Epilepsy with auditory features …

Eliane Kobayashi MD PhD

Epilepsy & Seizures

Updated 10.01.2024
Released 07.07.2004
Expires For CME 10.01.2027

Epilepsy with auditory features

Author: Eliane Kobayashi MD PhD

See Contributor Disclosures

Editor: Jerome Engel Jr MD PhD

Epilepsy with auditory features

In This Article

Quick Link

Introduction

Overview

In this article, the author reports on genetic findings in familial and sporadic epilepsy with auditory features, including pathogenic variants in the MICAL-1 gene.

Key points

	• Epilepsy with auditory features is typically characterized by auditory auras, but other types of ictal semiology, such as ictal aphasia, can be present.
	• Sporadic and familial cases share similar clinical, neuroimaging, and neurophysiology features.
	• Approximately 50% of families with epilepsy with auditory features have a genetic diagnosis clarified, of which mutations in the LGI1 gene or RELN gene are the most frequent. Other genes implicated with this syndrome include DEPDC5, SCNA1, and MICAL-1.
	• Drug-resistant seizures and neuroimaging abnormalities might be present in some affected individuals, described in association with RELN or LGI1 mutations.
	• Few cases in the literature report on surgical treatment of drug-resistant seizures, with good outcomes to date.

Historical note and terminology

Epilepsy with auditory features is an epilepsy syndrome previously most frequently known for its familial presentation, referred to as autosomal dominant lateral temporal lobe epilepsy, familial neocortical or lateral temporal lobe epilepsy, and autosomal dominant partial epilepsy with auditory features. This nomenclature was adopted following the position statement by the International League Against Epilepsy Task Force on Nosology and Definitions for epilepsy syndromes with a variable age of onset (80).

In the 1990s, several autosomal dominant forms of focal epilepsy were described by the group of Berkovic and colleagues (07). These included autosomal dominant nocturnal frontal lobe epilepsy, familial temporal lobe epilepsy, familial focal epilepsy with variable foci, and autosomal dominant rolandic epilepsy with speech dyspraxia. Familial temporal lobe epilepsy was included in the proposals for classification of epileptic syndromes by the International League Against Epilepsy, supporting it as a well-defined syndrome (33; 32; 04).

The first description of familial epilepsy with auditory features was in 1995 by Ottman and colleagues, who reported its familial occurrence as an autosomal dominant focal epilepsy syndrome with auditory features (73). Thus, the then-named autosomal dominant partial epilepsy syndrome with auditory features was regarded as a familial form of temporal lobe epilepsy with seizures semiology pointing to a neocortical or lateral temporal generator.

After detailed descriptions of many families with temporal lobe epilepsy, it has been possible to define two groups of familial temporal lobe epilepsy based on clinical and molecular characteristics (93): (1) familial mesial temporal lobe epilepsy with clinical features of mesial temporal onset and no clear-cut molecular definition to date (55; 52) and (2) familial epilepsy with auditory features, first described in association with LGI1 gene mutations in chromosome 10q (73; 49; 71). In the ILAE position statement, both familial mesial temporal lobe epilepsy and familial or nonfamilial epilepsy with auditory features are included as variable age of onset focal epilepsy syndromes (80).

It is impossible to distinguish patients with familial, nonfamilial, or sporadic temporal lobe epilepsy based solely on the clinical presentation for both mesial and lateral forms. As the family history is not always accurately documented and because some family members are asymptomatic or only mildly affected, many so-called “sporadic” or “isolated” patients may actually have a familial epilepsy syndrome.

The occurrence of sporadic epilepsy and auditory features without a positive family history was first highlighted by Bisulli and colleagues (12). The authors termed this syndrome idiopathic focal epilepsy with auditory features and performed a clinical and genetic study in 53 sporadic cases. Mutations or variants in LGI1 were excluded in all these patients although, except for the absence of family history, they had identical clinical manifestations to those seen in familial cases, including the prevalently good prognosis (12). After the first description of their large series, the same authors reported a de novo mutation in the LGI1 gene in one patient with sporadic epilepsy with auditory features (13). A de novo LGI1 mutation or variant has also been reported in a patient with idiopathic epilepsy and telephone-induced seizures (67). Overall, however, other series of patients with sporadic epilepsy with auditory features found no LGI1 mutations or variants (39; 15), with only approximately 2% of nonfamilial cases having an LGI1 mutation or variant identified (72).

Clinical manifestations

Presentation and course

The identification of a positive family history of seizures in patients with epilepsy with auditory features is not sufficient for a diagnosis of familial presentation of the syndrome. The best definition of familial epilepsy with auditory features is based on the familial recurrence of neocortical temporal lobe epilepsy (all affected individuals with a diagnosis in keeping with epilepsy with auditory features), defined by clinical-EEG criteria according to the ILAE recommendations, in the absence of any suggestion of other focal or generalized epilepsy syndromes in other affected family members, auditory symptoms that could be indicative of psychiatric etiology (such as hallucinations in the absence of an epileptic nature), or tinnitus in disorders of the peripheral auditory system (23; 80). Thus, the observation of at least two patients with epilepsy with auditory features in one family is necessary but not sufficient for the definition of familial epilepsy with auditory features. The observation of an autosomal dominant inheritance pattern with incomplete penetrance implies the presence of asymptomatic carriers of the genetic abnormalities, who can transmit the disease to their offspring. Therefore, we should consider including families not only with affected first-degree relatives but also with affected second- and third-degree relatives.

Age of onset is variable, usually in the second or third decades of life. Seizures are typically described in the literature as easily controlled with antiseizure drugs. Familial epilepsy with auditory features is an overall benign epilepsy syndrome characterized by but not limited to the occurrence of auditory auras (buzzing, roaring, radio- or motor-like sounds, distortions in sounds and words). Although other manifestations, such as psychic, cephalic, and other sensory and motor phenomena, can occur, the auditory auras are a landmark for this syndrome (73; 99; 98). Ictal aphasia and visual misperceptions can occur, and in rare families, focal to bilateral tonic-clonic seizures are frequent (79; 99; 98; 16; 44; 54; 69).

Bisulli and colleagues studied determinants of poor long-term outcomes in epilepsy with auditory features, identifying the following predictive factors: epilepsy onset earlier than 10 years of age, presence of focal epileptiform abnormality on EEG, and seizure semiology in keeping with focal aware cognitive seizures with complex auditory hallucinations (09).

Patients with rather psychic symptoms or with visual ictal manifestations in the context of familial epilepsy with auditory features associated with LGI1 mutations have also been described (89; 28). A report from the Epi4K Consortium highlighted that amongst kindreds with temporal lobe epilepsy, a small proportion of them presented affected individuals that could have either mesial or lateral temporal lobe seizure semiology (34). A family with a mother and her offspring with drug-resistant seizures with a combination of auditory symptoms and ictal fear of left temporal onset has been described (66).

EEGs may show temporal epileptiform discharges but are frequently normal. MRI studies who no clear-cut signs of hippocampal atrophy, but a range of anatomical variations have been described in rare cases. A lateral or neocortical temporal malformation pattern has been observed in 45% of affected individuals in one large Brazilian family with an LGI1 mutation, including one asymptomatic carrier (54). The left temporal lobes of these individuals seemed enlarged, and sometimes a lateral protrusion of the brain parenchyma could be identified, with an “encephalocele-like” appearance. In another study, anterior temporal lobe volumetry showed a significant global volume increase in only two individuals. Subtle abnormalities in the posterior aspect of the left middle temporal gyrus were identified in patients with epilepsy with auditory features compared to controls using voxel-based analysis of fractional anisotropy maps (92).

Functional neuroimaging has also been applied to investigate dysfunction in these patients. One patient with an RELN mutation with normal 3T MRI was shown to have altered functional connectivity in the left hemisphere (18). Two Italian patients (proband and mother) with a missense RELN variant [c.6631C>T (p.Arg2211Cys)] and refractory epilepsy had seizures with ictal onset over the left temporal region captured in video-EEG recording, as well as neuroimaging abnormalities. Structural and metabolic neuroimaging abnormalities were found: [18F]FDG-PET showed left temporal hypometabolism, and 3T MRI revealed a mild left temporal hypotrophy, slight blurring of the white and grey matter in the left temporal lobe, and hyperintensity of the left hippocampus (66).

Prognosis and complications

Epilepsy with auditory features has an overall benign clinical course with few refractory patients reported to date (73; 79; 99; 98; 16; 69; 66; 97). Many patients may present only a few episodes and then have spontaneous remission.

In the study reporting on long-term follow-up in patients with epilepsy with auditory features, including 123 patients with a median follow-up of 11 years, the cumulative rate of seizure remission in those followed for at least 5 consecutive years was 50% by 30 years from epilepsy diagnosis (09). Approximately 32% of these patients reported a family history of epilepsy; 15 of them (12.2%) belonged to 11 different familial epilepsy with auditory features pedigrees. The authors analyzed patients who were in seizure remission for at least 5 years at the last follow-up. Total remission after tapering off antiseizure medications might lead to relapses, but particular to this cohort is the marked heterogeneity in terms of phenotype (41). Poor prognostic factors for seizure control were: age at onset younger than 10 years, auditory aura characterized by complex auditory hallucinations, and focal epileptiform abnormalities on scalp EEG. When a structural lesion is identified on MRI, patients with drug-resistant seizures can be offered surgery (09).

Neurologic disabilities in the form of auditory and language processing dysfunction have also been documented in families with epilepsy with auditory features and LGI1 mutations (77; 74).

Biological basis

Etiology and pathogenesis

A molecular diagnosis can be determined in approximately 50% of families, in which identification of mutations or pathologic variants in the LGI1 as well as RELN genes have most often been described.

LGI1 gene mutation or variant can be found in approximately 30% of families with familial lateral temporal lobe epilepsy (05; 75). A large Italian study identified LGI1 mutations or variants in only 30% of kindreds (68). The identification of LGI1 mutations or variants in only half of the families presenting the typical phenotype (05; 75) suggests genetic heterogeneity in the families. A linkage to chromosome 19q13.11-q13.31 has been found in a large Brazilian kindred presenting with auditory auras (10).

A comprehensive review of LGI1 mutations or variants in epilepsy with auditory features can be found in a paper by Nobile and colleagues (72) and in a review on pathogenic mechanisms in LGI1 mutations or variants (102). The LGI1 gene was cloned from a glioblastoma cell line, and although previous studies have suggested that LGI1 represents a tumor suppressor gene (22), a subsequent study was unable to establish a correlation between the gene and malignant glioma suppression (43). LGI1 (also known as Epitempin) is a secreted neuronal protein characterized by a central leucine-rich repeat region (47), which is involved in regulating cell growth, adhesion, and migration.

Our understanding of the role of LGI1 in the epileptogenic process has significantly advanced with the finding that LGI1 binds to the postsynaptic membrane proteins A Disintegrin And Metalloprotease (ADAM) 22 and 23, thus linking LGI1 with modulation of glutamate-AMPA synaptic transmission by regulating the surface expression of AMPA receptors (40). In addition, defective LGI1 could lead to presynaptic changes in the inactivation kinetics of A-type potassium channels through an effect on voltage-gated potassium channel subunit (Kv1.1), thus increasing excitability (85).

Two protein isoforms of LGI1 are differentially expressed in the human brain, with a much higher concentration in the temporal neocortex than in the hippocampus, which could explain the characteristic auditory ictal manifestations in patients with LGI1 mutation (42). The association of neocortical temporal malformation patterns in some families may indicate a probable role of LGI1 in the development of the temporal lobes (54; 92).

At least 44 different LGI1 mutations or variants have been described today. Most LGI1 mutations in patients with familial epilepsy with auditory features are associated with loss of function, with the LGI1 protein either not secreted, misfolded, or unstable (78; 87; 58; 61). Mutations or variants described by Striano and colleagues and Di Bonaventura and colleagues do not affect LGI1 protein secretion (31; 89). Striano and colleagues also reported that the mutation or variant found in their family does not induce large structural rearrangements, although it could destabilize its interactions with target proteins. Investigating LGI1 mutations or variants described in familial epilepsy with auditory features as well as epilepsy due to LGI1 autoantibodies, Dazzo and colleagues have validated and introduced the concept that LGI1 mutations or variants can be secretion-defective or secretion-competent, the latter resulting in impaired interaction between secreted LGI1 with neuronal receptors ADAM22 and ADAM23 (25). To review the interactions between LGI1 and ADAM receptors, please refer to the paper by Yamagata and Fukai (102).

Many different mutations or variants have been described in different kindreds worldwide, all located in the coding region or exon splice sites (44; 49; 71; 38; 54; 69; 78; 05; 13; 46; 75; 77; 21; 72; 51; 31; 89; 28; 50; 60). Bovo and colleagues analyzed the promoter region of the LGI1 gene in patients with sporadic and familial epilepsy with auditory features and found no mutations or variants in the promoter sequence (15).

LGI1 mutations or variants have been identified in about 2% of nonfamilial cases (72). No mutations or variants in LGI2, LGI3, or LGI4 have been identified in 71 families with various types of temporal lobe epilepsy, including four with familial epilepsy with auditory features (05; 02). Finally, no mutations or variants related to the ADAM22 gene (19; 29) or Kv1 channel genes (29) have been identified in kindreds with familial epilepsy with auditory features without LGI1 mutations.

LGI1 microdeletions have been identified in families that tested negative for exon sequencing, suggesting that copy number variation analysis could further identify genes implicated in these patients or families (37; 36). This has not been confirmed in a series of eight families, and 20 sporadic patients tested negative for known LGI1 mutations (64).

Based on evidence from in vitro studies in transgenic mice (105), Anderson has proposed that LGI1 modulates a mechanism that could lead to epileptogenesis via persistent immaturity of glutamatergic circuitries (01). Interestingly, LGI1 has been demonstrated as the autoantigen for antibodies found in patients with limbic encephalitis, which had been previously attributed to voltage-gated potassium channels (57). These two observations point to a role of LGI1 in the maturation of glutamatergic neurotransmission and the etiology of acquired epilepsies.

Further insights about the mechanisms underlying epileptogenicity derived from LGI1 mutations or variants have been unraveled in vitro using hippocampal CA3 neurons (86). LGI1 deletion resulted in downregulation of axonal Kv1.1 and Kv1.2 channels, thus impairing the capacity of axonal D-type current to limit glutamate release. This could be a potential mechanism through which LGI1 regulates the intrinsic excitability of neurons and promotes the development of epileptogenicity.

Yokoi and colleagues aimed to investigate mechanisms through which levels of transsynaptic LGI1-ADAM22 protein complexes are regulated and what level of function or impairment of LGI1-ADAM22 complexes is required for disease symptomatology to occur (104). Their study demonstrated, using ADAM22 and LGI1 hypomorphic mice, that levels at approximately 50% of LGI1 and approximately 10% of ADAM22 are sufficient to prevent lethal epilepsy. In addition, it showed evidence that quantitative dual phosphorylation of ADAM22 by protein kinase A (PKA) mediates high-affinity binding of ADAM22 to dimerized 14-3-3, “protecting” LGI1-ADAM22 from endocytosis-dependent degradation. It remains to be further evidenced whether these results support increasing levels of LGI1-ADAM22 complexes as a potential pharmacological strategy for epilepsy treatment.

Heterozygous mutations in the gene encoding for the secreted protein reelin (RELN) on chromosome 7q have been found in 17% of kindreds that tested negative for LGI1 mutations or variants, providing an interesting venue for understanding the pathophysiology of this epilepsy syndrome (24; 70; 66). Homozygous RELN mutations or variants cause lissencephaly with cerebellar hypoplasia, and as the authors found an inhibitory effect of mutations on protein secretion and co-localization of LGI1 and RELN in many rat brain regions, they bring to discussion the regulatory role these two proteins exert in brain development.

It is estimated that disease-causing heterozygous mutations or variants in the RELN gene are segregated in about 20% of families with familial epilepsy with auditory features (26). Pathogenic mutations or variants, through impaired trafficking of mutant reelin along the secretory pathway as well as elimination through the autophagy pathway, result in abolished or significantly reduced reelin, which can be, nevertheless, partially rescued by small-molecule correctors.

Pippucci and colleagues used whole exome sequencing to investigate probands who tested negative for known LGI1 mutations or variants and found CNTNAP2 intragenic deletion, two truncating mutations of the DEPDC5 gene, and a missense SCN1A change (76). Interestingly, CNTNAP2 encodes Contactin-associated protein-like 2 (CASPR2), a cell adhesion protein of the neurexin family, which plays a role in the localization of the voltage-gated potassium channel complex composed of TAG-1, Kv1.1, and Kv1.2, with which LGI1 interacts. In contrast, DEPDC5 has been originally identified in familial focal epilepsy with variable foci and now in about 10% of focal epilepsies, including patients with an underlying malformation of cortical development. No DEPDC5 mutations were found in another cohort of patients with familial epilepsy with auditory features who tested negative for LGI1 mutations or variants (90).

In a subsequent study, Leonardi and colleagues screened 28 familial epilepsy with auditory features kindreds that had tested negative for LGI1 and RELN mutations or variants and found no CNTNAP2 (contactin-associated protein-like 2) mutations with next-generation sequencing and copy number variation analyses (59).

Using whole exome sequencing combined with genome-wide single-nucleotide polymorphism-array linkage analysis, Dazzo and colleagues described two variants in the MICAL-1 gene in two different families with epilepsy with auditory features (27). MICAL-1 had been described as an F-actin-disassembly factor critical in actin reorganization, providing a molecular conduit for axon navigation (63). Dysregulation of the actin cytoskeleton dynamics remain as a possible mechanism for these pathogenic variants in relation to epileptogenesis (27). More recently, a novel pathogenic variant in the MICAL-1 gene has been identified in a patient with sporadic epilepsy with auditory features, which was demonstrated in a cell-based assay to increase MICAL-1 oxidoreductase activity (14). This is expected to cause dysregulation of F-actin organization, which the authors associate with a gain-of-function mechanism for MICAL-1-mediated epilepsy pathogenesis. However, the phenotypic spectrum is still evolving, as a heterozygous MICAL-1 variant has been reported in a child with benign childhood epilepsy with centrotemporal spikes and her asymptomatic mother (103).

Finally, two possibly pathogenic missense variants in the SCN1A gene were identified in 3.8% of sporadic patients in a cohort of epilepsy with auditory features with no antecedent of febrile seizures (08). Patients within GEFS+ families could present with typical semiology with auditory features and carry SCN1A mutations or variants.

In the most recent and largest genetic study in epilepsy with auditory features including 112 unrelated cases (of whom 33 were familial patients), Bisulli and colleagues applied next-generation sequencing and confirmed an underlying genetic abnormality in 8% of individuals (11). Pathogenic or likely pathogenic variants were identified in LGI1 (2.7%), RELN (1.8%), SCN1A (2.7%), and DEPDC5 (0.9%). Amongst the familial cases in this cohort, the following was the proportion of variants found: LGI1 (3%), RELN (6.1%), SCN1A (3%), and DEPDC5 (3%).

Differential diagnosis

Associated or underlying disorders

The two main epilepsy differential diagnoses for familial epilepsy with auditory features are familial mesial temporal lobe epilepsy, which can be clarified most of the time with a detailed history and seizure description, and familial focal epilepsy with variable foci.

To date, no families with familial mesial temporal lobe epilepsy have been found to have an LGI1 mutation, even in those families in which one or more family members had auditory features alone or in association with mesial symptoms (81; 03; 05). This further supports the fact that familial epilepsy with auditory features and familial mesial temporal lobe epilepsy constitute distinct genetic syndromes. The implication of LGI1 with seizures of mesial temporal origin rather than neocortical onset is, however, suggested by the study of Chabrol and colleagues using LGI1 knockout mice (20). Frequent spontaneous seizures originating from the hippocampus were seen in homozygous animals, and hippocampal pathology consistent with sclerosis was observed. In contrast, heterozygous animals showed only auditory stimuli-induced seizures.

Patients with temporal lobe epilepsy are found in other familial epilepsy syndromes. In familial epilepsy with variable foci, different family members may present with various forms of epilepsy, including temporal lobe epilepsy (53), but the focus remains the same in each affected individual. Most reported families mapped to chromosome 22q (84; 101; 100; 17; 06). Subsequently, mutations or variants in the DEPDC5 gene encoding the DEP domain containing 5 protein were described not only in familial focal epilepsy with variable foci families but also in other familial focal epilepsies and patients with sporadic epilepsy (48; 30; 65).

In generalized epilepsy with febrile seizure plus (GEFS+), related to mutations or variants in genes SCN1A, SCN1B, SCN2A, and GABRG2 (96; 94; 95; 35; 62; 91; 45), patients may present heterogeneous epilepsy phenotypes. Febrile seizures are the most common phenotype, followed by febrile seizures plus (FS+), in which individuals have seizures with fever that may persist beyond the age of 6 years and may be associated with afebrile generalized tonic-clonic seizures (82; 88). Less frequent phenotypes seen in generalized epilepsy with febrile seizure plus involve other generalized seizure types, including temporal lobe epilepsy (82; 88; 95; 83). Patients with focal seizures typical of lateral temporal lobe epilepsy have been described within the context of GEFS+ kindreds, without febrile seizures and bearing an SCN1A mutation (08; 11).

It is essential to evaluate the phenotype of all possibly affected individuals before classifying the family to have a specific familial syndrome. In addition, because phenotypes may vary, we can never be absolutely sure that a patient with “isolated” or “sporadic” epilepsy with auditory features does not have familial epilepsy with auditory features. Molecular studies with testing for mutations of genes previously identified in these families, as well as other genes associated with related familial epilepsies, can be helpful.

References

01: Anderson MP. Arrested glutamatergic synapse development in human partial epilepsy. Epilepsy Curr 2010;10(6):153-8. PMID 21157544
02: Ayerdi-Izquierdo A, Stavrides G, Selles-Martinez JJ, et al. Genetic analysis of the LGI/Epitempin gene family in sporadic and familial lateral temporal lobe epilepsy. Epilepsy Res 2006;70:118-26. PMID 16707245
03: Badhwar A, Racacho L, D’Agostino D, et al. Absence of LGI1 mutations in familial mesial temporal lobe epilepsy with or without auditory features and in sporadic TLE with auditory features. Neurology 2004;62(Suppl 5):A252. PMID 15079010
04: Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia 2010;51(4):676-85. PMID 20196795
05: Berkovic SF, Izzillo P, McMahon JM, et al. LGI1 mutations in temporal lobe epilepsies. Neurology 2004a;62(7):1115-9. PMID 15079010
06: Berkovic SF, Serratosa JM, Phillips HA, et al. Familial partial epilepsy with variable foci: clinical features and linkage to chromosome 22q12. Epilepsia 2004b;45(9):1054-60. PMID 15329069
07: Berkovic SF, Steinlein OK. Genetics of partial epilepsies. Adv Neurol 1999;79:375-81. PMID 10514827
08: Bisulli F, Licchetta L, Baldassari S, et al. SCN1A mutations in focal epilepsy with auditory features: widening the spectrum of GEFS plus. Epileptic Disord 2019;21(2):185-91. PMID 30977726
09: Bisulli F, Menghi V, Vignatelli L, et al. Epilepsy with auditory features: long-term outcome and predictors of terminal remission. Epilepsia 2018;59(4):834-43. PMID 29464704
10: Bisulli F, Naldi I, Baldassari S, et al. Autosomal dominant partial epilepsy with auditory features: a new locus on chromosome 19q13.11-q13.31. Epilepsia 2014;55(6):841-8. PMID 24579982
11: Bisulli F, Rinaldi C, Pippucci T, et al. Epilepsy with auditory features: contribution of known genes in 112 patients. Seizure 2021;85:115-8.** PMID 33453592
12: Bisulli F, Tinuper P, Avoni P, et al. Idiopathic partial epilepsy with auditory features (IPEAF): a clinical and genetic study of 53 sporadic cases. Brain 2004a;127(Pt 6):1343-52. PMID 15090473
13: Bisulli F, Tinuper P, Scudellaro E, et al. A de novo LGI1 mutation in sporadic partial epilepsy with auditory features. Ann Neurol 2004b;56(3):455-6. PMID 15349881
14: Bonanni P, Giorda R, Michelucci R, Nobile C, Dazzo E. A de novo pathogenic variant in MICAL-1 causes epilepsy with auditory features. Epilepsia Open 2024;9(3):1083-7. PMID 38654463
15: Bovo G, Diani E, Bisulli F, et al. Analysis of LGI1 promoter sequence, PDYN and GABBR1 polymorphisms in sporadic and familial lateral temporal lobe epilepsy. Neurosci Lett 2008;436(1):23-6. PMID 18355961
16: Brodtkorb E, Gu W, Nakken KO, Fischer C, Steinlein OK. Familial temporal lobe epilepsy with aphasic seizures and linkage to chromosome 10q22-q24. Epilepsia 2002;43(3):228-35. PMID 11906506
17: Callenbach PM, van den Maagdenberg AM, Hottenga JJ, et al. Familial partial epilepsy with variable foci in a Dutch family: clinical characteristics and confirmation of linkage to chromosome 22q. Epilepsia 2003;44(10):1298-305. PMID 14510823
18: Ceska K, Aulická Š, Horák O, et al. Autosomal dominant temporal lobe epilepsy associated with heterozygous reelin mutation: 3 T brain MRI study with advanced neuroimaging methods. Epilepsy Behav Case Rep 2018;11:39-42. PMID 30619712
19: Chabrol E, Gourfinkel-An I, Scheffer IE, et al. Absence of mutations in the LGI1 receptor ADAM22 gene in autosomal dominant lateral temporal epilepsy. Epilepsy Res 2007a;76(1):41-8. PMID 17681454
20: Chabrol E, Navarro V, Provenzano G, et al. Electroclinical characterization of epileptic seizures in leucine-rich, glioma-inactivated 1-deficient mice. Brain 2010;133(9):2749-62. PMID 20659958
21: Chabrol E, Popescu C, Gourfinkel-An I, et al. Two novel epilepsy-linked mutations leading to a loss of function of LGI1. Arch Neurol 2007b;64(2):217-22. PMID 17296837
22: Chernova OB, Somerville RP, Cowell JK. A novel gene, LGI1, from 10q24 is rearranged and downregulated in malignant brain tumors. Oncogene 1998;17(22):2873-81. PMID 9879993
23: Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989;30(4):389-99. PMID 2502382
24: Dazzo E, Fanciulli M, Serioli E, et al. Heterozygous reelin mutations cause autosomal-dominant lateral temporal epilepsy. Am J Hum Genet 2015b;96(6):992-1000. PMID 26046367
25: Dazzo E, Leonardi E, Belluzzi E, et al. Secretion-positive LGI1 mutations linked to lateral temporal epilepsy impair binding to ADAM22 and ADAM23 receptors. PLoS Genet 2016;12(10):e1006376. PMID 27760137
26: Dazzo E, Nobile C. Epilepsy-causing Reelin mutations result in impaired secretion and intracellular degradation of mutant proteins. Hum Mol Genet 2022;31(5):665-73. PMID 34508592
27: Dazzo E, Rehberg K, Michelucci R, et al. Mutations in MICAL-1cause autosomal-dominant lateral temporal epilepsy. Ann Neurol 2018;83(3):483-93. PMID 29394500
28: Dazzo E, Santulli L, Posar A, et al. Autosomal dominant lateral temporal epilepsy (ADLTE): novel structural and single-nucleotide LGI1 mutations in families with predominant visual auras. Epilepsy Res 2015a;110:132-8. PMID 25616465
29: Diani E, Di Bonaventura C, Mecarelli O, et al. Autosomal dominant lateral temporal epilepsy: absence of mutations in ADAM22 and Kv1 channel genes encoding LGI1-associated proteins. Epilepsy Res 2008;80(1):1-8. PMID 18440780
30: Dibbens LM, de Vries B, Donatello S, et al. Mutations in DEPDC5 cause familial focal epilepsy with variable foci. Nat Genet 2013;45(5):546-51. PMID 23542697
31: Di Bonaventura C, Operto FF, Busolin G, et al. Low penetrance and effect on protein secretion of LGI1 mutations causing autosomal dominant lateral temporal epilepsy. Epilepsia 2011;52(7):1258-64. PMID 21504429
32: Engel J Jr. Report of the ILAE classification core group. Epilepsia 2006;47(9):1558-68. PMID 16981873
33: Engel J Jr; International League Against Epilepsy (ILAE). A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE Task Force on Classification and Terminology Epilepsia 2001;42(6):796-803. PMID 11422340
34: Epi4K Consortium. Phenotypic analysis of 303 multiplex families with common epilepsies. Brain 2017;140(8):2144-56. PMID 28899008
35: Escayg A, MacDonald BT, Meisler MH, et al. Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2. Nat Genet 2000;24(4):343-5. PMID 10742094
36: Fanciulli M, Pasini E, Malacrida S, et al. Copy number variations and susceptibility to lateral temporal epilepsy: a study of 21 pedigrees. Epilepsia 2014;55(10):1651-8. PMID 25243798
37: Fanciulli M, Santulli L, Errichiello L, et al. LGI1 microdeletion in autosomal dominant lateral temporal epilepsy. Neurology 2012;78(17):1299-303. PMID 22496201
38: Fertig E, Lincoln A, Martinuzzi A, Mattson RH, Hisama FM. Novel LGI1 mutation in a family with autosomal dominant partial epilepsy with auditory features. Neurology 2003;60:1687-90. PMID 12771268
39: Flex E, Pizzuti A, Di Bonaventura C, et al. LGI1 gene mutation screening in sporadic partial epilepsy with auditory features. J Neurol 2005;252(1):62-6. PMID 15654555
40: Fukata Y, Adesnik H, Iwanaga T, Bredt DS, Nicoll RA, Fukata M. Epilepsy-related ligand/receptor complex LGI1 and ADAM22 regulate synaptic transmission. Science 2006;313(5794):1744-5. PMID 16990550
41: Furia A, Licchetta L, Muccioli L, at al. Epilepsy with auditory features: from etiology to treatment. Front Neurol 2022;12:807939. PMID 35153984
42: Furlan S, Roncaroli F, Forner F, et al. The LGI1/epitempin gene encodes two protein isoforms differentially expressed in human brain. J Neurochem 2006;98(3):985-91. PMID 16787412
43: Gu W, Brodtkorb E, Piepoli T, Finocchiaro G, Steinlein OK. LGI1: a gene involved in epileptogenesis and glioma progression. Neurogenetics 2005;6(2):59-66. PMID 15827762
44: Gu W, Brodtkorb E, Steinlein OK. LGI1 is mutated in familial temporal lobe epilepsy characterized by aphasic seizures. Ann Neurol 2002;52(3):364-7. PMID 12205652
45: Harkin LA, Bowser DN, Dibbens LM, et al. Truncation of the GABA(A)-receptor gamma2 subunit in a family with generalized epilepsy with febrile seizures plus. Am J Hum Genet 2002;70(2):530-6. PMID 11748509
46: Hedera P, Abou-Khalil B, Crunk AE, Taylor KA, Haines JL, Sutcliffe JS. Autosomal dominant lateral temporal epilepsy: two families with novel mutations in the LGI1 gene. Epilepsia 2004;45:218-22. PMID 15009222
47: Hocking AM, Shinomura T, McQuillan DJ. Leucine-rich repeat glycoproteins of the extracellular matrix. Matrix Biol 1998;17(1):1-19. PMID 9628249
48: Ishida S, Picard F, Rudolf G, et al. Mutations of DEPDC5 cause autosomal dominant focal epilepsies. Nat Genet 2013;45(5):552-5. PMID 23542701
49: Kalachikov S, Evgrafov O, Ross B, et al. Mutations in LGI1 cause autosomal dominant partial epilepsy with auditory features. Nat Genet 2002;30(3):335-41. PMID 11810107
50: Kanwal S, Yoo DH, Tahir S, et al. A novel nonsense mutation in leucine-rich, glioma-inactivated-1 gene as the underlying cause of familial temporal lobe epilepsy. J Clin Neurol 2018;14(4):591-3. PMID 30284771
51: Kawamata J, Ikeda A, Fujita Y, et al. Mutations in LGI1 gene in Japanese families with autosomal dominant lateral temporal lobe epilepsy: the first report from Asian families. Epilepsia 2010;51(4):690-3. PMID 19780791
52: Kobayashi E, Andermann F, Andermann E. Familial mesial temporal lobe epilepsy. In: Gilman S, editor. MedLink Neurology. San Diego: MedLink Corporation. Available at www.medlink.com. Accessed June 2009a.
53: Kobayashi E, Andermann F, Andermann E. Familial partial epilepsy with variable foci. In: Gilman S, editor. MedLink Neurology. San Diego: MedLink Corporation. Available at www.medlink.com. Accessed June 2009b.
54: Kobayashi E, Santos NF, Torres FR, et al. Magnetic resonance imaging abnormalities in familial temporal lobe epilepsy with auditory auras. Arch Neurol 2003;60(11):1546-51. PMID 14623726
55: Kobayashi E, Sousa SC, Lopes-Cendes I, et al. Seizure outcome and hippocampal atrophy in familial mesial temporal lobe epilepsy. Neurology 2001;56(2):166-72. PMID 11160950
56: Koizumi S, Kawai K, Asano S, Ueki K, Suzuki I, Saito N. Familial lateral temporal lobe epilepsy confirmed with intracranial electroencephalography and successfully treated by surgery. Neurol Med Chir (Tokyo) 2011;51(8):604-10. PMID 21869587
57: Lai M, Huijbers MG, Lancaster E, et al. Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series. Lancet Neurol 2010;9(8):776-85. PMID 20580615
58: Lee MK, Kim SW, Lee JH, et al. A newly discovered LGI1 mutation in Korean family with autosomal dominant lateral temporal lobe epilepsy. Seizure 2014;23(1):69-73. PMID 24177143
59: Leonardi E, Dazzo E, Aspromonte MC, et al. CNTNAP2 mutations and autosomal dominant epilepsy with auditory features. Epilepsy Res 2018;139:51-3. PMID 29179159
60: Liu F, Du C, Tian X, et al. A novel LGI1 missense mutation causes dysfunction in cortical neuronal migration and seizures. Brain Res 2019;1721:146332. PMID 31301272
61: Liu J, Hu D, Zhang Z, Tang F, Yan Y, Ma Y. Autosomal dominant lateral temporal epilepsy in a family exhibiting a rare heterozygous mutation and deletion in the leucine-rich glioma inactivated 1 gene. Neurosci Lett 2022;782:136698. PMID 35643238
62: Lopes-Cendes I, Scheffer IE, Berkovic SF, Rousseau M, Andermann E, Rouleau GA. A new locus for generalized epilepsy with febrile seizures plus maps to chromosome 2. Am J Hum Genet 2000;66(2):698-701. PMID 10677328
63: Luo J, Xu Y, Zhu Q, et al. Expression pattern of Mical-1 in the temporal neocortex of patients with intractable temporal epilepsy and pilocarpine-induced rat model. Synapse 2011;65(11):1213-21. PMID 21638339
64: Manna I, Mumoli L, Labate A, et al. Autosomal dominant lateral temporal epilepsy (ADLTE): Absence of chromosomal rearrangements in LGI1 gene. Epilepsy Res 2014;108(3):597-9. PMID 24315022
65: Martin C, Meloche C, Rioux MF, et al. A recurrent mutation in DEPDC5 predisposes to focal epilepsies in the French-Canadian population. Clin Genet 2014;86(6):570-4. PMID 24283814
66: Michelucci R, Dazzo E, Volpi L, et al. Autosomal dominant lateral temporal lobe epilepsy associated with a novel reelin mutation. Epileptic Disord 2020;22(4):443-8. PMID 32723706
67: Michelucci R, Mecarelli O, Bovo G, et al. A de novo LGI1 mutation causing idiopathic partial epilepsy with telephone-induced seizures. Neurology 2007;68:2150-1. PMID 17562837
68: Michelucci R, Pasini E, Malacrida S, et al. Low penetrance of autosomal dominant lateral temporal epilepsy in Italian families without LGI1 mutations. Epilepsia 2013;54(7):1288-97. PMID 23621105
69: Michelucci R, Poza JJ, Sofia V, et al. Autosomal dominant lateral temporal epilepsy: clinical spectrum, new epitempin mutations, and genetic heterogeneity in seven European families. Epilepsia 2003; 44(10):1289-97. PMID 14510822
70: Michelucci R, Pulitano P, Di Bonaventura C, et al. The clinical phenotype of autosomal dominant lateral temporal lobe epilepsy related to reelin mutations. Epilepsy Behav 2017;68:103-7.** PMID 28142128
71: Morante-Redolat JM, Gorostidi-Pagola A, Piquer-Sirerol S, et al. Mutations in the LGI1/Epitempin gene on 10q24 cause autosomal dominant lateral temporal lobe epilepsy. Hum Mol Genet 2002;11(9):1119-28. PMID 11978770
72: Nobile C, Michelucci R, Andreazza S, Pasini E, Tosatto SC, Striano P. LGI1 mutations in autosomal dominant and sporadic lateral temporal epilepsy. Hum Mutat 2009;30(4):530-6. PMID 19191227
73: Ottman R, Risch N, Hauser WA, et al. Localization of a gene for partial epilepsy to chromosome 10q. Nat Genet 1995;10(1):56-60. PMID 7647791
74: Ottman R, Rosenberger L, Bagic A, et al. Altered language processing in autosomal dominant partial epilepsy with auditory features. Neurology 2008;71(24):1973-80. PMID 19064878
75: Ottman R, Winawer MR, Kalachikov S, et al. LGI1 mutations in autosomal dominant partial epilepsy with auditory features. Neurology 2004; 62(7):1120-6. PMID 15079011
76: Pippucci T, Licchetta L, Baldassari S, et al. Epilepsy with auditory features: a heterogeneous clinico-molecular disease. Neurol Genet 2015;1(1):e5. PMID 27066544
77: Pisano T, Marini C, Brovedani P, et al. Abnormal phonologic processing in familial lateral temporal lobe epilepsy due to a new LGI1 mutation. Epilepsia 2005;46:118-23. PMID 15660777
78: Pizzuti A, Flex E, Di Bonaventura C, et al. Epilepsy with auditory features: a LGI1 gene mutation suggests a loss-of-function mechanism. Ann Neurol 2003;53:396-9. PMID 12601709
79: Poza JJ, Saenz A, Martinez-Gil A, et al. Autosomal dominant lateral temporal epilepsy: clinical and genetic study of a large Basque pedigree linked to chromosome 10q. Ann Neurol 1999;45(2):182-8. PMID 9989620
80: Riney K, Bogacz A, Somerville E, et al. International League Against Epilepsy classification and definition of epilepsy syndromes with onset at a variable age: position statement by the ILAE Task Force on Nosology and Definitions. Epilepsia 2022;63(6):1443-74.** PMID 35503725
81: Santos NF, Sousa SC, Kobayashi E, et al. Clinical and genetic heterogeneity in familial temporal lobe epilepsy. Epilepsia 2002;43 Suppl 5:136. PMID 12121308
82: Scheffer IE, Berkovic SF. Generalized epilepsy with febrile seizures plus. A genetic disorder with heterogeneous clinical phenotypes. Brain 1997;120 (Pt 3):479-90. PMID 9126059
83: Scheffer IE, Harkin LA, Grinton BE, et al. Temporal lobe epilepsy and GEFS+ phenotypes associated with SCN1B mutations. Brain 2007;130(Pt 1):100-9. PMID 17020904
84: Scheffer IE, Phillips HA, O'Brien CE, et al. Familial partial epilepsy with variable foci: a new partial epilepsy syndrome with suggestion of linkage to chromosome 2. Ann Neurol 1998;44(6):890-9. PMID 9851433
85: Schulte U, Thumfart JO, Klöcker N, et al. The epilepsy-linked Lgi1 protein assembles into presynaptic Kv1 channels and inhibits inactivation by Kvbeta1. Neuron 2006;49(5):642-4. PMID 16504945
86: Seagar M, Russier M, Caillard O, et al. LGI1 tunes intrinsic excitability by regulating the density of axonal Kv1 channels. Proc Natl Acad Sci U S A 2017;114(29):7719-24.** PMID 28673977
87: Senechal KR, Thaller C, Noebels JL. ADPEAF mutations reduce levels of secreted LGI1, a putative tumor suppressor protein linked to epilepsy. Hum Mol Genet 2005;14(12):1613-20. PMID 15857855
88: Singh R, Scheffer IE, Crossland K, Berkovic SF. Generalized epilepsy with febrile seizures plus: a common childhood-onset genetic epilepsy syndrome. Ann Neurol 1999;45(1):75-81. PMID 9894880
89: Striano P, Busolin G, Santulli L, et al. Familial temporal lobe epilepsy with psychic auras associated with a novel LGI1 mutation. Neurology 2011;76(13):1173-6. PMID 21444903
90: Striano P, Serioli E, Santulli L, et al. DEPDC5 mutations are not a frequent cause of familial temporal lobe epilepsy. Epilepsia 2015;56(10):e168-71. PMID 26216793
91: Sugawara T, Tsurubuchi Y, Agarwala KL, et al. A missense mutation of the Na+ channel alpha II subunit gene Na(v)1.2 in a patient with febrile and afebrile seizures causes channel dysfunction. Proc Natl Acad Sci U S A 2001;98(11):6384-9. PMID 11371648
92: Tessa C, Michelucci R, Nobile C, et al. Structural anomaly of left lateral temporal lobe in epilepsy due to mutated LGI1. Neurology 2007;69(12):1298-300. PMID 17875918
93: Vadlamudi L, Scheffer IE, Berkovic SF. Genetics of temporal lobe epilepsy. J Neurol Neurosurg Psychiatry 2003;74(10):1359-61. PMID 14570824
94: Wallace RH, Scheffer IE, Barnett S, et al. Neuronal sodium-channel alpha1-subunit mutations in generalized epilepsy with febrile seizures plus. Am J Hum Genet 2001;68(4):859-65. PMID 11254444
95: Wallace RH, Scheffer IE, Parasivam G, et al. Generalized epilepsy with febrile seizures plus: mutation of the sodium channel subunit SCN1B. Neurology 2002;58(9):1426-9. PMID 12011299
96: Wallace RH, Wang DW, Singh R, et al. Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B. Nat Genet 1998;19(4):366-70. PMID 9697698
97: Wei Z, Ye X, Wang C, et al. Case report: stereoelectroencephalography and stereoelectroencephalography-guided radiofrequency thermocoagulation in familial lateral temporal lobe epilepsy. Front Neurol 2022;13:864070. PMID 35444610
98: Winawer MR, Martinelli Boneschi F, Barker-Cummings C, et al. Four new families with autosomal dominant partial epilepsy with auditory features: clinical description and linkage to chromosome 10q24. Epilepsia 2002;43(1):60-7. PMID 11879388
99: Winawer MR, Ottman R, Hauser WA, Pedley TA. Autosomal dominant partial epilepsy with auditory features: defining the phenotype. Neurology 2000;54(11):2173-6. PMID 10851389
100: Xiong L. Identification, clinical characterization, and molecular genetic studies of familial partial epilepsy with variable foci. PhD thesis, McGill University, 2002.
101: Xiong L, Labuda M, Li DS, et al. Mapping of a gene determining familial partial epilepsy with variable foci to chromosome 22q11-q12. Am J Hum Genet 1999;65(6):1698-710. PMID 10577924
102: Yamagata A, Fukai S. Insights into the mechanisms of epilepsy from structural biology of LGI1-ADAM22. Cell Mol Life Sci 2020;77(2):267-74.** PMID 31432233
103: Yang H, Liao H, Gan S, Xiao T, Wu L. A novel splicing variant in MICAL-1 gene is associated with epilepsy. Eur J Med Genet 2024;69:104946. PMID 38705457
104: Yokoi N, Fukata Y, Okatsu K, et al. 14-3-3 proteins stabilize LGI1-ADAM22 levels to regulate seizure thresholds in mice. Cell Rep 2021;37(11):110107. PMID 34910912
105: Zhou YD, Lee S, Jin Z, Wright M, Smith SE, Anderson MP. Arrested maturation of excitatory synapses in autosomal dominant lateral temporal lobe epilepsy. Nat Med 2009;15(10):1208-14. PMID 19701204

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Eliane Kobayashi MD PhD

Dr. Kobayashi of McGill University received honorariums for advisory board membership from Palladin Laboratories and Jazz Pharmaceuticals.
See Profile

Editor

Jerome Engel Jr MD PhD

Dr. Engel of the David Geffen School of Medicine at the University of California, Los Angeles, has no relevant financial relationships to disclose.
See Profile

Former Authors

Eva Andermann MD PhD
Frederick Andermann MD

Patient Profile

Age range of presentation: 6 to 44 years
Sex preponderance: male=female
Heredity: Autosomal dominant
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none

ICD & OMIM codes

ICD-10: Localization-related (focal)(partial) symptomatic epilepsy and epileptic syndromes with simple partial seizures: G40.1

Localization-related (focal)(partial) symptomatic epilepsy and epileptic syndromes with complex partial seizures: G40.2
ICD-11: Other specified genetic epileptic syndrome with adolescent or adult onset: 8A61.3Y
OMIM: Contactin-associated protein-like 2; CNTNAP2: *604569

DEP domain-containing protein 5; DEPDC5: *614191

Lateral temporal lobe epilepsy, autosomal dominant: #600512

Leucine-rich glioma inactivated 1 gene: *604619

MICAL1: *607129

Microtubule-associated monooxygenase, calponin and lim domains-containing, 1; Reelin; RELN: *600514

Sodium voltage-gated channel, alpha subunit 1; SCN1A: *182389

This is an article preview.
Start a Free Account
to access the full version.

Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660

Support: service@medlink.com

Editor: editor@medlink.com

ISSN: 2831-9125

Epilepsy with auditory features

Differential Diagnosis

familial mesial temporal lobe epilepsy
familial focal epilepsy with variable foci
generalized epilepsy with febrile seizures plus
idiopathic partial epilepsy with auditory features
isolated lateral temporal lobe epilepsy
- nonfamilial temporal lobe epilepsy

Also Relevant

Epilepsy
Familial focal epilepsy with variable foci
Familial mesial temporal lobe epilepsy
Mesial temporal lobe epilepsy with hippocampal sclerosis
Neocortical temporal lobe seizures

Clinical Categories

Epilepsy & Seizures

Patient Handouts

Seizure first aid

Web References

Guidelines

Epilepsy with auditory features …

Epilepsy with auditory features

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Associated or underlying disorders

Diagnostic workup

Management

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Photosensitive occipital lobe epilepsy

Intermittent explosive disorder

Pyridoxine/P5P-dependent developmental epileptic encephalopathy

Reflex seizures

Anti-LGI1 encephalitis

Self-limited (familial) neonatal epilepsy

Alcohol withdrawal seizures

Epileptic lesions due to malformation of cortical development

Epilepsy with auditory features

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Associated or underlying disorders

Diagnostic workup

Management

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Photosensitive occipital lobe epilepsy

Intermittent explosive disorder

Pyridoxine/P5P-dependent developmental epileptic encephalopathy

Reflex seizures

Anti-LGI1 encephalitis

Self-limited (familial) neonatal epilepsy

Alcohol withdrawal seizures

Epileptic lesions due to malformation of cortical development

This is an article preview.
Start a Free Account
to access the full version.