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Genetics of temporal lobe epilepsy
  1. L Vadlamudi,
  2. I E Scheffer,
  3. S F Berkovic
  1. Epilepsy Research Institute, University of Melbourne, Australia
  1. Correspondence to:
 Professor S Berkovic
 Epilepsy Research Institute, University of Melbourne, Austin Health, First Floor, Neurosciences Building, Banksia Street, Heidelberg West, VIC 3081, Australia;

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Our traditional understanding is that TLE is an acquired condition, but only now are we beginning to understand the extent of genetic involvement

In the second half of the 19th century, John Hughlings Jackson proposed the concept of partial epilepsy, including “uncinate seizures”, based on clinicopathological observations from patients with structural lesions and further supported by pioneering brain surgery.1,2

With the discovery of EEG in the early 20th century, the concepts of temporal lobe epilepsy (TLE) were further elucidated. Gibbs et al3 described widespread slow activity during “psychomotor attacks”; they proposed a diffuse underlying cerebral disturbance, which was not in line with Jackson’s observations. Jasper and Kershman4 then described focal temporal sharp waves in patients they diagnosed with “temporal lobe seizures”. By the middle of the 20th century, the term TLE was widely utilised and much of the subsequent understanding of this disorder was based on pre-surgical studies of intractable cases. Traditionally, TLE has been considered to be an acquired disorder secondary to lesions such as hippocampal sclerosis, tumours, trauma, vascular malformations, and neuronal migration disorders.5

Falconer et al, however, studied the aetiology of TLE in 110 refractory cases and demonstrated 95% of cases had underlying cerebral pathology, but also astutely stated, “these lesions, however may develop on a soil already predisposed to convulsions”.6 In the past 20 years, what is becoming more evident is this evolving key role of genetics in TLE.


In 1995, Ottman et al described partial epilepsy with auditory features linked to chromosome 10q7 and later termed the syndrome autosomal dominant partial epilepsy with auditory features (ADPEAF).8 Similar families mapping to the same region were described with prominent visual features or sensory dysphasia, all suggesting a lateral temporal origin.9,10 ADPEAF is a benign syndrome with onset in the first to third decades of life, no abnormalities on MRI, and no association with febrile seizures (table 1).

Table 1

Familial temporal lobe epilepsy (TLE) subtypes

Debate as to whether the families with somewhat differing clinical features were due to the same gene was settled when Kalachikov et al11 identified mutations in the leucine rich, glioma inactivated 1 (LGI1) gene in five families with ADPEAF and mutations in this gene were also found in families with prominent visual or dysphasic features. LGI1 mutations are not found in all families with ADPEAF, suggesting genetic heterogeneity.12,13 Specificity of LGI1 to ADPEAF has been confirmed by the absence of mutations in different TLE phenotypes (unpublished data, Berkovic et al).

LGI1 was first described in glial tumours where it may be deleted or rearranged, but glial tumours do not occur with increased frequency in ADPEAF. It has been suggested that LGI1 has a role in neuronal migration or cortical organisation.11 Given that the majority of LGI1 mutations cause protein truncation, loss of function is the likely underlying mechanism.11,14 All prior genes that have been discovered for idiopathic epilepsies have been associated with ion channels.15 This discovery suggests new neurobiological mechanisms for familial epilepsies.


In 1994, we described familial mesial temporal lobe epilepsy (FMTLE) as a benign syndrome with onset in the second to fifth decades of life, no temporal lobe or hippocampal abnormalities on MRI, and no association with febrile seizures (table 1).16,17 The nature of the aura, with prominent psychic and autonomic features, suggested mesial temporal origin. The commonest symptom was intense déjà vu; in some cases epilepsy had not been diagnosed and the intense déjà vu was regarded as “normal”. Inheritance is consistent with autosomal dominance with reduced penetrance, but no very large pedigrees have been reported and the disorder is yet to be mapped. The clinical features and good prognosis of FMTLE have since been described by others investigating idiopathic TLE.18–21

FMTLE, hippocampal sclerosis, and febrile seizures

The initial descriptions of ADPEAF and more common syndrome of FMTLE led to the idea of a clinicoradiological distinction between these benign TLE syndromes, without preceding febrile seizures or hippocampal sclerosis, and patients with severe “sporadic” TLE with hippocampal sclerosis and frequently preceding febrile seizures. Subsequently, it has become apparent that the relationship between FMTLE syndromes, hippocampal sclerosis, and febrile seizures is far more complex.

FMTLE often associated with hippocampal sclerosis

Heterogeneity of FMTLE was shown when multiple TLE families with more severe syndromes were described with onset in the first to third decades of life, frequent hippocampal sclerosis, and a variable association with febrile seizures (table 1).22,23 Inheritance in some families is autosomal dominant, but mapping studies are yet to be reported.

These new data add to the puzzle of the aetiology of hippocampal sclerosis. There remains debate as to whether hippocampal sclerosis is the consequence of an early childhood injury (such as prolonged febrile seizures and encephalitis),24 a consequence of ongoing seizures,25 or an early developmental lesion.26 Genetic factors have been implicated since Falconer’s pioneering studies and these large families with hippocampal pathology suggests a major genetic component to its aetiology, at least in certain cases.

FMTLE often associated with febrile seizures

Two large families and some smaller kindred’s have been described with many individuals with both TLE and febrile seizures. The TLE syndrome begins in the first to second decades of life, there are no temporal lobe or hippocampal abnormalities on MRI and the course is benign (table 1).27–29 Digenic inheritance was suggested for the French family, one locus with significant linkage at chromosomes 18qter and one with supportive linkage at 1q25–q31.28 Linkage was not found in the Belgian family to known candidate loci.27

Febrile seizures often associated with mesial TLE

It is more common to find families where there are multiple individuals with febrile seizures and a few with TLE. A large study of such families demonstrated a strong association between prolonged febrile seizures and hippocampal sclerosis.30 Another family has been described with generalised epilepsy with febrile seizures plus, with a few family members with TLE.31 The proband had TLE with hippocampal sclerosis. All affected family members had a sodium channel mutation (SCN1A).


Other familial partial epilepsies have recently been described that include seizures arising from the temporal lobe as part of their spectrum of clinical manifestations.

Familial partial epilepsy with variable foci (FPEVF) was first described by our group (in an Australian family) with onset in the first to third decades of life, heterogeneous seizures types including TLE within the same family, and without associated MRI abnormalities or febrile seizures (table 1).32 There was a suggestion of linkage to chromosome 2q. In 1999 a more definite linkage at chromosome 22q11–q12 was found in two large French–Canadian families with similar clinical features.33

Partial epilepsy with pericental spikes (PEPS) was described in a single Brazilian family as a generally benign syndrome with onset in the first to second decades of life, partial seizures including TLE, characteristic pericentral spikes on EEG, without associated MRI abnormalities or febrile seizures (table 1).34 Linkage was demonstrated to chromosome 4p15.34


The syndromes described above appear to segregate major autosomal dominant genes; these are studied by linkage analysis, a robust technique depending on large families. Many patients with TLE do not have such a strong family history, yet genetic factors are likely to be involved to some extent. Such susceptibility genes have been studied by association studies. Association studies involve large numbers of sporadic cases to determine if there is significant association of epilepsy with a particular polymorphism within a gene.

Identifying susceptibility genes remains challenging, as there is no single locus of large effect, but rather multiple loci probably exist.35 Determination of such genes by association studies has many methodological problems and replication of the initial observation is often negative. Methodological issues include power of the study, false positives and differing ethnic background. Currently four polymorphisms have been suggested as susceptibility genes for TLE.

There has been a reported increased risk of TLE in those with a family history of seizures with polymorphisms of the prodynorphin gene, which encodes dynorphin (anticonvulsant peptide), a strong candidate for a seizure suppressor gene,36 which has not been reproduced by other investigators.37

Polymorphisms of interleukin-1β (IL-1β), IL-1α, and IL-1 receptor antagonist genes have been studied, which encode proinflammatory cytokines that modulate neurotoxic neurotransmitters. Functional polymorphisms in the IL-1β gene associated with TLE and hippocampal sclerosis have been described,38 but not reproduced by others.39,40 Polymorphisms of IL-1 receptor antagonist have been described in susceptibility to febrile convulsions,41 but not found by other investigators.38

Apolipoprotein E (APOE) ε4 allele, promotes deposition of β-amyloid, and evidence from animal studies suggest the brain’s ability to repair damage is impaired by its presence, hence may result in an epileptogenic focus.42,43 It was found that the presence of APOE ε4 allele may shorten latency between initial injury and seizure onset in TLE,42 however associations between APOE polymorphism and TLE were not found in other studies.44,45

Polymorphisms of the GABA (B) receptor 1 gene, which encodes the major inhibitory neurotransmitter in the CNS, have been studied and an association between the G1465A polymorphism and increased susceptibility to TLE was recently described.46 To date, this is the only published study of this association.

We are only beginning to understand the genetics of TLE. Our traditional understanding was that it was an acquired condition, but only now are we beginning to understand the extent of genetic contribution to this condition. In the future we need to continue to find large families to perform linkage analysis in order to determine further candidate genes as well as continue the search for susceptibility genes through association studies.

Our traditional understanding is that TLE is an acquired condition, but only now are we beginning to understand the extent of genetic involvement



  • Competing interests: none declared