Channelopathies

Kelly Knupp, Amy R. Brooks-Kayal, in Swaiman's Pediatric Neurology (Sixth Edition), 2017

Introduction
Channelopathies are a group of genetically and phenotypically heterogeneous neurologic
disorders that result from genetically determined defects in ion-channel function. These are
considered heterogeneous because mutations in the same gene can cause different diseases and
mutations in different genes can result in the same disease phenotype. Mutations of ion channels
can alter the activation, ion selectivity, or inactivation of the mutated channel. Neurologic
manifestations of channelopathies fall into several clinical phenotypes: epilepsy, pain, migraine,
ataxia, movement disorders (all covered in this chapter; see Table 49-1), and muscle disorders
(myotonia and weakness; covered in Chapter 151).
TABLE 49-1 . Channelopathies Associated with Clinical Syndromes in Pediatric Neurology

Gene Type Epilepsy Headache Ataxia Pain Syndrome

SCN1a
SCN1b SCN9A
Sodium SCN2a SCN1A SCN11A
SCN2A1 SCN10A
SCN9a
GABAa
Chloride CLCN2
CLCN2
KCNQ2
KCNQ3 KCNA1
Potassium KCNJ11 KCNK18 KCNC3
KCNJ10 KCND3
KCNMA1
CACNA1A
Calcium CACN1A CACN1A
CACNB4
GABRG2
GABRB3
GABRD
GABRA1
EFHC1
PRRT2
Ligand-gated channels LGI1 ITPR1
ATP1A2
CHRNA4
CHRNA7
GRIN2A
GPR98
CHRNB2
Ion channels are transmembrane glycoprotein pores that control the excitability of neurons and
muscle cells by mediating the flow of charged ions in and out of cells. Channels are typically
composed of different protein subunits, each encoded by a different gene. There are two major
classes of ion channels: voltage-gated and ligand-gated. Voltage-gated ion channels are activated
and inactivated by changes in membrane voltage and are identified according to the principal ion
conducted through the channel (e.g., sodium, potassium, calcium, or chloride). Activation and
opening of voltage-gated channels have different effects (depolarization, repolarization, or
hyperpolarization of the cell membrane), depending on what ion they gate and that ion's charge,
the electrochemical gradient for that ion (which determines in which direction the ion flows
when the channel is opened), and where the channels are located on the cell. Sodium channel
opening results in the generation of the action potential (i.e., depolarization). Opening
of potassium channels repolarizes cell membranes after action potential firing and maintains
the resting membrane potential. Calcium channels are important for the generation of muscle
contraction, neurotransmitter release, and intracellular signaling via second messengers. Opening
of voltage-gated chloride channels results in the hyperpolarization of cells.
Ligand-gated channels are heterogeneous complexes composed of multiple protein subunits that
are activated by the binding of their respective agonists. Several ligand-gated channels are
present in the peripheral and central nervous systems. Gamma-aminobutyric
acid (GABA)A receptors mediate most of the fast synaptic inhibition in the brain beyond the fetal
and early neonatal periods. They are anion selective and gate primarily chloride, which flows
into the cell, causing hyperpolarization upon GABAA receptor activation. Glutamate is the
primary excitatory neurotransmitter in the central nervous system and binds to three types of
ligand-gated, cation-selective receptor channels: N-methyl-d-aspartate (NMDA), α-amino-3-
hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and kainate. Glutamate receptors gate
either sodium only (most AMPA and all kainate receptors) or sodium and calcium (NMDA
receptors and some subtypes of AMPA receptors). Nicotinic acetylcholine receptors are
nonselective cation channels permeable to Na+ and K+, and Ca2+ in some subtypes; they are
located on certain neurons and on the postsynaptic side of the neuromuscular junction. Opening
of nicotinic receptors causes depolarization of the plasma membrane and activation of voltage-
gated ion channels that can affect the release of neurotransmitters and activate intracellular
signaling cascades.
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Channelopathies
Richard T. MoxleyIII, Chad Heatwole, in Swaiman's Pediatric Neurology (Sixth Edition), 2017
 An expanded version of this chapter is available on www.expertconsult.com. See inside cover
for registration details.

The term channelopathies extends to include disorders affecting all organ systems. This chapter
focuses on channelopathies of skeletal muscle. It includes a number of diseases associated with
mutations in the genes for specific skeletal muscle channels for chloride, sodium, calcium, and
potassium ions. (Jurkat-Rott et al., 2015; Statland and Barohn, 2013; Suetterlin, Mannikko, and
Hanna, 2014; Heatwole, Statland, and Logigian, 2013; Matthews et al., 2010; Cannon, 2002)
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Nervous System1
Andrew D. Miller, James F. Zachary, in Pathologic Basis of Veterinary Disease (Sixth Edition),
2017
Channelopathies.
Channelopathies are a newly emerging group of inherited neuromuscular diseases of human
beings that affect the excitability of membranes of neurons and skeletal myocytes. These
diseases result from mutations in genes encoding ion channel proteins that regulate calcium,
sodium, and chloride channels and acetylcholine receptors. In human beings, neurologic
diseases, such as epilepsy and migraine headaches, have been attributed to channelopathies. In
veterinary neurology, channelopathies will likely be shown in the future to be the underlying
mechanism for epilepsy and other primary neuronal degenerations; however, investigation into
this type of neurologic disorder is still in its infancy in veterinary medicine. Examples of this
type of disorder are the recent demonstration of mutated cyclic nucleotide-gated ion channels in
several dog breeds with vision disorders.
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Molecular Basis of Cardiovascular Disease
Avrum I. Gotlieb MDCM, FRCPC, in Molecular Pathology (Second Edition), 2018
Channelopathies
Channelopathies are a group of cardiac conditions that display defects in ion channel and
transporter function. Most conditions are due to inherited mutations that disrupt ion channel
biophysical properties. However, other defects arise from disruptions in ion channel membrane
trafficking and post-translational modifications [153]. The most serious clinical conditions
resulting from arrhythmogenic channelopathies are sudden cardiac death and
ventricular tachyarrhythmias [154].
Congenital long QT syndromes, which affect about 1 in 3000 persons, are a potentially lethal
group of cardiac conditions characterized by delayed repolarization of the myocardium and QT
prolongation [155]. This arrhythmogenic disorder is characterized by a significant increased risk
of syncope, seizures, and sudden cardiac death. Since several mutations in genes that encode ion
channels or their associated proteins account for about 80% of cases, postmortem genetic testing
for sudden unexplained death in the young is very useful [151]. In addition, new cardiac
channel gene mutations and defects in associated proteins continue to be identified. Examples of
this include mutant Caveolin 3 [156], syntrophin mutation [157], and other ion channel
macromolecular complexes [158]. Comprehensive genetic testing for numerous heritable
channelopathies continues to evolve and is becoming useful clinically [159].
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Bipolar Disorder
Scott C. Fears, Victor I. Reus, in Rosenberg's Molecular and Genetic Basis of Neurological and
Psychiatric Disease (Fifth Edition), 2015
Channelopathies
Channelopathies refer to disorders resulting from defective ion channel functioning and include
neurological, cardiovascular, and muscle disorders.80 Ion channels are complex macromolecular
structures that span cellular membranes and regulate the flow of ion current. The identification of
altered calcium concentrations in cerebrospinal fluid of bipolar patients suggested that ion
imbalances might be involved in the pathophysiology of depression and mania.81 The finding of
elevated calcium levels in platelets and lymphoblasts from BP patients added additional support
to this hypothesis.82 Most recently, the identification of confirmed BP risk loci in
the CACNA1C and ANK3 gene regions in genome-wide association studies has highlighted their
potential role in neuropsychiatric disorders. CACNA1C encodes the alpha 1C subunit of the L-
type voltage-gated calcium channel and is involved in regulation of gene
expression, neurotransmitter release, and neuronal plasticity.83 The ANK3 gene encodes a protein
that is required to direct the localization of potassium channels to the axons and nodes of
Ranvier.84 Ion channels provide a tractable target for treatment and in fact, numerous
investigations have suggested that the therapeutic action of lithium may be related to ion flow
modulation.85,86 Additionally, some preliminary evidence suggests that calcium
channel antagonists, especially the dihydropyridine compounds, have mood stabilizing and
antidepressant effects.85
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Na Channels from Phyla to Function
J.J. Winters, L.L. Isom, in Current Topics in Membranes, 2016
6.2 Cardiac arrhythmia
Channelopathies, including mutations in VGSC α subunits, especially Nav1.5, have also been
linked to cardiac arrhythmias. Such mutations are linked to long QT syndrome (LQTS), Brugada
syndrome, and fatal ventricular fibrillation (VF) (Remme & Bezzina, 2010). Human mutations
in SCN1B, SCN2B, and SCN3B have all been associated with Brugada syndrome, which carries a
high risk of sudden cardiac death due to VF (Ishikawa & Takahashi, 2012; Riuró et al., 2013;
Watanabe et al., 2008). Other mutations in SCN1B, SCN2B, SCN3B, and SCN4B have been
linked to atrial fibrillation (Li et al., 2013; Olesen et al., 2011; Watanabe et al., 2009). Further, a
mutation in SCN4B has been linked to LQTS, in which slowed repolarization can lead to
arrhythmia and VF (Medeiros-Domingo et al., 2007). These findings suggest that all VGSC β
subunits are important for healthy cardiac function in humans.
In addition to epilepsy and cardiac arrhythmias, β subunits have been implicated in a number of
other pathological conditions, including sudden infant death syndrome, neuropathic pain,
neurodegenerative diseases such as Huntington's disease and multiple sclerosis, and even cancer
(O'Malley et al., 2009). Recent reviews provide a detailed treatment of the roles β subunits have
in pathophysiology (Calhoun & Isom, 2014; O'Malley & Isom, 2015).
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