Neurological channelopathies

Disorders of ion channels (channelopathies) are increasingly being identified, making this a rapidly expanding area of neurology. Ion channel function may be controlled by changes in voltage (voltage gated), chemical interaction (ligand gated), or by mechanical perturbation. The first disorders recognised as channelopathies were the voltage gated channelopathies causing inherited muscle diseases: the non-dystrophic myotonias and familial periodic paralyses. Paramyotonia congenita is due to mutations in the gene coding for the α1 subunit of the sodium channel, while Thomsen’s disease (autosomal dominant myotonia congenita) and Becker’s disease (autosomal recessive myotonia congenita) are allelic disorders associated with mutations in a gene coding for skeletal muscle chloride channel. Familial hyperkalaemic periodic paralysis is due to mutations in the same sodium channel gene as that affected in paramyotonia congenita, while familial hypokalaemic periodic paralysis results from mutations in the gene coding for the α1 subunit of a skeletal muscle calcium channel.¹

The first demonstration that channelopathies could affect nerves as well as muscles came in 1995, when researchers discovered that episodic ataxia type 1, a rare autosomal dominant disease, results from mutations in one of the potassium channel genes.² The impairment of potassium channel function, which normally limits nerve excitability, results in the rippling of the muscles (myokymia) of the face and limbs seen in this disease. Episodic ataxia type 2, also autosomal dominant, is not associated with myokymia but responds dramatically to acetazolamide, an unexpected feature it shares with many channelopathies. The suspicion that it too might be a channelopathy was confirmed when mutations in a gene coding for the α1 subunit of a brain specific calcium channel were found.³ Mutations in this same gene can also cause familial hemiplegic migraine and spinocerebellar degeneration type 6.⁴ It is unclear how different mutations of the same gene can give rise to such different phenotypes. In the case of myotonia congenita and familial hyperekplexia, point mutations in the same gene can result in either autosomal recessive or dominant inheritance.

Ligand gated channelopathies that have recently been described include familial startle disease, which is due to due to mutations of the α1 subunit of the glycine receptor, and dominant nocturnal frontal lobe epilepsy, which is due to mutations of the α4 subunit of the nicotinic acetylcholine receptor.⁵,⁶ A gene for familial paroxysmal choreoathetosis has been mapped to a region of chromosome 1p where a cluster of potassium channel genes is located.⁷

Channelopathies may be acquired as well as inherited. Recognised causes include toxins and autoimmune phenomena. The marine toxin ciguatoxin, which contaminates fish and shellfish, is a potent sodium channel blocker that causes a rapid onset of numbness, intense paraesthesia and dysaesthesia, and muscle weakness.⁸ Antibodies to peripheral nerve potassium channels may result in neuromyotonia (Isaac’s syndrome).⁹ Lambert-Eaton myasthenia, which is associated with small cell carcinoma of the lung in 60% of cases, is caused by autoantibodies directed against a presynaptic calcium channel at the neuromuscular junction and against multiple calcium channels expressed by lung cancer cells.¹⁰ The neurophysiological abnormalities seen in Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, and multiple sclerosis, traditionally regarded as the result of demyelination, could also be explained by sodium channel dysfunction. The transient nature of some symptoms in multiple sclerosis and the rapid recovery that is sometimes seen in multiple sclerosis and Guillain-Barré syndrome are more consistent with a temporary channelopathy mediated by antibodies than a longer process of demyelination and remyelination. In fact, cerebrospinal fluid from patients with Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy does cause a transient decrease in neuronal sodium currents.¹¹,¹²

All these channelopathies have surprisingly similar clinical features. Typically, there are paroxysmal attacks of paralysis, myotonia, migraine, and ataxia precipitated by physiological stresses. A channelopathy may cause an abnormal gain of function (such as myokymia, myotonia, and epilepsy) or an abnormal loss of function, (such as weakness or numbness) depending on whether loss of channel function leads to excessive membrane excitability or to membrane inexcitability.

Ion channels consist of multiple subunits, each with very similar structure but different electrophysiological characteristics. The differing neuronal expression and combination of these subunits into complexes gives rise to enormous diversity in the properties and distribution of ion channels, which is reflected in the variety of diseases that make up the neurological channelopathies. Many of the channelopathies respond predictably to membrane stabilising drugs such as mexilitine, as well as to acetazolamide. The neuronal specificity of ion channels allows the potential for targeted drug therapy akin to the selective receptor agonists and antagonists currently available: 3,4-diaminopyridine, a potassium channel blocker, can relieve symptoms in patients with Lambert-Eaton syndrome and improves leg strength in patients with multiple sclerosis.¹³,¹⁴ Specific channel modulating drugs are currently being developed for migraine, chronic pain, and cardiac dysrhythmias and these may be useful for neurological channelopathies.