Neurological Channelopathies T D Graves, M G Hanna
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20 Postgrad Med J: first published as 10.1136/pgmj.2004.022012 on 7 January 2005. Downloaded from REVIEW Neurological channelopathies T D Graves, M G Hanna ............................................................................................................................... Postgrad Med J 2005;81:20–32. doi: 10.1136/pgmj.2004.022012 Ion channels are membrane-bound proteins that perform neurological channelopathies are subdivided on the basis of channel type. Table 2 is a list of key functions in virtually all human cells. Such channels are genetic neurological channelopathies according critically important for the normal function of the excitable to ion type. Most ion channels have a similar tissues of the nervous system, such as muscle and brain. basic structure. All voltage gated ion channels have a large pore forming subunit, which sits Until relatively recently it was considered that dysfunction within the membrane. The pore forming subunit of ion channels in the nervous system would be (also called the a-subunit) contains a central incompatible with life. However, an increasing number of aqueous pore through which the relevant ion passes in response to voltage change induced human diseases associated with dysfunctional ion channels activation, also known as gating. In addition to are now recognised. Such neurological channelopathies the main a-subunit, it is common for voltage are frequently genetically determined but may also arise gated ion channels to possess accessory subunits, these subunits may be cytoplasmic or extracel- through autoimmune mechanisms. In this article clinical, lular. Generally, these have an important func- genetic, immunological, and electrophysiological aspects tion in modulating the basic conductance of this expanding group of neurological disorders are function of the a-subunits. The structural topol- ogy of all voltage gated ion channels is remark- reviewed. Clinical situations in which a neurological ably conserved through evolution. To date, most channelopathy should enter into the differential diagnosis genetic neurological channelopathies affecting are highlighted. Some practical guidance on how to the peripheral nervous system (PNS) and central nervous system (CNS) are caused by a-subunit investigate and treat this complex group of disorders is also mutations, resulting in dysfunction of voltage included. gated ion channels. However, examples of ........................................................................... genetic channelopathies due to dysfunction of ligand gated channels are recognised, particu- larly in the PNS and are emerging in the CNS. To date most autoimmune channelopathies affect n order for cells to retain their integrity to the PNS, although CNS examples are likely to water and yet permeate charged ions, trans- increase in the future. Imembrane proteins known as ion channels http://pmj.bmj.com/ have evolved. There is huge diversity of these ion channels. Some proteins are tissue specific, while INHERITED CHANNELOPATHIES others are widely distributed throughout the Muscle channelopathies body. The resting membrane potential of exci- Myotonic syndromes table cells is entirely due to the presence of such Myotonia is the term given to delayed relaxation ion channels. It is therefore unsurprising that of skeletal muscle after voluntary contraction. In these channels are integral to the fundamental most situations myotonia is most marked after on September 30, 2021 by guest. Protected copyright. processes of electrical signalling and excitation initial muscle contraction, and usually abates within the nervous system. It had been suspected after repeated muscle activity (the warm-up that genetic dysfunction of such critical mem- phenomenon). Electophysiologically, myotonia brane-bound proteins would be lethal. However, is a disturbance of the normal excitability of during the past few years there has been an the skeletal muscle membrane. There is an explosion in the discovery of disease-causing abnormally increased excitability of the mem- brane such that in response to a depolarising See end of article for mutations in genes coding for ion channel authors’ affiliations proteins and these disorders are known as stimulus, for example, a nerve impulse, rather ....................... channelopathies. We now recognise both genetic than a single muscle contraction being initiated, multiple contractions occur and this results in and autoimmune channelopathies affecting a Correspondence to: the delayed relaxation observed clinically. Dr Michael G Hanna, range of tissues. This review considers clinical, From a practical point of view a myotonic Department of Molecular genetic, autoimmune, and molecular pathophy- Neuroscience and Centre disorder should be considered in the differential for Neuromuscular siological features of the neurological channelo- Disease, National Hospital pathies. for Neurology and Neurosurgery, Queen Abbreviations: CMAP, compound muscle action Square, London WC1N CLASSIFICATION OF ION CHANNELS potential; CNS, central nervous system; HyperKPP, 3BG, UK; mhanna@ Different classifications of ion channels exist. For hyperkalaemic periodic paralysis; HypoKPP, ion.ucl.ac.uk the purpose of this review we have classified ion hypokalaemic periodic paralysis; LEMS, Lambert-Eaton myasthenic syndrome; PCD, paraneoplastic cerebellar Submitted 14 March 2004 channels into two broad categories depending on degeneration; PNS, peripheral nervous system; SCA6, Accepted 18 May 2004 their mode of activation—that is, voltage gated spinocerebellar ataxia type 6; SCLC, small cell lung ....................... and ligand gated. Table 1 shows how the genetic carcinoma www.postgradmedj.com Neurological channelopathies 21 Postgrad Med J: first published as 10.1136/pgmj.2004.022012 on 7 January 2005. Downloaded from sought on examination and may be a clue to a chloride Table 1 Classification of inherited neurological channel myotonia. channelopathies according to type of channel affected Muscle Central nervous system Myotonia congenita See table 3 for clinical features. Voltage gated Hypokalaemic Episodic ataxia type 1 channels periodic paralysis Hyperkalaemic Episodic ataxia type 2 Thomsen’s disease periodic paralysis Dr Thomsen initially described this in his own family in 1876. Andersen’s syndrome Familial hemiplegic migraine Patients usually present between infancy and adulthood with Myotonia congenita Several inherited epilepsy mild myotonia, which may be constant or intermittent. syndromes Paramyotonia congenita Marked improvement in myotonia is noted with repeated Malignant hyperthermia exercise of a given muscle, the warm-up phenomenon. While 90% show myotonia on electromyography, only 50% have Ligand gated Congenital Hyperekplexia percussion myotonia on examination. There is usually channels myasthenia gravis Autosomal dominant normal power at rest, although some have proximal weak- nocturnal frontal lobe ness, which can present with functional difficulties such as epilepsy climbing stairs. Some patients have muscle hypertrophy while others complain of myalgia. Electromyography shows myotonia with a distal predominance, which is present even in early childhood and the warm-up effect can be observed electrophysiologically. diagnosis of a patient complaining of muscle stiffness. Thomsen’s disease is caused by mutations in a muscle Myotonic dystrophy is a common and important cause of voltage gated chloride channel (CLCN1) located on chromo- myotonia but the presence of extramuscular systemic some 7q35.1 It is transmitted as an autosomal dominant trait symptoms and signs usually aid the diagnosis. The pure with variable penetrance, although 90% of affected indivi- myotonic disorders considered here do not cause multisystem duals are symptomatic. This channel exists as a dimer, disease. For these disorders, particular attention should be mutations may interfere with dimerisation by exerting a paid to any family history and to the precipitants of the dominant negative effect on the wild-type subunits.2 Since muscle stiffness, for example, temperature and whether the chloride conductance is necessary to stabilise the high resting patient’s stiffness reduces with exercise—the so called membrane potential of skeletal muscle, the loss of chloride warm-up phenomenon or whether stiffness increases with conductance caused by mutations results in partial depolar- exercise—so called paradoxical myotonia (see below). isation of the membrane allowing increased excitability and Furthermore the presence of muscle hypertrophy should be myotonia.3 Table 2 Classification of neurological channelopathies according to channel Channel Muscle Gene CNS Gene Sodium channel Hypokalaemic periodic SCN4A Generalised epilepsy with SCN1A paralysis febrile seizures plus SCN1B syndrome (GEFS+), SCN2A http://pmj.bmj.com/ severe myoclonic epilepsy of infancy Hyperkalaemic periodic SCN4A paralysis Paramyotonia congenita SCN4A Potassium aggravated SCN4A myotonia Chloride channel Myotonia congenita: CLCN1 on September 30, 2021 by guest. Protected copyright. Thomsen’s, Becker’s Calcium channel Hypokalaemic periodic CACNA1S Episodic ataxia type 2 CACNA1A paralysis Malignant hyperthermia CACNA1S Familial hemiplegic CACNL2A migraine Childhood absence epilepsy CACNA1H Potassium channel Andersen’s syndrome KCNJ2 Episodic ataxia type 1 KCNA1 Hypokalaemic periodic KCNE3 Benign familial KCNQ2 paralysis neonatal convulsions KCNQ3 Hyperkalaemic periodic KCNE3 paralysis Ryanodine receptor Malignant hyperthermia