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 lobe epilepsy. CNS nicotinic receptors mediate fast excitatory transmission to a subset of cortical interneurones. How mutations give rise to epilepsy remains unclear.
GABAA, Glycine and Glutamate Receptors
GABAA receptors are structurally homologous to nicotinic receptors but are permeable to chloride ions instead of sodium and potassium. They mediate fast inhibitory transmission and are the sites of action of benzodiazepines and other anti‐epileptic, and anxiolytic drugs. Loss‐of‐function mutations have been reported in epilepsy.
Glycine receptors also homologous to GABAA mediate fast inhibition in the spinal cord and brainstem. AD or AR loss‐of‐function mutations of GLRA1 cause familial hyperekplexia.
Glutamate receptors mutations have been described in schizophrenia, and in rolandic epilepsy.
Acquired Channelopathies
Several autoimmune disorders affect ion channels. Antibodies recognise extracellular epitopes, for example AChRs, P/Q‐type calcium channels, glycine and NMDA receptors. Aquaporin 4 (see antibodies in Devic’s, Chapter 11) is a transmembrane protein that permits the flow of water between glial cells. The way that an ion channel is affected is similar in both an acquired and hereditary channelopathy – as one might expect because each ion channel has a limited repertoire. More antibody‐channel interactions are likely to be discovered and to be of significance.
Acknowledgements
I am most grateful to Dimitri Kullmann, Henry Houlden & Michael Lunn for their contribution to Neurology A Queen Square Textbook Second Edition on which this chapter was based. I am also indebted to Simon Farmer & David Choi who wrote in Chapter 16 about spinal embryology in Neurology A Queen Square Textbook Second Edition.
Further Reading
1 Kullman D, Houlden H, Lunn M. Mechanisms of neurological disease: genetics, autoimmunity and ion channels. In Neurology A Queen Square Textbook, 2nd edn. Clarke C, Howard R, Rossor M, Shorvon S, eds. John Wiley & Sons, 2016. There are numerous references.
Also, please visit https://www.drcharlesclarke.com for free updated notes, potential links and references as these become available. You will be asked to log in, in a secure fashion, with your name and institution.
4 Examination, Diagnosis and the Language of Neurology
My purpose here is to outline how I approach day‐to‐day neurology:
To provide a framework for examination, diagnosis and investigation
To introduce terminology – the language and vocabulary we use.
There is some distance between anatomy, science, diagnosis and the words we use to communicate clinical features. I try to fill these gaps. Our first purpose is to answer one question: is there a recognisable disease? In no other speciality are clinical patterns more important, nor are they more reliable. Despite advances in imaging, neurogenetics and neuropathology, we follow a traditional approach:
Assemble clinical observations – history, symptoms and physical signs, and assess investigations.
Recognise, by sifting these, the site of the problem, and if possible a disease.
Good neurology is about getting this right. Failure to follow this approach can lead to over‐investigation or missing a serious disease.
Elements of Diagnosis
Diagnosis is the product of the history and examination. Many find neurology hard, both because of this interplay and also because of its breadth. In some conditions, such as migraine, a faint or a seizure, we rely on narratives. There are typically no physical signs. In others, examination is pivotal, for example signs of a spastic paraparesis. However, despite its sophistication the nervous system has a relatively limited repertoire. For example, a headache can be similar whether the problem is benign or sinister.
Try
