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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
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
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 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
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.
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
Table 2.
Distribution of Seizure Phenotypes in SCN1A-Related Seizure Disorders
Disorder Distribution
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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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].
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Management
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
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).
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.
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.
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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.
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.
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.
Fax: 203-907-1940
Email: info@dravetfoundation.org
www.dravetfoundation.org
www.epilepsymatters.com
Epilepsy Foundation
8301 Professional Place East
Suite 200
Landover MD 20785-7223
Email: ContactUs@efa.org
www.epilepsy.com
Bethesda MD 20824
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
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)
Contents
Search term
Figure 1
Table 1
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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).
Go to:
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:
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.
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).
Channelopathies
June-Bum Kim, MD, PhD
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
Fig. 3
Diagram showing a clinical spectrum of muscle channelopathies ranging from myotonia to flaccid
paralysis.
Table 1
Nervous system channelopathies
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
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).
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Table 3
Endocrine channelopathies
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).
Go to:
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:
Table 5
Autoimmune channelopathies
LGI1, leucine-rich glioma inactivated protein; CASPR2, contactin-associated protein 2; SCLC, small cell lung
cancer.
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.
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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
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.