Epilepsy, Familial Temporal Lobe, 2

Description

Familial temporal lobe epilepsy (FTLE, ETL) is a genetically heterogeneous syndrome characterized by relatively benign simple or complex partial seizures with intense psychic or autonomic auras (Berkovic et al., 1996).

For a discussion of genetic heterogeneity of temporal lobe epilepsy, see ETL1 (600512).

Clinical Features

Berkovic et al. (1996) reported 38 individuals from 13 unrelated families with familial temporal lobe epilepsy. Of 22 monozygotic twin pairs in which 1 or both twins had partial epilepsy, 5 pairs were concordant and all had cryptogenic TLE. Mean age of onset in all patients was 24 years, and none had a history of prenatal or perinatal insult or illness. Thirty-four individuals had simple partial seizures, with psychic or autonomic components suggestive of a limbic or mesial temporal origin. Twenty-five individuals had complex partial seizures, and 25 had rare generalized tonic-clonic seizures. Brain MRI of 17 patients showed no abnormalities. In most subjects, seizures were mild, infrequent, and responsive to treatment. Berkovic et al. (1996) noted that the mild and sometimes subtle nature of the symptoms were often not reported. Analysis of the families involved suggested autosomal dominant inheritance with incomplete penetrance. The authors noted that the disorder showed similarities to the 'El' mouse, a genetic model of TLE involving a major gene on mouse chromosome 9 (see ANIMAL MODEL).

Cendes et al. (1998) described the clinical characteristics of 30 patients with TLE from 11 kindreds. Mean age of onset was 12 years. Seizure types included simple partial (55%), complex partial (81%), and rare secondarily generalized tonic-clonic (75%). Those with simple partial seizures had psychic, autonomic, and sensory manifestations. Seizures were well-controlled only in some patients, and 11 of 18 patients with available MRI had findings compatible with mesial temporal sclerosis. Cendes et al. (1998) noted that some of their patients resembled those reported by Berkovic et al. (1996), but that many had a more severe course, indicating clinical heterogeneity, and possibly genetic heterogeneity.

Gambardella et al. (2000) reported a large kindred from southern Italy with benign familial temporal lobe epilepsy with age of onset ranging from 17 to 52 years (mean, 27 years). The disorder was characterized by partial seizures with vegetative or experiential phenomena, suggestive of a temporal origin. Rare complex partial seizures and generalized seizures also occurred. Neurologic examination and brain imaging were normal. Genealogic study strongly supported autosomal dominant inheritance with incomplete penetrance.

Santos et al. (2002) reported 14 unrelated families in which 72 members were affected with temporal lobe epilepsy with ictal semiology of a mesial temporal onset and MRI abnormalities in the mesial structures. In 1 large family, the authors excluded linkage to the locus on chromosome 10q for lateral temporal lobe epilepsy (ETL1; 600512). Santos et al. (2002) emphasized the clinical and genetic heterogeneity among familial forms of TLE.

Depondt et al. (2002) reported a 5-generation family affected by familial temporal lobe epilepsy and febrile seizures but without hippocampal sclerosis. The disease phenotype was characterized by temporal lobe epilepsy, no deja vu or auditory or visual hallucinations, a high incidence of febrile seizures, mean age at onset of afebrile seizures of 8 years, low incidence of epileptic features on electroencephalography, no hippocampal sclerosis, and a usually good prognosis. Of 22 patients in the family, 10 had febrile seizures and epilepsy, 11 had epilepsy only, and 1 had febrile seizures only. All febrile seizures ceased by the age of 6 years. Spontaneous remission occurred in 11 patients; 3 patients had refractory seizures. An autosomal dominant pattern of inheritance with reduced disease penetrance of 80% was seen.

Gurnett et al. (2007) reported a North American Caucasian family in which 7 members had febrile seizures, 3 of whom developed childhood afebrile seizures. Four individuals had febrile status epilepticus, 3 required intensive care unit hospitalization, and 1 had significant global developmental delay as a consequence. Seizures were generalized tonic-clonic, although 2 patients had febrile seizures with focal features. Gurnett et al. (2007) emphasized that none of the individuals manifested clear evidence of temporal lobe epilepsy.

Biochemical Features

In hippocampal tissue from 10 patients with intractable temporal lobe epilepsy, Henshall et al. (2004) found increased DAP kinase (600831) expression and phosphorylation compared to controls. In control brains, DAP kinase and the DAP kinase-interacting protein-1 (DIP1; 608677) colocalized within the mitochondria, whereas in epilepsy brain tissue, levels of both were increased in the cytoplasm and microsomal fractions (endoplasmic reticulum). Coimmunoprecipitation analysis showed increased DAP kinase binding to calmodulin (114180), DIP1, and the Fas-associated protein with death domain (FADD; 602457) in neurons of epilepsy brain tissue compared to controls. Henshall et al. (2004) suggested that DAP kinase is a molecular regulator of neuronal death in epilepsy.

Yang et al. (2004) found significantly decreased levels of cytosolic acyl-CoA hydrolase (ACOT7; 602587) in hippocampal tissue from 5 patients with mesial TLE compared to controls.

Laschet et al. (2007) found that cortical tissue isolated from epileptic patients, mostly with temporal lobe epilepsy, had decreased GAPDH (138400)-induced phosphorylation of the GABRA1 subunit (137160) compared to tissue from nonepileptic controls. There was no apparent difference in subunit composition between the 2 groups, suggesting a deficiency in endogenous phosphorylation. Patch-clamp studies on isolated neurons showed increased functional lability of GABAergic currents in epileptic tissue compared to normal controls.

Mapping

In the family reported by Depondt et al. (2002), Claes et al. (2004) conducted fine mapping and haplotype segregation analysis and narrowed the candidate region to a 10.35-cM (8.7-Mb) interval on 12q22-q23.3, between markers D12S101 and D12S360 (maximum 2-point lod score of 6.94 at theta = 0 for marker D12S1706).

In a 3-generation North American Caucasian family with febrile seizures and childhood afebrile seizures, Gurnett et al. (2007) found suggestive evidence of linkage to chromosome 12q (maximum 2-point lod score of 2.55 at D12S338). A common disease-associated 60-cM haplotype was defined between D12S297 and D12S2070, which included the region identified by Claes et al. (2004). Genetic analysis excluded mutations in the VGLUT3 (607557), ASCL1 (100790), ARL1 (603425), and TMEM16D (610111) genes.

Animal Model

Janjua et al. (1989) documented elevated plasma levels of glutamic acid in El mice, an inbred strain with a genetic predisposition to tonic-clonic seizures in response to vestibular stimulation. The epilepsy in El mice is similar to that of human temporal lobe epilepsy and is considered an excellent model of the latter.

In a study of the neurologic mutant mouse strain El, a model for complex partial seizures in humans, Rise et al. (1991) identified a major gene for this epileptic phenotype (El-1) on mouse chromosome 9. Evidence suggested that at least one other gene, linked to markers on mouse chromosome 2, influenced the seizure phenotype.

Bernard et al. (2004) reported a form of channelopathy that is acquired in experimental temporal lobe epilepsy in rats, corresponding to the most common form of epilepsy in human adults. The excitability of CA1 pyramidal neuron dendrites was increased in temporal lobe epilepsy because of decreased availability of A-type potassium ion channels due to transcriptional (loss of channels) and posttranslational (increased channel phosphorylation by extracellular signal-regulated kinase) mechanisms. Kinase inhibition partly reversed dendritic excitability to control levels. Bernard et al. (2004) suggested that such acquired channelopathy is likely to amplify neuronal activity and may contribute to the initiation and/or propagation of seizures in temporal lobe epilepsy.