Review Article

Genetics of Temporal Lobe Epilepsy: A Review

Table 2

Genomic variations associated which sporadic TLE cases.

GeneVariation
(accession number)
ReferenceGroup or subgroup of patientsPopulation originGenomic variation counts value
Patients, (%)Controls, (%)

GABBR1c.1465G>A → p.Gly489SerGambardella et al. 2003 [56]
Nonlesional TLECaucasian <0.0001
(CM031183)Initial studyA/A = 0 (0.0)A/A = 0 (0.0)
A/G = 24 (17.0)A/G = 2 (0.5)
G/G = 117 (83.0)G/G = 370 (99.5)
Cavalleri et al. 2005 [5]Nonlesional TLECaucasian NS
Replication studyA/A = 0 (0.0)A/A = 0 (0.0)
A/G = 2 (1.0)A/G = 8 (1.0)
G/G = 218 (99.0)G/G = 1062 (99.0)
Ma et al. 2005 [57]TLE-FS+Caucasian NS
A/A = 0 (0.0)A/A = 1 (0.85)
A/G = 1 (0.84)A/G = 0 (0.0)
G/G = 119 (99.16)G/G = 117 (99.15)
Salzmann et al. 2005 [58] Replication studyNonlesional TLECaucasian NS
A/A = (0.0)A/A = (0.0)
A/G = 2 (1.82)A/G = (0.0)
G/G = 108 (98.18)G/G = 145 (100)
Tan et al. 2005 [59] Replication studyNonlesional TLECaucasian NS
A/A = (0.0)A/A = (0.0)
A/G = 1 (0.4)A/G = 1 (0.6)
G/G = 233 (99.6)G/G = 163 (99.4)
Stögmann et al. 2006 [60]TLECaucasian NS
A/A = 0 (0.0)A/A = 0 (0.0)
A/G = 2 (1.1)A/G = 0 (0.0)
G/G = 186 (98.9)G/G = 259 (100)
Ren et al. 2005 [61]Nonlesional TLEChinese NS
A/A = 0 (0.0)A/A = 0 (0.0)
A/G = 0 (0.0)A/G = 0 (0.0)
G/G = 112 (100)G/G = 124 (100)
Wang et al. 2008 [62]TLEChinese NS
A/A = 0 (0.0)A/A = 0 (0.0)
A/G = 0 (0.0)A/G = 0 (0.0)
G/G = 315 (100)G/G = 318 (100)
Kauffman et al. 2008 [63]TLE-HS+Argentinean 3.788e−8
A/A = 0 (0.0)A/A = 0 (0.0)
A/G = 49 (48.0)A/G = 6 (8.5)
G/G = 53 (52.0)G/G = 65 (91.5)
GABBR2G>A → intron 1Wang et al. 2008 [62]TLEChinese 0.003
(rs967932)Initial studyA/A = 72 (22.64)A/A = 63 (20.0)
A/G = 164 (51.57)A/G = 136 (43.17)
G/G = 82 (25.79)G/G = 116 (36.83)
PDYN68 bp tandem repeat → promoter Stögmann et al. 2002 [64]Nonlesional TLE,Caucasian 0.005
H-allele = 3 or 4 repeatsInitial studyfamilial riskL/L = 10 (23.3)L/L = 18 (8.9)
L-allele = 1 or 2 repeatsL/H = 23 (53.5)L/H = 88 (43.6)
(rs71193945)H/H = 10 (23.3)H/H = 96 (47.5)
Gambardella et al. 2003 [65] Replication studyNonlesional TLE, familial riskCaucasian NS
L/L = 9 (7.8)L/L = 16 (6.2)
L/H = 40 (34.8)L/H = 105 (40.5)
H/H = 66 (57.4)H/H = 138 (53.3)
Tilgen et al. 2003 [66] Replication studyNonlesional TLE, familial riskCaucasian NS
L/L = 3 (7.0)L/L = 22 (11.0)
L/H = 21 (45.0)L/H = 84 (41.0)
H/H = 22 (48.0)H/H = 99 (48.0)
Cavalleri et al. 2005 [5] Replication studyNonlesional TLE, familial riskCaucasian NS
L/L = 8 (17.0)L/L = 30 (8.0)
L/H = 22 (47.0)L/H = 160 (44.0)
H/H = 17 (36.0)H/H = 175 (48.0)
Salzmann et al. 2008 [67] Replication studyNonlesional TLE, familial riskCaucasian NS
L/L = 2 (9.5)L/L = 14 (6.8)
L/H = 11 (52.4)L/H = 78 (37.9)
H/H = 8 (38.1)H/H = 114 (55.3)
Kauffman et al. 2008 [68]Nonlesional TLE, familial riskArgentinean NS
L/L = 1 (5.5)L/L = 8 (9.3)
L/H = 8 (44.5)L/H = 37 (43.0)
H/H = 9 (50.0)H/H = 41 (47.7)

ApoEIsoform ε4 (CI056481)Gambardella et al. 1999 [69]Nonlesional TLECaucasian NS
Initial studyε4+ = 5; years not indicated
ε4= 58; years not indicated
Briellmann et al. 2000 [70]Early onset of TLECaucasian 0.004
Replication studyassociated with ε4ε4+ = 10; years
ε4= 33; years
Cavalleri et al. 2005 [5]Early onset of TLECaucasian NS
Replication studyassociated with ε4ε4+ = 30; years
ε4= 151; years
Gambardella et al. 2005 [71]Early onset of TLECaucasian NS
Replication studyassociated with ε4ε4+ = 24; years
ε4= 114; years
Yeni et al. 2005 [72]Early onset ofTurkish NS
TLE-HS+ε4+ = 8; years
associated with ε4ε4 = 39; years
Salzmann et al. 2008 [67]Early onset of TLECaucasian 0.003
Replication studyassociated with ε4ε4+ = 26; years
ε4= 80; years
Kauffman et al. 2010 [73]Early onset ofArgentinean NS
TLE-HS+ε4+ = 23; years
associated with ε4ε4 = 55; years

IL-1αc.−889C>T → promoterKanemoto et al. 2000 [74]TLE-HS+/−JapaneseTLE-HS+ TLE-HS+ versus
Allele 1 = CInitial study 1/1 = 87 (77.7)controls = NS
Allele 2 = T (unknown)1/1 = 38 (76.0)1/2 = 25 (22.3)
1/2 = 10 (20.0)2/2 = 0 (0.0)
2/2 = 2 (4.0)
TLE-HSTLE-HS versus
controls = NS
1/1 = 44 (83.0)
1/2 = 8 (15.1)
2/2 = 1 (1.9)
Ozkara et al. 2006 [75]TLE-HS+Turkish NS
1/1 = 23 (48.9)1/1 = 37 (37.3)
1/2 = 23 (48.9)1/2 = 52 (52.5)
2/2 = 1 (2.1)2/2 = 10 (10.1)
Ozkara et al. 2006 [75]TLE-FS+/−TurkishTLE-FS+TLE-FS+ versus
Initial study TLE-FS = NS
1/1 = 16 (57.1)
1/2 = 12 (42.8)
2/2 = 0 (0.0)
TLE-FS
1/1 = 9 (47.3)
1/2 = 10 (52.6)
2/2 = 0 (0.0)
Salzmann et al. 2008 [67]TLE-HS+/−CaucasianTLE-HS+ TLE-HS+ versus
1/1 = 99 (42.1)controls = 0.027
1/1 = 50 (58.1)1/2 = 118 (50.2)
1/2 = 29 (33.7)2/2 = 8 (7.7)
2/2 = 7 (8.1)
TLE-HSTLE-HS versus
controls = NS
1/1 = 15 (65.2)
1/2 = 7 (30.4)
2/2 = 1 (4.4)
TLE-FSCaucasianTLE-FSTLE-FS+ versus
controls =0.0078
1/1 = 33 (61.1)
1/2 = 16 (29.6)
2/2 = 5 (9.3)
IL-1RA86 bp tandem repeat → intron 2Kanemoto et al. 2000 [74]TLE-HS+/−JapaneseTLE-HS+ TLE-HS+ versus
Allele 4 = 5 repeatsInitial study 1/1 = 102 (91.9)controls = NS
Allele 1 = 4 repeats1/1 = 46 (92.0)1/2 = 6 (5.4)
Allele 2 = 2 repeats1/2 = 3 (6.0)1/3 = 1 (0.9)
Allele 3 = 3 repeats1/3 = 1 (2.0)1/4 = 2 (1.8)
Allele 5 = 6 repeats (rs2234663)1/4 = 0 (0.0)
TLE-HSTLE-HS versus
controls = NS
1/1 = 52 (98.1)
1/2 = 1 (1.9)
1/3 = 0 (0.0)
1/4 = 0 (0.0)
Salzmann et al. 2008 [67]TLE-HS+/−CaucasianTLE-HS+ TLE-HS+ versus
1/1 = 128 (52.9)controls = NS
1/1 = 43 (50.0)1/2 = 90 (37.2)
1/2 = 36 (41.9)1/4 = 5 (2.1)
1/4 = 1 (1.2)1/5 = 0 (0.0)
1/5 = 0 (0.0)2/2 = 16 (6.6)
2/2 = 6 (7.0)2/4 = 3 (1.2)
2/4 = 0 (0.0)
TLE-HSTLE-HS versus
controls = 0.001
1/1 = 5 (21.7)
1/2 = 13 (56.5)
1/4 = 0 (0.0)
1/5 = 1 (4.3)
2/2 = 4 (17.4)
2/4 = 0 (0.0)

IL-1βc.−511C>T → promoterKanemoto et al. 2000 [74]TLE-HS+/−JapaneseTLE-HS+ TLE-HS+ versus
Allele 1 = CInitial study 1/1 = 31 (27.7)controls =0.0085
Allele 2 = T (rs1799916)1/1 = 9 (18.0)1/2 = 58 (51.8)
1/2 = 19 (38.0)2/2 = 23 (20.5)
2/2 = 22 (44.0)
TLE-HSTLE-HS versus
controls = NS
1/1 = 13 (24.5)
1/2 = 30 (56.6)
2/2 = 10 (18.9)
Kanemoto et al. 2003 [76]TLE-HS+/−JapaneseTLE-HS+ TLE-HS+ versus
16 TLE-HS+ and 11 TLE-HS 1/1 = 44 (27.0)controls =0.0028
were added to1/1 = 12(18.2)1/2 = 82 (50.3)
initial study [74]1/2 = 24 (36.4)2/2 = 37 (22.7)
2/2 = 30 (45.5)
TLE-HSTLE-HS versus
controls = NS
1/1 = 16 (25.0)
1/2 = 36 (56.3)
2/2 = 12 (18.7)
Heils et al. 2000 [77]TLE-HS+Caucasian NS
1/1 = 33 (38.0)1/1 = 57 (42.0)
1/2 = 42 (49.0)1/2 = 60 (45.0)
2/2 = 11 (13.0)2/2 = 16 (12.0)
Buono et al. 2001 [78]TLE-HS+Caucasian NS
1/1 = 31 (50.8)1/1 = 44 (37.0)
1/2 = 24 (39.3)1/2 = 68 (57.1)
2/2 = 6 (9.8)2/2 = 7 (5.9)
Jin et al. 2003 [79]TLE-HS+/−ChineseTLE-HS+ TLE-HS+ versus
1/1 = 26 (23.0)controls = NS
1/1 = 16 (24.0)1/2 = 62 (54.0)
1/2 = 32 (48.0)2/2 = 27 (23.0)
2/2 = 19 (28.0)
TLE-HSTLE-HS versus
controls = NS
1/1 = 12 (27.0)
1/2 = 24 (53.0)
2/2 = 9 (20.0)
Cavalleri et al. 2005 [5]TLE-HS+Caucasian NS
1/1 = 59 (45.0)1/1 = 161 (44.0)
1/2 = 57 (44.0)1/2 = 162 (45.0)
2/2 = 15 (11.0)2/2 = 41 (11.0)
Ozkara et al. 2006 [75]TLE-HS+Turkish NS
1/1 = 16 (34.0)1/1 = 41 (41.4)
1/2 = 21 (44.6)1/2 = 41 (41.4)
2/2 = 10 (21.2)2/2 = 17 (17.1)
Ozkara et al. 2006 [75]TLE-FS+/−TurkishTLE-FS +TLE-FS+ versus
Initial study TLE-FS = NS
1/1 = 9 (32.1)
1/2 = 13 (46.4)
2/2 = 6 (21.4)
TLE-FS
1/1 = 5 (26.3)
1/2 = 9 (47.3)
2/2 = 5 (26.3)
Salzmann et al. 2008 [67]TLE-HS+/−CaucasianTLE-HS+ TLE-HS+ versus
1/1 = 99 (43.6)controls = NS
1/1 = 35 (40.7)1/2 = 108 (47.6)
1/2 = 45 (52.3)2/2 = 20 (8.8)
2/2 = 6 (7.0)
TLE-HSTLE-HS versus controls = NS
1/1 = 12 (52.2)
1/2 = 9 (39.1)
2/2 = 2 (8.7)

IL-1βIL-1β + 3953 → exon 5
Kanemoto et al. 2000 [74]TLE-HS+/−JapaneseTLE-HS+ TLE-HS+ versus
Initial study 1/1 = 105 (93.8)controls = NS
Allele 1 and allele 21/1 = 45 (90.0)1/2 = 7 (6.3)
(CM040228)1/2 = 5 (10.0)2/2 = 0 (0.0)
2/2 = 0 (0.0)
TLE-HSTLE-HS versus
controls = NS
1/1 = 49 (92.5)
1/2 = 3 (5.7)
2/2 = 1 (1.9)
Ozkara et al. 2006 [75]TLE-HS+Turkish NS
1/1= 28 (59.5)1/1= 63 (63.6)
1/2 = 18 (38.2)1/2 = 30 (30.3)
2/2 = 1 (2.1)2/2 = 17 (17.1)
Ozkara et al. 2006 [75]TLE-FS+/−TurkishTLE-FS+TLE-FS+ versus
Initial study TLE-FS = NS
1/1 = 19 (67.8)
1/2 = 9 (32.1)
2/2 = 0 (0.0)
TLE-FS
1/1 = 12 (63.1)
1/2 = 7 (36.8)
2/2 = 0 (0.0)
Salzmann et al. 2008 [67]TLE-HS+/−CaucasianTLE-HS+ TLE-HS+ versus
1/1 = 118 (50.4)controls = NS
1/1 = 45 (52.3)1/2 = 101 (43.2)
1/2 = 34 (39.5)2/2 = 15 (6.4)
2/2 = 7 (8.2)
TLE-HSTLE-HS versus
controls = NS
1/1 = 14 (60.9)
1/2 = 8 (34.8)
2/2 = 1 (4.3)

PRNPp.Asn171Ser (CM971239)Walz et al. 2003 [80]RefractoryBrazilianSeizure-freeSeizure-free
Initial studyTLE-HS+ versus Seizure =
Asn/Asn = 70 (82.4)0.005
Asn/Ser = 15 (17.6)
Seizure
Asn/Asn = 6 (46.2)
Asn/Ser = 7 (53.8)
Cavalleri et al. 2005 [5]RefractoryCaucasian NS
TLE-HS+Asn/Asn = 109 (100)Asn/Asn = 360 (99.8)
Asn/Ser = 0 (0.0)Asn/Ser = 1 (0.2)
Ser/Ser = 0 (0.0)Ser/Ser = 0 (0.0)

PRNPp.Met129Val (CM890104)Labate et al. 2007 [81]Women,Caucasian 0.021
Initial studynonlesional TLEMet/Met = 64 (39.5)Met/Met = 77 (54.6)
Met/Val = 77 (47.5)Met/Val = 54 (38.3)
Val/Val = 21 (13.0)Val/Val = 10 (7.1)
Wang et al. 2008 [82]Women,Chinese NS
nonlesional TLEMet/Met = 146 (97.33)Met/Met = 302 (96.79)
Met/Val = 4 (2.67)Met/Val = 10 (3.31)
Val/Val = 0 (0.0)Val/Val = 0 (0.0)

5-HTT5-HTTLPR ins/del → 5′UTRManna et al. 2007 [83]Nonlesional TLECaucasian NS
S-allele = short variantInitial studyL/L = 77 (21.1)L/L = 90 (29.1)
L-allele = long variantL/S = 146 (60.6)L/S = 142 (46.0)
(rs12720056)S/S = 53 (18.3)S/S = 77 (24.9)
Stefulj et al. 2010 [84]TLECaucasian NS
L/L = 42 (41.6)L/L = 60 (35.3)
L/S = 45 (44.6)L/S = 93 (54.7)
S/S = 14 (13.9)S/S = 17 (10.0)
Schenkel et al. 2011 [85]TLEBrazilian NS
L/L = 48 (27.4)L/L = 54 (34.8)
L/S = 91 (52.0)L/S = 64 (41.3)
S/S = 36 (20.6)S/S = 37 (23.9)

5-HTT17 bp tandem repeat → intron 2Manna et al. 2007 [83]Nonlesional TLECaucasian 0.0145
9, 10 and 12 repeatsInitial study12/12 = 126 (48.6)12/12 = 115 (37.2)
(rs71360731)12/10 = 112 (46.2)12/10 = 136 (44.0)
10/10 = 38 (5.2)10/10 = 58 (18.8)
Kauffman et al. 2009 [86]Response toArgentineanNonresponsiveNonresponsive versus
treatment responsive =0.006
TLE-HS+12/12 = 40 (54.0)
12/10 = 23 (31.0)
10/10 = 10 (13.5)
12/9 = 1 (1.5)
Responsive
12/12 = 7 (22.6)
12/10 = 21 (67.7)
10/10 = 3 (9.7)
12/9 = 0 (0.0)
Stefulj et al. 2010 [84]TLECaucasian NS
12/12 = 30 (30.9)12/12 = 64 (39.5)
12/10 = 46 (47.4)12/10 = 74 (45.7)
10/10 = 21 (21.6)10/10 = 24 (14.8)
Schenkel et al. 2011 [85]TLEBrazilian NS
12/12 = 62 (35.4)12/12 = 67 (43.2)
12/10 = 81 (46.3)12/10 = 67 (43.2)
10/10 = 32 (18.3)10/10 = 21 (13.5)

5-HT1Bc.861C>G → synonymousStefulj et al. 2010 [84]TLECaucasian 0.0642
(rs6296)C/C = 2 (2.0)C/C = 14 (8.2)
G/C = 35 (34.7)G/C = 65 (38.2)
G/G = 64 (63.4)G/G = 91 (53.5)

CALHM1A>G → 3′UTR Lv et al. 2011 [87]
TLEChinese 0.004
(rs11191692)Initial studyA/A = 50 (9.1)A/A = 30 (7.5)
A/G = 257 (46.6)A/G = 149 (37.3)
G/G = 244 (44.3)G/G = 220 (55.1)
Lv et al. 2011 [87]TLEChinese 0.006
Replication studyA/A = 34 (9.4)A/A = 20 (6.8)
A/G = 168 (46.7)A/G = 111 (37.0)
G/G = 158 (43.9)G/G = 169 (56.2)

n: number of individuals; TLE: temporal lobe epilepsy; NS: nonsignificant; TLE-FS+/−: temporal lobe epilepsy with/without personal history of febrile seizures; TLE-HS+/−: temporal lobe epilepsy with/without hippocampal sclerosis; ε4+/−: ε4 present or not; significant -values are in italic.