In epilepsy, ion channel mutations can cause benign neonatal convulsions and early‐onset epileptic encephalopathies. In families with generalised epilepsy with febrile seizures plus (GEFS+), seizures may persist beyond early childhood. Mutations of at least four ion channel genes cause GEFS+. Other ion channel mutations have been described, such as malignant migrating partial seizures of infancy.
Paroxysmal dyskinesia, ataxia and hyperekplexia (exaggerated startle reaction) can be caused by channelopathies.
Nerve, Muscle and Neuromuscular Junction Diseases
Mutations of one sodium channel gene can cause either paroxysmal pain or congenital insensitivity to pain. Some potassium channel mutations lead to neuromyotonia. CMT X (an X‐linked hereditary neuropathy) is caused by mutations of connexin32. Connexins make up gap junction proteins.
Channelopathies can cause congenital myasthenic syndromes, periodic paralysis or myotonia. Myotonic dystrophy may have a similar mechanism – DMPK gene mutations alter mRNA processing that encodes the muscle chloride channel.
Disease Causation
To understand a channelopathy requires knowledge of the normal role of the ion channel, both in neurone or muscle excitability, action potential propagation and synaptic transmission and expression of the mutated ion channel. Mutations can have multiple effects – on channel genesis and operation.
Examples are:
Premature stop codons – the message to create a protein is incomplete.
Splice site mutations – alteration in the DNA sequence between an exon and an intron.
Other mutations can give rise to non‐functional subunits that fail to assemble normally, alter trafficking and voltage‐dependent or ligand‐dependent gating. Deletions and duplications of entire exons or genes also occur.
Voltage‐Gated Potassium Channels
Voltage‐gated potassium channels are the largest family. They are composed of four homologous pore‐forming subunits, and four intracellular beta subunits. They contribute to regulation of excitability and termination of action potentials. Each subunit of a voltage‐gated potassium channel typically contains six transmembrane α‐helices, of which the S4 segment acts as a voltage sensor. Such channels open in variable ways upon membrane depolarisation.
By contrast, the pore‐forming subunits of inward‐rectifying potassium channels lack the voltage‐sensing module S4. These channels conduct potassium ions preferentially at negative potentials and have an important role: they stabilise membrane potentials at rest.
Dominantly inherited loss‐of‐function mutations of KCNA1, that encodes the Kv1.1 potassium channel, cause episodic ataxia type 1, characterised by paroxysms of dyskinesia and neuromyotonia.
Some gain‐of‐function mutations of a calcium gated potassium channel (KCNMA1) and a sodium‐gated potassium channel (KCNT1) cause epilepsy.
Transient Receptor Potential Channels
Transient receptor potential (TRP) channels are related to voltage‐gated potassium channels. Several members are sensitive to temperature and chemical ligands and have a role in sensory transduction. Mutations of TRPV4 can cause abnormalities of peripheral nerve development and function. Mutations of TRPA1 – an ion channel best known as a sensor for pain and itch – can cause a paroxysmal pain disorder. Acquired changes may also explain some aspects of neuropathic pain.
Sodium Channels
Sodium channels open rapidly in response to depolarisation; influx of sodium underlies the upstroke of the action potential. They are structurally similar to voltage‐gated potassium channels. An important feature is that most close rapidly upon sustained depolarisation.
Impairment of such fast inactivation occurs in gain‐of‐function mutations that affect the muscle sodium channel NaV1.4 (encoded by SCN4A). Depending on severity, muscle fibres are either prone to repetitive firing (myotonia) or they enter a persistent depolarised state, with hyperkalaemia (hyperkalaemic periodic paralysis, Chapter 10).
Paradoxically, loss‐of‐function mutations of the SCN1A gene are an important cause of monogenic epilepsy. An explanation is that the α subunit of Nav1.1 is preferentially expressed in cortical interneurones. Impaired excitability of these interneurones predisposes to seizures. Other mutations of SCN1A are associated with familial hemiplegic migraine.
SCN9A, SCN10A and SCN11A encode different sodium channels expressed in peripheral nerves. Mutations that impair inactivation cause paroxysmal pain disorders. Recessive loss‐of‐function mutations can cause congenital insensitivity to pain.
Calcium Channels
Calcium channels are structurally similar to sodium channels, though with slower kinetics. There are three groups:
CaV1.1, one of the L‐type channels has a central role in excitation–contraction coupling in skeletal muscle.
P/Q type channels contribute to triggering neurotransmitter release at presynaptic terminals and are also expressed in the cerebellar cortex.
Transiently activating T‐type, low threshold channels have a role in burst‐firing of thalamic neurones.
Hypokalaemic periodic paralysis (Chapter 10) is caused by mutations of CACNA1S, which encodes the muscle calcium channel. However, mutations of the sodium channel gene SCN4A can give the same phenotype, and most mutations of either channel causing hypokalaemic paralysis affect arginine residues in the S4 voltage sensor. These are positively charged residues and sense the transmembrane potential gradient. Although loss of an arginine residue might be expected to alter voltage activation, hypokalaemic periodic paralysis is actually thought to result from an abnormal cation pathway through a cavity lining the S4 segment, arising from substitution of an arginine residue by a smaller amino acid side chain. The association of paralysis with hypokalaemia may reflect failure of inward‐rectifying potassium channels to stabilise the membrane potential, because these channels fail to conduct when the extracellular potassium concentration is low.
Loss‐of‐function mutations of CACNA1A, which encodes the pore‐forming subunit of the CNS calcium channel CaV2.1, cause episodic ataxia type 2, while gain‐of‐function mutations cause familial hemiplegic migraine.
Chloride and Ligand‐Gated Ion Channels
In skeletal muscle, dimeric ClC‐2 channels have an important role in setting the resting membrane potential. They activate further upon depolarisation. Loss‐of‐function mutations destabilise the membrane potential and predispose to repetitive discharges. Both dominantly inherited and recessive mutations occur – Thomsen and Becker myotonia.
Ligand‐gated ion channels mediate fast neurotransmission. Many mutations have been identified.
Acetylcholine Receptors
At the neuromuscular junction ACh opens nicotinic receptors made up of α1, β1, δ and ε subunits, encoded by CHRNA1, CHRNB1, CHRND and CHRNE. Mutations of these subunits can cause a congenital myasthenic syndrome.
Of the receptor subunits expressed in the CNS, mutations have been identified in CHRNA4, CHRNA2 and CHRNB2 (encoding the α4, α2 and β2 subunits, respectively) in autosomal dominant nocturnal frontal