Generalized epilepsy with febrile seizures plus explained

GEFS+
Field:Neurology

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

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

Type 1

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

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.

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
V144fsX148 D1S1
G177fsX180 D1S2-S3
D188V D1S2-S3 Yes Hyperexcitable [16]
F190R D1S3
S219fsX275 D1S4 [17]
R222X D1S4
G265W D1S5
G343E D1S5-S6
E435X D1-2
R613X D1-2 [18]
R701X D1-2
P707fsX715 D1-2
R712X D1-2
Q732fsX749 D1-2
Y779C D2S1 [19]
T808S D2S2 Yes Hyperexcitable
R859C D2S4 Yes Hypoexcitability
T875M D2S4 Yes [20] [21] [22] [23] [24]
F902C D2S5 No Hypoexcitable [25]
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 [26]
N1011I D2-3 Yes Hyperexcitable
K1100fsX1107 D2-3
L1156fsX1172 D2-3
W1204R D2-3 Yes Hyperexcitable [27]
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 [28] [29]
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 [30] [31]
I1656M D4S4 Yes
R1657C D4S4 Yes Hypoexcitable [32]
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 [33]
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

Notes and References

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  2. Spampanato J, Escayg A, Meisler M, Goldin A . 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 . 2003 . 12535936 . 10.1016/S0306-4522(02)00698-X. 28204501 .
  3. Singh R, Andermann E, Whitehouse W, Harvey A, Keene D, Seni M, Crossland K, Andermann F, Berkovic S, Scheffer I . Severe myoclonic epilepsy of infancy: extended spectrum of GEFS+? . Epilepsia . 42 . 7 . 837–44 . 2001 . 11488881 . 10.1046/j.1528-1157.2001.042007837.x. 7256994 .
  4. Scheffer, Ingrid. Epilepsy and mental retardation limited to females: an under-recognized disorder . 2007 . Brain . 131 . 4 . 918–927 . 10.1093/brain/awm338. etal . 18234694. free .
  5. Wallace R, Wang D, Singh R, Scheffer I, George A, Phillips H, Saar K, Reis A, Johnson E, Sutherland G, Berkovic S, Mulley J . Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B . Nat Genet . 19 . 4 . 366–70 . 1998 . 9697698 . 10.1038/1252. 20962841 .
  6. Rhodes T, Vanoye C, Ohmori I, Ogiwara I, Yamakawa K, George A . Sodium channel dysfunction in intractable childhood epilepsy with generalized tonic–clonic seizures . J Physiol . 569 . Pt 2 . 433–45 . 2005 . 16210358 . 10.1113/jphysiol.2005.094326 . 1464244.
  7. Tammaro P, Conti F, Moran O . Modulation of sodium current in mammalian cells by an epilepsy-correlated beta 1-subunit mutation . Biochem Biophys Res Commun . 291 . 4 . 1095–101 . 2002 . 11866477 . 10.1006/bbrc.2002.6570.
  8. Meadows L, Malhotra J, Loukas A, Thyagarajan V, Kazen-Gillespie K, Koopman M, Kriegler S, Isom L, Ragsdale D . 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 . 2002 . 12486163. 6758463 . 10.1523/JNEUROSCI.22-24-10699.2002 .
  9. Lucas P, Meadows L, Nicholls J, Ragsdale D . 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 . 2005 . 15922564 . 10.1016/j.eplepsyres.2005.03.003. 22127664 .
  10. Audenaert D, Claes L, Ceulemans B, Löfgren A, Van Broeckhoven C, De Jonghe P . A deletion in SCN1B is associated with febrile seizures and early-onset absence epilepsy . Neurology . 61 . 6 . 854–6 . 2003 . 14504340 . 10.1212/01.wnl.0000080362.55784.1c. 20308172 .
  11. Cossette P, Loukas A, Lafrenière R, Rochefort D, Harvey-Girard E, Ragsdale D, Dunn R, Rouleau G . 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 . 2003 . 12576172 . 10.1016/S0920-1211(02)00259-0. 38953878 .
  12. Escayg. Andrew. Goldin. Alan L.. September 2010. Sodium channel SCN1A and epilepsy: mutations and mechanisms. Epilepsia. 51. 9. 1650–1658. 10.1111/j.1528-1167.2010.02640.x. 0013-9580. 2937162. 20831750.
  13. Barela A, Waddy S, Lickfett J, Hunter J, Anido A, Helmers S, Goldin A, Escayg A . An epilepsy mutation in the sodium channel SCN1A that decreases channel excitability . J Neurosci . 26 . 10 . 2714–23 . 2006 . 16525050 . 6675156 . 10.1523/JNEUROSCI.2977-05.2006.
  14. 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 . 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 . 2004 . 14738421 . 10.1111/j.0013-9580.2004.15103.x. 26120232 .
  15. Fujiwara T, Sugawara T, Mazaki-Miyazaki E, Takahashi Y, Fukushima K, Watanabe M, Hara K, Morikawa T, Yagi K, Yamakawa K, Inoue Y . 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 . 2003 . 12566275 . 10.1093/brain/awg053. free .
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  28. Ito M, Nagafuji H, Okazawa H, Yamakawa K, Sugawara T, Mazaki-Miyazaki E, Hirose S, Fukuma G, Mitsudome A, Wada K, Kaneko S . 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 . 2002 . 11823106 . 10.1016/S0920-1211(01)00313-8. 25555020 .
  29. Ito M, Yamakawa K, Sugawara T, Hirose S, Fukuma G, Kaneko S . Phenotypes and genotypes in epilepsy with febrile seizures plus . Epilepsy Res . 70 . 2–3 Suppl . 199–205 . 2006 . 16884893 . 10.1016/j.eplepsyres.2005.11.028. 994890 .
  30. Baulac S, Gourfinkel-An I, Picard F, Rosenberg-Bourgin M, Prud'homme J, Baulac M, Brice A, LeGuern E . A Second Locus for Familial Generalized Epilepsy with Febrile Seizures Plus Maps to Chromosome 2q21-q33 . Am J Hum Genet . 65 . 4 . 1078–85 . 1999 . 10486327 . 10.1086/302593 . 1288241.
  31. Vanoye C, Lossin C, Rhodes T, George A . Single-channel Properties of Human NaV1.1 and Mechanism of Channel Dysfunction in SCN1A-associated Epilepsy . J Gen Physiol . 127 . 1 . 1–14 . 2006 . 16380441 . 10.1085/jgp.200509373 . 2151481.
  32. Nagao Y, Mazaki-Miyazaki E, Okamura N, Takagi M, Igarashi T, Yamakawa K . 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 . 2005 . 15715999 . 10.1016/j.eplepsyres.2004.11.005. 37140042 .
  33. Pineda-Trujillo N, Carrizosa J, Cornejo W, Arias W, Franco C, Cabrera D, Bedoya G, Ruíz-Linares A . A novel SCN1A mutation associated with severe GEFS+ in a large South American pedigree . Seizure . 14 . 2 . 123–8 . 2005 . 15694566 . 10.1016/j.seizure.2004.12.007. free .

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