Biomedical Engineering Reference
In-Depth Information
sodium channel Na
v
1.7, cause two rare but extremely severe pain syndromes:
inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD)
[
46
-
48
]. In IEM, pain is localized to feet and hands and electrophysiological studies
have linked painful states in this disorder with hyperpolarization of the mutated
channel and to increased current magnitude. In contrast to IEM, PEPD-related pain
affects mostly rectal but also ocular and mandibular areas and has been linked with
delayed or absent inactivation of mutant channels. Congenital insensitivity to pain
(CIP), a hereditary syndrome in which affected individuals are unable to experience
pain, is characterized by recessive loss-of-function mutations in
SCN9A
. Notewor-
thy, CIP patients report normal sensory function, with the exception of impaired
olfaction, and do not display any motor, cognitive, sympathetic, or gastrointestinal
deficits [
49
-
51
].
2.4.3 Migraine
Familial hemiplegic migraine (FHM) is a severe autosomal dominant inherited
headache characterized by visual aura and hemiparesis during attacks [
52
]. A large
body of evidence indicates that cortical spreading depression (CSD) is the electro-
physiologic event underlying migraine aura and possibly leading to headache [
53
].
CSD is a slowly propagating wave of transient neuronal and glial depolarization
accompanied by increases in potassium ion concentrations, which can activate the
meningeal trigeminovascular system and downstream pain pathways and thus cause
headache [
54
]. FHM type 3 is associated with mutations in the
SCN1A
gene
encoding the
-subunit of Na
v
1.1 VGSCs [
55
]. The reported effects range from
gain of function to complete loss of function and the pathogenic mechanisms have
not been entirely clarified yet. Nonetheless, a current hypothesis suggests that
mutated channels engender neuronal hyperexcitability, increased neurotransmitter
release, and abnormal accumulation of extracellular potassium, contributing to
CDS and thus to migraine [
52
].
a
2.4.4 Myotonic Syndromes
Sodium channelopathies involving skeletal muscles are characterized by mutations
in
SCN4A
[
56
,
57
]. Under physiologic conditions, muscular Na
v
1.4 channels
transform nerve stimulation into action potentials that trigger muscle contraction.
Immediately after that, the sodium channel subunits undergo fast inactivation to
prevent recurrent discharges and persistent depolarization of muscle fibers. The
majority of
SCN4A
mutations, typical of myotonias and periodic paralysis, are
located in regions of the Na
v
1.4 channels associated with fast inactivation, and
lead to an impairment of the channel ability to inactivate. Muscular disorders
associated with sodium channelopathies include paramyotonia congenita (PMC),
potassium-aggravated myotonias (PAMs), and periodic paralyses (PPs). Gain-of-
function mutations in PMC and PAMs generate either altered channel gating, which
