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Generalized epilepsy with febrile seizures plus

Generalized epilepsy with febrile seizures plus (GEFS+) is a syndromic autosomal dominant disorder where affected individuals can exhibit numerous epilepsy phenotypes.[1] 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).[2][3] 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.[4] Penetrance for this disorder is estimated at 60%.[5]

Signs and symptoms edit

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.[1][6]

Pathophysiology edit

Type 1 edit

 
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.[5][7] 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.[8][9]

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.[10]

Type 2 edit

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.[11] 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.[12]

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.[13] 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.[citation needed]

Table 1. Summary of mutations found in patients diagnosed with GEFS+ type 2
Mutation Region Functional? Excitability Prediction References
R101Q N-Terminus [14]
S103G N-Terminus [15]
T112I N-Terminus [15]
V144fsX148 D1S1 [14]
G177fsX180 D1S2-S3 [15]
D188V D1S2-S3 Yes Hyperexcitable [11][16]
F190R D1S3 [14]
S219fsX275 D1S4 [17]
R222X D1S4 [14][17]
G265W D1S5 [15]
G343E D1S5-S6 [15]
E435X D1-2 [14]
R613X D1-2 [18]
R701X D1-2 [14]
P707fsX715 D1-2 [18]
R712X D1-2 [15]
Q732fsX749 D1-2 [15]
Y779C D2S1 [19]
T808S D2S2 Yes Hyperexcitable [6][15]
R859C D2S4 Yes Hypoexcitability [13]
T875M D2S4 Yes Hyperexcitable* [20][21][22][23][24]
F902C D2S5 No Hypoexcitable [25]
S914fsX934 D2S5-6 [18]
M924I D2S5-6 [14]
V934A D2S5-6 [14]
R936C D2S5-6 [14]
R936H D2S5-6 [14]
W942X D2S5-6 [14]
R946fsX953 D2S5-6 [15]
W952X D2S5-6 [15]
D958fsX973 D2S5-6 [15]
M960V D2S5-6 [15]
G979R D2S6 No Hypoexcitable [6][15]
V983A D2S6 Yes Hyperexcitable [6][15]
N985I D2S6 [15]
L986F D2S6 No Hypoexcitable [17][26]
N1011I D2-3 Yes Hyperexcitable [6][15]
K1100fsX1107 D2-3 [17]
L1156fsX1172 D2-3 [14]
W1204R D2-3 Yes Hyperexcitable [2][24][27]
W1204X D2-3 [15]
R1213X D2-3 [15]
S1231R D3S1 [15]
S1231T D3S1 [18]
F1263L D3S2 [15]
W1284X D3S3 [15]
L1345P D3S5 [14]
V1353L D3S5 No Hypoexcitable [16][26]
Splice Exon 4 [15][17]
R1397X D3S5-6 [14]
R1407X D3S5-6 [15]
W1408X D3S5-6 [15]
V1428A D3S6 [28][29]
S1516X D3-4 [15]
R1525X D3-4 [18]
M1549del D4S1 [14]
V1611F D4S3 Yes Hyperexcitable [6][15]
P1632S D4S3 Yes Hyperexcitable [6][15]
R1635X D4S4 [14]
R1648C D4S4 Yes Hyperexcitable [25]
R1648H D4S4 Yes Hyperexcitable [21][23][24][30][31]
I1656M D4S4 Yes [16][26]
R1657C D4S4 Yes Hypoexcitable [26][31][32]
F1661S D4S4 Yes Hyperexcitable [25]
L1670fsX1678 D4S4-5 [15][17]
G1674R D4S4-5 No Hypoexcitable [25]
F1682S D4S5 [14]
Y1684C D4S5 [14]
A1685V D4S5 No Hypoexcitable [26][28][29]
A1685D D4S5 [15]
T1709I D4S5-6 No Hypoexcitable [6][15]
D1742G D4S5-6 [33]
G1749E D4S6 Yes Hypoexcitable [25]
F1756del D4S6 [14]
F1765fsX1794 D4S6 [15]
Y1771C D4S6 [14]
1807delMFYE C-Terminus [15]
F1808L C-Terminus Yes Hyperexcitable [6][15]
W1812G C-Terminus [15]
F1831S C-Terminus [15]
M1841T C-Terminus [19]
S1846fsX1856 C-Terminus [17][18]
R1882X C-Terminus [14]
D1886Y C-Terminus Yes Hyperexcitable [34]
R1892X C-Terminus [15]
R1902X C-Terminus [14]
Q1904fsX1945 C-Terminus [15]
*
Results are dependent on experimental paradigm

Type 3 edit

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.[35]

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.[36][37]

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.[38]

SCN2A mutations edit

 
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.[29][39]

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.[40]

Management edit

Long term management is by use of anticonvulsant medication, principally valproate, stiripentol, topiramate or clobazam.[41] Ketogenic diet has also been found useful in certain cases [42]

Management of breakthrough seizures is by benzodiazepine such as midazolam.[citation needed]

See also edit

References edit

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  40. ^ Kamiya K, Kaneda M, Sugawara T, Mazaki E, Okamura N, Montal M, Makita N, Tanaka M, Fukushima K, Fujiwara T, Inoue Y, Yamakawa K (2004). "A nonsense mutation of the sodium channel gene SCN2A in a patient with intractable epilepsy and mental decline". J Neurosci. 24 (11): 2690–8. doi:10.1523/JNEUROSCI.3089-03.2004. PMC 6729532. PMID 15028761.
  41. ^ British National Formulary for Children (May 2014)
  42. ^ "Search Results | Great Ormond Street Hospital".

External links edit

generalized, epilepsy, with, febrile, seizures, plus, gefs, redirects, here, online, flight, simulator, gefs, online, smeb, redirects, here, league, legends, player, smeb, this, article, multiple, issues, please, help, improve, discuss, these, issues, talk, pa. GEFS redirects here For the online flight simulator see GEFS Online SMEB redirects here For the League of Legends player see Smeb This article has multiple issues Please help improve it or discuss these issues on the talk page Learn how and when to remove these template messages This article may be too technical for most readers to understand Please help improve it to make it understandable to non experts without removing the technical details October 2013 Learn how and when to remove this message This article possibly contains original research Please improve it by verifying the claims made and adding inline citations Statements consisting only of original research should be removed October 2013 Learn how and when to remove this message Learn how and when to remove this message Generalized epilepsy with febrile seizures plus GEFS is a syndromic autosomal dominant disorder where affected individuals can exhibit numerous epilepsy phenotypes 1 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 2 3 There are at least six types of GEFS delineated by their causative gene Known causative gene mutations are in the sodium channel a subunit genes SCN1A an associated b subunit SCN1B and in a GABAA receptor g 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 4 Penetrance for this disorder is estimated at 60 5 GEFS SpecialtyNeurology Contents 1 Signs and symptoms 2 Pathophysiology 2 1 Type 1 2 2 Type 2 2 3 Type 3 2 4 SCN2A mutations 3 Management 4 See also 5 References 6 External linksSigns and symptoms editIndividuals 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 1 6 Pathophysiology editType 1 edit nbsp 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 b subunit The b 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 a subunits in oocytes and other cells results in channels that inactivate more slowly Expression of C121W mutant along with wild type a subunits produces current indistinguishable from that through a subunits alone 5 7 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 8 9 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 10 Type 2 edit A second subtype of GEFS type 2 is the result of mutations in SCN1A a gene encoding a sodium channel a 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 gt 1000ms 11 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 12 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 13 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 citation needed Table 1 Summary of mutations found in patients diagnosed with GEFS type 2 Mutation Region Functional Excitability Prediction References R101Q N Terminus 14 S103G N Terminus 15 T112I N Terminus 15 V144fsX148 D1S1 14 G177fsX180 D1S2 S3 15 D188V D1S2 S3 Yes Hyperexcitable 11 16 F190R D1S3 14 S219fsX275 D1S4 17 R222X D1S4 14 17 G265W D1S5 15 G343E D1S5 S6 15 E435X D1 2 14 R613X D1 2 18 R701X D1 2 14 P707fsX715 D1 2 18 R712X D1 2 15 Q732fsX749 D1 2 15 Y779C D2S1 19 T808S D2S2 Yes Hyperexcitable 6 15 R859C D2S4 Yes Hypoexcitability 13 T875M D2S4 Yes Hyperexcitable 20 21 22 23 24 F902C D2S5 No Hypoexcitable 25 S914fsX934 D2S5 6 18 M924I D2S5 6 14 V934A D2S5 6 14 R936C D2S5 6 14 R936H D2S5 6 14 W942X D2S5 6 14 R946fsX953 D2S5 6 15 W952X D2S5 6 15 D958fsX973 D2S5 6 15 M960V D2S5 6 15 G979R D2S6 No Hypoexcitable 6 15 V983A D2S6 Yes Hyperexcitable 6 15 N985I D2S6 15 L986F D2S6 No Hypoexcitable 17 26 N1011I D2 3 Yes Hyperexcitable 6 15 K1100fsX1107 D2 3 17 L1156fsX1172 D2 3 14 W1204R D2 3 Yes Hyperexcitable 2 24 27 W1204X D2 3 15 R1213X D2 3 15 S1231R D3S1 15 S1231T D3S1 18 F1263L D3S2 15 W1284X D3S3 15 L1345P D3S5 14 V1353L D3S5 No Hypoexcitable 16 26 Splice Exon 4 15 17 R1397X D3S5 6 14 R1407X D3S5 6 15 W1408X D3S5 6 15 V1428A D3S6 28 29 S1516X D3 4 15 R1525X D3 4 18 M1549del D4S1 14 V1611F D4S3 Yes Hyperexcitable 6 15 P1632S D4S3 Yes Hyperexcitable 6 15 R1635X D4S4 14 R1648C D4S4 Yes Hyperexcitable 25 R1648H D4S4 Yes Hyperexcitable 21 23 24 30 31 I1656M D4S4 Yes 16 26 R1657C D4S4 Yes Hypoexcitable 26 31 32 F1661S D4S4 Yes Hyperexcitable 25 L1670fsX1678 D4S4 5 15 17 G1674R D4S4 5 No Hypoexcitable 25 F1682S D4S5 14 Y1684C D4S5 14 A1685V D4S5 No Hypoexcitable 26 28 29 A1685D D4S5 15 T1709I D4S5 6 No Hypoexcitable 6 15 D1742G D4S5 6 33 G1749E D4S6 Yes Hypoexcitable 25 F1756del D4S6 14 F1765fsX1794 D4S6 15 Y1771C D4S6 14 1807delMFYE C Terminus 15 F1808L C Terminus Yes Hyperexcitable 6 15 W1812G C Terminus 15 F1831S C Terminus 15 M1841T C Terminus 19 S1846fsX1856 C Terminus 17 18 R1882X C Terminus 14 D1886Y C Terminus Yes Hyperexcitable 34 R1892X C Terminus 15 R1902X C Terminus 14 Q1904fsX1945 C Terminus 15 Results are dependent on experimental paradigm Type 3 edit Patients with GEFS type 3 have mutations in the GABRG2 gene which encodes the GABAA g2 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 a1 b2 and g2 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 g subunits are required Because of these results it is believed that the GEFS phenotype in these individuals is a result of hyperexcitability 35 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 g 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 36 37 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 a and b subunits it produces non functional receptors Since wild type a and b 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 a and b 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 38 SCN2A mutations edit nbsp 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 a 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 29 39 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 40 Management editLong term management is by use of anticonvulsant medication principally valproate stiripentol topiramate or clobazam 41 Ketogenic diet has also been found useful in certain cases 42 Management of breakthrough seizures is by benzodiazepine such as midazolam citation needed See also editFebrile seizures Idiopathic generalized epilepsy Dravet Syndrome Foundation International Dravet Epilepsy Action LeagueReferences edit a b Scheffer I Berkovic S 1997 Generalized epilepsy with febrile seizures plus A genetic disorder with heterogeneous clinical phenotypes Brain 120 3 479 90 doi 10 1093 brain 120 3 479 PMID 9126059 a b Spampanato J Escayg A Meisler M Goldin A 2003 Generalized epilepsy with febrile seizures plus type 2 mutation W1204R alters voltage dependent gating of Na v 1 1 sodium channels Neuroscience 116 1 37 48 doi 10 1016 S0306 4522 02 00698 X PMID 12535936 S2CID 28204501 Singh R Andermann E Whitehouse W Harvey A Keene D Seni M Crossland K Andermann F Berkovic S Scheffer I 2001 Severe myoclonic epilepsy of infancy extended spectrum of GEFS Epilepsia 42 7 837 44 doi 10 1046 j 1528 1157 2001 042007837 x PMID 11488881 S2CID 7256994 Scheffer Ingrid et al 2007 Epilepsy and mental retardation limited to females an under recognized disorder Brain 131 4 918 927 doi 10 1093 brain awm338 PMID 18234694 a b Wallace R Wang D Singh R Scheffer I George A Phillips H Saar K Reis A Johnson E Sutherland G Berkovic S Mulley J 1998 Febrile seizures and generalized epilepsy associated with a mutation in the Na channel beta1 subunit gene SCN1B Nat Genet 19 4 366 70 doi 10 1038 1252 PMID 9697698 S2CID 20962841 a b c d e f g h i Rhodes T Vanoye C Ohmori I Ogiwara I Yamakawa K George A 2005 Sodium channel dysfunction in intractable childhood epilepsy with generalized tonic clonic seizures J Physiol 569 Pt 2 433 45 doi 10 1113 jphysiol 2005 094326 PMC 1464244 PMID 16210358 Tammaro P Conti F Moran O 2002 Modulation of sodium current in mammalian cells by an epilepsy correlated beta 1 subunit mutation Biochem Biophys Res Commun 291 4 1095 101 doi 10 1006 bbrc 2002 6570 PMID 11866477 Meadows L Malhotra J Loukas A Thyagarajan V Kazen Gillespie K Koopman M Kriegler S Isom L Ragsdale D 2002 Functional and biochemical analysis of a sodium channel beta1 subunit mutation responsible for generalized epilepsy with febrile seizures plus type 1 J Neurosci 22 24 10699 709 doi 10 1523 JNEUROSCI 22 24 10699 2002 PMC 6758463 PMID 12486163 Lucas P Meadows L Nicholls J Ragsdale D 2005 An epilepsy mutation in the beta1 subunit of the voltage gated sodium channel results in reduced channel sensitivity to phenytoin Epilepsy Res 64 3 77 84 doi 10 1016 j eplepsyres 2005 03 003 PMID 15922564 S2CID 22127664 Audenaert D Claes L Ceulemans B Lofgren A Van Broeckhoven C De Jonghe P 2003 A deletion in SCN1B is associated with febrile seizures and early onset absence epilepsy Neurology 61 6 854 6 doi 10 1212 01 wnl 0000080362 55784 1c PMID 14504340 S2CID 20308172 a b Cossette P Loukas A Lafreniere R Rochefort D Harvey Girard E Ragsdale D Dunn R Rouleau G 2003 Functional characterization of the D188V mutation in neuronal voltage gated sodium channel causing generalized epilepsy with febrile seizures plus GEFS Epilepsy Res 53 1 2 107 17 doi 10 1016 S0920 1211 02 00259 0 PMID 12576172 S2CID 38953878 Escayg Andrew Goldin Alan L September 2010 Sodium channel SCN1A and epilepsy mutations and mechanisms Epilepsia 51 9 1650 1658 doi 10 1111 j 1528 1167 2010 02640 x ISSN 0013 9580 PMC 2937162 PMID 20831750 a b Barela A Waddy S Lickfett J Hunter J Anido A Helmers S Goldin A Escayg A 2006 An epilepsy mutation in the sodium channel SCN1A that decreases channel excitability J Neurosci 26 10 2714 23 doi 10 1523 JNEUROSCI 2977 05 2006 PMC 6675156 PMID 16525050 a b c d e f g h i j k l m n o p q r s t u v Fukuma G Oguni H Shirasaka Y Watanabe K Miyajima T Yasumoto S Ohfu M Inoue T Watanachai A Kira R Matsuo M Muranaka H Sofue F Zhang B Kaneko S Mitsudome A Hirose S 2004 Mutations of neuronal voltage gated Na channel alpha 1 subunit gene SCN1A in core severe myoclonic epilepsy in infancy SMEI and in borderline SMEI SMEB Epilepsia 45 2 140 8 doi 10 1111 j 0013 9580 2004 15103 x PMID 14738421 S2CID 26120232 a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak Fujiwara T Sugawara T Mazaki Miyazaki E Takahashi Y Fukushima K Watanabe M Hara K Morikawa T Yagi K Yamakawa K Inoue Y 2003 Mutations of sodium channel alpha subunit type 1 SCN1A in intractable childhood epilepsies with frequent generalized tonic clonic seizures Brain 126 Pt 3 531 46 doi 10 1093 brain awg053 PMID 12566275 a b c Wallace R Scheffer I Barnett S Richards M Dibbens L Desai R Lerman Sagie T Lev D Mazarib A Brand N Ben Zeev B Goikhman I Singh R Kremmidiotis G Gardner A Sutherland G George A Mulley J Berkovic S 2001 Neuronal Sodium Channel a1 Subunit Mutations in Generalized Epilepsy with Febrile Seizures Plus Am J Hum Genet 68 4 859 65 doi 10 1086 319516 PMC 1275639 PMID 11254444 a b c d e f g Claes L Del Favero J Ceulemans B Lagae L Van Broeckhoven C De Jonghe P 2001 De Novo Mutations in the Sodium Channel Gene SCN1A Cause Severe Myoclonic Epilepsy of Infancy Am J Hum Genet 68 6 1327 32 doi 10 1086 320609 PMC 1226119 PMID 11359211 a b c d e f Kearney J Wiste A Stephani U Trudeau M Siegel A RamachandranNair R Elterman R Muhle H Reinsdorf J Shields W Meisler M Escayg A 2006 Recurrent de novo mutations of SCN1A in severe myoclonic epilepsy of infancy Pediatr Neurol 34 2 116 20 doi 10 1016 j pediatrneurol 2005 07 009 PMID 16458823 a b Annesi G Gambardella A Carrideo S Incorpora G Labate A Pasqua A Civitelli D Polizzi A Annesi F Spadafora P Tarantino P Ciro Candiano I Romeo N De Marco E Ventura P LePiane E Zappia M Aguglia U Pavone L Quattrone A 2003 Two novel SCN1A missense mutations in generalized epilepsy with febrile seizures plus Epilepsia 44 9 1257 8 doi 10 1046 j 1528 1157 2003 22503 x PMID 12919402 S2CID 31365865 Moulard B Guipponi M Chaigne D Mouthon D Buresi C Malafosse A 1999 Identification of a New Locus for Generalized Epilepsy with Febrile Seizures Plus GEFS on Chromosome 2q24 q33 Am J Hum Genet 65 5 1396 400 doi 10 1086 302621 PMC 1288292 PMID 10521305 a b Escayg A MacDonald B Meisler M Baulac S Huberfeld G An Gourfinkel I Brice A LeGuern E Moulard B Chaigne D Buresi C Malafosse A 2000 Mutations of SCN1A encoding a neuronal sodium channel in two families with GEFS 2 Nat Genet 24 4 343 5 doi 10 1038 74159 PMID 10742094 S2CID 29543172 Alekov A Rahman M Mitrovic N Lehmann Horn F Lerche H 2001 Enhanced inactivation and acceleration of activation of the sodium channel associated with epilepsy in man Eur J Neurosci 13 11 2171 6 doi 10 1046 j 0953 816x 2001 01590 x PMID 11422459 S2CID 15745798 a b Spampanato J Escayg A Meisler M Goldin A 2001 Functional effects of two voltage gated sodium channel mutations that cause generalized epilepsy with febrile seizures plus type 2 PDF J Neurosci 21 19 7481 90 doi 10 1523 JNEUROSCI 21 19 07481 2001 PMC 6762922 PMID 11567038 a b c Lossin C Wang D Rhodes T Vanoye C George A 2002 Molecular basis of an inherited epilepsy Neuron 34 6 877 84 doi 10 1016 S0896 6273 02 00714 6 PMID 12086636 a b c d e Rhodes T Lossin C Vanoye C Wang D George A 2004 Noninactivating voltage gated sodium channels in severe myoclonic epilepsy of infancy Proc Natl Acad Sci USA 101 30 11147 52 Bibcode 2004PNAS 10111147R doi 10 1073 pnas 0402482101 PMC 503754 PMID 15263074 a b c d e Lossin C Rhodes T Desai R Vanoye C Wang D Carniciu S Devinsky O George A 2003 Epilepsy associated dysfunction in the voltage gated neuronal sodium channel SCN1A J Neurosci 23 36 11289 95 doi 10 1523 JNEUROSCI 23 36 11289 2003 PMC 6740520 PMID 14672992 Escayg A Heils A MacDonald B Haug K Sander T Meisler M 2001 A Novel SCN1A Mutation Associated with Generalized Epilepsy with Febrile Seizures Plus and Prevalence of Variants in Patients with Epilepsy Am J Hum Genet 68 4 866 73 doi 10 1086 319524 PMC 1275640 PMID 11254445 a b Ito M Nagafuji H Okazawa H Yamakawa K Sugawara T Mazaki Miyazaki E Hirose S Fukuma G Mitsudome A Wada K Kaneko S 2002 Autosomal dominant epilepsy with febrile seizures plus with missense mutations of the Na channel alpha 1 subunit gene SCN1A Epilepsy Res 48 1 2 15 23 doi 10 1016 S0920 1211 01 00313 8 PMID 11823106 S2CID 25555020 a b c Ito M Yamakawa K Sugawara T Hirose S Fukuma G Kaneko S 2006 Phenotypes and genotypes in epilepsy with febrile seizures plus Epilepsy Res 70 2 3 Suppl 199 205 doi 10 1016 j eplepsyres 2005 11 028 PMID 16884893 S2CID 994890 Baulac S Gourfinkel An I Picard F Rosenberg Bourgin M Prud homme J Baulac M Brice A LeGuern E 1999 A Second Locus for Familial Generalized Epilepsy with Febrile Seizures Plus Maps to Chromosome 2q21 q33 Am J Hum Genet 65 4 1078 85 doi 10 1086 302593 PMC 1288241 PMID 10486327 a b Vanoye C Lossin C Rhodes T George A 2006 Single channel Properties of Human NaV1 1 and Mechanism of Channel Dysfunction in SCN1A associated Epilepsy J Gen Physiol 127 1 1 14 doi 10 1085 jgp 200509373 PMC 2151481 PMID 16380441 Nagao Y Mazaki Miyazaki E Okamura N Takagi M Igarashi T Yamakawa K 2005 A family of generalized epilepsy with febrile seizures plus type 2 a new missense mutation of SCN1A found in the pedigree of several patients with complex febrile seizures Epilepsy Res 63 2 3 151 6 doi 10 1016 j eplepsyres 2004 11 005 PMID 15715999 S2CID 37140042 Pineda Trujillo N Carrizosa J Cornejo W Arias W Franco C Cabrera D Bedoya G Ruiz Linares A 2005 A novel SCN1A mutation associated with severe GEFS in a large South American pedigree Seizure 14 2 123 8 doi 10 1016 j seizure 2004 12 007 PMID 15694566 Spampanato J Kearney J de Haan G McEwen D Escayg A Aradi I MacDonald B Levin S Soltesz I Benna P Montalenti E Isom L Goldin A Meisler M 2004 A novel epilepsy mutation in the sodium channel SCN1A identifies a cytoplasmic domain for beta subunit interaction J Neurosci 24 44 10022 34 doi 10 1523 JNEUROSCI 2034 04 2004 PMC 6730248 PMID 15525788 Baulac S Huberfeld G Gourfinkel An I Mitropoulou G Beranger A Prud homme J Baulac M Brice A Bruzzone R LeGuern E 2001 First genetic evidence of GABA A receptor dysfunction in epilepsy a mutation in the gamma2 subunit gene Nat Genet 28 1 46 8 doi 10 1038 88254 PMID 11326274 Wallace R Marini C Petrou S Harkin L Bowser D Panchal R Williams D Sutherland G Mulley J Scheffer I Berkovic S 2001 Mutant GABA A receptor gamma2 subunit in childhood absence epilepsy and febrile seizures Nat Genet 28 1 49 52 doi 10 1038 88259 PMID 11326275 Marini C Harkin L Wallace R Mulley J Scheffer I Berkovic S 2003 Childhood absence epilepsy and febrile seizures a family with a GABA A receptor mutation Brain 126 Pt 1 230 40 doi 10 1093 brain awg018 PMID 12477709 Harkin L Bowser D Dibbens L Singh R Phillips F Wallace R Richards M Williams D Mulley J Berkovic S Scheffer I Petrou S 2002 Truncation of the GABAA Receptor g2 Subunit in a Family with Generalized Epilepsy with Febrile Seizures Plus Am J Hum Genet 70 2 530 6 doi 10 1086 338710 PMC 384926 PMID 11748509 Sugawara T Tsurubuchi Y Agarwala K Ito M Fukuma G Mazaki Miyazaki E Nagafuji H Noda M Imoto K Wada K Mitsudome A Kaneko S Montal M Nagata K Hirose S Yamakawa K 2001 A missense mutation of the Na channel aII subunit gene Nav1 2 in a patient with febrile and afebrile seizures causes channel dysfunction Proc Natl Acad Sci USA 98 11 6384 9 Bibcode 2001PNAS 98 6384S doi 10 1073 pnas 111065098 PMC 33477 PMID 11371648 Kamiya K Kaneda M Sugawara T Mazaki E Okamura N Montal M Makita N Tanaka M Fukushima K Fujiwara T Inoue Y Yamakawa K 2004 A nonsense mutation of the sodium channel gene SCN2A in a patient with intractable epilepsy and mental decline J Neurosci 24 11 2690 8 doi 10 1523 JNEUROSCI 3089 03 2004 PMC 6729532 PMID 15028761 British National Formulary for Children May 2014 Search Results Great Ormond Street Hospital External links edit Retrieved from https en wikipedia org w index php title Generalized epilepsy with febrile seizures plus amp oldid 1184152174, 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