Ictal auditory features commonly include simple unformed sounds (buzzing, ringing, clicking, humming), but may also include complex auditory features (voices, music), distorted auditory features (volume changes, muffling), cognitive auditory features (receptive aphasia), reflex auditory features (seizures precipitated by sounds)
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 ... 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 (61163), which maps to chromosome 4q; ETL4 (611631), which maps to chromosome 9q; and ETL5 (614417), caused by mutation in the CPA6 gene (609562) on chromosome 8q13.
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 ... 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.
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, ... 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.
The diagnosis of autosomal dominant partial epilepsy with auditory features (ADPEAF), also known as autosomal dominant lateral temporal epilepsy (ADLTE), is based on the following:...
DiagnosisClinical DiagnosisThe diagnosis of autosomal dominant partial epilepsy with auditory features (ADPEAF), also known as autosomal dominant lateral temporal epilepsy (ADLTE), is based on the following:A clinical history consistent with focal (partial or localization-related) epilepsy from the affected individual and witnesses. Other causes of epilepsy (antecedent illness or injury to the central nervous system, such as severe head trauma, stroke, and brain tumor) must be excluded. Family history consistent with autosomal dominant inheritance (with reduced and age-dependent penetrance).Two or more family members (including the proband) must have a history of focal epilepsy with either ictal auditory symptoms or ictal aphasia; other family members may have different epilepsy types or symptoms. Auditory symptoms must occur in temporal association with seizures (as an aura immediately preceding generalized tonic-clonic convulsions or as a component of simple partial or complex partial seizures). Note: Auditory symptoms may be underreported; therefore, specific questions to elicit occurrence of auditory symptoms should be included in the clinical history.Aphasia that accompanies seizure onset may be difficult to distinguish from nonspecific confusion or alteration of consciousness; therefore, specific questions to assess the inability to understand spoken language in the absence of general confusion should be included in the clinical history. Clinical imaging (MRI or CT) is normal.The interictal EEG is often normal, although focal epileptiform abnormalities (usually localized to the temporal region) are found in up to two thirds of cases.Molecular Genetic TestingGene. Mutations in the leucine-rich, glioma-inactivated-1 gene (LGI1) have been identified in approximately 33% of families with ADPEAF [Gu et al 2002a, Kalachikov et al 2002, Morante-Redolat et al 2002, Michelucci et al 2003, Ottman et al 2004, Nobile et al 2009]. Clinical testing Table 1. Summary of Molecular Genetic Testing Used in Autosomal Dominant Partial Epilepsy with Auditory FeaturesView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityPositive Family HistoryNegative Family HistoryLGI1Sequence analysis Sequence variants 233% 31.9% 4ClinicalDeletion / duplication analysis 5Exonic and whole-gene deletions1 family 6Unknown1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.3. With autosomal dominant inheritance (defined as two or more family members with idiopathic focal epilepsy with ictal auditory symptoms or receptive aphasia) [Michelucci et al 2003; Berkovic et al 2004a; Ottman et al 2004; Ottman, unpublished findings]. 4. Germline mutations in LGI1 are rarely found in simplex cases (i.e., individuals with symptoms consistent with ADPEAF who do not have a family history). De novo mutations were identified in two of 104 simplex cases (1.9%) [Bisulli et al 2004a, Bisulli et al 2004b, Flex et al 2005, Michelucci et al 2007, Michelucci et al 2009]. 5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.6. Deletion encompassing first four exons [Fanciulli et al 2012]Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing Strategy To confirm/establish the diagnosis in a probandSingle gene testing. One strategy for molecular diagnosis of a proband suspected of having ADPEAF is sequence analysis of LGI1 followed by deletion/duplication analysis if a disease-causing mutation is not identified. If the family history is consistent with autosomal dominant inheritance and at least two family members have idiopathic focal epilepsy with ictal auditory symptoms or receptive aphasia, identification of an LGI1 mutation in the proband would provide strong evidence in favor of the diagnosis of ADPEAF in the family. However, absence of a mutation in LGI1 would not rule out the diagnosis because approximately 67% of families who meet diagnostic criteria for ADPEAF do not have a mutation in LGI1. In an individual with idiopathic focal epilepsy with auditory symptoms or receptive aphasia who does not have a family history of epilepsy, sequencing of LGI1 may reveal a mutation in fewer than 2% of cases, and in these cases the mutation is very likely to be de novo. Identification of such a mutation would confirm the diagnosis in the individual; however, failure to identify a mutation would be uninformative.Multi-gene panel. Another strategy for molecular diagnosis of a proband suspected of having ADPEAF is use of a multi-gene panel. See Differential Diagnosis. Multi-gene panels may be more cost effective and informative, particularly because the clinical symptoms of different epilepsy syndromes can vary widely enough that interrogation of other epilepsy-causing genes may reveal a diagnosis that was not suspected based on clinical features alone. Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersLGI1 was previously reported to be associated with progression of glial cell tumors [Chernova et al 1998]. However, families with ADPEAF have not been found to have an excess of brain tumors or other malignancies [Brodtkorb et al 2003]. LGI1 was also identified as the autoantigen involved in limbic encephalitis, a severe autoimmune disorder manifesting with subacute memory impairment, mood disturbance, and seizures [Lai et al 2010]. No other disorders have been found to be related to mutations in LGI1.
Autosomal dominant partial epilepsy with auditory features (ADPEAF) is characterized by focal epilepsy not caused by a previous illness or injury, with auditory symptoms and/or receptive aphasia as prominent ictal manifestations. Age at onset has ranged from four to 50 years in previously reported families [Winawer et al 2000, Brodtkorb et al 2002, Winawer et al 2002, Michelucci et al 2003], but is usually in adolescence or early adulthood. The prominent auditory symptoms and aphasia are thought to reflect a localization of the epileptogenic zone in the lateral temporal lobe; accordingly ADPEAF is also known as autosomal dominant lateral temporal epilepsy (ADLTE)....
Natural HistoryAutosomal dominant partial epilepsy with auditory features (ADPEAF) is characterized by focal epilepsy not caused by a previous illness or injury, with auditory symptoms and/or receptive aphasia as prominent ictal manifestations. Age at onset has ranged from four to 50 years in previously reported families [Winawer et al 2000, Brodtkorb et al 2002, Winawer et al 2002, Michelucci et al 2003], but is usually in adolescence or early adulthood. The prominent auditory symptoms and aphasia are thought to reflect a localization of the epileptogenic zone in the lateral temporal lobe; accordingly ADPEAF is also known as autosomal dominant lateral temporal epilepsy (ADLTE).Affected individuals have secondarily generalized seizures, usually accompanied by simple partial and complex partial seizures, with auditory symptoms as a major simple partial seizure manifestation. The most common auditory symptoms are simple unformed sounds such as humming, buzzing, or ringing. Less frequently, other types of auditory symptoms occur, including complex sounds (e.g., specific songs or voices) or distortions (e.g., volume changes). Some persons have seizures precipitated by specific sounds, such as a telephone ringing [Michelucci et al 2003, Michelucci et al 2004].Another distinctive feature is ictal receptive aphasia (i.e., sudden onset of an inability to understand language, in the absence of general confusion). Ictal aphasia was the most prominent symptom in one large Norwegian family with an LGI1 mutation [Brodtkorb et al 2002, Brodtkorb et al 2005a] (although auditory symptoms also occurred) and in a small Japanese family [Kanemoto & Kawasaki 2000]. Aphasia has also been reported in other families with LGI1 mutations [Michelucci et al 2003, Ottman et al 2004, Di Bonaventura et al 2009].In families with ADPEAF, affected individuals also have other ictal symptoms, either in isolation or accompanying auditory symptoms or aphasia. These occur less frequently than auditory symptoms, and include other sensory symptoms (visual, olfactory, vertiginous, or cephalic) as well as motor, psychic, and autonomic symptoms [Poza et al 1999, Winawer et al 2000, Winawer et al 2002, Michelucci et al 2003, Hedera et al 2004, Ottman et al 2004]. Also, although most individuals in families with ADPEAF have focal epilepsy, idiopathic generalized epilepsy was reported in four individuals with LGI1 mutations in two previously reported families [Ottman et al 2004]. The occurrence of idiopathic generalized epilepsies in these families may be explained either as an effect of LGI1 on risk for idiopathic generalized epilepsy, or by a co-occurring mutation in these families in another (unidentified) gene that influences risk for idiopathic generalized epilepsy specifically.Febrile seizures do not occur with increased frequency in ADPEAF.The clinical course of ADPEAF is usually benign. For example, in a series of 34 affected individuals in seven Spanish and Italian families [Michelucci et al 2003], secondarily generalized seizures occurred only once or twice per year. The frequency of simple or complex partial seizures ranged from twice per year to several times per month. After initiation of medical therapy, seizures were well controlled by any of a variety of medications (carbamazepine, phenobarbital, or phenytoin), sometimes at low doses. In the Norwegian family with prominent ictal aphasia [Brodtkorb et al 2002], all individuals had been free from secondarily generalized seizures for two or more years, and simple partial seizures occurred infrequently in most patients. However, two family members with epilepsy died suddenly in their sleep, both at age 28 years; a relationship to seizures was suspected but could not be confirmed. In one other family with an LGI1 mutation [Di Bonaventura et al 2009] an unusual clinical picture was described with high seizure frequency and antiepileptic drug resistance. EEG. Interictal EEGs may be normal in persons with ADPEAF; however, epileptiform interictal EEG abnormalities are found in up to two thirds of affected individuals [Poza et al 1999, Winawer et al 2000, Brodtkorb et al 2002, Winawer et al 2002, Fertig et al 2003, Michelucci et al 2003, Pizzuti et al 2003, Hedera et al 2004, Ottman et al 2004, Pisano et al 2005]. Ictal EEGs have been reported in three persons [Winawer et al 2002, Brodtkorb et al 2005a, Di Bonaventura et al 2009]. One of these showed left mid- and anterior temporal onset [Winawer et al 2002], and another onset in the left frontotemporal region with bilateral and posterior spreading, documented during a video-recorded aphasic seizure [Brodtkorb et al 2005a]. The third was recorded during a prolonged seizure cluster lasting several hours in a patient with prominent ictal aphasia; the EEG pattern consisted of low-voltage fast activity followed by delta activity and rhythmic sharp waves located in the anterior and middle left temporal regions [Di Bonaventura et al 2009].Findings from magnetoencephalography (MEG) with auditory stimuli showed significantly delayed peak 2 auditory evoked field latency in individuals with LGI1 mutations [Ottman et al 2008]. Another study using MEG detected significantly large N100m signals in three out of five patients, contralateral to the auditory stimulation [Usui et al 2009].Neuroimaging. Findings from routine neurologic examination and routine clinical imaging (MRI or CT) are normal. An interictal single-photon emission computed tomographic (SPECT) scan in one person identified hypoperfusion in the left temporal lobe [Poza et al 1999].A left lateral temporal lobe malformation was identified through high-resolution MRI in ten individuals in a Brazilian family with an LGI1 mutation [Kobayashi et al 2003]. However, other studies using high-resolution MRI in families with LGI1 mutations have not confirmed this finding [Tessa et al 2007, Ottman et al 2008]. Diffusion tensor imaging identified a region of increased fractional anisotropy in the left temporal lobe in individuals with an LGI1 mutation [Tessa et al 2007].In functional MRI with an auditory description decision task, persons with epilepsy in families with an LGI1 mutation had significantly less activation than controls [Ottman et al 2008]. These results suggest that individuals with ADPEAF have functional impairment in language processing.Other investigations. Asymmetry of long-latency auditory evoked potentials (with reduced left N1-P2 amplitudes) was shown in the Norwegian family with aphasic seizures [Brodtkorb et al 2005b]. Abnormal phonologic processing was demonstrated in four persons in a Sardinian family by means of a fused dichotic listening task [Pisano et al 2005]. The above data, though based on a small sample size, seem to suggest the existence of some structural abnormalities in the lateral temporal neuronal network.
A study of 36 published ADPEAF families with LGI1 mutations evaluated mutation clustering within the gene and associations of phenotypic features with both mutation location (N-terminal leucine-rich repeats [LRR] domain and C-terminal epitempin repeat [EPTP] domain) and predicted effect (truncation or missense) [Ho et al 2012]. Mutations clustered significantly in the LRR domain of LGI1. Also, auditory symptoms were less frequent in individuals with truncation mutations in the EPTP domain than in those with other mutation type/domain combinations. ...
Genotype-Phenotype CorrelationsA study of 36 published ADPEAF families with LGI1 mutations evaluated mutation clustering within the gene and associations of phenotypic features with both mutation location (N-terminal leucine-rich repeats [LRR] domain and C-terminal epitempin repeat [EPTP] domain) and predicted effect (truncation or missense) [Ho et al 2012]. Mutations clustered significantly in the LRR domain of LGI1. Also, auditory symptoms were less frequent in individuals with truncation mutations in the EPTP domain than in those with other mutation type/domain combinations. No phenotypic differences have been found between simplex cases who did not have an LGI1 mutation and the published familial cases [Bisulli et al 2004a, Bisulli et al 2004b, Flex et al 2005, Michelucci et al 2007, Michelucci et al 2009].
Differential DiagnosisTable 2. Epilepsy, Familial Temporal Lobe: OMIM Phenotypic SeriesView in own windowPhenotypePhenotype MIM NumberGene/LocusGene/Locus MIM NumberEpilepsy, familial mesial temporal lobe 611630 FMTLE, ETL3 611630 Epilepsy, familial temporal lobe, 1 600512 LGI1, EPT, ETL1, ADLTE, ADPEAF 604619 Epilepsy, familial temporal lobe, 2 608096 ETL2, FTLE 608096Epilepsy, familial temporal lobe, 4 611631 ETL4, ETOLM 611631 Epilepsy, familial temporal lobe, 5 614417 CPA6, CPAH, ETL5, FEB11 609562 Data from Online Mendelian Inheritance in ManEpilepsy multi-gene panels may include testing for a number of the genes associated with disorders discussed in this section. Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time; a panel may not include a specific gene of interest.Tinnitus and other auditory disturbances may be reported as incidental findings in a person with epilepsy; thus, care should be taken in obtaining the medical history to document a consistent temporal association of auditory symptoms with seizure events.Persons with epilepsy may report the inability to comprehend speech at the onset of seizures as a result of nonspecific confusion or alteration in consciousness; thus, care should be taken in obtaining the medical history to distinguish this confusion from specific symptoms of aphasia (i.e., an inability to understand language in the absence of alteration in consciousness).The following three other forms of Mendelian focal epilepsy have been identified. Distinguishing among these disorders can be challenging because the symptoms in affected family members are variable and no operational criteria for classification of families are yet available [Picard et al 2000]. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is characterized by clusters of nocturnal motor seizures varying from simple arousals from sleep to dramatic, often bizarre, hyperkinetic events with tonic or dystonic features. A minority of individuals experience daytime seizures. In contrast, the seizures in ADPEAF are most often associated with auditory or other sensory symptoms, and usually occur during the day (although nocturnal seizures have been observed in some cases). The diagnosis of ADNFLE is made on clinical grounds. A detailed history from the affected individual and witnesses, supplemented if necessary by video-EEG monitoring, is the key to diagnosis. Clinically available molecular genetic testing reveals mutations in CHRNA4, CHRNB2, or CHRNA2 in approximately 10%-20% of individuals with a positive family history and fewer than 5% of individuals with a negative family history. Familial mesial temporal lobe epilepsy (FMTLE) is characterized by seizures with symptoms suggesting a mesial temporal lobe localization of the epileptogenic zone [Andermann et al 2005], in contrast to ADPEAF, in which symptoms are more suggestive of a lateral temporal localization. In the initial description of the syndrome by Berkovic et al [1996], affected individuals had simple and complex partial seizures, and less commonly, secondarily generalized seizures. The seizure semiology most often involved psychic symptoms, with déjà vu the most common among them. Autonomic or special sensory components were observed in about half of cases; auditory symptoms were found in fewer than 10% of cases. As with ADPEAF, age at onset was usually in late adolescence or early adulthood; neuroimaging results were normal; interictal epileptiform EEG abnormalities were found in a minority (~20%) of cases; febrile seizures were not more common than in the general population; and the clinical course was benign, with long remissions and good response to a range of therapies (carbamazepine, phenytoin, or valproate). Subsequent studies demonstrated clinical heterogeneity in FMTLE, with some families having hippocampal atrophy and a less benign clinical course [Cendes et al 1998, Kobayashi et al 2001]. Families with temporal lobe epilepsy and prominent febrile seizures have also been described [Baulac et al 2001, Depondt et al 2002]. Because of the similarities between ADPEAF and FMTLE and the great intrafamilial variability of symptoms in both syndromes, differential diagnosis is challenging and relies mainly on the semiology of seizures observed in affected family members. In ADPEAF, auditory symptoms are most common, and autonomic or psychic symptoms occur in fewer than 25% of cases [Ottman et al 2004], whereas in FMTLE, psychic symptoms (particularly déjà vu) are most common, and auditory symptoms are seldom seen. In FMTLE, mutations in LGI1 have not been found [Berkovic et al 2004a], and no genes have yet been identified, although evidence for linkage to several different regions has been reported [Baulac et al 2001, Claes et al 2004, Hedera et al 2007].Familial partial epilepsy with variable foci (FPEVF) is characterized by autosomal dominant inheritance of focal epilepsy, with different localization of the epileptogenic zone (frontal, temporal, or occipital) in different family members [Scheffer et al 1998, Xiong et al 1999, Callenbach et al 2003, Berkovic et al 2004b]. Frontal lobe seizures are the most common type. However, in FPEVF the seizures occur less frequently and more in the daytime than in ADNFLE. Auditory symptoms and aphasia have not been described in families with FPEVF. Linkage to chromosome 22q12 has been found in five families with FPEVF; the involved gene has yet to be identified [Xiong et al 1999, Callenbach et al 2003, Berkovic et al 2004b]. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with autosomal dominant partial epilepsy with auditory features (ADPEAF), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with autosomal dominant partial epilepsy with auditory features (ADPEAF), the following evaluations are recommended:A clinical history from the patient and witnesses to establish seizure types and their frequencies, and symptoms associated with each seizure type Routine interictal EEG Routine clinical imaging to rule out structural abnormalities Medical genetics consultationTreatment of ManifestationsADPEAF is a benign syndrome in the great majority of cases. No clinical trials of different antiepileptic medications have been carried out, but most patients have been readily able to achieve seizure control with medications used routinely in clinical practice (e.g., carbamazepine, phenytoin, valproate). Evaluation of Relatives at RiskInterview of relatives at risk to identify symptoms possibly related to seizures is advisable so that early treatment may be initiated in those who develop seizures.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Autosomal Dominant Partial Epilepsy with Auditory Features: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDLGI110q23.33Leucine-rich glioma-inactivated protein 1LGI1 homepage - Mendelian genesLGI1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Autosomal Dominant Partial Epilepsy with Auditory Features (View All in OMIM) View in own window 600512EPILEPSY, FAMILIAL TEMPORAL LOBE, 1; ETL1 604619LEUCINE-RICH GENE, GLIOMA-INACTIVATED, 1; LGI1Normal allelic variants. LGI1 has eight exons. The longest full-length transcript includes all eight exons, a 224-bp 5' untranslated region, a 1674-bp coding region (spanning 225-1898 bp including stop-codon "TGA"), and a 356-bp 3' untranslated region. LGI1 is a member of a subfamily of leucine-rich repeat (LRR)-encoding genes, denoted LGI1, LGI2, LGI3, and LGI4 [Gu et al 2002b]. Pathologic allelic variants. Disease-causing mutations have been found throughout the gene, without apparent clustering in any region. Two thirds of the reported pathologic variants have been missense; the remaining one third are truncating. Three intronic mutations have been reported, in each case leading to protein truncation [Kalachikov et al 2002, Kobayashi et al 2003, Chabrol et al 2007]. Almost all of the identified pathologic variants have been unique to an individual family. The exceptions were: p.Cys46Arg, identified in one Norwegian and one Italian family without known shared antecedents [Gu et al 2002a, Pizzuti et al 2003, Pizzuti & Giallonardo 2003]; p.Ala253Valfs*32, identified in two Spanish families from the same region [Morante-Redolat et al 2002, Michelucci et al 2003]; p.Ser473Leu, identified in one Australian and one Japanese family [Berkovic et al 2004a, Kawamata et al 2010]; and p.Arg474X, identified in a Basque family and in a sporadic case from Italy, as a de novo mutation [Morante-Redolat et al 2002, Bisulli et al 2004b]. In addition, two of the reported missense mutations – p.Cys42Arg (c.124T>C) and p.Cys42Gly (c.124T>G) – affected the same nucleotide [Berkovic et al 2004a, Ottman et al 2004]. See Table 3. For additional pathologic variants, see Table 4 (pdf). A microdeletion about 81 kb in size encompassing the first four exons of LGI1 was identified in a family with ADPEAF in which exon sequencing revealed no point mutation [Fanciulli et al 2012]. Families with ADPEAF in which no point mutations are revealed by direct exon sequencing should be screened for possible genomic deletion mutations using CMA analysis.Table 3. Selected LGI1 Pathologic Allelic Variants View in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.124T>Cp.Cys42ArgNM_005097.2 NP_005088.1c.124T>Gp.Cys42Glyc.136T>Cp.Cys46Argc.758delCp.Ala253Valfs*32c.1420C>Tp.Arg474XDeletion 81,245 bp (including exons 1-4) 1See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1. Fanciulli et al [2012]Normal gene product and possible pathogenic mechanism. The main transcription product is predicted to encode a protein, Lgi1, of 557 amino acids, with a structure consisting of an amino-terminal signal peptide sequence and two distinct structural domains, each spanning about half of the protein. The N-terminal half consists of 3.5 leucine-rich repeat (LRR) sequences flanked on both sides by typical cysteine-rich repeat sequence clusters [Kobe & Kajava 2001]. The C-terminal half consists of seven copies of a novel repeat of about 45 residues, named the epitempin (EPT) [Staub et al 2002] or epilepsy-associated repeat (EAR) [Scheel et al 2002] region, which is reminiscent of the beta-propeller structural domain [Paoli 2001]. This domain is shared with the protein encoded by GPR98 (formerly known as MASS1), which is mutated in the Frings mouse model of audiogenic epilepsy [Skradski et al 2001]. The four paralogs of the LGI subfamily all have the same structure of LRRs and EAR domains [Gu et al 2002b, Scheel et al 2002, Staub et al 2002]. LRR and beta-propeller motifs are found in many other proteins and often mediate protein-protein interactions. LGI1 is expressed primarily in the brain, and in situ hybridization studies in mouse showed that expression is predominantly neuronal [Kalachikov et al 2002].Abnormal gene product. The function of the normal gene product, Lgi1, and the mechanism by which alterations in the protein cause epilepsy remain poorly understood, but there have been several important findings. Based on protein homology, initially Lgi1 was hypothesized to influence risk for epilepsy through a mechanism related to central nervous system development [Kalachikov et al 2002]. A 2006 study showed that Lgi1 interacts with presynaptic Kv1 potassium channels, selectively removing rapid inactivation mediated by the Kvβ1 subunit; truncated proteins encoded by mutations found in humans failed to slow inactivation by Kvβ1 [Schulte et al 2006]. However, another study demonstrated that Lgi1 is secreted and mutations lead to defects in secretion [Senechal et al 2005]. The establishment of Lgi1 secretion is difficult to reconcile with a potassium channel mechanism.Further evidence shows that there are two protein isoforms, with different expression patterns in human brain [Furlan et al 2006]. The long isoform is secreted, whereas the short isoform is retained in an intracellular pool [Sirerol-Piquer et al 2006]. ADPEAF-related mutants of the long form are defective for secretion, and the normal secreted protein specifically binds to the cell surface of differentiated PC12 cells [Sirerol-Piquer et al 2006].Another study suggested that Lgi1 may influence risk for epilepsy through a glutamatergic mechanism: Lgi1 binds selectively to ADAM22, a neuronal membrane protein, and this binding facilitates glutamate-AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor-mediated neurotransmission [Fukata et al 2006, Snyder 2006]. Studies in transgenic mice showed that mutations in Lgi1 cause epilepsy by impairing the postnatal development of glutamatergic circuits in the hippocampus [Zhou et al 2009].In research using a mouse knock-out model, extracellularly secreted Lgi1 was found to link two epilepsy-related receptors – ADAM22 and ADAM23 – in the brain and to organize a transsynaptic protein complex that includes presynaptic potassium channels and postsynaptic AMPA receptor scaffolds. A lack of Lgi1disrupts this synaptic protein connection and selectively reduces AMPA receptor-mediated synaptic transmission in the hippocampus [Fukata et al 2010].LGI1 expression is absent or significantly downregulated in many high-grade but not low-grade gliomas, suggesting a role for LGI1 in glial tumor progression [Chernova et al 1998, Somerville et al 2000], although no excess of brain tumors or other malignancies has been found in families with ADPEAF.