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Generalized epilepsy with febrile seizures plus
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Generalized epilepsy with febrile seizures plus

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GEFS+
Specialty Neurology

Generalized epilepsy with febrile seizures plus (GEFS+) is a syndromic autosomal dominant disorder where affected individuals can exhibit numerous epilepsy phenotypes. GEFS+ can persist beyond early childhood (i.e., 6 years of age). GEFS+ is also now believed to encompass three other epilepsy disorders: severe myoclonic epilepsy of infancy (SMEI), which is also known as Dravet's syndrome, borderline SMEI (SMEB), and intractable epilepsy of childhood (IEC). There are at least six types of GEFS+, delineated by their causative gene. Known causative gene mutations are in the sodium channel α subunit genes SCN1A, an associated β subunit SCN1B, and in a GABAA receptor γ subunit gene, in GABRG2 and there is another gene related with calcium channel the PCDH19 which is also known as Epilepsy Female with Mental Retardation.Penetrance for this disorder is estimated at 60%.

Signs and symptoms

Individuals with GEFS+ present with a range of epilepsy phenotypes. These include febrile seizures that end by age 6 (FS), such seizures extending beyond age 6 that may include afebrile tonic-clonic, myoclonic, absence, atonic seizures and myoclonic-astatic epilepsy. Individuals may also present with SMEI, characterized by generally tonic-clonic seizures, impaired psychomotor development, myoclonic seizures, ataxia, and poor response to many anticonvulsants.

Pathophysiology

Type 1

Figure 1. Schematic structure of SCN1B with GEFS+ type 1 mutations shown in red. The single red spot is the C121W mutant at the disulfide bond (black) and the stretch of red the I70_E74del mutation.

GEFS+ type 1 is a subtype of GEFS+ in which there are mutations in SCN1B, a gene encoding a sodium channel β subunit. The β subunit is required for proper channel inactivation. There are two known mutations in SCN1B that lead to GEFS+ (Figure 1). The first and best characterized of these mutations is C121W. This mutation alters a cysteine involved in a disulfide bond in the extracellular N-terminus of the protein. This extracellular region is similar to the cell adhesion molecule contactin and other cell adhesion molecules. It is believed that the disulfide bond disrupted by the C121W mutation is required for the proper folding of this N-terminus motif. Coexpression of SCN1B with sodium channel α subunits in oocytes and other cells results in channels that inactivate more slowly. Expression of C121W mutant along with wild-type α subunits produces current indistinguishable from that through α subunits alone. Further investigation of this mutation has indicated that it results in decreased frequency dependent rundown and, thus, likely hyperexcitability when compared to cells expressing the wild-type subunit. This mutation also disrupts the subunit's ability to induce cellular aggregation. The importance of this last fact is unclear, though it is presumed that proper channel aggregation within cells and cell-cell contact are required for normal neuronal function.

A second mutation has been found in one kindred with GEFS+ type 1. This mutation is in a splice acceptor site of exon 3. The loss of this acceptor site reveals a downstream cryptic acceptor site and a protein missing 5 amino acids in the N-terminus (I70_E74del). This mutation has not been further characterized.

Type 2

A second subtype of GEFS+, type 2, is the result of mutations in SCN1A, a gene encoding a sodium channel α subunit. There are currently almost 90 known mutations in the SCN1A gene throughout the entirety of the channel (see table 1). These mutations result in almost any imaginable mutation type in the gene, short of duplications. The results of these mutations are highly variable, some producing functional channels while others result in non-functional channels. Some functional channels result in membrane hyperexcitability while others result in hypoexcitability. Most of the functional mutant channels result in hyperexcitability due to decreased frequency dependent rundown. An example of this is the D188V mutation. A 10 Hz stimulation of wild-type channels causes current to decrease to approximately 70% of maximum whereas the same stimulation of mutant channels results in rundown to 90% of maximum. This is caused by an expedited recovery from inactivation for mutant channels versus wild-type. The D188V mutant, for example, recovers to 90% maximal current in 200ms while wild-type channels are unable to recover to this degree in >1000ms. Some other functional mutations that lead to hyperexcitability do so by other means, such as decreasing the rate of entrance into the slow inactivated state.

Some of the other functional mutations are believed to result in hypoexcitability. The R859C mutation, for example, has a more depolarized voltage dependence of activation, meaning that the membrane must be more depolarized for the channel to open. This mutant also recovers more slowly from inactivation. The nonfunctional channels are believed to produce similar changes in cell excitability. Likewise, many of the nonsense mutations likely result in nonfunctional channels and hypoexcitability, though this has yet to be tested. It is also unclear how this membrane hypoexcitability leads to the GEFS+ phenotype.

Table 1. Summary of mutations found in patients diagnosed with GEFS+ type 2
Mutation Region Functional? Excitability Prediction References
R101Q N-Terminus
S103G N-Terminus
T112I N-Terminus
V144fsX148 D1S1
G177fsX180 D1S2-S3
D188V D1S2-S3 Yes Hyperexcitable
F190R D1S3
S219fsX275 D1S4
R222X D1S4
G265W D1S5
G343E D1S5-S6
E435X D1-2
R613X D1-2
R701X D1-2
P707fsX715 D1-2
R712X D1-2
Q732fsX749 D1-2
Y779C D2S1
T808S D2S2 Yes Hyperexcitable
R859C D2S4 Yes Hypoexcitability
T875M D2S4 Yes Hyperexcitable*
F902C D2S5 No Hypoexcitable
S914fsX934 D2S5-6
M924I D2S5-6
V934A D2S5-6
R936C D2S5-6
R936H D2S5-6
W942X D2S5-6
R946fsX953 D2S5-6
W952X D2S5-6
D958fsX973 D2S5-6
M960V D2S5-6
G979R D2S6 No Hypoexcitable
V983A D2S6 Yes Hyperexcitable
N985I D2S6
L986F D2S6 No Hypoexcitable
N1011I D2-3 Yes Hyperexcitable
K1100fsX1107 D2-3
L1156fsX1172 D2-3
W1204R D2-3 Yes Hyperexcitable
W1204X D2-3
R1213X D2-3
S1231R D3S1
S1231T D3S1
F1263L D3S2
W1284X D3S3
L1345P D3S5
V1353L D3S5 No Hypoexcitable
Splice Exon 4
R1397X D3S5-6
R1407X D3S5-6
W1408X D3S5-6
V1428A D3S6
S1516X D3-4
R1525X D3-4
M1549del D4S1
V1611F D4S3 Yes Hyperexcitable
P1632S D4S3 Yes Hyperexcitable
R1635X D4S4
R1648C D4S4 Yes Hyperexcitable
R1648H D4S4 Yes Hyperexcitable
I1656M D4S4 Yes
R1657C D4S4 Yes Hypoexcitable
F1661S D4S4 Yes Hyperexcitable
L1670fsX1678 D4S4-5
G1674R D4S4-5 No Hypoexcitable
F1682S D4S5
Y1684C D4S5
A1685V D4S5 No Hypoexcitable
A1685D D4S5
T1709I D4S5-6 No Hypoexcitable
D1742G D4S5-6
G1749E D4S6 Yes Hypoexcitable
F1756del D4S6
F1765fsX1794 D4S6
Y1771C D4S6
1807delMFYE C-Terminus
F1808L C-Terminus Yes Hyperexcitable
W1812G C-Terminus
F1831S C-Terminus
M1841T C-Terminus
S1846fsX1856 C-Terminus
R1882X C-Terminus
D1886Y C-Terminus Yes Hyperexcitable
R1892X C-Terminus
R1902X C-Terminus
Q1904fsX1945 C-Terminus
*
Results are dependent on experimental paradigm

Type 3

Patients with GEFS+ type 3 have mutations in the GABRG2 gene, which encodes the GABAA γ2 subunit (figure 2). The first mutation discovered in GABRG2 was K289M, in the extracellular region linking membrane-spanning domains M2 and M3. Oocytes injected with α1, β2, and γ2 subunits produce large GABA inducible currents whereas those injected with K289M mutant instead of wild-type subunits produce currents much smaller (about 10% of wild-type). This abnormal current is not the result of non-incorporation of mutant subunits since mutant containing receptors are still sensitive to benzodiazepines, a property for which functional γ subunits are required. Because of these results, it is believed that the GEFS+ phenotype in these individuals is a result of hyperexcitability.

Concurrent with the previous mutation, a second group found a second mutation in GABRG2 associated with GEFS+. This mutation, R43Q, is located in the one of two benzodiazepine binding-sites located in the extracellular N-terminus. Benzodiazepines, such as Diazepam, potentiate GABA induced current. This potentiation is abolished in cells expressing the R43Q mutant subunit instead of the wild-type γ subunit. This mutation does not affect the subunit's ability to coassemble into function receptors as it still confers resistance to GABA current blockade by zinc. As with the previous mutation, this mutation is expected to result in neuronal hyperexcitability.

The final known GEFS+ type 3 mutation is a nonsense mutation, Q351X, located in the intracellular region linking the third and fourth membrane spanning segments. When this mutant subunit is expressed in cells with wild-type α and β subunits it produces non-functional receptors. Since wild-type α and β subunits expressed alone are able to produce GABA inducible current this indicates that the mutation either prevents both coassembly of the mutant and wild-type subunits but also coassembly of the wild-type α and β subunits or prevents proper trafficking of the formed receptor to the membrane. Fusion of GFP onto this mutated subunit has indicated that it is localized to the endoplasmic reticulum instead of the cell membrane. As with other known GEFS+ type 3 mutation, Q351X likely results in neuronal hyperexcitability.

SCN2A mutations

Figure 3. Schematic structure of SCN2A with GEFS+ associated mutation positions indicated by red dots.

The final type of GEFS+ is caused by mutations in the SCN2A gene, which encodes a sodium channel α subunit. The first associated mutation in this gene is R187W, located on the intracellular region linking membrane spanning units two and three in the first domain (D1S2-S3, figure 3). Patients with this mutation have both febrile and afebrile seizures. Electrophysiological examination of this mutant revealed that it increases the time constant for inactivation, presumably increasing sodium current and leading to hyperexcitability. However, this mutation also yields channels that inactivate at more hyperpolarized potentials relative to wild-type channels, indicative of hypoexcitability. Whether the result on membrane excitability of this mutation is hyperexcitability or hypoexcitability is, as yet, unclear.

The second known mutation in SCN2A associated with GEFS+ is R102X. This mutation is located in the intracellular N-terminus (figure 3) and results in SMEI in patients. The result of this mutation is completely non-functional channels and membrane hypoexcitability. The truncated mutant protein also seems to cause wild-type channels to inactivate at more hyperpolarized potentials, indicating that it also acts in a dominant negative manner.

Management

Long term management is by use of anticonvulsant medication, principally valproate, stiripentol, topiramate or clobazam. Ketogenic diet has also been found useful in certain cases

Management of breakthrough seizures is by benzodiazepine such as midazolam.

See also

External links


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