EDITORIAL 1359 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.74.10.1362 on 20 October 2003. Downloaded from Temporal lobe epilepsy and good prognosis of FMTLE have ....................................................................................... since been described by others investi- gating idiopathic TLE.18–21 Genetics of temporal lobe epilepsy FMTLE, hippocampal sclerosis, and febrile seizures L Vadlamudi, I E Scheffer, S F Berkovic The initial descriptions of ADPEAF and more common syndrome of FMTLE led ................................................................................... to the idea of a clinicoradiological Our traditional understanding is that TLE is an acquired condition, distinction between these benign TLE syndromes, without preceding febrile but only now are we beginning to understand the extent of genetic seizures or hippocampal sclerosis, and involvement patients with severe ‘‘sporadic’’ TLE with hippocampal sclerosis and fre- quently preceding febrile seizures. n the second half of the 19th century, MRI, and no association with febrile Subsequently, it has become apparent John Hughlings Jackson proposed the seizures (table 1). that the relationship between FMTLE concept of partial epilepsy, including Debate as to whether the families I syndromes, hippocampal sclerosis, and ‘‘uncinate seizures’’, based on clinico- with somewhat differing clinical fea- febrile seizures is far more complex. pathological observations from patients tures were due to the same gene was with structural lesions and further sup- settled when Kalachikov et al11 identified ported by pioneering brain surgery.12 mutations in the leucine rich, glioma FMTLE often associated with With the discovery of EEG in the early inactivated 1 (LGI1) gene in five hippocampal sclerosis 20th century, the concepts of temporal families with ADPEAF and mutations Heterogeneity of FMTLE was shown lobe epilepsy (TLE) were further eluci- in this gene were also found in families when multiple TLE families with more dated. Gibbs et al3 described widespread with prominent visual or dysphasic severe syndromes were described with slow activity during ‘‘psychomotor features. LGI1 mutations are not found onset in the first to third decades of life, frequent hippocampal sclerosis, and a attacks’’; they proposed a diffuse under- in all families with ADPEAF, suggesting variable association with febrile seizures lying cerebral disturbance, which was genetic heterogeneity.12 13 Specificity of (table 1).22 23 Inheritance in some not in line with Jackson’s observations. LGI1 to ADPEAF has been confirmed by families is autosomal dominant, but Jasper and Kershman4 then described the absence of mutations in different mapping studies are yet to be reported. focal temporal sharp waves in patients TLE phenotypes (unpublished data, These new data add to the puzzle of they diagnosed with ‘‘temporal lobe Berkovic et al). the aetiology of hippocampal sclerosis. copyright. seizures’’. By the middle of the 20th LGI1 was first described in glial There remains debate as to whether century, the term TLE was widely tumours where it may be deleted or hippocampal sclerosis is the conse- utilised and much of the subsequent rearranged, but glial tumours do not quence of an early childhood injury understanding of this disorder was occur with increased frequency in (such as prolonged febrile seizures and based on pre-surgical studies of intract- ADPEAF. It has been suggested that encephalitis),24 a consequence of able cases. Traditionally, TLE has been LGI1 has a role in neuronal migration or ongoing seizures,25 or an early develop- considered to be an acquired disorder 11 cortical organisation. Given that the mental lesion.26 Genetic factors have secondary to lesions such as hippo- majority of LGI1 mutations cause pro- been implicated since Falconer’s pio- campal sclerosis, tumours, trauma, tein truncation, loss of function is the neering studies and these large families vascular malformations, and neuronal 11 14 likely underlying mechanism. All with hippocampal pathology suggests a migration disorders.5 prior genes that have been discovered major genetic component to its aetiol- Falconer et al, however, studied the for idiopathic epilepsies have been asso- ogy, at least in certain cases. http://jnnp.bmj.com/ aetiology of TLE in 110 refractory cases ciated with ion channels.15 This discov- and demonstrated 95% of cases had ery suggests new neurobiological FMTLE often associated with underlying cerebral pathology, but also mechanisms for familial epilepsies. astutely stated, ‘‘these lesions, however febrile seizures Two large families and some smaller may develop on a soil already predis- FAMILIAL MESIAL TEMPORAL kindred’s have been described with posed to convulsions’’.6 In the past 20 LOBE EPILEPSY many individuals with both TLE and years, what is becoming more evident is In 1994, we described familial mesial febrile seizures. The TLE syndrome this evolving key role of genetics in TLE. on September 30, 2021 by guest. Protected temporal lobe epilepsy (FMTLE) as a begins in the first to second decades of benign syndrome with onset in the life, there are no temporal lobe or AUTOSOMAL DOMINANT second to fifth decades of life, no hippocampal abnormalities on MRI PARTIAL EPILEPSY WITH temporal lobe or hippocampal abnorm- and the course is benign (table 1).27–29 AUDITORY FEATURES alities on MRI, and no association with Digenic inheritance was suggested for In 1995, Ottman et al described partial febrile seizures (table 1).16 17 The nature the French family, one locus with epilepsy with auditory features linked to of the aura, with prominent psychic and significant linkage at chromosomes chromosome 10q7 and later termed the autonomic features, suggested mesial 18qter and one with supportive linkage syndrome autosomal dominant partial temporal origin. The commonest symp- at 1q25–q31.28 Linkage was not found in epilepsy with auditory features tom was intense de´ja` vu; in some cases the Belgian family to known candidate (ADPEAF).8 Similar families mapping epilepsy had not been diagnosed and the loci.27 to the same region were described with intense de´ja` vu was regarded as ‘‘nor- prominent visual features or sensory mal’’. Inheritance is consistent with Febrile seizures often associated dysphasia, all suggesting a lateral tem- autosomal dominance with reduced with mesial TLE poral origin.910 ADPEAF is a benign penetrance, but no very large pedigrees It is more common to find families where syndrome with onset in the first to third have been reported and the disorder is there are multiple individuals with feb- decades of life, no abnormalities on yet to be mapped. The clinical features rile seizures and a few with TLE. A large www.jnnp.com 1360 EDITORIAL J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.74.10.1362 on 20 October 2003. Downloaded from Table 1 Familial temporal lobe epilepsy (TLE) subtypes TLE in broader partial epilepsy syndromes Familial mesial (FM) TLE syndromes* syndrome FMTLE no HS no FMTLE often HS FMTLE with FS Syndrome ADPEAF7–11 FS16–20 +/2FS22 23 usually no HS27 28 FPEVF32 33 PEPS34 Typical age of onsetÀ 8 years to 4th decade 10 years to 4th 1 year to 3rd 1 year to 2nd 1 year to 4th decade 2 years to 2nd decade decade decade decade Characteristic features Auditory, sensory aura Psychic, autonomic Seizures with different Multiple seizure types aura focal origin in family in the same individual members EEG Rare temporal discharges Rare temporal Frequent temporal Occasional Occasional temporal Frequent peri-central discharges discharges temporal discharges spikes discharges MRI Normal Normal HS Normal Normal Normal Outcome Generally benign Generally benign Often refractory Variable Variable Generally benign Linkage 10q – 18qt,1q (?) 22q,2q (?)4p Genes LGI1 – – – – – *These divisions are preliminary and they are probably overlapping mesial TLE syndromes. ÀRange of onset ages reflects the majority of reported cases. Some ‘‘outliers’’ may begin earlier or later, but most family members fall within the stated ranges. ADPEAF, autosomal dominant partial epilepsy with auditory features; HS, hippocampal sclerosis; FS, febrile seizures; FPEVF, familial partial epilepsy with variable foci; PEPS, partial epilepsy with pericentral spikes. study of such families demonstrated a analysis, a robust technique depending evidence from animal studies suggest strong association between prolonged on large families. Many patients with the brain’s ability to repair damage is febrile seizures and hippocampal sclero- TLE do not have such a strong family impaired by its presence, hence may sis.30 Another family has been described history, yet genetic factors are likely to result in an epileptogenic focus.42 43 It with generalised epilepsy with febrile be involved to some extent. Such sus- was found that the presence of APOE e4 seizures plus, with a few family members ceptibility genes have been studied by allele may shorten latency between with TLE.31 The proband had TLE with association studies. Association studies initial injury and seizure onset in hippocampal sclerosis. All affected family involve large numbers of sporadic cases TLE,42 however associations between members had a sodium channel muta- to determine if there is significant APOE polymorphism and TLE were not tion (SCN1A). association of epilepsy with a particular found in other studies.44 45 polymorphism within a gene. Polymorphisms of the GABA (B) copyright. Identifying susceptibility genes TLE