Update of Neurological Channelopathies

In order for cells to retain their integrity to water and yet permeate charged ions, transmembrane proteins known as ion channels have evolved. There is huge diversity of these ion channels. Some proteins are tissue specific, while others are widely distributed throughout the body. The resting membrane potential of excitable cells is entirely due to the presence of such ion channels. It is therefore unsurprising that these channels are integral to the fundamental processes of electrical signalling and excitation within the nervous system. Ion channels are membrane-bound proteins that perform key functions in virtually all human cells. Such channels are critically important for the normal function of the excitable tissues of the nervous system, such as muscle and brain. Until relatively recently it was considered that dysfunction of ion channels in the nervous system would be incompatible with life. However, an increasing number of human diseases associated with dysfunctional ion channels are now recognized. Collectively, these disorders are known as the neurological channelopathies. Such neurological channelopathies are frequently genetically determined but may also arise through autoimmune mechanisms. Different classifications of ion channels exist. Essentially ion channels have been classified into two broad categories depending on their mode of activation—that is, voltage gated and ligand gated. Most ion channels have a similar basic structure. All voltage gated ion channels have a large pore forming subunit, which sits within the membrane. The pore forming subunit (also called the α-subunit) contains a central aqueous pore through which the relevant ion passes in response to voltage change induced activation, also known as gating. In addition to the main α-subunit, it is common for voltage gated ion channels to possess accessory subunits, these subunits may be cytoplasmic or extracellular. Generally, these have an important function in modulating the basic conductance function of the α-subunits. To date, most genetic neurological channelopathies affecting the peripheral nervous system (PNS) and central nervous system (CNS) are caused by α-subunit mutations, resulting in ysfunction of voltage gated ion channels. However, examples of genetic channelopathies due to dysfunction of ligand gated channels are recognized, particularly in the PNS and are emerging in the CNS. To date, most autoimmune channelopathies affect the PNS, although CNS examples are likely to increase in the future. It is evident that the PNS and CNS may be affected in isolation or in combination. In addition, it has become clear that either genetic or autoimmune insults to the relevant channel may underlie disease pathogenesis. Indeed, it may well transpire that for each genetic channelopathy there will be its autoimmune counterpart. To date, autoimmune channelopathies affecting the CNS are relatively uncommon but are likely to increase as further antibodies are identified. For many channelopathies an accurate genetic or autoimmune diagnosis can be achieved. Genetic diagnosis is clearly important in order to allow accurate genetic counselling in appropriate families and will often inform treatmentchoices. 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. Despite their clinical diversity, the genetic neurological channelopathies exhibit at least three common features. First, they are paroxysmal, that is, patients usually experience episodes of impaired neurological function separated by periods of normality. Second, episodes are triggered by environmental factors, such as temperature and physical or emotional stress. Third, the genetic neurological channelopathies tend to share a common natural history: over time, the frequency of attacks usually declines, but the patients are often left with fixed tissue dysfunction and, therefore, some persisting neurological disability. Although individually uncommon, the genetic neurological channelopathies are becoming widely recognized as a group, and cases will be encountered by clinicians in most branches of clinical neurology. At least ۴۰ separate single gene neurological channelopathies have now been identified. The range of clinical presentations is somewhat bewildering, and in part reflects the tissue distribution of the mutated ion channel. Clinical phenotypes include muscle disorders such as periodic paralysis and myotonia (muscle stiffness), disorders of peripheral nerve excitability such as neuromyotonia, and brain disorders migraine and epilepsy. Neuronal ion channels associated with human inherited epilepsies include voltage-gated channels (Na+, K+, Ca۲+, Cl) as well as ligand-gated channels (nicotinic ACh receptors, GABA receptors). Genotype-phenotype relationships in epilepsy are complex. Mutations of several different ion channels can cause remarkably similar phenotypes (locus heterogeneity), while distinct mutations of the same gene can cause variable phenotypes (allelic heterogeneity), and furthermore, even the same mutation could lead to variable phenotypes depending on factors like age and brain maturation. Parallels are seen in the molecular findings of non-epileptic paroxysmal neurological diseases where ion channels are also responsible, for example, mutations in Na+ channels are associated with periodic paralysis, calcium channel mutations are associated with Familial Hemiplegic Migraine (FHM) and Episodic Ataxia (EA-۲), arising from defects of the same gene (FHM and EA-۲ can be considered as allelic channelopathies).

کلیدواژه ها:

Channelopathies ، Pediatrics ، Paroxysmal Neurological Diseases ، Epilepsy