encephalitides.
Interferons act at least in part via modulation of the cytokine network.
Steroids, oral azathioprine, methotrexate, mycophenolate, and ciclosporin and IV cyclophosphamide immunosuppress non‐selectively.
IVIg is a replacement therapy in hypogammaglobulinaemias.
Discussion related to therapies in MS: see Chapter 11.
Targeted Ablative Therapies
Anti‐CD20 and anti‐CD52 monoclonal antibodies are increasingly used, sometimes in combination with other immunosuppressants such as rituximab or methotrexate. Idiosyncratic rare complications are limiting factors. For example, PML (progressive multifocal leukoencephalopathy) is a known, usually fatal complication of rituximab, natalizumab and others. When death or severe disability is not an outcome of the primary disease, these medications are ethically questionable.
Specifically Targeted Molecules
Anti‐TNF, anti‐VEGF and anti‐IL‐6: some of these are targeted therapies, such as etanercept, widely used in rheumatoid. Others are antibodies with anticytokine activity such as bevacizumab which acts as an anti‐VEGF agent, or tocilizumab which is anti‐IL‐6.
Ion Channels and Inherited Mutations
Changes in ion channels can explain clinical features. Monogenic channelopathies provide insights into disease mechanisms and whilst they are rare, they frequently have features seen in common sporadic disorders such as epilepsy and migraine. The study of channelopathies can identify signalling pathways in many diseases. One feature is that many channelopathies cause discrete paroxysms; function returns to normal between attacks. Most channelopathies are AD inherited but this may simply reflect that AR disorders are hard to identify.
Channelopathies can present in all areas of neurology. The broad groups are summarised here.
Migraine, Epilepsy, Movement Disorders and Ataxias
In AD familial hemiplegic migraine two genes identified encode ion channels.
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
