibodies recognize the alpha3 subunit of the ganglionic AChR, and thus do not bind non-specifically to other nicotinic AChR. Patients with high levels of ganglionic AChR antibodies typically present with rapid onset of severe autonomic failure, with orthostatic hypotension, gastrointestinal dysmotility, anhidrosis, bladder dysfunction and sicca symptoms. Impaired pupillary light reflex is often seen. Like myasthenia gravis, AAG is an antibody-mediated neurological disorder. Antibodies from patients with AAG inhibit ganglionic AChR currents and impair transmission in autonomic ganglia. An animal model of AAG in the rabbit recapitulates the important clinical features of the human disease and provides additional evidence that AAG is an antibody-mediated disorder caused by impairment of synaptic transmission in autonomic ganglia.     

Characterization of ganglionic acetylcholine receptor autoantibodies

In myasthenia gravis (MG), autoantibodies bind to the alpha1 subunit and other subunits of the muscle nicotinic acetylcholine receptor (AChR). Autoimmune autonomic ganglionopathy (AAG) is an antibody-mediated neurological disorder caused by antibodies against neuronal AChRs in autonomic ganglia. Subunits of muscle and neuronal AChR are homologous. We examined the specificity of AChR antibodies in patients with MG and AAG. Ganglionic AChR autoantibodies found in AAG patients are specific for AChRs containing the alpha3 subunit. Muscle and ganglionic AChR antibody specificities are distinct. Antibody crossreactivity between AChRs with different alpha subunits is uncommon but can occur.     

Physiologic principles underlying ion channelopathies

The ion channelopathies are a diverse array of human disorders caused by mutations in genes coding for ion channels. More than 40 different channelopathies have been identified, with representative disorders from every major class of ion channel and affecting all electrically excitable tissues: brain, peripheral nerve, skeletal muscle, smooth muscle, and heart. This review provides an overview of ion channel classification, structure, and function as a framework for understanding which ion channel properties are altered by disease-associated mutations and how these changes disrupt cellular excitability for channelopathies affecting skeletal muscle and the CNS.     

Invited Article: Autonomic ganglia: target and novel therapeutic tool

Nicotinic acetylcholine receptors (AChR) are ligand-gated cation channels that are present throughout the nervous system. The muscle AChR mediates transmission at the neuromuscular junction; antibodies against the muscle AChR are the cause of myasthenia gravis. The ganglionic (alpha 3-type) neuronal AChR mediates fast synaptic transmission in sympathetic, parasympathetic, and enteric autonomic ganglia. Impaired cholinergic ganglionic synaptic transmission is one important cause of autonomic failure. Pharmacologic enhancement of ganglionic synaptic transmission may be a novel way to improve autonomic function. Ganglionic AChR antibodies are found in patients with autoimmune autonomic ganglionopathy (AAG). Patients with AAG typically present with rapid onset of severe autonomic failure. Major clinical features include orthostatic hypotension, gastrointestinal dysmotility, anhidrosis, bladder dysfunction, and sicca symptoms. Impaired pupillary light reflex is often seen. Like myasthenia, AAG is an antibody-mediated neurologic disorder. The disease can be reproduced in experimental animals by active immunization or passive antibody transfer. The patient may improve with plasma exchange treatment or other immunomodulatory treatment. Antibodies from patients with AAG inhibit ganglionic AChR currents. Other phenotypes of AAG are now recognized based on the results of antibody testing. These other presentations are generally associated with lower levels of ganglionic AChR antibodies. A chronic progressive form of AAG may resemble pure autonomic failure. Milder forms of dysautonomia, such as postural tachycardia syndrome, are associated with ganglionic AChR in 10-15% of cases. Since ganglionic synaptic transmission is a common pathway for all autonomic traffic, enhancement of autonomic function through inhibition of acetylcholinesterase is a potential specific therapeutic strategy for autonomic disorders. Increasing the strength of ganglionic transmission can ameliorate neurogenic orthostatic hypotension without aggravating supine hypertension. Recent evidence also suggests a potential role for acetylcholinesterase inhibitors in the treatment of postural tachycardia syndrome.     

Central nervous system neuronal surface antibody associated syndromes: review and guidelines for recognition

The concept of antibody mediated CNS disorders is relatively recent. The classical CNS paraneoplastic neurological syndromes are thought to be T cell mediated, and the onconeural antibodies merely biomarkers for the presence of the tumour. Thus it was thought that antibodies rarely, if ever, cause CNS disease. Over the past 10 years, identification of autoimmune forms of encephalitis with antibodies against neuronal surface antigens, particularly the voltage gated potassium channel complex proteins or the glutamate N-methyl-D-aspartate receptor, have shown that CNS disorders, often without associated tumours, can be antibody mediated and benefit from immunomodulatory therapies. The clinical spectrum of these diseases is not yet fully explored, there may be others yet to be discovered and some types of more common disorders (eg, epilepsy or psychosis) may prove to have an autoimmune basis. Here, the known conditions associated with neuronal surface antibodies are briefly reviewed, some general aspects of these syndromes are considered and guidelines that could help in the recognition of further disorders are suggested.     

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.     

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.     

Ion channel and striational antibodies define a continuum of autoimmune neuromuscular hyperexcitability

Neuromuscular hyperexcitability is a characteristic of Isaacs' syndrome. Autoantibodies specific for voltage-gated potassium channels (VGKC) or ganglionic nicotinic acetylcholine receptors (AChR) are markers of this disorder. To determine the frequency of these ion channel antibodies and of related neuron- and muscle-specific antibodies in patients with acquired neuromuscular hyperexcitability, we tested serum specimens from 77 affected patients (35 neuromyotonia, 32 cramp-fasciculation syndrome, 5 rippling muscle syndrome, and 5 focal neuromuscular hyperexcitability) and 85 control subjects. Among study patients, 14% had coexisting myasthenia gravis, and 16% had an associated neoplasm. We found that 35% had VGKC antibodies, 12% ganglionic AChR antibodies, 16% muscle AChR antibodies, and 10% striational antibodies. Overall, 55% had serological evidence of neurological autoimmunity compared to 2% of control subjects. Patients with neuromyotonia were more frequently seropositive (71%) than patients with cramp-fasciculation syndrome (31%). We conclude that acquired neuromuscular hyperexcitability consists of a continuum of clinical disorders with a common autoimmune pathogenesis.     

Paraneoplastic neurological disorders

The article provides an overview on the diagnosis and pathogenesis of paraneoplastic neurological disorders (PNDs), and subsequently the current therapeutic strategies in these patients. PNDs are nervous system dysfunctions in cancer patients, which are not due to a local effect of the tumor or its metastases. Most of these clinically defined syndromes in adults are associated with lung cancer, especially small-cell lung cancer, lymphoma and gynecological tumors. In a part of the PND, an overlapping of different clinical syndromes can be observed. Highly specific autoantibodies directed against onconeuronal antigens led to the current hypothesis of an autoimmune pathophysiology. Whereas the most central nervous PNDs are more T-cell-mediated, limbic encephalitis can be caused by pathogenic receptor autoantibodies. The PND of the neuromuscular junction and paraneoplastic autonomic neuropathy are mainly associated with receptor or ion channel autoantibodies. The childhood opsoclonus-myoclonus syndrome and the PNDs associated with receptor/ion channel autoantibodies often respond to immunosuppressive therapies, plasmapheresis and intravenous immunoglobulins. By contrast, most CNS PNDs associated with defined antineuronal antibodies directed against intracellular antigens only stabilize after tumor treatment.     

Myasthenia gravis with autoimmune autonomic neuropathy

The autoantibodies that impair neuromuscular junction transmission in myasthenia gravis are specific for the nicotinic acetylcholine receptor (AChR) of muscle. Antibodies specific for AChRs in ganglionic neurons are found in a majority of patients with subacute autonomic neuropathy. Dysautonomia is not a recognized feature of myasthenia gravis, but there have been rare reports of myasthenia gravis coexisting with autonomic failure, usually in association with thymoma. Here we report seven patients who had myasthenia gravis with subacute autonomic failure. Their autonomic dysfunction ranged from isolated gastroparesis to severe panautonomic failure. Gastrointestinal dysmotility was a common feature. All had antibodies against muscle AChR, and three (all of whom had thymoma) had antibodies against neuronal ganglionic AChRs. In several patients, gastrointestinal function improved clinically after administration of an acetylcholinesterase inhibitor. These observations support a rare but definite clinical association between myasthenia gravis and autonomic failure and strengthen the concept that subacute autonomic neuropathy is an autoimmune disorder.     

Clinical aspects of neuromuscular transmission disorders

Autoimmune disorders of neuromuscular transmission are caused by antibodies (abs) directed against membrane proteins at the motor end-plate. Myasthenia gravis (MG) is due, in most cases, to abs against the nicotinic acetylcholine receptor (AChR). Anti-AChR-positive MG actually includes different disease entities: weakness can be confined to extrinsic ocular muscles or can be generalized; patients with generalized MG (G-MG) can be subdivided on the basis of age of onset, HLA association and thymic pathology. About 15% of G-MG patients are anti-AChR-negative; in a proportion of these cases serum abs against the muscle- specific kinase (MuSK) are found. Anti-MuSK-positive MG is characterized by predominant involvement of bulbar muscles and very low frequency of thymic pathology. The Lambert-Eaton myasthenic syndrome (LEMS) is caused by abs against voltage-gated calcium channels at nerve terminal. LEMS is characterized by muscle weakness and autonomic disturbances and it is paraneoplastic in over 50% of the cases. In neuromyotonia and cramp-fasciculation syndrome, that are thought to be due to anti-voltage-gated potassium channel abs, signs of peripheral nerve hyperexcitability can be associated with CNS features.     

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。     

乙酰胆碱受体抗体与大鼠中枢神经元烟碱型乙酰胆碱受体之间免疫结合反应

本研究旨在探讨长期以来无定论的重症肌无力（MG）患者血和脑脊液（CSF）中的乙酰胆碱受体抗体（AChRab）能否与中枢神经元烟碱型乙酰胆碱受体（神经-nAChR）结合，并引起中枢神经系统（CNS）功能障碍。用免疫亲和层析法从AChRab阳性的全身型MG患者血中提取纯化AChRab，然后用免疫组化法探讨AChRab与大鼠中枢神经-nAChR之间的免疫结合反应。结果首次表明，AChRab与神经-nAChR之间的阳性免疫结合反应广泛分布于大鼠大脑皮层、脑干颅神经运动核团、脊髓前角运动神经元等部位，提示MG患者AChRab不仅可与神经肌接头（NMJ）处肌-nAChR结合引起肌无力等症状，还可与CNS神经-nAChR结合，并可能引起CNS功能障碍。     

Calcium channels in neurological disease

Channels involved in the influx and intracellular mobilization of calcium have been implicated as targets of diverse genetic and immune-mediated neurological diseases. These include the L-type voltage-gated calcium channel of skeletal muscle (hypokalemic periodic paralysis), the neuronal P/Q-type voltage-gated calcium channel (familial hemiplegic migraine, episodic ataxia type 2, spinocerebellar ataxia 6, and Lambert–Eaton myasthenic syndrome), and the skeletal muscle ryanodine receptor (malignant hyperthermia and central core disease). The discovery of these and other calcium channelopathies should help to clarify how different mutations affect shannel function and how altered channel function produces disease, and may lead to new treatments for these conditions.     

Antibodies against neuronal nicotinic receptor subtypes in neurological disorders

Patients with myasthenia gravis (MG) have antibodies to the muscle nicotinic acetylcholine receptor (mAChR) which are responsible for their muscle weakness: but some patients with MG and other neuroimmunological disorders have autonomic symptoms. We characterised the neuronal forms of AChRs (nAChRs) into two neuroblastoma cell lines and developed immunoprecipitation assays to test for antibodies to the alpha7- and alpha3-containing nAChR subtypes, present in the autonomic ganglia. We then tested 70 sera samples from MG patients, 38 from subjects with other neurological diseases, and 30 from healthy individuals, for antibodies to these two forms of neuronal AChR subtypes. We used the alpha7 subtype extracted from the human neuroblastoma IMR32 cell line labeled with 125IalphaBungarotoxin (alphaBgtx), and the alpha3-containing subtype extracted from the human neuroblastoma SY5Y cell line labeled with 3H-Epibatidine (Epi). Nine subjects (five MG, one GBS, one CIPD and two LEMS) were positive for the alpha7 subtype; and four for the alpha3-containing subtype (two MG patients, one LEMS and the same GBS patient). None of the MG patients with undetectable levels of antibodies against muscle AChR were positive. The patients with serum antibodies to alpha7 or alpha3-containing neuronal AChRs showed a range of clinical features including autonomic symptoms and thymoma in two MG patients. These results indicate that patients with MG and other immune-mediated disorders can have antibodies to neuronal AChRs, and that these may contribute to the clinical characteristics of the diseases.     

Limbic encephalitis: etiology, pathogenesis, diagnosis and therapy]

Limbic encephalitis affects the mesial temporal lobes and is characterized by subacute onset of memory impairment, personal change, temporal seizures and autonomic nervous disorders. It can occur as viral infections, especially caused by Herpes simplex, paraneoplastic syndrome as a remote effect of cancer, CNS complication of well defined autoimmune diseases. Recently acute reversible limbic encephalitis which probably autoimmune mediated disorders has been reported. Anti-immunotherapy including steroids, plasma exchange and intravenous immunoglobulin often improves this condition and anti-voltage gated potassium channel (VGKC) antibody or anti-glutamate receptor epsilon2 antibody has been detected in some patients. Establishing the means of early detection of these antibodies as well as other characteristic paraneoplastic antibodies should now be the aim. Detection of neurotropic viral genomes in CSF by PCR is also important for differential diagnosis. As complete recovery of higher cerebral function is generally difficult, immunotherapy and anti-convulsants in addition to vitamin B, and acyclovir should be considered in an early stage of disease.     

Channelopathy]

Recently, a variety of ion channel defects have been identified as the biological basis of certain familial epilepsies, paroxysmal movement disorders, myopathies and some degenerative disorders of central nervous system. Ion channel defects were mainly caused by genetic and autoimmune mechanisms. Here, we reviewed several channelopathies including spinocerebellar ataxia type 6, familial hemiplegic migraine, episodic ataxia type 2, familial hypokalemic periodic paralysis, congenital myotonia, malignant hyperthermia, epilepsy, Gitelman syndrome and Lambert-Eaton syndrome.     

Neuromuscular disease and calcium channels.

Calcium channels that are regulated by voltage have an important role in linking cellular stimulation to physiological responses in the nervous system. In addition, a number of autoimmune or genetic disorders that affect calcium channels (channelopathies) have been identified, including several that affect neuromuscular function. These include the Lambert-Eaton myasthenic syndrome, which is associated with autoantibodies directed against neuronal calcium channels, as well as at least two inherited neuromuscular diseases-hypokalemic periodic paralysis and some varieties of malignant hyperthermia-that affect calcium channels in skeletal muscle. Preliminary progress has been achieved in understanding the relationship between these immunological or genetic abnormalities and the alterations in channel function that they produce. A major challenge that remains is to determine how calcium channelopathies lead to the curious assortment of paroxysmal and progressive disorders that are observed clinically.     

Myasthenia, thymoma, presynaptic antibodies, and a continuum of neuromuscular hyperexcitability.

BACKGROUND: Autoantibodies specific for the nicotinic acetylcholine receptor (AChR) of skeletal muscle impair neuromuscular transmission in myasthenia gravis (MG). Autoantibodies specific for alpha3 neuronal AChRs or voltage-gated potassium channels have been reported in patients with Isaacs syndrome, an acquired disorder of continuous muscle fiber activity characterized by neuromyotonia. OBJECTIVE: To report the neuromuscular autoantibody profiles of three patients with a syndrome of MG and neuromuscular hyperexcitability. RESULTS: All three patients reported here had clinical and electrophysiologic evidence of MG and neuromuscular hyperexcitability. None had neuromyotonia. Thymoma was proven in two patients and suspected in the third. One had MG and thymoma and subsequently developed cramp-fasciculation syndrome; MG and rippling muscle syndrome appeared simultaneously in the other two. All patients had muscle and neuronal AChR binding antibodies and striational antibodies. Only one had antibodies reactive with alpha-dendrotoxin-complexed potassium channels. CONCLUSIONS: The coexistence of cramp-fasciculation syndrome and acquired rippling muscle syndrome with MG, thymoma, and neuronal AChR autoantibodies suggests that there is a continuum of autoimmune neuromuscular hyperexcitability disorders related pathogenically to Isaacs syndrome. Manifestations of neuromuscular hyperexcitability may be altered and less apparent in the context of MG because of the coexisting defect of neuromuscular transmission.