KCNQ2/KCNQ3 K+ channels and the molecular

pathogenesis of epilepsy: implications for therapy.

Rogawski MA1.
Author information
Abstract
In 1998, the discovery of two novel genes KCNQ2 and KCNQ3, mutated in a rare inherited form
of epilepsy known as benign familial neonatal convulsions, for the first time enabled insight into
the molecular etiology of a human idiopathic generalized epilepsy syndrome. These disease
genes encode subunits of neuronal M-type K+ channels, key regulators of brain excitability.
Analogies between benign familial neonatal convulsions and other channelopathies of skeletal
and cardiac muscle, including periodic paralysis, myotonia and the long QT syndrome, provide
clues about the nature of epilepsy-susceptibility genes and about the fundamental basis of
epilepsy as an episodic disorder. It now appears that the KCNQ2/KCNQ3 K+ channels that are
mutated in benign familial neonatal convulsions represent an important new target for anti-
epileptic drugs. In the future, the identification of ion channel defects as predisposing factors in
the common epilepsies could herald a new era of genotype-specific therapies.

SCN1A-Related Seizure Disorders

Ian O Miller, MD and Marcio A Sotero de Menezes, MD.

Author Information

Initial Posting: November 29, 2007; Last Update: May 15, 2014.

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Summary

Clinical characteristics.
SCN1A-related seizure disorders encompass a spectrum that ranges from simple febrile
seizures (FS) and generalized epilepsy with febrile seizures plus (GEFS+) at the mild end to
Dravet syndrome and intractable childhood epilepsy with generalized tonic-clonic seizures
(ICE-GTC) at the severe end. Phenotypes with intractable seizures including Dravet
syndrome (also known as severe myoclonic epilepsy in infancy [SMEI] or polymorphic
myoclonic epilepsy in infancy [PMEI]) are usually associated with progressive dementia.
Less commonly observed phenotypes include myoclonic-astatic epilepsy (MAE or Doose
syndrome), Lennox-Gastaut syndrome (LGS), infantile spasms, and vaccine-related
encephalopathy and seizures. The phenotype of SCN1A-related seizure disorders can vary
even within the same family.

Diagnosis/testing.
The diagnosis of SCN1A-related seizure disorders relies on detection of
a heterozygous pathogenic variant in SCN1A.
Management.
Treatment of manifestations: Antiepileptic drugs (AEDs) include benzodiazepines (diazepam
and clonazepam), stiripentol (used in Europe; not currently FDA approved for use in the US),
topiramate, and valproic acid. Clobazam can be used for the treatment of seizures in Lennox-
Gastaus syndrome. Phenobarbital is effective but poorly tolerated because of its effects on
cognition. Use of the ketogenic diet to decrease seizure frequency has been beneficial in
some affected individuals.
Prevention of secondary complications: Use of protective helmets by individuals with atonic
seizures or myoclonic-astatic epilepsy.
Surveillance: Serial neuropsychological evaluation for neurologic, cognitive, and behavioral
deterioration; EEG monitoring for new or different seizure types.
Agents/circumstances to avoid: AEDs: carbamazepine, lamotrigine, and vigabatrin, which can
induce or increase myoclonic seizures; phenytoin, which can induce choreoathetosis.
Activities in which a sudden loss of consciousness could lead to injury or death (e.g., bathing,
swimming, driving, or working/playing at heights).
Pregnancy management: Pregnant women should receive counseling regarding the risks and
benefits of the use of antiepileptic drugs during pregnancy; the advantages and disadvantages
of increasing maternal periconceptional folic acid supplementation to 4000 µg daily; the
effects of pregnancy on anticonvulsant metabolism; and the effect of pregnancy on maternal
seizure control.
Other: The AEDs clobazam and stiripentol, used in treatment of SMEI, are not FDA-
approved for this use in the US. Sleep deprivation and illness can exacerbate seizures.
Persons with epilepsy should be made aware of motor vehicle driving laws.

Genetic counseling.
SCN1A-related seizure disorders are inherited in an autosomal dominant manner.
A proband with an SCN1A-related seizure disorder may have an inherited or de
novo pathogenic variant. The proportion of cases caused by de novo pathogenic variants
varies by phenotype: the percentage of probands with an SCN1A-related seizure disorder and
an affected parent decreases as the severity of the phenotype in the proband increases; thus,
most SCN1A-related SMEI and ICE-GTC are the result of de novo mutation. Each child of an
individual with an SCN1A-related seizure disorder has a 50% chance of inheriting the
pathogenic variant; however, the risk of developing seizures is less than 100% because of
reduced penetrance. Prenatal diagnosis for pregnancies at increased risk is possible if the
pathogenic variant in the family is known.
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GeneReview Scope

SCN1A-Related Seizure Disorders: Included Phenotypes 1

 Generalized epilepsy with febrile seizures plus

SCN1A-Related Seizure Disorders: Included Phenotypes 1

 Intractable childhood epilepsy with generalized tonic-clonic seizures

 Intractable infantile partial seizures
 Myoclonic-astatic epilepsy
 Severe myoclonic epilepsy in infancy
 Simple febrile seizures

For synonyms and outdated names see Nomenclature.

1.

For other genetic causes of these phenotypes see Differential Diagnosis.

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Diagnosis
SCN1A-related seizure disorders encompass a spectrum of phenotypes that ranges from mild
to severe. Because clinical findings alone cannot establish the diagnosis, detection of
a heterozygous pathogenic SCN1A variant is necessary. Identification of
an SCN1A pathogenic variant may also have implications for medical management of
the affected individual’s seizure disorder (see Treatment of
Manifestations and Agents/Circumstances to Avoid).
The phenotypes seen in SCN1A-related seizure disorders include the following*:
 Febrile seizures (FS), which may or may not have features suggestive of an SCN1A-related
condition
 Generalized epilepsy with febrile seizures plus (GEFS+)
 Dravet syndrome, also known as severe myoclonic epilepsy in infancy
(SMEI) or polymorphic myoclonic epilepsy in infancy (PMEI)
Note: The term "Dravet syndrome" is preferred because the myoclonic seizures implied by
the descriptive name(s) can be absent in children whose seizures are otherwise similar.
 Severe myoclonic epilepsy, borderline (SMEB)
 Intractable childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC), which does
not represent an epilepsy defined by ILAE, and is most similar to late-onset Dravet syndrome
in the ILAE classification system
Note: This classification is widely used in the SCN1A literature and is thus included for
completeness.
 Infantile partial seizures with variable foci, also referred to as migrating partial seizures of
infancy, cryptogenic focal epilepsy, or severe infantile multifocal epilepsy per Harkin et al
[2007]
*Note: Terms used in the literature to describe the phenotypes sometimes differ from the
standard epilepsy syndrome terminology as defined by the International League Against
Epilepsy (ILAE).
Less commonly associated phenotypes
 Myoclonic-astatic epilepsy (MAE, Doose syndrome), initially defined conceptually as a group
of individuals with a genetic predisposition to generalized epilepsies. In the ILAE classification
system it is a superset including Dravet syndrome, benign myoclonic epilepsy, and childhood-
onset epilepsies with primarily generalized seizures.
 Lennox-Gastaut syndrome (LGS), associated with slow-spike wave on EEG, generalized
seizures, and intellectual disability. Selmer et al [2009] reported finding one adult with LGS in
a cohort of 22 who had an SCN1A pathogenic variant.
 Infantile spasms
 Vaccine-related encephalopathy and seizures

The clinical suspicion of SCN1A-related seizure disorders is complicated by the following

three issues:
 The phenotypes cover a broad spectrum of severity, even within the same family.
 The epilepsy phenotypes are incompletely specific (i.e., they are seen in other conditions as
well).
 Some epilepsy phenotypes refer to features observed in the family, rather than in a particular
individual in the family.

Familial features that have some specificity for SCN1A-related seizure disorders include
the following.
 One or more family members with epilepsy, especially of more than one type
 Febrile seizures:
o Before age one year [Bonanni et al 2004]

o After age six years [Scheffer & Berkovic 1997]

o With unusual severity (including status epilepticus) [Baulac et al 1999]

o That precede unprovoked (i.e., afebrile) seizures (which may be generalized tonic-
clonic, myoclonic, myoclonic-astatic, or absence) [Scheffer & Berkovic 1997]
 A history of seizures following vaccination
 Hemiconvulsive seizures
 Seizures triggered by environmental stimuli, including heat, temperature changes, bright
lights, or busy, noisy environments

Note: Because the suggestive features may occur in some members of the family and not
others, a complete family history must be taken.
The diagnosis of an SCN1A-related seizure disorder requires detection of
a heterozygous pathogenic SCN1A variant. See Table 1.
  One approach is molecular genetic testing of SCN1A. Sequence analysis of the entire coding
region of SCN1A is performed first. If a pathogenic variant is not
identified, deletion/duplication analysis is performed.
 An alternative approach is use of a multi-gene panel that includes SCN1A and other genes of
interest (see Differential Diagnosis). Note: The genes included and the methods used in
multi-gene panels vary by laboratory and over time.

Table 1.
Summary of Molecular Genetic Testing Used in SCN1A-Related Seizure Disorders

Proportion of Probands with a Pathogenic Variant

Gene 1 Test Method
Detectable by This Method

Sequence analysis 2 73%-92% 3

SCN1
A
Deletion/duplicationanalysis 4 8%-27% 5, 6, 7, 8

1.

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for
information on allelic variants.
2.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely
pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions
and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications
are not detected. For issues to consider in interpretation of sequence analysis results, click here.
3.

Estimated value based on subtracting experimental values of deletion frequencies of 8%-27% from
100% (see footnote 5).
4.

Testing that identifies exon or whole-gene deletions/duplications not readily detectable by sequence
analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of
methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe
amplification (MLPA), and chromosomal microarray (CMA) that includes this
gene/chromosome segment.
5.
 Using a variety of methods to identify deletions encompassing the SCN1A locus in individuals with
SMEI who did not have an SCN1A pathogenic variant identified on sequence analysis, Madia et al
[2006] found deletions in three of 39 (8%), Mulley et al [2006] found deletions in two of 13 (15%),
and Suls et al [2006] found deletions in three of 11 (27%). In these three studies a total of eight of 63
(12%) individuals with SMEI who did not have a sequence variant identified on sequence analysis had
an identifiable SCN1A deletion.
6.

Marini et al [2009] found that 12.5% of individuals with Dravet syndrome who did not have
a pathogenic variant identified on sequence analysis had copy number variations that were detectable
by MLPA.
7.

It is not known if the percent of exon and whole-gene deletions is the same for the other phenotypes in
the spectrum of SCN1A-related seizure disorders.
8.

A contiguous gene deletion syndrome of severe epilepsy, intellectual disability,

and dysmorphic features that includes the genes SCN1A and SCN2A at chromosomal locus2q23-q24.
One affected individual has been described [Pereira et al 2004].

Secondary or modulatory genes in individuals with SCN1A pathogenic variants

 SCN9A. Pathogenic variants in SCN9A are thought to have a role in modulating disease
resulting from SCN1A variants; in some cases isolated SCN9A variants
(without SCN1A alterations) have been associated with Dravet Syndrome [Singh et al
2009, Mulley et al 2013] (see Differential Diagnosis).
 CACNB4. An individual with a missense variant (Arg468Gln) of CACNB4 in addition to a de
novo SCN1A nonsense variant (Arg568Ter) showed a Dravet phenotype. The phenotype of
Dravet syndrome was thought to be due at least in part to the augmentation of the
excitatory neurotransmitter release mediated by the increased Ca(v)2.1 currents [Ohmori et
al 2008b].
 CACNA1A. A larger study of 48 people with Dravet syndrome with SCN1A pathogenic
variants found that 21/48 had alterations of CACNA1A that appeared to be common variants
(polymorphisms). The authors then compared the clinical features of affected individuals
with documented SCN1A pathogenic variants who had a CACNA1Apolymorphism to those
affected individuals who did not have a CACNA1A polymorphism. Forty individuals in the
study had documented SCN1A pathogenic variants and Dravet syndrome; of these 40
individuals, the clinical features of 20 individuals with a CACNA1Apolymorphism were
compared to the phenotypes of 20 without a CACNA1A polymorphism [Ohmori et al 2013].
Affected individuals with a CACNA1A polymorphism had earlier onset of seizures, more
frequent prolonged seizures before age one year, and more frequent absence seizures
[Ohmori et al 2013].
  POLG. Gaily et al [2013] reported two individuals with the combination of
a heterozygous POLG variant (p.Trp748Ser or p.Gly517Val) and a
heterozygous SCN1A pathogenic variant. The affected individuals had prolonged seizures
with acute encephalopathy and persistent neurologic deficits postictally. The observation
requires further confirmation because heterozygous POLG variants have not generally been
associated with seizures and deterioration, which are more typically present in those
with compound heterozygous or homozygous POLG pathogenic variants.

Note: The role of the so-called modulatory genes must be interpreted with caution given the
phenotypic variability in Dravet syndrome associated with a given pathogenic variant. That
said, the phenotypic variability in Dravet syndrome will be only explained when a
comprehensive list of possible modifier factors has been compiled.
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Clinical Characteristics

Clinical Description
The natural history of SCN1A-related seizure disorders is strongly influenced by
seizure phenotype, which can range from simple febrile seizures (FS) and generalized
epilepsy with febrile seizures plus (GEFS+) at the mild end to severe myoclonic epilepsy of
infancy (SMEI) and intractable childhood epilepsy with generalized tonic-clonic seizures
(ICE-GTC) at the severe end [Kimura et al 2005, Mantegazza et al 2005, Fujiwara
2006, Gennaro et al 2006].
The phenotype varies even among family members with the same pathogenic variant. Figure
1 shows a pedigree that demonstrates variable expressivity. As a result of this variable
expressivity, long-term prognosis is difficult to predict.

Figure 1.
Findings in a family illustrating variable expressivity among individuals with the same
pathogenic variant. The proband, a boy (arrow) with febrile convulsions since age seven
months, had frequent, difficult-to-control partial seizures beginning at age (more...)
Features associated with poor cognitive outcome include early myoclonic and absence
seizures [Ragona et al 2011].
Seizures tend to lessen in severity after puberty; however, they rarely resolve completely.
Only approximately 16% of individuals with Dravet syndrome had complete resolution of
their seizures, meaning that anticonvulsant treatment is usually lifelong. Complete resolution
tended to occur in individuals with less severe seizures earlier in life. Akiyama et al
[2010]found that resolution of seizures correlated with having less than three lifetime
episodes of convulsive status epilepticus.
Phenotypes with intractable seizures (e.g., Dravet syndrome) usually cause epileptic
encephalopathy, a form of progressive dementia. The root cause of the encephalopathy is
unknown: the effects of seizures, the most obvious explanation, cannot be separated from the
effects of medication or the effects of mutation of SCN1A on cognition [Riva et al 2009].
In addition to having seizures in response to strong environmental stimuli, individuals with
mutation of SCN1A often have an ADHD-like phenotypecharacterized by impulsivity,
inattentiveness, and distractibility. Possibly related to the inability of the GABA system to
“filter out” unimportant sensory input, these symptoms tend to be fairly unresponsive to
conventional stimulant medications.
Individuals with severe epilepsy phenotypes often develop the locomotor findings of postural
change (flexion at the hips, knees, and trunk, giving a “hunched over” appearance) and
ataxia. In spite of the gait being commonly described as “ataxic”, affected individuals seem to
be quite a bit more skilled than one would expect from how crouched they appear. The gait
changes tend to be more prevalent in older children. In one study these changes were absent
before age 5 years, but present in 5/10 children ages 6-12 years and in 8/9 children age 13
years or older [Rodda et al 2012]. In one cohort, 5/10 adults with Dravet syndrome had
crouched gait [Rilstone et al 2012]. The patterns that worsened with increasing age were:
decreased passive knee extension and hip extension; increased external tibial torsion; and pes
planovalgus [Rodda et al 2012]. The hip internal rotation did not show age-related changes.
The gait changes usually begin in childhood, but often develop after the onset of epilepsy.
The degree of ataxia in affected individuals is greater than would be expected by the use of
anticonvulsant medications alone.
The phenotypes in SCN1A-related seizure disorders, summarized in Table 2, include the
following:
Febrile seizures (FS). These childhood seizures occur only in association with fever. The
epidemiologic definition requires the following:
 Onset on or after age six months
 Resolution by age five years
 Fever higher than 38° C (without other evidence of CNS infection)
 No other identifiable cause

Febrile seizures are divided into simple febrile seizures and complex febrile seizures. Febrile
seizures are considered complex if any of the following is present:
 Duration greater than 15 minutes
 Occurrence of more than one seizure within 24 hours
 Presence of any partial (focal) features during the seizure

Febrile seizures plus (FS+). This subset of febrile seizures (simple or complex) has any of
the following features:
 Onset before age one year
 Persistence beyond age six years
 Unusual severity (including status epilepticus)
 Occurrence of unprovoked (i.e., afebrile) seizures of any kind

Generalized epilepsy. This phenotype is otherwise indistinguishable

from idiopathic generalized epilepsy with onset in childhood or adolescence. Generalized
epilepsies caused by mutation of SCN1A are most often tonic, clonic, tonic-clonic,
myoclonic, or absence.
Generalized epilepsy with febrile seizures plus (GEFS+).This term refers to the findings in
a family rather than an individual [Arzimanoglou et al 2004].
In a family with GEFS+, epilepsy with variable expressivity and incomplete penetrance is
inherited in an autosomal dominant manner. Although the complete range of associated
phenotypes can be seen within any family, the seizure phenotypes tend toward the mild end
of the spectrum [Scheffer & Berkovic 1997] because the more severe seizure types have a
reproductive disadvantage and, thus, are less likely to be familial [Claes et al 2001].
Affected individuals within a family with GEFS+ often have febrile seizures (or FS+) in early
childhood, followed by occasional tonic, clonic, myoclonic, or absence seizures which
respond to medication and remit by late childhood or early adolescence. The proportion of
children with GEFS+ whose first seizure occurs in the context of immunization appears to be
greater than the proportion of children with febrile seizures unrelated to FS+ and GEFS+.
Dravet syndrome. This phenotype is defined as seizures with onset during the first year of
life (usually around age six months; in some cases before age three months) that do not remit,
and usually evolve to include myoclonic seizures.
 Early seizures are often prolonged febrile seizures. Seizures can sometimes be provoked by
modest hyperthermia (e.g., a hot bath, physical exertion).
 Any seizure type is possible; generalized tonic-clonic, myoclonic, and hemiconvulsive seizures
are most common.
 Myoclonic seizures tend to appear later in the course, often coinciding with the appearance
of cognitive dysfunction, ataxia, and psychomotor regression.
 Status epilepticus is common, and pharmacologic management is difficult.
 The initial EEGs are often normal, but over time epileptiform activity appears. Patterns can
include generalized spike and wave discharges, multiple spike and wave (also referred to as
polyspike and wave) discharges, and multifocal spikes.

Severe myoclonic epilepsy, borderline (SMEB).This description is sometimes used for

children who have some but not all of the features of SMEI [Fukuma et al 2004].
Intractable childhood epilepsy with generalized tonic-clonic seizures (ICE-
GTC). This phenotype is defined as generalized seizures including absence seizures and
generalized tonic-clonic seizures with onset in infancy or childhood. However, partial
seizures can occur in up to 13% of affectedindividuals [Bonanni et al 2004]. Localized
epilepsy, either alternating hemiconvulsive or complex partial seizures, may also be seen.
Children with frequent generalized tonic-clonic seizures often develop cognitive impairment.
The distinction between ICE-GTC and Dravet syndrome is not clear, and the former is not
included in the ILAE classification system.
Infantile partial seizures with variable foci. This phenotype is defined as focal seizures
beginning in infancy with multiple independent zones of seizure onset involving both
hemispheres. Multifocal partial seizures are often the first manifestation; however, in some
children the first manifestation is febrile seizures. Severity varies and pharmacoresistance is
common, but not absolute. Myoclonic seizures are rare but may be precipitated by
administration of medications that inactivate the sodium channel, including phenytoin,
carbamazepine, or lamotrigine. Cognitive deterioration may occur, especially when seizure
control is incomplete. Electroencephalography shows multifocal independent spikes;
generalized spike and wave discharges may be seen.

Table 2.
Distribution of Seizure Phenotypes in SCN1A-Related Seizure Disorders

Disorder Distribution

Simple febrile seizures (FS) Unknown

Febrile seizures plus (FS+) Unknown

Generalized epilepsy with febrile seizures plus (GEFS+) 5%-10% 1

Severe myoclonic epilepsy in infancy (SMEI) 33%-90% 2

Intractable childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC) 70% 3

1.

Marini et al [2007]
2.

Mulley et al [2005]
3.

Fujiwara et al [2003]

The features and course for the less common phenotypes associated with mutation
of SCN1A include the following:
Myoclonic-astatic epilepsy (MAE, also called Doose syndrome).This phenotype is defined
as the combination of myoclonic, atonic, and atypical absence seizures. Onset is usually after
age two years (range: 7 months - 8 years).
Although isolated myoclonic seizures as well as tonic seizures can occur, they are not
characteristic of this syndrome (which distinguishes them from Lennox-Gastaut syndrome).
Development prior to seizure onset is often normal. The course can range from spontaneous
seizure resolution without cognitive impairment to intractable seizures with severe
intellectual disability [Arzimanoglou et al 2004].
Ebach et al [2005] compared two cohorts in order to determine if the MAE phenotype was
more specific for the presence of an SCN1A pathogenic variantthan the
severe idiopathic generalized epilepsy of infancy (SIGEI) phenotype. They found one
pathogenic variant in 20 children with MAE and two pathogenic variants in 18 children with
SIGEI; the small sample size precluded a statistically significant result.
Lennox-Gastaut syndrome (LGS). This phenotype is defined as slow spike-waves on EEG,
developmental delay, and multiple types of generalized seizures (particularly atypical
absence, tonic, and atonic seizures). LGS usually begins during childhood (ages 2-14 years).
Any type of seizure can be seen in this syndrome; status epilepticus is common
[Arzimanoglou et al 2004]. Only a minority of persons with the LGS phenotype have
an SCN1Apathogenic variant, usually in the context of a family in which Dravet syndrome
occurs [Singh et al 2001]. This subset remains poorly characterized. It is unclear
whether SCN1A-associated LGS differs phenotypically from LGS of other etiologies.
Infantile spasms. This phenotype is defined as clustered seizures that show brief (<1 second)
axial contractions associated with a slow-wave transient on EEG, often followed by
generalized attenuation of the background. Both findings may be intermixed with fast
activity. The resting EEG (between seizures) shows high-voltage slowing and a multifocal
spike pattern known as hypsarrhythmia [Arzimanoglou et al 2004]. Association of
an SCN1Apathogenic missense variant with infantile spasms has been reported once [Wallace
et al 2003]. The single case represents fewer than 1% of reported cases, although publication
bias makes it difficult to estimate the actual proportion.
Vaccine-related encephalopathy and seizures. This phenotype is defined as sudden onset of
seizures and encephalopathy in infants 48 hours after immunization. Berkovic et al
[2006] identified an SCN1A pathogenic variantin 11/14 children diagnosed with post-vaccine
encephalopathy. Tro-Baumann et al [2011] reported that 19 of 70 individuals with
an SCN1A pathogenic variant and the Dravet phenotype had a history of seizures following
vaccination.
Brain MRI is most often normal early in the course of the disease; however, it often evolves
to show cortical atrophy, cerebellar atrophy, white matter hyperintensity, ventricular
enlargement, hippocampal sclerosis, or cortical dysplasia [Striano et al 2007]. Individuals
with a more severe phenotype early in life often have more atrophic changes seen on MRI
later in life.

Genotype-Phenotype Correlations
Mulley et al [2005] found that most SCN1A pathogenic variants cluster in the C-terminus and
in the pore loops connecting S5 and S6 especially in the first three domains of the protein
(Figure 2).

Figure 2.
Topologic diagram of Nav1.1, the alpha subunit of the neuronal voltage-gated sodium channel
encoded by SCN1A. Nav1.1 is 2,000 amino acids in size and has four homologous domains
(D1-D4) that fold around a central pore and are connected by cytoplasmic (more...)
Pathogenic nonsense variants and missense variants in the voltage sensor or pore region often
lead to a more severe phenotype [Zuberi et al 2011]; a truncation variant, however, does not
necessarily result in a severe phenotype [Suls et al 2010, Yu et al 2010].
Affected individuals with missense variants in the pore-forming region and truncations in the
SCN1A protein are more prone to have gait changes [Kanai et al 2004, Rilstone et al 2012].
These changes may be due to a direct effect of the SCN1A pathogenic variant in the cerebellar
Purkinje cells [Catterall et al 2010].
An estimated 5% of individuals with molecularly confirmed SMEI have
a familial missense SCN1A variant that is associated with a milder phenotype(i.e., GEFS+) in
other family members [Mulley et al 2005].

Nomenclature
Generalized epilepsy with febrile seizures plus has been referred to as GEFS+ type 2.
Intractable infantile partial seizures has been referred to as ICEGTC.

Penetrance
SCN1A-related seizure disorders show incomplete penetrance and variable expressivity.
Penetrance varies by phenotype. For example, Bonanni et al [2004] estimated
the penetrance to be 70% for the GEFS+ phenotype, whereas Mantegazza et al
[2005] reported the penetrance to be 90% for the familial simple febrile seizure phenotype.

Anticipation
Anticipation is not observed in SCN1A-related seizure disorders.

Prevalence
The prevalence of SCN1A-related seizure disorders is unknown.
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Genetically Related (Allelic) Disorders

Other phenotypes associated with pathogenic variants in SCN1A:
 Panayiotopolous syndrome [Grosso et al 2007]
 Familial hemiplegic migraine [Dichgans et al 2005]
 Familial autism [Weiss et al 2003]
 Rasmussen encephalitis associated with the pathogenic variantp.Arg1575Cys [Ohmori et al
2008a]
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Differential Diagnosis
The phenotypes typically seen with mutation of SCN1A are neither necessary nor sufficient to
diagnose an SCN1A-related seizure disorder. Other conditions (including those caused by
mutation of other genes) may be associated with the same phenotypes.
It is most important to distinguish SCN1A-related seizure disorders from potentially treatable
conditions, including the following [Arzimanoglou et al 2004, Roger et al 2006]:
 Pyridoxine-dependent seizures and B6-related epilepsies
 "Folinic acid-responsive" seizures, a rare cause of epilepsy that improves with daily folinic
acid administration
 Inborn errors of metabolism, including mitochondrial dysfunction, which may be diagnosed
by the presence of abnormal serum concentrations of lactate, ketones, ammonia, amino
acids, and/or abnormal concentrations of urine organic acids (see Mitochondrial Diseases
Overview)
 Biotinidase deficiency, which is usually identified during newborn screening
 Glucose transporter type 1 deficiency, which is diagnosed by low CSF glucose concentrations,
and responds to the ketogenic diet
 Hepatic porphyrias, which usually demonstrate photosensitive porphyrins in the urine and
reduced monopyrrole porphobilinogen (PBG) deaminase in red cells (See Acute Intermittent
Porphyria, Porphyria Cutanea Tarda, Hepatic Coproporphyria, and Variegate Porphyria.)

If the family history is negative or unavailable, sporadic epilepsies (i.e., those without a
genetic cause) need to be included in the differential diagnosis, as does any cause of epilepsy
with nonspecific imaging findings. Some general categories of injury to consider include the
following [Arzimanoglou et al 2004, Roger et al 2006]:
 Trauma
 Hypoxia
 Sequelae of meningitis or hemorrhage
 Infectious or autoimmune cerebritis
 Vasculitis
 Paraneoplastic syndrome
 Toxins (including drug withdrawal)
 Endocrinopathy

If the family history is positive for other individuals with epilepsy, the differential diagnosis
includes the following inherited epilepsy syndromes [Arzimanoglou et al 2004, Roger et al
2006]:
 Benign familial neonatal seizures (see KCNQ2-Related Disorders, KCNQ3-Related Disorders)
 Benign familial infantile seizures (see KCNQ3-Related Disorders)
 Benign childhood epilepsy with centrotemporal spikes (rolandic epilepsy) (see KCNQ2-
Related Disorders, KCNQ3-Related Disorders)
  Childhood occipital epilepsy
 Absence epilepsies
 Autosomal dominant nocturnal frontal lobe epilepsy
 Familial temporal lobe epilepsies
 Familial focal epilepsy with variable foci
 Generalized epilepsy with febrile seizures plus (GEFS+)

To date, at least 12 loci associated with familial febrile seizures and at least eight loci
associated with generalized epilepsy febrile seizures plus (GEFS+) have been identified.
The phenotype in simple febrile seizures is usually less severe than that of febrile seizures
associated with GEFS+ (see Clinical Description) [Nakayama & Arinami 2006].
See OMIM Phenotypic Series: Seizures, familial febrile and Epilepsy, generalized, with
febrile seizures plus to view genes associated with this phenotype in OMIM.
Genetic loci known to be associated with GEFS+ include the following:
 Voltage-gated sodium channel genes
o SCN1A (locus name: GEFSP2) [Escayg et al 2000, Escayg et al 2001, Wallace et al
2001b]
o SCN1B (locus name: GEFSP1) [Wallace et al 1998, Wallace et al 2002, Audenaert et al
2003], mutation of which may be an autosomal recessive cause of Dravet syndrome
[Patino et al 2009], with later onset than that associated
with SCN1A or GABRG2 [Sijben et al 2009]
o SCN2A [Sugawara et al 2001], mutation of which can also cause a phenotype with
severe myoclonic epilepsy, ataxia, and pain [Liao et al 2010]. In children with Dravet
syndrome, pathogenic variants in SCN1A are more frequently identified than
pathogenic variants in SCN2A by a ratio of about 9:1 [Shi et al 2009].
o Occasionally, isolated SCN9A pathogenic variants (without SCN1A alterations)
associated with Dravet Syndrome [Singh et al 2009]; the frequency of this
occurrence is unknown. Familial studies have shown a relatively high occurrence
of SCN9Apathogenic variants in individuals with Dravet syndrome in whom
an SCN1A pathogenic variant has not been identified.
 GABAA receptor genes
o GABRG2 (locus name: GEFSP3) [Baulac et al 2001, Wallace et al 2001a], which is
much less common than SCN1A. Shi et al [2010] found one of 140 individuals with
childhood epilepsy in the Dravet-GEFS+ spectrum with a GABRG2 pathogenic variant.
o GABRD (locus name: GEFSP5) [Dibbens et al 2004]

 PCDH19, encoding protocadherin [Depienne et al 2009, Marini et al 2010] and located on the
X chromosome. Mutation of PCDH19 can cause a Dravet syndrome phenotype; most
symptomatic individuals are female. The syndrome is characterized by early normal
development followed by febrile and temperature-induced seizures that tend to occur in
clusters. The onset of seizures tends to be a little later (age ≥12 months). Although these
individuals may have fewer myoclonic jerks and absence seizures than individuals with
an SCN1A pathogenic variant, the phenotype may be quite similar to that of Dravet
 syndrome; furthermore, these individuals often respond to the same medications (e.g.,
stiripentol) [Nikanorova et al 2011].
 GEFSP6 (8p23-p21), a region with no known ion channel genes [Baulac et al 2008]

Persons with seizures who have a 2q24.2 deletion may have a deletion of SCN1A or the
candidate gene SLC4A10 [Krepischi et al 2010].
Go to:

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with an SCN1A-
related seizure disorder, the following evaluations are recommended:
 Neurologic examination
 Cognitive neuropsychological evaluation
 Behavioral neuropsychological evaluation
 Electroencephalogram (EEG), including video EEG telemetry where ictal onset or semiology is
unclear
 Clinical genetics evaluation [Pal et al 2010]

Treatment of Manifestations
Care is best provided by a physician (e.g., pediatric epileptologist) familiar with the
pharmacotherapy for this disorder. Seizure control is critical because children with SCN1A-
related seizure disorder are at high risk for sudden unexplained death in epilepsy (SUDEP).
In addition, prolonged acute seizures may cause permanent injury [Chipaux et al
2010, Takayanagi et al 2010].
Pharmacologic treatment focuses on the observations that abnormal SCN1A channels
disproportionately affect GABA neurons [Yu et al 2006] and that the associated seizures
respond optimally to antiepileptic drugs (AEDs) that bind to the GABA receptor:
 Clobazam (0.2-1 mg mg/kg/day), part of the standard of care in Europe, is now approved by
the FDA in the US. Clobazam is FDA approved for the treatment of seizures in Lennox-Gastaut
syndrome [Selmer et al 2009].
 Stiripentol (30-100 mg/kg/day) is accepted by epileptologists as an effective therapeutic
agent in SCN1A-related seizure disorders. It is part of the early standard of care in Europe,
and is used in the US after other conventional anticonvulsants have failed. It is not approved
by the FDA for use in the US, but the evidence of effectiveness in SCN1A-related epilepsy is
more specific than for any other agent (based on double-blind evaluation of seizure
reduction in severe myoclonic epilepsy in infancy (SMEI) [Chiron et al 2000]). As a result,
stiripentol is not considered an “investigational” therapy.

Thanh et al [2002] demonstrated efficacy of the drug when compared with placebo; only
moderate side effects including drowsiness, loss of appetite, and occasional neutropenia in
infants and young children were observed. In a recent US survey of 82 children with Dravet
 syndrome, stiripentol was found to be effective in reducing prolonged seizures [Wirrell et al
2013].

Stiripentol, which acts directly on GABA A receptors [Quilichini et al 2006], is also a potent
inhibitor of the hepatic enzymes CYP3A4, CYP1A2, and CYP2C19. As a result, it increases the
serum concentration of several common AEDs, including valproic acid, clobazam, and its
metabolite nor-clobazam [Thanh et al 2002]. Doses above 50 mg/kg/day are usually not
tolerated when used in conjunction with valproic acid and clobazam.

Children older than age 12 years may not tolerate stiripentol because of digestive tract side
effects and nausea [Thanh et al 2002].
 Benzodiazepines. Individuals taking stiripentol must exercise caution in the use of
benzodiazepines [Thanh et al 2002]. A single infusion of diazepam and clonazepam appears
to be safe [Thanh et al 2002].
 Topiramate [Coppola et al 2002]
 Valproic acid (10-30 mg/kg/day) [Thanh et al 2002]
 Ethosuximide. Can be effective for absence seizures. The dose is usually limited by
gastrointestinal side effects, which can be minimized by more frequent dosing.
 Levetiracetam (20-80 mg/kg/day). Often effective, but may make seizures worse in some
individuals [Caraballo et al 2010].
 Potassium bromide. Not FDA-approved in the US, but widely used in Japan with reasonable
effectiveness [Tanabe et al 2008].
 Phenobarbital. Although effective, phenobarbital is poorly tolerated because of its effects on
cognition. When it is taken in combination with stiripentol, the serum concentration of
phenobarbital is increased because stiripentol slows the metabolism and excretion of
barbiturates.
 Ketogenic diet. Dressler et al [2010] report that seizures were reduced by more than 50% in
62.5% of persons with Dravet syndrome who stayed on the diet for six months. The findings
of Nabbout et al [2011]in 15 individuals also support the use of the ketogenic diet in Dravet
syndrome.

Sleep deprivation and illness can exacerbate SCN1A-related seizures; thus, good sleep
hygiene should be encouraged. Comorbidity with sleep apnea can also occur frequently in
individuals with epilepsy [Malow et al 2000], and can influence seizure control, behavior,
and cognition. Polysomnography should be considered if obstructive or central sleep apnea is
suspected.
Due to the sedating effects of seizure medications and the possibility of respiratory
depression (especially with benzodiazepines and barbiturates), parents are advised to take a
CPR course. Routine seizure and personal safety counseling is indicated.
Seizures are not always responsive to conventional AEDs. Anecdotal evidence suggests that
the following drugs/treatment modalities may be effective for SCN1A-related SMEI seizures
[Dravet et al 2002]:
 Ethosuximide and high-dose piracetam for myoclonic seizures
 Corticosteroids
  Immunoglobulins

Non-medical interventions that families have reported to be helpful include the following
[Nolan et al 2008]:
 Placement of an indwelling venous access device
 Creating a portable microenvironment
 Having a written emergency department protocol
 Establishing emergency routines for the family
 Assigning a parent on call to lessen the effect on the siblings
 Creating personal time to decrease parent stress
 Finding respite care
 Contacting an internet support group

Prevention of Secondary Complications

Individuals experiencing atonic seizures or myoclonic-astatic epilepsy should be advised to
wear a protective helmet.
Although immunization may trigger a seizure, it does not affect the natural course of the
disorder. McIntosh et al [2010] looked retrospectively at a cohort of 14 individuals with
Dravet syndrome, and found no effect of immunization on cognitive outcome. These authors
suggest that the immunization schedule not be altered and that the risk for fever following
immunization could be reduced by providing a scheduled, long-acting NSAID (e.g.,
naproxen). The treating neurologist may also consider increasing the anticonvulsant dose(s)
temporarily around the time of the immunization.

Surveillance
Serial neuropsychological evaluation for neurologic, cognitive, and behavioral deterioration
is appropriate.
EEG monitoring is appropriate when new or different seizure types are suspected.

Agents/Circumstances to Avoid
Several antiepileptic drugs (AEDs) which are effective for most forms of epilepsy can make
seizures due to heterozygous SCN1A pathogenic variants worse:
 Carbamazepine, lamotrigine, and vigabatrin, which can induce or increase myoclonic
seizures [Horn et al 1986, Guerrini et al 1998, Ceulemans et al 2004a]
 Phenytoin, which may worsen seizures and can induce choreoathetosis [Saito et al 2001]
 Rufinamide, which has a pharmacologic mechanism similar to carbamazepine and phenytoin
and may exacerbate seizures as well
 Acetaminophen, which is hepatotoxic in overdose. Given the possibility of interaction with
anticonvulsant medications, especially valproate and topiramate [Nicolai et al 2008],
 acetaminophen should be avoided. Any of the NSAIDs are effective as antipyretics, and
represent much lower risk.

Activities in which a sudden loss of consciousness could lead to injury or death should be
avoided (e.g., bathing, swimming, driving, or working/playing at heights).

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic
counseling purposes.

Pregnancy Management
In addition to the considerations described in Genetic Counseling, other pregnancy-related
considerations include the following:
 Risk of major malformations (especially due to valproic acid exposure in utero [Samrén et al
1997]) and minor anomalies
 Advantages and disadvantages of increasing maternal periconceptional folic acid
supplementation to 4000 µg daily, particularly when women are taking valproic acid or
carbamazepine during pregnancy
 Effect of in utero exposure to anticonvulsants on future cognitive development [Meador et al
2009]
 Effect of anticonvulsants on hormonal methods of birth control
 Effects of anticonvulsants on conception; the risk for complications in mothers who are on
anticonvulsants
 Effect of pregnancy on anticonvulsant metabolism
 Effect of pregnancy on maternal seizure control

Pregnancy, family planning, and contraception are issues that should be raised with every
female near childbearing age who has epilepsy. These considerations are not unique to or
(aside from medication selection) significantly influenced by the presence of an SCN1A-
related seizure disorder.

Therapies Under Investigation

Cannabis-derived compounds (including cannabidiol [CBD], tetrahydrocannabinol [THC],
and marijuana oils), collectively called “cannabinoids,” have received much attention from
the media based on anecdotal experiences; however, there is currently no scientific evidence
that they are effective. As a result, they should never be used in place of treatments that are
known to be effective. A randomized clinical trial is required to determine whether
cannabinoid treatment is effective. There has been rapid progress in starting such a trial, and
it is expected to begin in 2014. Cannabinoids are bioactive and may have psychotropic and/or
systemic side effects; they also may act as an immunosuppressant and an anti-inflammatory
in animal models and thus should be studied carefully in immature humans before
widespread use is considered [Rieder et al 2010, Bergamaschi et al 2011].
Thalamic deep brain stimulation (DBS) was reported by Andrade et al [2010] in two
children with Dravet syndrome with ten-year follow up. One showed “marked improvement”
after implantation, whereas the other received no benefit.
Lacosamide has not been studied in SCN1A-related seizure disorders; however, there are
theoretic reasons why it may be effective [Curia et al 2009].
Verapamil was reported to help two girls with severe epilepsy resulting from mutation
of SCN1A [Iannetti et al 2009]; however, it has not been formally studied.
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of
diseases and conditions.

Other
Persons with epilepsy should be made aware of local motor vehicle driving laws and
physician reporting laws.
Hippocampal sclerosis can occur as a secondary feature of SCN1A-related seizure disorders
[Livingston et al 2009], but there is no proven role for surgery given the widespread
epileptogenic potential in this disorder. Of note, Scheffer et al [2007] reported good outcomes
after temporal lobe surgery in two persons with mutation of SCN1B.
Go to:

Genetic Counseling
Genetic counseling is the process of providing individuals and families with information on
the nature, inheritance, and implications of genetic disorders to help them make informed
medical and personal decisions. The following section deals with genetic risk assessment and
the use of family history and genetic testing to clarify genetic status for family members. This
section is not meant to address all personal, cultural, or ethical issues that individuals may
face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance
SCN1A-related seizure disorders are inherited in an autosomal dominantmanner.
Note: Most SCN1A-related severe myoclonic epilepsy in infancy (SMEI) and intractable
childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC) are the result of a de
novo heterozygous pathogenic variant.

Risk to Family Members

Parents of a proband
 A parent of the proband is presumed to have an SCN1A pathogenic variant if he/she has
additional family members who have seizures.
 A proband with an SCN1A-related seizure disorder may have the disorder as the result of
a de novo pathogenic variant. The proportion of cases caused by de novo variants differs
by phenotype. The percentage of probands with an SCN1A-related seizure disorder and
an affectedparent decreases as the severity of the phenotype in the proband increases.
 o More than 95% of individuals with GEFS+ have a parent with the
same SCN1A pathogenic variant.
o Only approximately 5% of probands with SMEI have a parent with the
same SCN1A pathogenic variant [Wallace et al 2003, Ceulemans et al 2004b, Fukuma
et al 2004].
o Testing of parents of children who had SMEI and a confirmed SCN1A pathogenic
variant showed that in 95% (76/80) of the children the pathogenic variant was de
novo in the proband. Of the four children who had a parent with the pathogenic
variant, two had a missense variant and two had a truncation variant; the parents
were either asymptomatic or had mild epilepsy [Gennaro et al 2003, Nabbout et al
2003].
o Berkovic et al [2006] found an SCN1A pathogenic variant in 11/14 children diagnosed
with post-vaccine encephalopathy; in nine the variant was de novo in the proband.
 If a pathogenic variant found in the proband cannot be detected in DNA extracted from the
leukocytes of either parent, the risk to either parent of having the pathogenic variant is low,
but greater than that of the general population because of the possibility of germline
mosaicism. Germline mosaicism has been documented [Gennaro et al 2006, Selmer et al
2009, Azmanov et al 2010], and may occur in up to 7% of families with Dravet syndrome
[Depienne et al 2010].
 In one series, 75% of de novo pathogenic variants originated on the paternally
inherited chromosome [Heron et al 2010].
 Recommendations for the evaluation of parents of a proband with an apparent de
novo pathogenic variant include molecular genetic testing.
 An apparently negative family history cannot be confirmed until appropriate evaluations
have been performed. Although 95% of individuals with SCN1A-related GEFS+ have
an affected parent, the family history may appear to be negative because of failure to
recognize the disorder in family members or because of early death before the onset of
symptoms. If the parent is the individual in whom the pathogenic variant first occurred, s/he
may have somatic mosaicism for the pathogenic variant and may be only mildly or minimally
affected [Gennaro et al 2006].

Sibs of a proband
 The risk to the sibs of a proband depends on the genetic status of the proband's parents: if a
parent of the proband is affected (i.e., has the pathogenic variant documented by molecular
genetic testing) or is presumed to have a pathogenic variant (based on family history), the
risk to the sibs of inheriting the pathogenic variant is 50%.
 If a sib has epilepsy, he/she is presumed to be affected (and therefore to have a pathogenic
variant).
 If a sib does not have epilepsy, the prior probability of the sib having inherited
the pathogenic variant is 50%; however, the probability of the sib developing symptoms
depends on the penetrance, which can only be estimated. For example, for an estimated
penetrance of 70% for the GEFS+ phenotype, the probability of the asymptomatic sib having
inherited the pathogenic variant is 23%.
  If a pathogenic variant is found in the proband but cannot be detected in the DNA of either
parent, the risk to sibs is low but greater than that of the general population because of the
possibility of germline mosaicism[Gennaro et al 2006].

Offspring of a proband
 Each child of an individual with an SCN1A-related seizure disorder has a 50% chance of
inheriting the pathogenic variant.
 Penetrance is incomplete (see Penetrance) and varies by phenotype.
 The likelihood that the child of an individual with an SCN1A-related seizure disorder will
develop the same phenotype is the probability of inheriting the pathogenic variant (50%)
times the penetrance for that particular phenotype.
 Individuals with GEFS+ may have offspring who are more severely affected than they are. For
example, they may have a child with Dravet syndrome.

Other family members of a proband. The risk to other family members depends on the
status of the proband's parents: if a parent is affected or has a pathogenic variant, the other
family members are at greater risk than the general population.

Related Genetic Counseling Issues

Interpreting test results in at-risk asymptomatic relatives. Counseling asymptomatic
family members who are identified to have the family-specific pathogenic variant should
include information on reduced penetrance and the limited ability to predict phenotype based
on molecular genetic testing alone.
Considerations in families with an apparent de novo pathogenic variant.When neither
parent of a proband with an autosomal dominant condition has the pathogenic variant or
clinical evidence of the disorder, the variant is likely de novo. However, possible non-medical
explanations including alternate paternity or maternity (e.g., with assisted reproduction) or
undisclosed adoption could also be explored.
Family planning
 The optimal time for determination of genetic risk and discussion of the availability of
prenatal testing is before pregnancy.
 It is appropriate to offer genetic counseling (including discussion of potential risks to
offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible
future use. Because it is likely that testing methodology and our understanding of genes,
allelic variants, and diseases will improve in the future, consideration should be given to
banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the SCN1A pathogenic variant has been identified in an affected family member,
prenatal testing and preimplantation genetic diagnosis for a pregnancy at increased risk for
a SCN1A-related seizure disorder are possible options.
Go to:
Resources
GeneReviews staff has selected the following disease-specific and/or umbrella support
organizations and/or registries for the benefit of individuals with this disorder and their
families. GeneReviews is not responsible for the information provided by other organizations.
For information on selection criteria, click here.
 Dravet Syndrome Foundation
Phone: 203-392-1950

Fax: 203-907-1940

Email: info@dravetfoundation.org

www.dravetfoundation.org

 My46 Trait Profile

SCN1A-related seizure disorders

 American Epilepsy Society (AES)

www.aesnet.org

 Canadian Epilepsy Alliance

Canada

Phone: 1-866-EPILEPSY (1-866-374-5377)

www.epilepsymatters.com

 Epilepsy Foundation
8301 Professional Place East

Suite 200

Landover MD 20785-7223

Phone: 800-332-1000 (toll-free)

Email: ContactUs@efa.org

www.epilepsy.com

 National Institute of Neurological Disorders and Stroke (NINDS)

PO Box 5801

Bethesda MD 20824

Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)

Febrile Seizures Fact Sheet

 National Institute of Neurological Disorders and Stroke (NINDS)

PO Box 5801
 Bethesda MD 20824

Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)

Epilepsy Information Page

Go to:

Molecular Genetics
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in
the GeneReview: tables may contain more recent information. —ED.

Table A.
SCN1A-Related Seizure Disorders: Genes and Databases

Gene Chromosome Protein Locus-Specific Databases HGMD ClinVar

Locus

SCN1 2q24.3 Sodium channel Familial Hemiplegic Migraine SCN1A SCN1A

A protein type 1 subunit (FHM) Variation Database
alpha (SCN1A)

Data are compiled from the following standard references: gene from HGNC; chromosome locus
from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to
which links are provided, click here.

Table B.
OMIM Entries for SCN1A-Related Seizure Disorders (View All in OMIM)

182389 SODIUM CHANNEL, NEURONAL TYPE I, ALPHA SUBUNIT; SCN1A

604233 GENERALIZED EPILEPSY WITH FEBRILE SEIZURES PLUS, TYPE 1; GEFSP1

604403 GENERALIZED EPILEPSY WITH FEBRILE SEIZURES PLUS, TYPE 2; GEFSP2

607208 EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 6; EIEE6

Molecular Genetic Pathogenesis
SCN1A encodes the alpha subunit (also known as Nav1.1) of the neuronal voltage-gated
sodium channel. SCN1A-related seizure disorders are therefore best conceptualized as a
"channelopathy" with seizures (and their sequelae) as their primary manifestation. The
molecular abnormality causes neuronal dysfunction, and ultimately hyperexcitability at the
level of the cortical network: the sine qua non of epilepsy.
SCN1A is part of a cluster of sodium channel genes encoded on chromosome2q24 that
includes SCN2A and SCN3A [Mulley et al 2005]. The alpha subunit of sodium channels
forms the membrane pore. Each alpha subunit protein has four domains with six
transmembrane segments connected by loops (Figure 2). Pore-lining residues are found in S5,
S6, and the P-loop, the latter connecting S5 with S6. The voltage sensor is in S4, where
positively charged residues allow for the sensing of membrane potential changes [Catterall
2000]. Although epilepsy-associated pathogenic variants are found in all parts of Nav1.1, they
occur more frequently in the C-terminus, to some extent in the N-terminus, in the P-loops of
D1-D5, and in the voltage sensor [Ceulemans et al 2004b, Mulley et al 2006].
Gene structure. SCN1A spans approximately 84 Mb of genomic DNA and has a transcript of
8,100 bp (reference sequence NM_006920.4). The genecomprises 26 exons that encode a
protein of 1,998 amino acid residues (reference sequence NP_008851.3). Splicing variability
has been reported [Wallace et al 2001b]. For a detailed summary of gene and protein
information, see Table A, Gene.
Pathogenic allelic variants
 Generalized epilepsy with febrile seizures plus (GEFS+). SCN1Apathogenic variants
associated with GEFS+ are mostly missense and familial (i.e., inherited) [Mulley et al 2005].
 Dravet syndrome. Almost half the pathogenic variants associated with the severe myoclonic
epilepsy in infancy (SMEI) phenotype are truncating variants [Mulley et al 2006]. The
remainder includes missense variants (39%-43%; fewer than the GEFS+ phenotype, but with
a similar topologic distribution within Na v1.1), splice site variants (7%), and deletions (3%)
[adapted from Mulley et al 2005].
 Intractable childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC). Seven out
of ten individuals with ICE-GTC had an SCN1A missense pathogenic variant [Mulley et al
2005]. In the two cases with an inherited pathogenic variant, the parents had GEFS+.
 Infantile partial seizures with variable foci. In the authors' experience, such cases often
have missense pathogenic variants affecting the pore region or the carboxy-terminus of
Nav1.1.
 Infantile spasms. The literature cites an isolated case of infantile spasms and
an SCN1A missense pathogenic variant [Wallace et al 2003].
 Vaccine-related encephalopathy and seizures. There are five reports of pathogenic variants
causing Nav1.1 truncation and six reports of missense pathogenic variants in conserved
regions of Nav1.1 [Berkovic et al 2006].

Normal gene product. See Molecular Genetic Pathogenesis.

Abnormal gene product. The molecular pathogenesis of SCN1A-related seizure disorders
may vary depending on the specific pathogenic variant type (loss of function vs. alteration in
activity). The pathophysiology is an active area of investigation; it appears likely that the
 predominant effect is the loss of excitability in inhibitory GABAergic neurons [Escayg &
Goldin 2010].

Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th edition.

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GABAA Receptor Subunit Mutations and Genetic

Epilepsies
Robert L. Macdonald, Jing-Qiong Kang, and Martin J. Gallagher.
Author Information

Mutations in inhibitory GABAA receptor subunit genes (GABRA1,

GABRB3, GABRG2 and GABRD) have been associated with idiopathic
epilepsy syndromes (IES) including childhood absence epilepsy (CAE),
juvenile myoclonic epilepsy (JME), pure febrile seizures (FS), generalized
epilepsy with febrile seizures plus (GEFS+), and Dravet syndrome (DS)
(also known as severe myoclonic epilepsy in infancy, SMEI). These
mutations are found in both translated and untranslated gene regions and
have been shown to affect the GABAA receptors by altering receptor
function and/or by impairing receptor biogenesis by multiple mechanisms
including reducing subunit mRNA transcription or stability, impairing
subunit folding, stability, or oligomerization or by inhibiting receptor
trafficking. While a clear genotype/phenotype correlation has not been
established, mutations of GABRB3 and GABRA1 are associated with CAE
or JME while mutations and variants of GABRG2 and GABRD are
associated with FS, FS with CAE, GEFS+, and DS.
Go to:
INTRODUCTION
Idiopathic epilepsy syndromes (IES) are common and constitute about
50% of the epilepsies diagnosed worldwide (1). IES vary in severity from
the relatively benign febrile seizures (FS) and childhood absence epilepsy
(CAE) to the severe epilepsy syndrome Dravet syndrome (DS). A common
IES is febrile seizures plus (FS+), which develops early in childhood with
multiple febrile seizures (FSs) that continue to occur later than six years of
age or are associated with afebrile seizures (2). Generalized epilepsy with
febrile seizures plus (GEFS+) is a familial epilepsy syndrome in which
multiple family members have either febrile seizures, FS+, myoclonic-
astatic epilepsy (MAE) and DS (2).
Most IES have been thought to have a genetic basis (3, 4), and although
complex polygenic inheritance is likely associated with most genetic
epilepsy syndromes, rare monogenic mutations of transmembrane ion
channels associated with IES in several large pedigrees and in sporadic
cases with de novo mutations have been identified (4, 5, 6). Mutations of ion
channels that either increase excitatory or reduce inhibitory
neurotransmission would produce neuronal hyperexcitability, thereby
predisposing individuals harboring the mutant gene to experience seizures.
In this review we will focus on mutations in inhibitory GABA A receptor
subunit genes that have been associated with IES.
Go to:

GABAA RECEPTOR SUBUNIT GENES

GABAA receptors are members of the cys-loop family of ligand-gated ion
channels that also includes glycine, nicotinic cholinergic and serotonin 5-
HT3 receptors and are the primary mediators of fast inhibitory synaptic
transmission in the central nervous system. GABAA receptors are formed
by pentameric assembly of different subunit subtypes (α1-α6, β1-β3, γ1-
γ3, δ, ɛ, π, θ, and ρ1-ρ3) to form chloride ion channels (7), and most
GABAA receptors are thought to contain two α subunits, two β subunits,
and one γ or δ subunit (8). GABAA receptors mediate both phasic synaptic
and tonic perisynaptic or extrasynaptic inhibition, and several antiepileptic
drugs including benzodiazepines and barbiturates act by enhancing
GABAA receptor currents (9). Therefore, it is not surprising that several
different IES have been associated with mutations and variants in several
GABAAreceptor subunit genes GABRs including GABRA1, GABRB3,
GABRDand GABRG2 (see Figure 1, Table 1) (10, 11). The position of mutant
amino acids in GABRA1, GABRB3 and GABRD associated with IES have
been designated in the immature peptide that includes the signal sequence,
but mutations in GABRG2 have been designated in the mature peptide. For
consistency, in this review we will also designate the position
of GABRG2 mutations in the immature peptide.

Figure 1

GABAA receptor subunit gene mutations associated with genetic epilepsy

syndromes.

Table 1

Go to:

IES ASSOCIATED WITH GABAA RECEPTOR SUBUNIT

MUTATIONS
A wide range of IES have been shown to be associated with
GABAAreceptor subunit mutations (11; Table 1). CAE alone has been
associated with GABRB3 missense mutations located in the β3 subunit
signal peptide (P11S, S15F) and the N-terminal region of the mature
subunit (G32R) (12), as well as with a specific haplotype of
the GABRB3 promoter (13). In addition, CAE is also associated with a
frame shift mutation in GABRA1 (975delC, S326fs328X) (6) that produces
a premature translation-termination codon (PTC). The β3 subunit (P11S)
mutation has also been associated with autism pedigrees with some
patients who also had epilepsy (14, 15). Juvenile myoclonic epilepsy (JME)
has been associated with a missense mutation in GABRA1 (A322D) (16)
and a variant in GABRD (R220H) (17). FSs alone have been associated
with missense mutations in GABRG2 that are located N-terminal region of
the mature γ2 subunit (R82Q, R177G) (5, 18) and in the intron 6 splice donor
site (IVS6 2T-> G) (19). GEFS+ has been associated with missense and
nonsense mutations in GABRG2 (Q40X, K328M, Q390X, W429X) (20 –
23) and with variants in GABRD (E177A, R220C) (17). While a clear
genotype/phenotype correlation has not been well established, to date
mutations in GABRB3 and GABRA1 have been associated with CAE or
JME alone while GABRG2 mutations and other GABRD variants have
been associated with FS, FS with CAE and GEFS+.
 Go to:

PATHOPHYSIOLOGY OF GABAA RECEPTOR SUBUNIT

MUTATIONS ASSOCIATED WITH CAE AND JME
GABRB3(P11S, S15F, G32R)
GABRB3 has an alternative exon 1 (exon 1a) that encodes a variant signal
peptide that translates a β3 subunit of identical length but with an altered
mature peptide sequence. The two transcripts have different relative
expression levels and distributions in fetal and adult brain, with exon 1a
expression being enriched in fetal brain (24). The GABRB3 mutations,
P11S and S15F, are located in exon 1a in the β3 subunit signal peptide.
The GABRB3 mutation, G32R, is in exon 2 and is located in the mature β3
subunit peptide near the N terminus. In HEK293T cells coexpressing each
of the three β3 mutant subunits with α1 and γ2 subunits, whole cell peak
currents and cell surface expression levels of the mutant β3 subunits were
reduced (12, 14). It was suggested that these β3 subunit mutations may reduce
GABAAreceptor cell surface expression and whole cell current amplitudes
by altering N-linked glycosylation of the β3 subunit (12, 14). However, the
basis for the altered glycosylation of β3 subunits is unclear and whether or
not the altered glycosylation reduces receptor surface levels is also unclear.
Furthermore, it is also uncertain how the two signal peptide mutations alter
the function of the mature β3 subunits since they are presumably cleaved
prior to subunit folding and receptor assembly. Reduced expression of β3
subunit-containing GABAAreceptors due to these mutations would be
consistent with an epilepsy phenotype and would be expected to cause
epilepsy early in development, since exon 1a is selectively expressed in
fetal brain, and to remit in young adulthood since exon 1 is selectively
expressed later in development.
In GABRB3, one of four haplotypes (haplotype 2) in the region from the
exon 1a promoter to the beginning of intron 3 had a significant association
with CAE (13). Using an in vitro reporter gene assay with exon 1a
promoter constructs, the haplotype 2 promoter was found to cause less
transcriptional activity than the haplotype 1 promoter. Thus it was
suggested that the thymine to cytosine substitution in the haplotype 2
promoter impaired binding of the neuron-specific transcriptional activator
N-Oct-3, leading to decreased transcription of GABRB3 and thus
presumably to a decrease in β3 subunit levels.
GABRA1(975delC, S326fs328X)
The GABRA1 deletion mutation, 975delC, S326fs328X, causes a
frameshift in GABRA1 that produces a premature translation-termination
codon (PTC) and is associated with CAE (6; see Figure 1, Table 1). PTCs
in the last exon of a multi-exon gene or less than 50–55 nucleotides
upstream of the last exon–exon junction result in production of a truncated
protein. In contrast, PTCs not in the last exon of a multi-exon gene or
more than 50–55 nucleotides upstream of the last exon–exon junction
produce mRNA degradation through activation of nonsense-mediated
decay (NMD), a cellular mRNA quality-control system that activates
degradation of mutant mRNA to substantially reduce production of
truncated proteins (25). The GABRA1 mutation, 975delC, S326fs328X, is
in the 8th exon and is 84 base pairs upstream of intron 8, and thus, this PTC
activated NMD and reduced mutant α1 subunit mRNA (26). However, the
NMD was incomplete, but the truncated α1 subunit protein that was
translated was degraded by endoplasmic reticulum (ER) associated
degradation (ERAD). These results suggested that the GABRA1 mutation,
S326fs328X, resulted in functional haploinsufficiency by reducing both
mutant mRNA and subunit protein.

GABRA1(A322D)
The GABRA1 missense mutation, A322D, is a missense mutation that
replaces a small, neutral residue with a larger negatively charged aspartate
residue in the M3 transmembrane helix and is associated with an AD form
of JME (16; see Figure 1, Table 1, MIM #254770). This nonconserved
mutation was shown to impair α1 subunit folding by destabilizing insertion
of the M3 domain into the lipid bilayer (27). When mutant α1(A322D), β2
and γ2 subunits were co-expressed in HEK293T cells, both total and
surface α1 subunit levels were reduced and an intermediate effect was
found with heterozygous subunit expression. Loss of the misfolded mutant
subunit was due to ERAD (28) and lysosomal degradation (29). Peak
GABA-evoked currents were significantly reduced with both heterozygous
and homozygous α1(A322D) subunit expression, consistent with the
impaired folding and assembly of the mutant α1(A322D) subunits (6, 30, 31).
Recently, we have demonstrated that the presence of the nondegraded,
misfolded α 1(A322D) subunit produces small dominant negative effects
that alter the composition and further reduce the expression of wild type
GABAA receptors (32).
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PATHOPHYSIOLOGY OF GABAA RECEPTOR SUBUNIT
MUTATIONS ASSOCIATED WITH FS WITH OR WITHOUT
CAE
In contrast to CAE and JME without FSs being associated with mutations
in GABRB3 and GABRA1, FSs with or without CAE have only been
associated with mutations in GABRG2. Two GABRG2missense mutations,
R82Q (5) and R177G (18) and one splice donor site mutation in GABRG2,
IVS6+2T→G (19), have been associated with FSs with or without CAE.

GABRG2(R82Q)
The GABRG2 missense mutation, R82Q, is located in the distal N-
terminus and is associated with FS (5; see Figure 1, Table 1). An AD form
of CAE was also present in the family pedigree, and it was demonstrated
that an interaction of the γ2 subunit gene with another gene or genes is
required for the CAE phenotype in this family (33). Alignment of γ2
subunit and acetylcholine binding protein sequences revealed that R82 is
positioned at the γ2/β2 subunit-subunit interface, and it was demonstrated
that the mutation impaired γ2 and β2 subunit oligomerization (34). This
impaired oligomerization is likely the basis for this mutation’s reduction of
surface α1β2γ2 receptors (35–38), ER retention of unassembled γ2(R82Q)
subunits (35, 37) and reduction of GABAA receptor currents (39, 35). Similarly,
the R82Q mutation also caused intracellular retention and reduced surface
expression of GABAA receptors in cortical pyramidal neurons (40),
reduced miniature inhibitory postsynaptic currents (IPSCs) in layer II/III
cortical neurons and electrographic and behavioral seizures in R82Q knock
in mice. Endogenous expression of α5 subunits in cultured hippocampal
neurons was reduced when coexpressed with γ2(R82Q) subunits,
indicating that γ2(R82Q) subunits conferred a dominant negative effect
(38). In addition, it is possible that a deficit in γ2 subunits caused a
compensatory increase in other subunits such as δ or β subunits. Since αβδ
and αβ receptors are extrasynaptic or perisynaptic, this compensatory
increase may result in a relative increase in tonic currents. Recently, it has
been reported that extrasynaptic GABAergic “tonic” inhibition was
increased in thalamocortical neurons from both genetic and
pharmacological models of absence epilepsy (41), consistent with this
conclusion.

GABRG2(R177G)
The GABRG2 missense mutation, R177G, is located in the N-terminus and
has been associated with FS (18; see Figure 1, Table 1). The γ2 subunit
R177 residue is conserved among γ2 subunits across species. Basic
residues are conserved among other γ subunits, and in other cys-loop
receptors, polar and charged amino acid residues occur at this position.
Mutant α1β3γ2L(R177G) receptors had altered current kinetics and
reduced benzodiazepine sensitivity (18), but the underlying molecular
mechanisms for FSs associated with this mutation are unclear.

GABRG2(IVS6 + 2T→G)
The GABRG2 splice-donor site mutation, IVS6 + 2T→G, is located in
intron 6 and was identified in a family with FS and CAE (19; see Figure
1, Table 1). The effect of this mutation on GABAA receptor function is
unknown but was predicted to impair splicing of the 6thintron. It was
suggested that the mutation most likely would lead to a nonfunctional
protein through exon skipping, which would result in a PTC at the 5th and
7th exon junction site. If correct, the exon skipping induced PTC would
trigger NMD. However, when the mutation is made in the GABRG2 intron
6 cloned in a bacterial artificial chromosome, a cryptic splice donor site in
intron 6 was activated resulting in retention of a portion of intron 6 and a
frame shift that resulted in a premature translation-termination codon
(PTC) in exon 7 (Tian and Macdonald, unpublished). This exon 7 PTC had
an exon-exon junction downstream and thus activated nonsense mediated
mRNA decay and loss of most of the mutant mRNA.
Go to:

PATHOPHYSIOLOGY OF GABAA RECEPTOR SUBUNIT

MUTATIONS ASSOCIATED WITH GEFS+ AND DRAVET
SYNDROME
GEFS+ and Dravet syndrome have only been associated
with GABRG2 and GABRD mutations. One GABRG2 missense mutations,
K328M (21), three GABRG2 nonsense mutations, Q40X, Q390X and
W429X (20, 22, 23), one GABRD mutation, R220C (17), and a GABRDvariant,
E177A, (17) have been associated with GEFS+ with or without Dravet
syndrome.

GABRG2(K328M)
The GABRG2 missense mutation, K328M, is located in the short
extracellular loop between transmembrane domains M2 and M3 and is
associated with an AD GEFS+ (21; see Figure 1, Table 1). Brief GABA-
evoked currents recorded from α1β3γ2L(K328M) receptors had
unchanged current amplitudes but had accelerated deactivation (39, 42). In
transfected hippocampal neurons, the K328M mutation also accelerated
deactivation of IPSCs, thus reducing their duration (38). Single channel
currents from α1β3γ2(K328M) receptors had reduced mean open times,
consistent with accelerated macroscopic current deactivation (39).
Therefore, the γ2L(K328M) subunit mutation would reduce IPSC duration
by accelerating its deactivation due to impaired stability of the channel
open state.

GABRG2(Q390X)
The GABRG2 nonsense mutation, Q390X, is located in the intracellular
loop between transmembrane domains M3 and M4 and was identified in a
family with GEFS+ and DS (22; see Figure 1, Table 1). The PTC is located
in the last (9th) exon, and therefore, would not be expected to activate
NMD. When cDNAs containing the mutant subunit were transfected into
HEK293T cells, translation resulted in production of a truncated protein
that lacked its C-terminal 78 amino acids and was retained in the ER (43).
Because the γ2 subunit mutation (Q351X) prevents the cell surface
trafficking of both α1β2γ2(Q351X) and α1β2 receptors, no GABA-evoked
currents were recorded from cells transfected with α1, β2, and γ2(Q351X)
subunits (22, 43). The γ2(Q390X) subunit also caused a dominant negative
effect on wildtype receptors. Currents recorded following heterozygous
expression of α1β2γ2/α1β2γ2(Q351X) receptors were reduced relative to
hemizygous control currents, and γ2S and γ2S(Q390X) subunits and
partnering α1 and β2 subunit levels were all reduced more than with
hemizygous expression with only one wildtype allele, suggesting that the
mutation produced a loss of function of the mutant allele and a dominant
negative effect of the mutant γ2S(Q390X) subunit on wildtype receptor
channels.

GABRG2(Q40X and W429X)

The two GABRG2 nonsense mutations, Q40X and W429X, have been
associated with, DS and GEFS+, respectively (20, 23). The Q40X mutation
likely triggers NMD, although this has not yet been demonstrated. In
contrast, the W429X mutation, which generates a PTC in the
last GABRG2 exon, would not be predicted to activate NMD, and
therefore, would be expected to produce a truncated protein with loss of
the C-terminal 39 amino acids.

GABRD(E177A, R220H and R220C)

The GABRD susceptibility variant, E177A, and the GABRD mutation,
R220C, are located in the δ subunit N terminus and are associated with an
AD generalized epilepsy similar to GEFS+ (17; see Figure 1, Table 1).
The GABRD(E177A) variant is adjacent to one of the two cysteines that
form a disulfide bond, the signature feature of cys-loop receptors, and
the GABRD(R220C) mutation is located between the cys-loop and the
beginning of the first transmembrane domain (M1). The macroscopic
current amplitudes of heterozygous and homozygous α1β2δ receptors
containing the δ(E177A) subunit were significantly reduced due primarily
to reduced single channel mean channel open time (44). There was also a
small but significant reduction of mutant subunit surface levels with
homozygous expression of receptors containing either variant.
Go to:

DISCUSSION
Phenotype/genotype Correlations
The pathophysiology of GABAA receptor subunit gene mutations
associated with CAE and JME appears to involve a mechanism that
produces developmentally regulated epilepsy and FSs. Down regulation
of GABRB3(exon 1a) function by decreasing β3 subunit surface expression
(GABRB3(P11S, S15F)) or by decreasing GABRB3transcription (promoter
mutation) associated with CAE should both result in epilepsy syndromes
that have early onset and remit with age due to the expression
of GABRB3 exon 1a only early in development. In contrast,
the GABRA1 frame shift mutation (975delC, S326fs328X) should also
occur early in development corresponding to the onset
of GABRA1 expression but should not remit with age if there is no
functional compensation from other functionally equivalent subunits. In
general, these patterns of epilepsy expression and genotype appear to be
consistent. That said, it is unclear why mutations in GABRG2and GABRD,
but not GABRA1 and GABRB3, are associated with FSs. It is tempting to
speculate that this difference may have something to do with the ability of
the nervous system to compensate for the loss of a GABAA receptor
subunit. There are multiple α (α2–α6) and β (β1, β3) subunit subtypes that
can substitute for α1 or β3 subunits and lessen the molecular defect caused
by the impaired subunit function or expression but γ2 or δ subunits do not
have subunits that can readily be upregulated to compensate for their loss.
Alternatively or in addition, it may be that decreased expression of γ2 or δ
subunits may have some inherent temperature-sensitivity that further
reduces their expression or function (45).

Expression of GABAA Receptor Subunit Mutations in

Heterologous Cells and Neurons
The pathophysiology of mutant GABAA receptor subunits have been
primarily evaluated by expressing them in heterologous cells, but it is
likely that GABAA receptor expression and function in heterologous cells
and in neurons differ. While many fundamental features of subunit
translation, folding and oligomerization and receptor assembly and
trafficking are likely similar, if not identical, in heterologous cells and
neurons, heterologous cells do not express neuron-specific
GABAA receptor-associating proteins that are involved in GABAAreceptor
biosynthesis, trafficking, and cell surface stability (46). The processes
involved in targeting GABAA receptors to dendrites in polar neurons and to
subsynaptic and extrasynaptic sites are clearly not recapitulated in
heterologous cells. Some, but not all, of these concerns can be overcome
by expressing wild type and mutant GABAAreceptor subunits in cultured
neurons. In addition to expressing neuron specific proteins, cultured
neurons also form functional GABAergic synapses which obviate the need
for exogenous GABA applications. Many of the initial observations
obtained in heterologous cells have been confirmed by study of mutant
γ2(R82Q), γ2(K328M), γ2(Q390X), and α1(A322D) subunits transfected
into cultured neurons (32, 37, 38, 43). For example, rapid agonist perfusion
techniques applied to transfected HEK293T cells revealed that
α1β2γ2(K328M) receptors deactivated significantly faster than wild type
receptors (39), and miniature inhibitory post synaptic currents (mIPSCs)
recorded from hippocampal neurons transfected with γ2(K328M) subunits
had shorter deactivation times than mIPSCs recorded from untransfected
neurons or from neurons transfected with wild type γ2 subunits (38). In
addition, studies in transfected neurons revealed new findings that could
not have been predicted from heterologous expression alone. For example,
while endoplasmic reticulum retention of mutant γ2(R82Q) subunits
transfected into HEK293T cells (35, 36) was confirmed in transfected
hippocampal neurons (37, 38), expression of γ2(R82Q) subunits in cultured
neurons also reduced nonsynaptic “tonic” GABA currents and reduced
surface expression of α5 subunits (37). These observations could not have
been obtained in HEK293T cells that do not express neuron-specific
proteins such as radixin which associates with the α5 subunit (47).
Although expression of mutant GABAA receptor subunits in cultured
neurons has been useful, it is still likely that the details of the
pathophysiology are incomplete using this approach. With transfection, it
is not possible to regulate the levels of subunit transcription and translation
and therefore the relative amounts of wild type and mutant subunits and
assembly partners will not be physiologically correct. In addition, the
epilepsy mutations may have different actions in different brain regions or
in different neuronal cell types and thus could modify neuronal network
function differently in different nervous system locations. Ultimately,
many of these questions must be answered by studying genetically
modified animals as well as human patients who possess these mutations.
Thus far, only the GABRG2(R82Q) mutation knock in mouse has been
made and studied (40, 48). Consistent with the reports in transfected
heterologous cells and neurons, γ2(R82Q) subunit neuronal surface
expression was reduced (40). Unexpectedly, mIPSC amplitudes were
reduced in cortical neurons, but not in thalamic relay or reticular nuclei
neurons (40). Interestingly, the GABRG2(R82Q) subunit mutation
produced an epilepsy phenotype only when expressed at a critical time in
development (48), indicating a long-term impact of the presence of mutant
GABRG2(R82Q) protein by unknown mechanisms.

Pathophysiological Mechanisms of GABAA Receptor Subunit

Mutations
As noted in this review, the types and locations of mutations in
GABAA receptor subunit genes varied substantially. Missense and
nonsense mutations have been reported in coding and non coding regions.
In general, there is an association of the epilepsy syndrome type with the
gene as noted above (i.e. CAE and JME associated
with GABRB3 and GABRA1 mutations and FS with or without CAE,
GEFS+ and Dravet syndrome associated
with GABRG2 and GABRDmutations) and a loose correlation with the
severity of the mutation and the epilepsy phenotype (Figure 1). Missense
mutations in GABRB3, GABRG2 and GABRD are associated with CAE,
FS, JME and GEFS+ while nonsense mutations in GABRG2 have been
associated with FS, GEFS+ and Dravet syndrome. In addition, mutations
in noncoding regions in GABRG2 or GABRB3 and mutations in the signal
peptide of GABRB3 are associated with less severe epilepsies, FS and
CAE but mutations in the mature peptide are also associated with GEFS+
and Dravet syndrome in addition to FS and CAE. Whether or not the
presence of these correlations are due only to chance due to the small
numbers of reported mutations or to fundamental differences in the loss of
function of specific subunits due to specific types of mutations remains to
be seen.
It is also clear that the mutations, while all different, have some common
pathophysiological features. Distal N terminal missense mutations
(GABRB3(P11S, S15F, G32R) and GABRG2(R82Q, R177G) are
associated with the less severe epilepsies CAE and FS, and proximal N
terminal missense mutations GABD(E177A, R220H) are associated with
the more severe epilepsy GEFS+. The cytoplasmic M3/M4 loop nonsense
mutations GABRG2(Q390X, W429X) are associated with the more severe
epilepsies GEFS+ and Dravet syndrome.

Channelopathies
June-Bum Kim, MD, PhD

Author information Article notes Copyright and License information Disclaimer

This article has been cited by other articles in PMC.

Abstract
Go to:

Introduction
Channelopathies are diseases that develop because of defects in ion channels caused by either
genetic or acquired factors (Fig. 1). Mutations in genes encoding ion channels, which impair
channel function, are the most common cause of channelopathies. Consistent with the
distribution of ion channels throughout the human body, ion channel defects have been
implicated in a wide variety of diseases, including epilepsy, migraine, blindness, deafness,
diabetes, hypertension, cardiac arrhythmia, asthma, irritable bowel syndrome, and cancer1-3).

Fig. 1
Two main types of channelopathies.
There are remarkable causal heterogeneity (especially genetic) and phenotypic variability in
channelopathies, which make the diseases challenging to classify. This review will categorize
channelopathies based on the organ system with which they are predominantly associated in
both clinical and pathophysiological respects. Nomenclature of genetic diseases described in
this article can be found at the Online Mendelian Inheritance in Man (OMIM)
website: http://www.ncbi.nlm.nih.gov/omim.
Go to:

Ion channels
Ion channels are transmembrane proteins that allow the passive flow of ions, both in and out
of cells or cellular organelles, following their electrochemical gradients. Because the flux of
ions across a membrane results in electrical currents, ion channels play a key role in
generating membrane potential and function in diverse cellular activities, such as signal
transduction, neurotransmitter release, muscle contraction, hormone secretion, volume
regulation, growth, motility, and apoptosis. Ion channels can be classified according to the
types of ions passing through them, the factors of their gating, their tissue expression
patterns, and their structural characteristics. Ion channels typically exist in one of the three
states: open, inactivated closed (refractory period), and resting closed (Fig. 2). The gating
(opening and closing) of ion channels is controlled by diverse factors, such as membrane
potential (voltage), ligands (e.g., hormones and neurotransmitters), second messengers (e.g.,
calcium and cyclic nucleotides), light, temperature, and mechanical changes. Ion channels are
formed from either a single protein (e.g., cystic fibrosis transmembrane conductance
regulator, a chloride channel) or, more commonly, from an assembly of several subunits, each
a protein encoded by a different gene. More than 400 ion channel genes have been
identified4). Further diversity comes from a number of mechanisms, which include the use of
multiple promoters, alternative splicing, posttranslational modifications, heteromeric
assembly of different principal subunits, and interaction with accessory proteins5).

Fig. 2

Three dimensional models depicting voltage-gated sodium channels in 3 different states.

Go to:

Channelopathies in the nervous system

Ion channels are fundamental in neuronal signaling and thus, channelopathies can be found in
a large and growing number of nervous system disorders (Table 1). Among the first
genetically characterized and best-understood channelopathies are those that lead to primary
skeletal muscle disorders. These muscle disorders exhibit a clinical spectrum ranging from
myotonia (muscle hyperexcitability) to flaccid paralysis (muscle hypoexcitability) (Fig. 3).
Patients with myotonia congenita present with attacks of extreme muscle stiffness because of
delayed relaxation caused by sustained electrical activities in muscle. Both the dominant
(Thomsen disease) and the recessive (Becker disease) types of the disease are caused by loss-
of-function mutations in a single gene, CLCN1, which encodes the skeletal muscle chloride
channel, ClC-1. ClC-1 channels stabilize the resting membrane potential and contribute to
membrane repolarization after action potentials in skeletal muscle cells. When action
potentials are elicited, potassium ions flow out of the cell and into the extracellular fluid and
the transverse tubular system. According to the Nernst equation, the membrane tends to
depolarize as extracellular potassium levels rise. Functional loss of ClC-1 channels reduces
the inward chloride current required to compensate for the depolarization induced by
potassium accumulation in the transverse tubules, thus resulting in spontaneous repetitive
firing of action potentials and a slower rate of repolarization7).

Fig. 3

Diagram showing a clinical spectrum of muscle channelopathies ranging from myotonia to flaccid
paralysis.

Table 1
Nervous system channelopathies

Open in a separate window

Nomenclature is based on the OMIM and the current report of the International League Against Epilepsy
Commission6).

Hyperkalemic periodic paralysis is an autosomal-dominant disease characterized by recurrent

attacks of muscle weakness and mild myotonia with concomitant transient hyperkalemia. The
symptoms usually last for minutes to hours and are triggered by fasting, ingestion of
potassium-containing foods, or vigorous exercise. Transient normokalemia, or even
hypokalemia, can be measured during attacks, thus making the disease occasionally
challenging to diagnose8). Gain-of-function mutations in the skeletal muscle voltage-gated
sodium channel gene, SCN4A, impair channel inactivation and cause a persistent inward
sodium current, which leads to increased membrane excitability and myotonia or reduced
excitability with flaccid paralysis depending on the degree of membrane depolarization. Mild
membrane depolarization allows wild-type sodium channels to oscillate between recovery
from inactivation and reactivation by mutant channels, which results in the repetitive action-
potential firing that can lead to myotonia. More severe depolarization inactivates most
sodium channels and causes membrane inexcitability and flaccid paralysis7). Prolonged
membrane depolarization enhances the activity of voltage-gated potassium channels, which
amplifies potassium efflux from muscle cells and thereby increases in serum potassium
levels9). Allelic disorders with certain phenotypes overlapping those of hyperkalemic
periodic paralysis are potassium-aggravated myotonia and paramyotonia congenita, in which
mutations in SCN4A result in a similar gain-of-channel function as described above. Exercise
worsens muscle stiffness in paramyotonia congenita, whereas classical myotonia is alleviated
by exercise (hence paradoxical myotonia or paramyotonia).
Hypokalemic periodic paralysis is the most common form of periodic paralysis and the
majority of the cases are caused by mutations in the skeletal muscle voltage-gated calcium
channel gene, CACNA1S, or the sodium channel gene, SCN4A10). Being located at the
hypoexcitable end of the spectrum of muscle channelopathies, myotonia is not detected in
this disease. The duration of paralytic attacks is longer than that in hyperkalemic periodic
paralysis (usually for hours and sometimes days). Although respiratory and cardiac muscles
generally remain unaffected in hypokalemic periodic paralysis, life-threatening respiratory
insufficiency and cardiac arrhythmias have been reported in and out of the country10-12).
The mutant channels responsible for hypokalemic periodic paralysis have been known to
generate an inward cation leakage current (referred to as the gating-pore current), which
renders muscle fibers of patients susceptible to aberrant depolarization in response to low
extracellular potassium levels13,14). Alterations in the expression, subcellular localization,
and/or kinetics of non-mutated potassium channels, which reduce outward potassium
currents, have been implicated in the development of hypokalemia as well as pathological
depolarization15-17). The reason why potassium channels are affected by mutations in
the CACNA1S or SCN4A gene has long remained elusive. However, given that skeletal
muscle fibers from patients with hypokalemic periodic paralysis have been found to possess
higher intracellular calcium levels than normal cells17), it now appears that calcium-activated
potassium channels hold the key to this conundrum. Indeed, we have recently identified
altered subcellular distribution of a calcium-activated potassium channel in skeletal muscle
cells of patients with hypokalemic periodic paralysis (in preparation).
Andersen-Tawil syndrome is another example of channelopathies that exhibits dyskalemic
(hyper- or, more typically, hypo-kalemic) periodic paralysis together with characteristic
dysmorphic features (e.g., craniofacial, dental, and skeletal anomalies) and cardiac
arrhythmias by mutations in an inwardly-rectifying potassium channel, Kir2.1. Kir2.1
stabilizes the resting membrane potential in cardiac and skeletal muscle cells and is
responsible for terminating the repolarization phase of the cardiac action potential. Loss-of-
function mutations that alter the kinetics or membrane trafficking of Kir2.1 channels result in
sustained depolarization and delayed cardiac repolarization with an increased risk of
arrhythmia in Andersen-Tawil syndrome18).
Congenital myasthenic syndrome is a heterogeneous group of genetic disorders of the
neuromuscular junction that can arise from presynaptic, synaptic, or postsynaptic defects.
Most of the defects are postsynaptic, with the majority of these being caused by mutations in
the muscle nicotinic acetylcholine receptor (nAChR), a ligand-gated non-selective cation
channel. Activation of nAChRs by acetylcholine released from motor nerve terminals causes
sodium influx into muscle cells, which induces cell membrane depolarization and the
subsequent cytosolic release of calcium from the sarcoplasmic reticulum (SR) that is required
for muscle contraction. Thus, defects in nAChRs lead to the failure of synaptic transmission
at the neuromuscular junction and the consequent symptoms of congenital myasthenic
syndrome, which include fatigable weakness of ocular, bulbar, and limb muscles occurring
shortly after birth or in early childhood. Decreased nAChR activity can also result from
defective channel assembly caused by mutations in rapsyn (receptor-associated protein of the
synapse) or MuSK (muscle-specific kinase)19). Mutations in nAChRs can also cause
multiple pterygium syndromes comprising a group of disorders with multiple congenital
anomalies, suggesting that the nAChR is vital for organogenesis as well as neuromuscular
signal transduction. The phenotypic features of congenital myasthenic syndrome are similar
to those of myasthenia gravis, but congenital myasthenic syndrome is not an autoimmune
disease. Neurological channelopathies with an autoimmune etiology will be discussed in the
section on the immune system.
Channelopathies that primarily affect neurons include certain types of epilepsy, ataxia,
migraine, hyperekplexia, blindness, deafness, and peripheral pain syndromes. Generalized
epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome that displays a
broad spectrum of clinical phenotypes ranging from classical febrile seizures to Dravet
syndrome20). Dravet syndrome (also known as severe myoclonic epilepsy of infancy) is the
most severe form that results from mutations in a voltage-gated sodium channel
gene, SCN1A, or a γ-aminobutyric acid (GABA) receptor gene, GABRG221). Patients with
Dravet syndrome suffer from refractory seizures, ataxia, and severe developmental delay with
poor outcomes. The Nav1.1 channel, which is encoded by SCN1A, is one of nine α subtypes
(Nav1.1-Nav1.9) of voltage-gated sodium channels and this subtype is preferentially
expressed in GABAergic neurons. The GABAA receptor, which is encoded by GABRG2, is
the major inhibitory neurotransmitter receptor in the central nervous system (CNS).
Dysfunction of Nav1.1 channels or GABAA receptors can lead to reduced excitability of
GABAergic neurons, thus resulting in brain hyperexcitability in patients with Dravet
syndrome. A correlation between an increase in the severity of Nav1.1 dysfunction and the
phenotypic severity in the GEFS+ spectrum has been proposed: mild impairment causes
febrile seizures and severe defect leads to Dravet syndrome20). Mutations in
GABAA receptors have also been identified in other types of epilepsy, such as juvenile
myoclonic epilepsy and childhood absence epilepsy22-25).
Other examples of allelic channelopathies in the CNS include familial hemiplegic migraine
type 1 (FHM1), episodic ataxia type 2 (EA2), and spinocerebellar ataxia type 6 (SCA6), each
of which is associated with different mutations in the same gene, CACNA1A, that encodes the
pore-forming α1 subunit of the P/Q type voltage-gated calcium channel, Cav2.1. Mutations
responsible for FHM1 produce gain-of-function effects on Cav2.1 channels, which increase
channel activity, synaptic transmission, and susceptibility to cortical spreading depression26),
whereas the allelic mutations responsible for EA2 induce a loss-of-channel function, which
results in decreased calcium currents through Cav2.127). Cav2.1 is highly expressed in
cerebellar Purkinje cells, in which the channel mediates neurotransmitter release. Reduced
Cav2.1 channel activity can lead to a decrease in output signals from Purkinje cells and
thereby contributes to cerebellar dysfunction in EA2. SCA6 is caused by CAG repeat
expansions in CACNA1A that confer a toxic gain-of-function effect: mutant Cav2.1 channels
are incompletely degraded and form insoluble aggregates and inclusion bodies within
Purkinje cells28).
Familial paroxysmal dyskinesias, which include paroxysmal kinesigenic dyskinesia,
paroxysmal nonkinesigenic dyskinesia, paroxysmal exertion-induced dyskinesia, and
paroxysmal hypnogenic dyskinesia, are an emerging group of channelopathies. Paroxysmal
hypnogenic dyskinesia, which is also referred to as autosomal-dominant nocturnal frontal
lobe epilepsy in certain cases, is a partial epilepsy that is characterized by brief seizures
during sleep. The disease has been associated with mutations in neuronal nAChR genes
(CHRNA2, CHRNA4, and CHRNB2) and a calcium-activated potassium channel gene
(KCNT1)29). Mutations in neuronal nAChR genes result in either increased acetylcholine
sensitivity or reduced calcium dependence of the receptor response30).
Hereditary hyperekplexia, also called startle disease or stiff baby syndrome, is one of the first
ligand-gated channelopathies to be characterized; this disease is caused by mutations that
alter the kinetics or membrane density of the heteromeric α1β glycine receptor chloride
channel. Glycine is a major inhibitory neurotransmitter in the CNS, and glycine receptors are
predominantly expressed by the inhibitory interneurons of the spinal cord and brainstem.
Impaired function of glycine receptors or associated proteins manifests the characteristic
clinical symptoms of hyperekplexia, including exaggerated startle responses and marked
hypertonia in response to sudden tactile or auditory stimuli. The onset of the initial episode
occurs as early as in the neonatal period and the symptoms tend to resolve with age31).
A multifaceted syndrome called EAST (epilepsy, ataxia, sensorineural deafness, and
tubulopathy) or SeSAME (seizures, sensorineural deafness, ataxia, mental retardation, and
electrolyte imbalance) was recently described by two independent groups32,33). This
syndrome is caused by loss-of-function mutations in an inwardly-rectifying potassium
channel, Kir4.1, which has a pivotal role in glial function, neuronal excitability, and systemic
potassium homeostasis33).
Pain channelopathies are another emerging class of neurological disorders in which
dysfunctional channels represent potential pharmaceutical targets. A number of different
channels are widely expressed in nociceptive neurons, and deficits in channels have been
found to be associated with diverse steps of defective pain pathways. Familial episodic pain
syndrome, primary erythermalgia (or erythromelalgia), and paroxysmal extreme pain
disorder, all of which typically begin in childhood or infancy, are known to result from gain-
of-function mutations of a voltage-gated sodium channel, Nav1.7, or a transient receptor
potential (TRP) cation channel, TRPA1, that cause abnormal electrical firing, thus rendering
neurons hyperexcitable34). Conversely, loss-of-function mutations of Nav1.7 lead to
congenital indifference to pain35). Hereditary motor and sensory neuropathy type IIC (also
known as Charcot-Marie-Tooth disease type 2C), congenital distal spinal muscular atrophy,
and scapuloperoneal spinal muscular atrophy are allelic disorders with overlapping
phenotypes derived from mutations in a TRP cation channel gene, TRPV4. TRPV4 mutations
have also been implicated in skeletal dysplasias that include metatropic dysplasia,
spondylometaphyseal dysplasia Kozlowski type, brachyolmia type 3, spondyloepiphyseal
dysplasia Maroteaux type, familial digital arthropathy with brachydactyly, and
parastremmatic dysplasia36). TRP channels are non-selective cation channels that play
critical roles in intracellular signaling and homeostasis of calcium and/or magnesium.
Mammalian TRP channels belong to six subfamilies: TRP canonical (TRPC), TRP vanilloid
(TRPV), TRP melastatin (TRPM), TRP ankyrin (TRPA), TRP polycystin (TRPP), and TRP
mucolipin (TRPML). Mutations of the TRPML1 channel (also termed mucolipin 1), a
member of the TRPML subfamily, cause mucolipidosis type IV, an autosomal-recessive
neurodegenerative lysosomal storage disorder that is characterized by severe psychomotor
delay and visual impairment worsening over time. Loss-of-function mutations of TRPML1
channels have been shown to disturb calcium permeability and lysosomal acidification in
affected cells37), but the precise pathophysiological mechanism underlying the clinical
manifestations of the mutations remains to be elucidated.
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Channelopathies in the cardiovascular system

Cardiac action potentials are generated from a delicate balance of several ionic
currents38) (Fig. 4). When this balance is disturbed by ion channel dysfunction, life-
threatening cardiac arrhythmias may occur. Cardiac channelopathies are likely responsible for
approximately half the sudden arrhythmic death syndrome cases39)and for at least one out of
five sudden infant death syndrome cases40). Mutations in calcium, sodium, potassium, and
TRP channel genes have been identified to cause a variety of cardiac arrhythmic disorders
(Table 2), and polymorphisms have been suggested to be risk factors41).
 Open in a separate window

Fig. 4

Major ionic currents that contribute to the cardiac myocyte action potential in relation to the surface
electrocardiogram. Ito1, transient outward potassium current; ICa,L, L-type inward calcium current; IKr,
rapid delayed-rectifier potassium current; IKs, slow delayed-rectifier potassium current; IK1, inwardly-
rectifying potassium current.

Table 2
Cardiac channelopathies

Alternative names are in parentheses.

The first genetically identified cardiac disorder is congenital long QT syndrome (LQTS).
Congenital LQTS, the most common form of cardiac channelopathy, is characterized by
prolonged ventricular repolarization, predisposing to a high risk of ventricular
tachyarrhythmias (e.g., torsade de pointes), syncope, and sudden cardiac death. To date, 13
types of LQTS have been linked to mutations in genes that encode ion channels or associated
proteins42). LQTS can also be induced by acquired factors, such as acquired diseases, drugs,
and electrolyte abnormalities (hypocalcemia, hypokalemia, and hypomagnesemia). Loss-of-
function mutations of potassium channel genes (KCNQ1, KCNH2, KCNE1, KCNE2, KCNJ2,
and KCNJ5) in LQTS reduce the repolarizing currents (IKr, IKs, and IKir) required to terminate
the cardiac action potential, leading to a prolongation of the QT interval. Gain-of-function
mutations in calcium channel (CACNA1C) and sodium channel genes (SCN5A and SCN4B) in
LQTS cause delayed channel closing and inactivation, responsible for prolonged inward
currents and depolarization with a resultant increased QT interval. By contrast, loss-of-
function mutations in calcium channel genes (CACNA1C, CACNB2, and CACNA2D1) and
gain-of-function mutations in potassium channel genes (KCNH2, KCNQ1, and KCNJ2)
enhance repolarization, resulting in the abnormal shortening of the cardiac action potential in
short QT syndrome43). Loss-of-function mutations in sodium channel genes have been
identified to cause Brugada syndrome, familial atrial fibrillation, sick sinus syndrome,
familial heart block, and atrial standstill44). It is noteworthy that both gain-of-function
mutations (which decrease action potential duration) and loss-of-function mutations (which
increase action potential duration) in potassium channel genes predispose to atrial
fibrillation45). This demonstrates a precise atrial electrophysiological balance in which minor
disturbances in either direction can cause atrial fibrillation.
Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels contribute to the
pacemaker current (If) that is responsible for generating and regulating heart rhythm. Loss-of-
function mutations of HCN4, the major HCN channel subunit in pacemaker cells, cause
bradycardia46). Moreover, cardiac tachyarrhythmias have also been shown to be associated
with dysfunctional HCN4 channels47,48). Although the pathogenic role of HCN channel
mutations in cardiac tachyarrhythmias remains to be determined, one of the clues can be
found in the suggested function of If in preventing bradycardia-induced ventricular
arrhythmias by inhibiting early after-depolarization48).
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterized by the
development of bidirectional polymorphic ventricular tachycardia upon exposure to
adrenergic stimulation in an otherwise normal heart. Experiencing emotional or physical
stress can induce dizziness, syncope, and/or sudden cardiac death in patients with CPVT.
Manifestations occur in childhood or adolescence, with the average onset at age 7-9 years49).
CPVT can be inherited in an autosomal-dominant or recessive manner. The autosomal-
dominant form of CPVT (CPVT type 1) is caused by gain-of-function mutations in RYR2, the
gene that encodes the cardiac ryanodine receptor 2 (RYR2), a major component of RYR2
channels. RYR2 channels mediate calcium release from the SR into the cytosol upon cell
membrane depolarization. Defective closure of RYR2 channels results in intracellular
calcium leakage from the SR, which leads to increased potential for delayed after-
depolarizations and subsequent ventricular tachycardia50).
Go to:

Channelopathies in the respiratory system

There are a number of ion channels expressed in airway cells that have been evaluated, the
function of which may contribute to pathogenic conditions, but channelopathies in the
respiratory system may not represent common pathologies in Asian populations. This is
partly because cystic fibrosis (CF)-the first identified and the most common channelopathy
that affects the respiratory system in Western populations-is rarely diagnosed in Asian people.
CF is the most prevalent genetic disorder in the Caucasian population, with an incidence of
approximately 1 in 2,500 live births51). Patients with CF are vulnerable to severe and chronic
pulmonary infections and inflammation, which lead to irreversible airway damage and
respiratory failure in most cases. CF exhibits a broad spectrum of symptoms: mild forms can
be nearly asymptomatic, being diagnosed in middle age as affecting a single organ, whereas
severe forms manifest not only in airways but also in digestive and reproductive systems,
with some of the symptoms occurring as early as in the prenatal period51).
CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator
(CFTR) gene. CFTR functions as a chloride channel in the apical membrane of epithelia,
where the channel controls the volume of liquid on epithelial surfaces by secreting chloride
and inhibiting sodium absorption. More than 1,600 mutations in the CFTR gene have been
identified51). These mutations, which produce varying functional effects on CFTR, are
considered to cause an abnormal transepithelial flux of chloride and sodium, which is
accompanied by the passive flow of water and results in liquid depletion on the epithelial
surface layer. Depletion of the airway surface liquid, which impairs ciliary function and
mucociliary clearance, may lead to recurrent pulmonary infections and chronic inflammation
in CF patients52). Increased knowledge of the molecular pathophysiological mechanism
underlying CF has led to a variety of active clinical trials to identify targeted treatments, such
as channel-specific drugs and gene therapy.
Deficiencies in ion transport have also been implicated in the pathophysiology of asthma. Of
particular interest is the role of ion channels in the intracellular calcium homeostasis in
asthmatic airways, which may contribute to smooth muscle contraction in the short term and
airway remodeling in the long term53). A rise in the cytosolic calcium level ([Ca2+]c) activates
almost all cells of the lung, including epithelial, endothelial, and smooth muscle cells,
immune cells, and vagal neurons54). Increasing evidence indicates that an altered control of
intracellular calcium homeostasis may be the fundamental biochemical basis of asthma.
Several TRP channels, which play a critical role in cellular calcium homeostasis, have been
associated with bronchial hyper-responsiveness and airway remodeling55-59). Multiple
independent genome-wide association studies of childhood asthma revealed a consistent and
strong association with ORMDL3, a gene that codes for an endoplasmic reticulum (ER)
protein that regulates ER-mediated calcium homeostasis60). Furthermore, reduced expression
of sarco/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2) has been demonstrated to underlie
the abnormal secretory and hyperproliferative phenotype of airway smooth muscle (ASM) in
asthma. After ASM cells are activated by an elevation of [Ca2+]c, SERCA2 reuptakes cytosolic
calcium into the SR to restore normal [Ca2+]c. Thus, decreased expression and activity of
SERCA2 cause a sustained increase in [Ca2+]c, which leads to slower return to the resting state
of ASM cells in asthma61).
Respiratory symptoms can also develop in channelopathies associated with other systems,
such as life-threatening respiratory insufficiency in hypokalemic periodic paralysis11),
congenital myasthenic syndrome62), and long QT syndrome63). Respiratory manifestations
typically occur when symptoms of the diseases are severe. Appropriate management of
channelopathies thus often requires interdisciplinary approaches.
Go to:

Channelopathies in the endocrine system

Electrical activity plays an essential role in insulin secretion from the pancreatic β cell64).
Endocrine cells, like neurons and other excitable cells, use the electrical activity of ion
channels to maintain or regulate various physiological functions. Defects in ion channels
have been increasingly shown to cause endocrine disorders, including those not generally
thought of as channelopathies (Table 3).

Table 3
Endocrine channelopathies

The adenosine triphosphate-sensitive potassium (KATP) channel is involved in a wide spectrum

of insulin secretory disorders ranging from neonatal diabetes mellitus to familial
hyperinsulinemic hypoglycemia (also known as congenital hyperinsulinism). The
KATP channel is a hetero-octameric complex of 4 inwardly-rectifying potassium channel
subunits, Kir6.x, that form the pore, and 4 sulfonylurea receptors, SURx, that regulate
channel function. KATP channels are found in various organs and/or tissues, such as the
pancreas, brain, heart, smooth muscle, and skeletal muscle16,65). In pancreatic β cells, the
KATP channel is composed of Kir6.2 and SUR1 subunits and functions as a key regulator of
insulin release. ATP and phosphatidylinositol 4,5-bisphosphate directly affect the Kir6.2
subunit, whereas sulfonylurea and Mg-nucleotides control the channel activity through the
SUR1 subunit. The intracellular [ATP]/[ADP] ratio primarily determines KATPchannel activity.
An increase in glucose metabolism leads to elevated intracellular [ATP], and the binding of
ATP to Kir6.2 closes KATP channels, which results in membrane depolarization, calcium
influx, and insulin secretion. Conversely, when glucose levels are low, Mg-ADP opens
KATP channels through the SUR1 subunit, inducing potassium efflux, membrane
hyperpolarization, and reduced excitability of pancreatic β cells65). Thus, the KATPchannel
couples metabolism to electrical activity.
Increased KATP channel activity in pancreatic β cells reduces insulin secretion, whereas
decreased channel activity increases insulin secretion. Therefore, defects in KATP channel
activity can lead to either a diabetic or a hyperinsulinemic state. Gain-of-function mutations
in ABCC8 and KCNJ11, the genes that encode the SUR1 and Kir6.2 subunits of the
KATP channel, respectively, keep the channels open and cause neonatal diabetes mellitus. By
contrast, loss-of-function mutations in the same genes close KATPchannels and cause
hyperinsulinemic hypoglycemia. The mechanism underlying the gain-of-function mutations
in neonatal diabetes mellitus is either a reduced sensitivity to the inhibitory action of ATP or
an increased sensitivity to the stimulatory action of ADP66). Neonatal diabetes mellitus is
usually diagnosed within the first 6 months of life. Transient neonatal diabetes mellitus is
differentiated from permanent neonatal diabetes mellitus based on its remission typically
within 18 months, with a possible relapse during adolescence. Sulfonylureas act directly on
the SUR1 subunit in an ATP-independent manner and can inactivate KATP channels even when
mutations are present. Therefore, sulfonylureas provide glycemic control that is as good, or
better, than that achieved with insulin therapy in most cases of neonatal diabetes
mellitus66,67).
The extent of KATP channel activity has been demonstrated to be correlated with the severity of
insulin secretory disorders68) (Fig. 5). Complete loss-of-function mutations of KATP channels
lead to a severe phenotype of familial hyperinsulinemic hypoglycemia, whereas mutations
disrupting channel function only partially result in a less severe phenotype, as in leucine-
induced hypoglycemia of infancy. Similarly, the most potent gain-of-function mutations of
KATP channels underlie the triad of developmental delay, epilepsy, and neonatal diabetes
(DEND) syndrome, the most severe form of diabetic phenotypes69). DEND syndrome is a
multi-organ syndromic, permanent form of neonatal diabetes mellitus in which patients
exhibit, besides diabetes mellitus, developmental delay, epilepsy, and muscle weakness.
Kir6.2 and SUR1 subunits are expressed in extrapancreatic tissues, including the brain
(Kir6.2 and SUR1) and skeletal muscle (Kir6.2), which accounts for the neurological
symptoms triggered by the overactive KATP channels in DEND syndrome. Mutations that
result in smaller functional gain of KATP channels produce a milder phenotype, as in transient
neonatal diabetes mellitus68).

Fig. 5

Diagram illustrating the relationship between KATP channel activity and insulin secretory disorders.
Type 2 diabetes is widely recognized to be a polygenic disorder that is associated with
polymorphisms in many distinct genes; the combined effect of these polymorphisms
contributes to the development of the disease, together with environmental factors, age, and
obesity. A single nucleotide polymorphism at codon 23 of the KCNJ11 gene, which causes a
glutamic acid-to-lysine substitution (E23K) in Kir6.2, has been strongly associated with an
increased susceptibility to type 2 diabetes across various ethnic groups, albeit the underlying
pathogenic mechanism has yet to be defined69). The E23K variant may possibly cause a
reduction in the ATP sensitivity of KATP channels, but the functional effects of individual
polymorphisms linked to polygenic disorders are considered to be small.
Thyrotoxic periodic paralysis (TPP) is a sporadic disorder characterized by episodic attacks
of flaccid paralysis, hypokalemia, and hyperthyroidism. TPP, which is clinically similar to
familial hypokalemic periodic paralysis, is considered as a potentially life-threatening
condition because of hypokalemia-induced cardiopulmonary compromise. The pathogenesis
of TPP has long been attributed to increased activity of Na+-K+ ATPase stimulated by elevated
levels of thyroid hormone, catecholamines, and insulin. Recently, mutations in KCNJ18, the
gene that codes for Kir2.6 channels, have been identified in certain TPP patients70). Kir2.6 is
an inwardly-rectifying potassium channel that mediates the potassium efflux from skeletal
muscle cells. It has been reported that the outward Kir current is low in intercostal muscle
fibers of patients with TPP17). Accumulating evidence suggests that loss of Kir2.6 function,
together with increased activity of Na+-K+ATPase, contributes to the development of
hypokalemia and paralysis in patients with TPP. Catecholamines and insulin not only
stimulate Na+-K+ ATPase but also inhibit Kir channels71). KCNJ18 has a thyroid hormone
responsive element in its promoter region, and the expression of this gene is regulated by
thyroid hormones at both transcriptional and post-translational levels70). Therefore, the
genetic susceptibility resulting from mutations in KCNJ18, combined with thyrotoxicosis, is
considered to predispose certain TPP patients to recurrent attacks of hypokalemic periodic
paralysis. Mutations in other channel genes associated with the TPP phenotype may be found
in patients without KCNJ18mutations.
Primary aldosteronism (PA) is the most frequent cause of secondary hypertension. Patients
with PA exhibit hypertension, high plasma aldosterone levels, low plasma renin activity, and
varying degrees of hypokalemia and metabolic alkalosis. Aldosterone-producing adrenal
adenoma and adrenal hyperplasia are common causes of PA. Recently, mutations in KCNJ5,
the gene that encodes an inwardly-rectifying potassium channel, Kir3.4, have been shown to
be involved in both inherited and acquired PA. Gain-of-function effects of Kir3.4 mutations
have been suggested to result in a loss of channel selectivity for potassium and increased
sodium conductance, which induce the membrane depolarization responsible for aldosterone
secretion and cell proliferation in the adrenal cortex72).
Osteopetrosis is an inherited metabolic bone disease that is characterized by an increased
skeletal mass, which is caused by the impaired bone resorption that results from a lack or
dysfunction of osteoclasts. Together, osteopetrosis and osteoporosis constitute major human
skeletal pathologies caused by the imbalance between bone formation and resorption. Loss-
of-function mutations in CLCN7, which encodes the voltage-gated chloride channel 7 (ClC-
7), cause autosomal-dominant osteopetrosis type 2 and autosomal-recessive osteopetrosis
type 4. Loss-of-function mutations in OSTM1, which codes for the auxiliary β subunit of the
ClC-7 channel, give rise to autosomal-recessive osteopetrosis type 5. ClC-7 channels provide
the chloride conductance required for extracellular acidification, an essential process for bone
resorption by osteoclasts73). Studies have been performed to identify specific ClC-7 ligands
that allow selective modulation of ClC-7 channel activity, which can be used to treat
osteopetrosis (ClC-7 openers) and osteoporosis (ClC-7 blockers)74).
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Channelopathies in the urinary system

In the urinary system, there are well-characterized channelopathies affecting the renal tubular
system (Table 4). With most of these channelopathies, abnormal endocrinological findings
have been reported, but the etiologic origin places these diseases in this category.

Table 4
Renal channelopathies
Mutations in the renal epithelial sodium channel (ENaC), a heteromeric complex of 3
subunits (α, β, and γ), result in either hereditary hypotension or hypertension. ENaC is
located in the apical membrane of epithelial cells predominantly in the kidney, colon, and
lung, and the channel plays a major role in sodium reabsorption. Loss-of-function mutations
in the α, β, and γ subunits of ENaC cause autosomal-recessive pseudohypoaldosteronism type
1 that is characterized by marked hypotension, hyponatremia, hyperkalemia, metabolic
acidosis, and failure to thrive during the neonatal period. Plasma renin and aldosterone levels
are grossly elevated, reflecting a peripheral resistance75). This is a potentially lethal salt-
losing disorder in neonates and infants, which persists into adulthood and thus requires
lifelong treatment. By contrast, gain-of-function mutations in the β and γ subunits of ENaC
result in Liddle syndrome, an autosomal-dominant disorder characterized by hypertension,
hypokalemia, and metabolic alkalosis. These mutations enhance ENaC activity by either
increasing open probability or increasing channel number in the apical membrane. The
overactivity of ENaC leads to excessive sodium reabsorption in the distal part of the renal
tubule. Plasma renin and aldosterone levels are low76).
Nephrogenic diabetes insipidus (NDI), which can be inherited or acquired and is caused by
an impaired response of the kidney to the antidiuretic hormone (ADH), results in a decreased
ability to concentrate urine, which leads to polyuria and compensatory polydipsia. Over 50
mutations in AQP2, the gene that encodes the water channel aquaporin 2 (AQP2), have been
identified to cause autosomal-dominant or recessive forms of hereditary NDI. These
mutations affect the function or membrane trafficking of the AQP2. Acquired causes of NDI
include drugs, renal diseases, and electrolyte imbalance (hypokalemia and hypercalcemia),
which have been reported to induce either reduced expression of AQP2 or defective AQP2
trafficking to the apical plasma membrane77).
Bartter syndrome is a clinically and genetically heterogeneous group of salt-wasting
tubulopathies characterized by metabolic alkalosis, hypokalemia, hyperreninemia and
hyperaldosteronemia with varying severity. Bartter syndrome occurs in five types, among
which types 2, 3, and 4 result from mutations in ion channel genes. Bartter syndrome type 2
is caused by loss-of-function mutations in KCNJ1 encoding an inwardly-rectifying potassium
channel, Kir1.1. Kir1.1 is the apical renal outer medullary potassium channel that mediates
potassium secretion from the renal epithelial cells into the tubular lumen, which is essential
for sodium chloride reabsorption by the apical sodium-potassium-chloride cotransporter in
the Henle loop and which also produces the driving force for paracellular absorption of
calcium and magnesium. Patients with Bartter syndrome type 2 uniquely present with initial
transient hyperkalemia in the neonatal period, which is because Kir1.1 is involved in distal
potassium secretion78). Bartter syndrome type 3 results from loss-of-function mutations
in CLCNKB, which codes for kidney chloride channel B (ClC-Kb). On the basolateral
membrane of the renal epithelial cells, chloride exits through at least two chloride channels,
ClC-Ka (in the thick ascending limb) and ClC-Kb (in the thick ascending limb and distal
convoluted tubule). These chloride channels require a β subunit, named barttin, for proper
function and membrane localization. Bartter syndrome type 4A is caused by loss-of-function
mutations in BSND, which encodes barttin. Heteromeric complexes of the chloride channels
(ClC-Ka/ClC-Kb) and barttin are critical for renal salt reabsorption and potassium recycling
in the inner ear. Therefore, Bartter syndrome type 4A caused by barttin dysfunction and
Bartter syndrome type 4B caused by loss-of-function of both ClC-Ka and ClC-Kb show
sensorineural deafness as well as renal salt-wasting tubulopathy78).
Familial hypomagnesemia with secondary hypocalcemia (HSH) is an autosomal-recessive
disorder resulting from mutations in TRPM6, the gene that encodes the TRPM6 channel.
Patients present with severe hypomagnesemia and hypocalcemia, which lead to generalized
seizures and tetany shortly after birth, typically during the first month of life. If the disease is
left untreated, most patients die or suffer severe neurological damage. Hypocalcemia is
secondary to parathyroid failure and parathyroid hormone resistance due to chronic and
severe magnesium deficiency. TRPM6 is a magnesium- and calcium-permeable cation
channel that is predominantly expressed in intestinal epithelia and kidney tubules. Loss-of-
function mutations in TRPM6, which inactivate TRPM6 channel function, have been reported
to cause defective intestinal absorption of magnesium and abnormal renal loss in HSH79).
Gain-of-function mutations in TRPC6 channels have been identified to cause an autosomal-
dominant form of focal segmental glomerulosclerosis (FSGS), FSGS type 2, which is
characterized by proteinuria and progressive decline in renal function. TRPC6, which plays a
crucial role in intracellular calcium signaling, is expressed in the glomerular epithelial cells
(podocytes) and associates with nephrin and podocin, key components of the glomerular slit
diaphragm. TRPC6 activity at the slit diaphragm is considered critical for regulating podocyte
structure and function. Foot processes of podocytes and the slit diaphragm form an essential
part of the glomerular permeability barrier. In FSGS, the loss of the permeability barrier's
integrity results in proteinuria. Dominant gain-of-function effects of TRPC6 mutations have
been demonstrated to increase channel activity and calcium influx by altering the channel's
gating property or enhancing channel density in the membrane80). Intracellular calcium
overload is thought to induce podocyte injury and dysfunction, disrupting the integrity of the
permeability barrier.
Autosomal-dominant polycystic kidney disease (ADPKD), the most common inherited
kidney disease, results from mutations in polycystin 1 or 2. Polycystin 2 is the TRPP2
channel, a member of the TRP family, which mediates intracellular calcium signaling and
regulates cell growth and differentiation. TRPP2 channels localize to the cilia of renal
epithelial cells, where they function as mechano-sensors that allow calcium influx in response
to changes in fluid flow. Mutations altering the subcellular localization and/or function of
TRPP2 have been described in approximately 15% of patients with ADPKD (designated as
PKD type 2). Most of these mutations have gain-of-function effects on TRPP2, which
increase channel activity and calcium influx. Enhanced calcium influx in affected cells may
lead to impaired cell growth and differentiation, which predispose to tubular cyst
formation81). Although the precise mechanism by which increased calcium currents
contribute to pathologic manifestations of this disease remains unknown, one of the clues
may be found in a recent demonstration that impaired activity and abnormal subcellular
localization of non-mutated TRPV4 channels contribute to renal cystogenesis in a rat model
of autosomal-recessive polycystic kidney disease82).
Go to:

Channelopathies in the immune system

Antibodies against ion channels and associated proteins expressed on the surface of neurons
or muscle cells have been implicated in a variety of neurological pathologies ranging from
myasthenia gravis (MG) to certain forms of encephalitis (Table 5). Typical paraneoplastic
antibodies generally target intracellular antigens and are not likely pathogenic. However,
antibodies responsible for autoimmune channelopathies, often arising under paraneoplastic
conditions, directly affect the kinetics and/or membrane density of ion channels or damage
cells expressing the channels, which accounts for the favorable response shown by most
patients to immunotherapies. Autoimmune channelopathies have been increasingly found in
all age group84).

Table 5
Autoimmune channelopathies

LGI1, leucine-rich glioma inactivated protein; CASPR2, contactin-associated protein 2; SCLC, small cell lung
cancer.

MG is the prototype of autoimmune channelopathies. Most MG patients have autoantibodies

against muscle nAChRs expressed on the postsynaptic membrane of muscle cells. These
antibodies reduce functional nAChRs by direct block of function, complement-mediated
damage to the cell membrane, and increased receptor endocytosis and degradation (a process
referred to as antigenic modulation)85). Antibodies against MuSK, which is required for
nAChR clustering, have been identified in a subset of MG patients without nAChR
antibodies, reminiscent of the pathogenesis of certain cases of congenital myasthenic
syndrome that is a clinically similar but distinct disorder (see p. 5).
Autoimmune autonomic ganglionopathy (AAG, also called autoimmune autonomic
neuropathy) is an acquired form of autonomic neuropathies in which autoantibodies bind to
the α3 subunit of the neuronal nAChR located in ganglionic synapses of sympathetic,
parasympathetic, and enteric nervous systems. Patients present with symptoms of diffuse
autonomic failure, such as orthostatic hypotension, hypohidrosis, fixed and dilated pupils, dry
eyes and mouth, urinary retention, and constipation or diarrhea. Ganglionic nAChRs mediate
fast synaptic transmission in autonomic ganglia. Autoantibodies against ganglionic nAChRs
impair cholinergic synaptic transmission, leading to the consequent symptoms of autonomic
failure in AAG86).
Lambert-Eaton myasthenic syndrome (LEMS) is a presynaptic disorder that is characterized
by proximal muscle weakness, autonomic dysfunction, and areflexia. LEMS results from an
autoimmune process in which autoantibodies react against presynaptic P/Q type voltage-
gated calcium channels (VGCCs). Presynaptic VGCCs are involved in the depolarization-
induced calcium influx that causes neurotransmitter release from nerve terminals.
Autoantibodies against VGCCs are known to deplete the channels, reduce calcium influx, and
cause a reduction of acetylcholine release. Approximately 50% of patients with LEMS have
an underlying malignancy, such as small cell lung cancer (SCLC) in which SCLC cells
express VGCCs on their surface, suggesting a cross reactivity of antibodies with presynaptic
VGCCs. Accumulating evidence indicates that VGCCs also play a pathogenic role in certain
patients with paraneoplastic cerebellar degeneration associated with SCLC87).
Neuromyotonia (NMT) is a form of peripheral nerve hyperexcitability that is characterized by
muscle fasciculations, cramps, pseudomyotonia (slow relaxation following muscle
contraction), hyperhidrosis, and variable paraesthesias. NMT can be inherited or acquired.
Evidence of a channelopathy can be found in one type of acquired NMT, called Isaac
syndrome, in which autoantibodies are directed against α-dendrotoxin (α-DTX)-sensitive
voltage-gated potassium channel (VGKC) complexes expressed in motor and sensory nerves.
The α-DTX-sensitive VGKC complex consists of a VGKC (a Kv1 tetramer with auxiliary β
subunits) and associated proteins, such as leucine-rich glioma inactivated protein 1 (LGI1),
contactin-associated protein 2 (CASPR2), and contactin-288). VGKCs help repolarize
depolarized cells and prevent repetitive discharges. Autoantibodies against components of
VGKC complexes result in loss of functional VGKCs, reduced outward potassium currents,
and spontaneous repetitive firing of action potentials, which leads to peripheral nerve
hyperexcitability and enhanced muscle contraction89). A combination of NMT and CNS
manifestations (e.g., insomnia, confusion, hallucination, delirium, and amnesia) can be
detected in Morvan syndrome, in which most patients have VGKC complex antibodies,
predominantly against CASPR284). Cramp-fasciculation syndrome is another phenotype of
peripheral nerve hyperexcitability that can be caused by VGKC complex antibodies, and this
disease is characterized by the occurrence of severe muscle ache, cramps, and twitching in
otherwise healthy individuals90).
Limbic encephalitis (LE) is the most common CNS syndrome associated with increased
levels of VGKC complex antibodies. LE is characterized by acute or subacute amnesia,
confusion, seizures, and personality change or psychosis, with a high signal in the medial
temporal lobes on MRI (indicating swelling and/or inflammation). Autoantibodies against ion
channels other than VGKC have also been reported in LE patients, including antibodies
against α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR),
GABAB receptor, and N-methyl-D-aspartate receptor (NMDAR)88). LE can arise as a
paraneoplastic syndrome. Most LE patients have antibodies against the LGI1 component of
VGKC complexes and do not usually have a tumor, whereas a small proportion of LE
patients have CASPR2 antibodies and display an increased incidence of thymomas84).
Anti-NMDAR encephalitis is characterized by sequential clinical manifestations that proceed
from psychosis, amnesia, confusion, dysphasia, and seizures into dyskinesias, and autonomic
and breathing instability, typically requiring management in the intensive care unit. Anti-
NMDAR encephalitis is recognized as the most prevalent antibody-associated encephalitis
and the second most common immune-mediated encephalitis after acute disseminated
encephalomyelitis91). A substantial proportion of patients with this disease are children and
young adults with or without an associated tumor. The frequency of underlying tumors
(usually ovarian teratoma) depends on age and sex and is lower in younger patients. Patients
have antibodies against the NMDAR in blood and cerebrospinal fluid and exhibit high
intrathecal synthesis of the antibodies. The NMDAR, a non-selective cation channel, is a
glutamate receptor that modulates excitatory neurotransmission and synaptic plasticity in the
CNS and plays a critical role in memory, learning, mood, and behavior. Anti-NMDAR
antibodies have been demonstrated to lower the membrane density of postsynaptic NMDARs
by enhancing receptor internalization and degradation, which can lead to reduced excitability
of GABAergic neurons expressing NMDARs at high levels and to the deregulation of
excitatory pathways91). In more than 50% of patients with systemic lupus erythematosus
(SLE), autoantibodies that react with NMDARs also cause neurological and psychological
manifestations, which are often described as neuropsychiatric SLE92).
Neuromyelitis optica (NMO) is a severe inflammatory demyelinating disorder that primarily
affects the optic nerves and spinal cord. Patients develop symptoms of optic neuritis and
transverse myelitis, including blindness, paralysis, sensory defects, and bladder dysfunction,
with frequent relapse and increasing disability. Most patients have autoantibodies against
aquaporin-4 (AQP4), the main water channel in the CNS that is predominantly expressed on
astrocytes93). Astrocytes perform many important functions in the CNS, including the
regulation of neurotransmission, immune responses, blood flow, and energy metabolism, and
the maintenance of the blood-brain barrier (BBB)94). Autoantibodies against AQP4 have
been suggested to induce complement-mediated astrocyte damage, local inflammatory
reactions, and BBB disruption. These initial reactions are predicted to lead to oligodendrocyte
injury, demyelination, neuronal damage, and the subsequent clinical manifestations of
NMO93). Alternative underlying mechanisms for the disorder have also been proposed,
including antibody-mediated internalization of AQP4s and glutamate transporters, and
antibody-induced activation of effector cells, such as natural-killer cells, which cause
cytotoxicity in astrocytes95).
Go to:

Future perspectives
The list of channelopathies is expanding so rapidly because of recent advances in our
understanding of the role of ion channels in human physiology and pathophysiology.
Emerging topics regarding potential entries to the list include certain types of cancer96),
leukemia97), psychiatric disorders98), gastrointestinal diseases3), and additional nervous
system disorders99,100). As for disease mechanisms, pathogenic alterations of the
expression, localization, and/or function of non-mutated ion channels or proteins that are not
ion channels may be found in many channelopathies, as exemplified in familial hypokalemic
periodic paralysis and congenital myasthenic syndrome. These mechanisms may provide new
targets and approaches for devising novel therapeutic strategies.
Gap junctions are specialized plasma membrane domains in which arrays of channels mediate
the passage of ions and small molecules between cells. Although gap junction channels have
not yet been classified into specific channel families described in this review, they share ion
channel properties and modulate both electrical and metabolic intercellular communication.
As predicted, dysfunction of gap junction channels causes a wide range of diseases, including
blindness, deafness, hereditary spastic paraplegia, cardiac arrhythmia, X-linked dominant
Charcot-Marie-Tooth disease, certain integumentary disorders, and craniofacial, dental, and
skeletal anomalies. Ongoing research on gap junction physiology may offer novel insights
into the molecular and cellular mechanisms of channelopathies.
Although most channelopathies affect only one or a few organ systems as described herein,
this general theme may not be just because the associated channel subtype has a tissue/organ-
specific expression pattern. For example, AQP4 and TRPC6, which are involved in NMO and
FSGS type 2, respectively, are also expressed in other tissues or organs, such as the kidney
(AQP4) and smooth muscle (TRPC6), in which they do not manifest pathological
phenotypes. It is possible that a milieu or associated protein(s) make ion channels at a
specific location exhibit increased susceptibility to a pathological condition. Better
understanding of the structure and function of ion channels and their related proteins should
elucidate the mechanisms that can provide molecular targets for intervention in the
pathophysiological process of diseases in this rapidly growing field of medicine.
Go to:

Acknowledgements
This work was supported by the 12th Seokcheon Research Award funded by the Korean
Pediatric Society. The author thanks Moon-Yong Park for assistance with illustrations.

Neurological channelopathies
Dysfunctional ion channels may cause many neurological diseases 
Michael R Rose, Consultant and honorary senior lecturer in neurology

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Disorders of ion channels (channelopathies) are increasingly being identified, making this a
rapidly expanding area of neurology. Ion channel function may be controlled by changes in
voltage (voltage gated), chemical interaction (ligand gated), or by mechanical perturbation.
The first disorders recognised as channelopathies were the voltage gated channelopathies
causing inherited muscle diseases: the non-dystrophic myotonias and familial periodic
paralyses. Paramyotonia congenita is due to mutations in the gene coding for the α1 subunit
of the sodium channel, while Thomsen’s disease (autosomal dominant myotonia congenita)
and Becker’s disease (autosomal recessive myotonia congenita) are allelic disorders
associated with mutations in a gene coding for skeletal muscle chloride channel. Familial
hyperkalaemic periodic paralysis is due to mutations in the same sodium channel gene as that
affected in paramyotonia congenita, while familial hypokalaemic periodic paralysis results
from mutations in the gene coding for the α1 subunit of a skeletal muscle calcium channel.1
The first demonstration that channelopathies could affect nerves as well as muscles came in
1995, when researchers discovered that episodic ataxia type 1, a rare autosomal dominant
disease, results from mutations in one of the potassium channel genes.2 The impairment of
potassium channel function, which normally limits nerve excitability, results in the rippling of
the muscles (myokymia) of the face and limbs seen in this disease. Episodic ataxia type 2,
also autosomal dominant, is not associated with myokymia but responds dramatically to
acetazolamide, an unexpected feature it shares with many channelopathies. The suspicion that
it too might be a channelopathy was confirmed when mutations in a gene coding for the α1
subunit of a brain specific calcium channel were found.3 Mutations in this same gene can also
cause familial hemiplegic migraine and spinocerebellar degeneration type 6.4 It is unclear
how different mutations of the same gene can give rise to such different phenotypes. In the
case of myotonia congenita and familial hyperekplexia, point mutations in the same gene can
result in either autosomal recessive or dominant inheritance.
Ligand gated channelopathies that have recently been described include familial startle
disease, which is due to due to mutations of the α1 subunit of the glycine receptor, and
dominant nocturnal frontal lobe epilepsy, which is due to mutations of the α4 subunit of the
nicotinic acetylcholine receptor.5,6 A gene for familial paroxysmal choreoathetosis has been
mapped to a region of chromosome 1p where a cluster of potassium channel genes is located.7
Channelopathies may be acquired as well as inherited. Recognised causes include toxins and
autoimmune phenomena. The marine toxin ciguatoxin, which contaminates fish and shellfish,
is a potent sodium channel blocker that causes a rapid onset of numbness, intense
paraesthesia and dysaesthesia, and muscle weakness.8Antibodies to peripheral nerve
potassium channels may result in neuromyotonia (Isaac’s syndrome).9 Lambert-Eaton
myasthenia, which is associated with small cell carcinoma of the lung in 60% of cases, is
caused by autoantibodies directed against a presynaptic calcium channel at the neuromuscular
junction and against multiple calcium channels expressed by lung cancer cells.10 The
neurophysiological abnormalities seen in Guillain-Barré syndrome, chronic inflammatory
demyelinating polyneuropathy, and multiple sclerosis, traditionally regarded as the result of
demyelination, could also be explained by sodium channel dysfunction. The transient nature
of some symptoms in multiple sclerosis and the rapid recovery that is sometimes seen in
multiple sclerosis and Guillain-Barré syndrome are more consistent with a temporary
channelopathy mediated by antibodies than a longer process of demyelination and
remyelination. In fact, cerebrospinal fluid from patients with Guillain-Barré syndrome or
chronic inflammatory demyelinating polyneuropathy does cause a transient decrease in
neuronal sodium currents.11,12
All these channelopathies have surprisingly similar clinical features. Typically, there are
paroxysmal attacks of paralysis, myotonia, migraine, and ataxia precipitated by physiological
stresses. A channelopathy may cause an abnormal gain of function (such as myokymia,
myotonia, and epilepsy) or an abnormal loss of function, (such as weakness or numbness)
depending on whether loss of channel function leads to excessive membrane excitability or to
membrane inexcitability.
Ion channels consist of multiple subunits, each with very similar structure but different
electrophysiological characteristics. The differing neuronal expression and combination of
these subunits into complexes gives rise to enormous diversity in the properties and
distribution of ion channels, which is reflected in the variety of diseases that make up the
neurological channelopathies. Many of the channelopathies respond predictably to membrane
stabilising drugs such as mexilitine, as well as to acetazolamide. The neuronal specificity of
ion channels allows the potential for targeted drug therapy akin to the selective receptor
agonists and antagonists currently available: 3,4-diaminopyridine, a potassium channel
blocker, can relieve symptoms in patients with Lambert-Eaton syndrome and improves leg
strength in patients with multiple sclerosis.13,14 Specific channel modulating drugs are
currently being developed for migraine, chronic pain, and cardiac dysrhythmias and these
may be useful for neurological channelopathies.

Genes and mutations in idiopathic epilepsy.

Steinlein OK1.
Author information
Abstract
Partial or generalized idiopathic epilepsies, which account for up to 40% of all epilepsies, are
characterized by a mostly benign course and no apparent etiology other than a genetic
predisposition. So far, the genetic defects underlying three different idiopathic epilepsy
syndromes have been identified: mutations in the CHRNA4- or CHRNB subunits of the neuronal
nicotinic acetylcholine receptor are found in familial nocturnal frontal lobe epilepsy, while defects
in the voltage-gated potassium channels KCNQ2 and KCNQ3 have recently been identified in
benign familial neonatal convulsions. The syndrome of "generalized epilepsy with febrile seizures
plus" can be caused by mutations affecting the voltage-gated sodium channel subunits SCN1B
and SCN1A or the gamma 2-subunit of the GABA(A) receptor. The results of recent molecular
studies contributed largely to our understanding of the etiology and pathophysiology of idiopathic
epilepsies.