Epilepsy, Familial Temporal Lobe, 1

A number sign (#) is used with this entry because autosomal dominant familial temporal lobe epilepsy-1 (ETL1) is caused by heterozygous mutation in the LGI1 gene (604619) on chromosome 10q24.

Description

Autosomal dominant lateral temporal lobe epilepsy is a specific form of temporal lobe epilepsy characterized by partial seizures originating from the temporal lobe. Seizures are usually accompanied by sensory symptoms, most often auditory in nature (summary by Winawer et al., 2000).

Genetic Heterogeneity of Temporal Lobe Epilepsy

See also ETL2 (608096), which maps to chromosome 12q; ETL3 (611630), which maps to chromosome 4q; ETL4 (611631), which maps to chromosome 9q; ETL5 (614417), caused by mutation in the CPA6 gene (609562) on chromosome 8q13; ETL6 (615697), which maps to chromosome 3q25-q26; ETL7 (616436), caused by mutation in the RELN gene (600514) on chromosome 7q22; and ETL8 (616461), caused by mutation in the GAL gene (137035) on chromosome 11q13.

Clinical Features

Most partial or focal epilepsies in which seizures begin in a specific brain region are assumed to be nongenetic. However, relatives of probands with partial epilepsy have an increased risk of epilepsy compared with the general population, suggesting a genetic influence on at least some partial epilepsies (Ottman et al., 1995).

Ottman et al. (1995) studied a family in which 11 individuals in 3 generations had partial epilepsy classified as idiopathic/cryptogenic. Epilepsy was clearly localization-related in all but 1 of the individuals; the remaining person had only nocturnal seizures and thus could not be classified. In 6 of those with idiopathic/cryptogenic epilepsy and in 1 with remote symptomatic epilepsy, nonspecific auditory disturbances (such as a ringing noise that grew louder or a humming like a machine) were reported as a simple partial component of their seizures. None of the interictal EEGs showed an epileptiform abnormality. The age at onset of epilepsy ranged from 8 to 19 years. All family members had normal intelligence. Seizures occurred infrequently; 7 of the 11 had been free of seizures for 3 years or more before interview. Phenytoin was the primary anti-seizure medication prescribed in 10 of the 11 subjects; the remaining subject received carbamazapine. Ottman et al. (1995) noted that the auditory features suggested a neocortical (or lateral) temporal lobe origin.

Winawer et al. (2000) described the family reported by Ottman et al. (1995) in further detail. Partial seizures were characterized most frequently by sensory symptoms (73% of subjects), including a high frequency of auditory symptoms (55% of subjects), followed in frequency by cephalic, visual, olfactory, and vertiginous symptoms. Somatosensory auras were not reported. Autonomic symptoms (visceral/epigastric and cardiac palpitations) occurred in 45% of patients. Occasional psychic/emotional symptoms were reported (e.g., fear, deja vu, panic, depersonalization). The auditory symptoms ranged from unformed sounds, such as humming and ringing, to distortions and volume changes. Some reported formed sounds, singing and voices, and one subject's description suggested seizures provoked by auditory stimuli. Winawer et al. (2000) emphasized that the features suggested a lateral temporal lobe onset zone.

Brodtkorb et al. (2002) reported a large Norwegian family in which 20 members over 5 generations had seizures in an autosomal dominant pattern. Twelve affected members were studied: mean age of onset was 18 years (range 4-42); 11 had simple partial seizures, 8 of which were characterized by aphasic features, and many experienced auditory hallucinations; all had secondary generalized tonic-clonic seizures that improved with age. EEG recordings in 4 patients showed temporal lobe activity and the symptoms suggested localization to the lateral neocortical temporal lobe. Two patients died unexpectedly in their twenties.

In 3 of 10 families with autosomal dominant partial epilepsy with auditory features, Ottman et al. (2004) identified different mutations in the LGI1 gene that cosegregated with the disease phenotype. Including data from an earlier report (Kalachikov et al., 2002), Ottman et al. (2004) estimated a disease penetrance of 54% (35 to 73%) and noted that LGI1 mutations had been identified in approximately 50% of families tested, suggesting genetic heterogeneity. There were no specific clinical features unique to those patients with LGI1 mutations, but autonomic symptoms were less common and auditory symptoms more common in those with LGI1 mutations. The most common auditory symptoms were simple, unformed sounds, such as buzzing and ringing. A subset of patients with mutations also had idiopathic generalized epilepsy.

In affected members of 2 of 4 families with ADPEAF, Berkovic et al. (2004) identified heterozygous mutations in the LGI1 gene. One of the families was of Ashkenazi Jewish descent and the other, previously reported by Berkovic et al. (1996), was Australian of British descent. Age at onset ranged from 8 to 50 years (mean, 19.2 years), and auditory auras occurred in 10 of 14 affected individuals. Five individuals had visual symptoms and 7 had secondarily generalized seizures.

Michelucci et al. (2007) reported a 36-year-old woman with lateral temporal lobe epilepsy manifest as telephone-induced seizures. She had an 11-year history of recurrent partial complex and secondarily generalized seizures evoked almost exclusively by answering the telephone. Other auditory stimuli could also elicit seizures. The seizures were accompanied by distortion or attenuation of sound, inability to understand language, and inability to speak appropriately, all consistent with lateral temporal lobe involvement. Genetic analysis identified a de novo mutation in the LGI1 gene (604619.0010).

Using high-resolution structural brain MRI, Ottman et al. (2008) found no evidence for structural brain anomalies in any of 17 affected individuals from 7 families with genetically-confirmed ADPEAF. However, functional MRI and magnetoencephalography indicated that that individuals with ADPEAF have deficits in auditory and language processing.

Inheritance

ADPEAF follows autosomal dominant inheritance with decreased penetrance. By analyzing data from 24 previously published families with ADPEAF and mutations in the LGI gene, Rosanoff and Ottman (2008) found that the overall penetrance of the disorder was 67% and did not vary according to mutation type or location in the gene.

Mapping

In the family with 11 affected individuals studied by Ottman et al. (1995), linkage analysis showed strong evidence for localization of a gene for partial epilepsy on 10q. They obtained a maximum 2-point lod score for D10S192 of 3.99 at theta = 0.0. All affected persons shared a single haplotype for 7 tightly linked contiguous markers; the maximum lod score for this haplotype was 4.83 at theta = 0.0. Key recombinants placed the susceptibility locus within a 10-cM interval. The cytogenetic location of the locus as determined by Ottman et al. (1995) was 10q22-q24.

Poza et al. (1999) described autosomal dominant lateral temporal epilepsy in a large Basque pedigree showing linkage to 10q. Mautner et al. (2000) reported findings consistent with linkage to 10q in a 4-generation family with 9 individuals with temporal partial epilepsy. The phenotype was characterized by a short acoustic aura followed by rapid secondary generalization.

By 2-point linkage analysis in their large Norwegian family, Brodtkorb et al. (2002) defined a region on chromosome 10q22-q24 that overlapped with the regions defined by Ottman et al. (1995) and Poza et al. (1999).

Molecular Genetics

Kalachikov et al. (2002) constructed a complete, 4.2-Mb physical map across the genetically implicated disease-gene region, identified 28 putative genes, and resequenced all or part of 21 genes before identifying presumptive mutations in 1 copy of the leucine-rich, glioma-inactivated-1 gene (604619.0001-604619.0003) in each of 5 families with ADPEAF. Previous studies had indicated that loss of both copies of LGI1 promotes glial tumor progression. Kalachikov et al. (2002) showed that the expression pattern of mouse Lgi1 is predominantly neuronal and is consistent with the anatomic regions involved in temporal lobe epilepsy. Although it was not clear how the homozygous loss of a predominantly neuronal gene resulted in glial tumor progression, it was considered that such an effect is possible because neurons are known to inhibit glial mitosis and because interactions between neurons and glia apparently establish precisely regulated homeostasis in these 2 tissues.

In the Norwegian family reported by Brodtkorb et al. (2002), Gu et al. (2002) identified a cys46-to-arg mutation (C46R; 604619.0004) in the LGI1 gene.

In affected members of 2 of 4 families with ADPEAF, Berkovic et al. (2004) identified heterozygous mutations in the LGI1 gene. In affected members of the other 2 unrelated families with ADPEAF, they did not identify mutations in the LGI1, LGI2 (608301), LGI3 (608302), or LGI4 (608303) genes. Furthermore, Berkovic et al. (2004) did not identify mutations in the LGI1 gene in 50 unrelated families or in 21 individuals with other forms of temporal lobe epilepsy, suggesting that LGI1 mutations are specific for ADPEAF.

Fanciulli et al. (2012) identified a heterozygous 81-kb deletion encompassing a portion of the upstream region and the first 4 exons of the LGI1 gene (604619.0012) in affected members of a 3-generation Italian family with classic ADLTE. The deletion was found by CNV analysis after exon sequencing of the gene failed to identify a point mutation. The findings suggested that CNV analysis is a useful diagnostic tool for this disorder.

Nomenclature

Winawer et al. (2000) referred to the disorder as autosomal dominant partial epilepsy with auditory features (ADPEAF).

Brodtkorb et al. (2002) suggested the term '10q-linked partial epilepsy' for this disorder.