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Autosomal Dominant Epilepsy with Auditory Features

Synonyms: ADEAF, Autosomal Dominant Lateral Temporal Epilepsy (ADLTE)

, MD, PhD and , PhD.

Author Information

Initial Posting: ; Last Update: January 10, 2019.

Estimated reading time: 29 minutes

Summary

Clinical characteristics.

Autosomal dominant epilepsy with auditory features (ADEAF) is a focal epilepsy syndrome with auditory symptoms and/or receptive aphasia as prominent ictal manifestations. The most common auditory symptoms are simple unformed sounds including humming, buzzing, or ringing; less common forms are distortions (e.g., volume changes) or complex sounds (e.g., specific songs or voices). Ictal receptive aphasia consists of a sudden onset of inability to understand language in the absence of general confusion. Less commonly, other ictal symptoms may occur, including sensory symptoms (visual, olfactory, vertiginous, or cephalic) or motor, psychic, and autonomic symptoms. Most affected individuals have focal to bilateral tonic-clonic seizures, usually accompanied by "focal aware" and "focal impaired-awareness" seizures, with auditory symptoms as a major focal aware seizure manifestation. Some persons have seizures precipitated by sounds such as a ringing telephone. Age at onset is usually in adolescence or early adulthood (range: age 4-50 years). The clinical course of ADEAF is benign. Seizures are usually well controlled after initiation of medical therapy.

Diagnosis/testing.

The clinical diagnosis of ADEAF is established in a proband with characteristic clinical features, normal brain imaging (MRI or CT), and family history consistent with autosomal dominant inheritance. Identification of a heterozygous pathogenic variant in LGI1, MICAL1, or RELN by molecular genetic testing establishes the diagnosis if other findings are inconclusive.

Management.

Treatment of manifestations: Seizure control is usually readily achieved with antiepileptic drugs used routinely in clinical practice (including but not limited to carbamazepine, phenytoin, valproate, and levetiracetam).

Evaluation of relatives at risk: Interviewing relatives at risk to identify those with suggestive findings may enable early treatment in those who develop seizures.

Genetic counseling.

ADEAF is inherited in an autosomal dominant manner. Most individuals with ADEAF have an affected parent; the proportion of cases caused by a de novo pathogenic variant is believed to be very low. Each child of an individual with ADEAF has a 50% chance of inheriting the pathogenic variant. The chance that the offspring who inherits the pathogenic variant will manifest ADEAF is between 55% and 78%, depending on the penetrance. While prenatal diagnosis for pregnancies at increased risk and preimplantation genetic diagnosis are possible if the pathogenic variant in the family is known, prenatal testing and preimplantation genetic diagnosis are rarely requested for conditions that (like ADEAF) do not affect intellect and are usually easily treated.

Diagnosis

Suggestive Findings

Autosomal dominant epilepsy with auditory features (ADEAF) should be suspected in individuals with the following clinical, imaging, and EEG findings and family history.

Clinical findings

  • A history consistent with focal epilepsy from the affected individual and witnesses. Other causes of epilepsy (e.g., antecedent illness or injury to the central nervous system, such as severe head trauma, stroke, and brain tumor) must be excluded.
  • Auditory symptoms that occur in temporal association with seizures as one of the following:
    • An aura immediately preceding generalized tonic-clonic convulsions
    • A component of focal aware or focal impaired-awareness seizures
    • The only ictal symptom
    Note: Auditory symptoms may be underreported; therefore, specific questions to elicit occurrence of auditory symptoms should be included in the clinical history. Since tinnitus and other auditory disturbances may be reported as incidental findings in a person with epilepsy, care should be taken in obtaining the medical history to document a consistent temporal association of auditory symptoms with seizure events or to raise a strong suspicion of the ictal nature of the auditory symptom if not associated with other clinical features.
  • Aphasia that accompanies seizure onset. Aphasia 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. Note: 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).

Brain imaging (MRI or CT). Normal

Interictal EEG. Often normal. However, focal epileptiform abnormalities (usually localized to the temporal region) are found in up to two thirds of individuals.

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 seizure types, usually tonic-clonic (undetermined whether focal or generalized).

Establishing the Diagnosis

The clinical diagnosis of ADEAF is established in a proband with the above clinical features, normal brain imaging studies (MRI or CT), and family history consistent with autosomal dominant inheritance. Identification of a heterozygous pathogenic variant in LGI1, MICAL1, or RELN by molecular genetic testing (Table 1) establishes the diagnosis if other findings are inconclusive.

A multigene panel that includes LGI1, MICAL1, RELN, and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Note: Serial single-gene testing of LGI1, MICAL1, and RELN is impractical given the relatively large number of exons in the latter two genes.

Table 1.

Molecular Genetic Testing Used in Autosomal Dominant Epilepsy with Auditory Features

Gene 1, 2Proportion of ADEAF 3 Attributed to Pathogenic Variants in This GeneProportion of Pathogenic Variants 4 in This Gene Detectable by This Method
Sequence analysis 5Gene-targeted deletion/duplication analysis 6
LGI130% 795%5% 8
MICAL17% 990%-95%Unknown
RELN17%-18% 790%-95%% 10Unknown
Unknown 11~50%NA
1.

Genes are listed in alphabetic order.

2.
3.

Autosomal dominant inheritance defined as ≥2 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, Michelucci et al 2013].

4.

See Molecular Genetics for information on allelic variants detected in these genes.

5.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

7.
8.

A deletion encompassing the first four exons of LGI1 was identified in one family [Fanciulli et al 2012], and a deletion encompassing the second exon in another family [Dazzo et al 2015b]. No structural variants were identified by MLPA in 43 other families [Magini et al 2014, Manna et al 2014, Dazzo et al 2015b].

9.
10.
11.

A locus on 19q13.11-q13.31 likely to harbor a gene associated with ADEAF was identified in a large Brazilian family [Bisulli et al 2014]. In 21 families with ADEAF, 12 rare CNVs were identified by genome-wide SNP microarray analysis that segregated with ADEAF in single families, including rare microdeletions within or near RBFOX1 and NRXN1, and a microduplication in the proximal region of chromosome 1q21.1, where duplications have been associated with various neurodevelopmental disorders and epilepsy [Fanciulli et al 2014]. Deletions/duplications at these loci confer susceptibility to other forms of genetic epilepsy.

Clinical Characteristics

Clinical Description

Autosomal dominant epilepsy with auditory features (ADEAF) 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, Michelucci et al 2013], 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, ADEAF is also known as autosomal dominant lateral temporal epilepsy (ADLTE).

Epilepsy. Affected individuals have focal to bilateral tonic-clonic seizures, usually accompanied by focal aware or focal impaired-awareness seizures, with auditory symptoms as a major focal aware seizure manifestation occurring in around two thirds of affected individuals. Some individuals have seizures precipitated by specific sounds, such as a telephone ringing [Michelucci et al 2003, Michelucci et al 2004, Michelucci et al 2007].

Although most individuals in families with ADEAF have focal epilepsy, idiopathic generalized epilepsy was reported in four individuals with LGI1 pathogenic variants 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 the risk for idiopathic generalized epilepsy, or by the co-occurring pathogenic variant in these families of another (unidentified) gene that specifically influences risk for idiopathic generalized epilepsy.

Febrile seizures do not occur with increased frequency in ADEAF.

Auditory symptoms. 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). Negative auditory symptoms, such as sudden decrease or disappearance of the surrounding noises, are reported by a minority of patients.

Aphasia. 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 pathogenic variant [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 pathogenic variants [Michelucci et al 2003, Ottman et al 2004, Di Bonaventura et al 2009].

Other ictal symptoms. In families with ADEAF, 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, Michelucci et al 2013, Dazzo et al 2015b].

Non-epileptic manifestations associated with ADEAF on rare occasion include the following:

  • Behavioral problems (e.g., explosive violent behaviors, impulsiveness) and depression (with suicide attempts) have been reported in single pedigrees [Chabrol et al 2007, Kawamata et al 2010]. However, a systematic study investigating a possible shared genetic susceptibility to epilepsy and depression in families with an LGI1 pathogenic variant did not find such an association; rather, the depression appeared to be related to the epilepsy or antiepileptic treatment [Heiman et al 2010].
  • Migraine segregating with occipito-temporal epilepsy resembling ADEAF has been described in one family [Deprez et al 2007].

Prognosis. The clinical course of ADEAF is usually benign. The following are offered as examples.

  • In a series of 34 affected individuals in seven Spanish and Italian families, focal to bilateral tonic-clonic seizures occurred only once or twice per year. The frequency of focal aware or focal impaired-awareness 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 [Michelucci et al 2003].
  • In a Norwegian family with prominent ictal aphasia, all individuals had been free from focal to bilateral tonic-clonic seizures for two or more years, and focal aware seizures occurred infrequently in most individuals. 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 [Brodtkorb et al 2002].
  • In one other family with an LGI1 pathogenic variant, an unusual clinical picture with high seizure frequency and antiepileptic drug resistance was described [Di Bonaventura et al 2009].

EEG. Interictal (routine and sleep-deprived) EEGs may be normal in persons with ADEAF; 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]. Interestingly, a left predominance of the abnormalities has been observed in some clinical series [Michelucci et al 2003, Di Bonaventura et al 2009].

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 an individual 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 pathogenic variants [Ottman et al 2008]. Another study using MEG detected significantly large N100m signals in three of five individuals, 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 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 pathogenic variant [Kobayashi et al 2003]. However, other studies using high-resolution MRI in families with LGI1 pathogenic variants 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 pathogenic variant [Tessa et al 2007].

In functional MRI with an auditory description decision task, persons with epilepsy in families with an LGI1 pathogenic variant had significantly less activation than controls [Ottman et al 2008]. These results suggest that individuals with ADEAF 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, would appear to suggest the existence of some structural abnormalities in the lateral temporal neuronal network.

Genotype-Phenotype Correlations

Auditory symptoms were less frequent with LGI1 pathogenic variants that predict truncation in the terminal epitempin repeat domain than with other LGI1 pathogenic variant type/domain combinations [Ho et al 2012].

Phenotypic features are the same in published familial cases with LGI1, MICAL1, or RELN pathogenic variants [Dazzo et al 2015a, Michelucci et al 2017, Dazzo et al 2018].

No significant clinical differences are observed between families with an LGI1 pathogenic variant and families without an identified pathogenic variant [Michelucci e al 2013].

No phenotypic differences have been found between simplex cases (i.e., a single occurrence in a family) and published familial cases [Bisulli et al 2004a, Bisulli et al 2004b, Flex et al 2005, Michelucci et al 2007, Michelucci et al 2009].

Penetrance

Estimates of penetrance in studies of families with ADEAF range from 54% to 85% [Ottman et al 1995, Poza et al 1999, Ottman et al 2004, Wang et al 2006]. This variability may in part result from the use of different statistical models.

LGI1. Based on analysis of obligate heterozygotes in 24 published families, penetrance of LGI1 pathogenic variants was estimated at 67% (95% CI 55%-77%) [Rosanoff & Ottman 2008].

More recently, in a study of 33 families in which probands were excluded, penetrance for epilepsy was estimated at 61% in ten families with an LGI1 pathogenic variant and 35% in families without an identified pathogenic variant, suggesting that inheritance may be complex in some families [Michelucci et al 2013].

All of these estimates are likely to be inflated by ascertainment bias, since they are based on families selected for study because they comprised many affected individuals.

RELN. Twenty (60%) of 33 individuals heterozygous for a RELN pathogenic variant (from 7 families) had epilepsy [Dazzo et al 2015a].

MICAL1. Penetrance is unknown.

Prevalence

The prevalence of ADEAF is unknown but likely to be very low. Fewer than 3% of persons with epilepsy have a significant family history of epilepsy and only a fraction of these have clinical features consistent with ADEAF.

Whereas Mendelian epilepsy syndromes account for a very small fraction of all epilepsy, findings from one study suggest that among Mendelian forms of focal epilepsy, ADEAF may not be rare as 9/48 (19%) of families with two or more individuals with idiopathic focal epilepsy met criteria for ADEAF (i.e., they comprised ≥2 individuals with ictal auditory symptoms) [Ottman et al 2004].

Differential Diagnosis

Table 2 summarizes Mendelian focal epilepsy disorders. Distinguishing among these disorders can be challenging because the manifestations in affected family members are variable and no operational criteria for classification of families are yet available [Picard et al 2000]. Moreover, these different forms of focal epilepsy have shared genetic mechanisms; pathogenic variants in DEPDC5 have been identified in all of them [Poduri 2014], and were found in ten (12%) of 82 families with two or more individuals with focal epilepsy who did not have a detectable structural etiology [Dibbens et al 2013]. However, to date, pathogenic variants in DEPDC5 have not been identified in families with ADEAF. (See also DEPDC5-Related Epilepsy.)

Table 2.

Mendelian Focal Epilepsy Disorders

DisorderGene(s)MOIClinical Features
Localization of
epileptogenic
zone
Seizure semiologyAge at onsetNeuroimagingEEGOther
Autosomal dominant epilepsy w/auditory features (ADEAF)LGI1
MICAL1
RELN
ADLateral temporal
  • Auditory symptoms are most common.
  • Autonomic or psychic symptoms occur in <25% of individuals. 1
Usually late adolescence or early adulthoodNormal
  • Interictal EEGs may be normal.
  • Epileptiform interictal EEG abnormalities found in ≤2/3s of affected individuals 2
  • Ictal EEGs reported in 3 persons 3
Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE)CHRNA4
CHRNB2
CHRNA2
KCNT1
DEPDC5
CRH 4
ADFrontal lobe (rarely from extrafrontal areas - e.g., temporal, insular, & parietal regions)Asymmetric tonic/dystonic posturing &/or complex hyperkinetic seizures, mostly during sleep1st 2 decades of life in ~80% (mean age of onset 10 yrs)Normal
  • Interictal & ictal scalp EEG features may be normal.
  • Prolonged video-EEG recording is best diagnostic test to assess seizure occurrence.
  • Characterized by clusters of nocturnal motor seizures, often stereotyped & brief (5 secs - 5 mins)
  • Clinical neurologic exam normal & intellect usually preserved, but psychiatric comorbidity or cognitive deficits may occur
  • Manifestations may vary considerably w/in a family.
Familial mesial temporal lobe epilepsy (FMTLE)
(OMIM PS600512)
UnknownAD
AR
Mesial temporal lobe 5
  • Psychic symptoms (esp. déjà vu) most common
  • Autonomic or special sensory components in ~50%
  • Auditory symptoms in <10%
Usually late adolescence or early adulthoodNormalInterictal epileptiform EEG abnormalities in ~20%
  • Febrile seizure frequency as in general population
  • Benign clinical course, w/long remissions & good response to range of therapies (carbamazepine, phenytoin, or valproate)
Familial partial epilepsy w/variable foci (FPEVF)
(OMIM PS604364)
DEPDC5
NPRL2
NPRL3
AD
  • Epileptogenic zone (frontal, temporal, or occipital) differs among family members. 6
  • Frontal lobe seizures most common
Auditory symptoms & aphasia not described in families w/FPEVFUsually middle childhood to early adulthoodNormalInterictal & ictal EEG abnormalities localized in different areas (frontal, temporal, occipital)Seizures in FPEVF occur less frequently than in ADNFLE; when they occur it is more often in daytime.
1.
2.
3.
4.

Molecular genetic testing reveals pathogenic variants in CHRNA4, CHRNB2, CHRNA2, KCNT1, DEPDC5, or CRH in approximately 20% of individuals with a positive family history and fewer than 5% of individuals with a negative family history.

5.
6.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with autosomal dominant epilepsy with auditory features (ADEAF), consultation with a clinical geneticist and/or genetic counselor is recommended.

Treatment of Manifestations

ADEAF is benign in the great majority of individuals. No clinical trials of different antiepileptic medications have been carried out, but seizure control is achieved in most individuals with medications used routinely in clinical practice (e.g., carbamazepine, phenytoin, valproate).

Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see Epilepsy & My Child Toolkit.

Surveillance

No surveillance guidelines for ADEAF have been developed.

  • As in any other form of focal epilepsy, routine interictal EEG may be performed to detect focal epileptiform abnormalities.
  • Brain MRI may be repeated to rule out structural abnormalities.

Evaluation of Relatives at Risk

It is appropriate to evaluate relatives at risk in order to identify as early as possible those who would benefit from initiation of treatment and measures to minimize risk in the event of seizure onset (e.g., avoidance of unattended swimming).

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

In general, women with epilepsy or a seizure disorder from any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of antiepileptic medication during pregnancy reduces this risk. However, exposure to antiepileptic medication may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from antiepileptic medication exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of antiepileptic medication to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given antiepileptic drug during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [Sarma et al 2016].

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Autosomal dominant epilepsy with auditory features (ADEAF) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

Sibs of a proband. The risk to sibs of a proband depends on the clinical/genetic status of the parents:

  • If a parent has clinical characteristics consistent with ADEAF and/or has the pathogenic variant identified in the proband, the likelihood that each sib will inherit the pathogenic variant is 50%. The chance that a sib who inherits the pathogenic variant will manifest ADEAF ranges from 54% to 85%, depending on the assumed penetrance. (See Penetrance.)
  • If a parent has clinical characteristics consistent with ADEAF and does not have the LGI1, MICAL1, or RELN pathogenic variant identified in the proband, the recurrence risk to sibs might be as low as 35%, especially in small-sized (nuclear) families (see Penetrance.)
  • If the proband has a known LGI1, MICAL1, or RELN pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
  • If the parents have not been tested for the ADEAF-related pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for ADEAF because of the possibility of reduced penetrance in a parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Offspring of an individual with ADEAF who is heterozygous for a pathogenic variant have a 50% chance of inheriting the pathogenic variant; the chance that offspring who inherit the pathogenic variant will manifest ADEAF ranges from 54% to 85% depending on the assumed penetrance.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has phenotypic features consistent with ADEAF or has a pathogenic variant in LGI1, MICAL1, or RELN, his or her family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Diagnostic testing for LGI1, MICAL1, or RELN pathogenic variants in individuals with ADEAF has limited clinical utility because identification of a pathogenic variant would not lead to a change in treatment or management [Ottman et al 2010]. On the other hand, identification of the genetic basis of ADEAF enables informed genetic counseling and benefits individuals interested in knowing the cause of their epilepsy.

The utility of presymptomatic testing is limited because:

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the LGI1, MICAL1, or RELN pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information 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 Epilepsy with Auditory Features: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Autosomal Dominant Epilepsy with Auditory Features (View All in OMIM)

600512EPILEPSY, FAMILIAL TEMPORAL LOBE, 1; ETL1
600514REELIN; RELN
604619LEUCINE-RICH GENE, GLIOMA-INACTIVATED, 1; LGI1
607129MICROTUBULE-ASSOCIATED MONOOXYGENASE, CALPONIN AND LIM DOMAINS-CONTAINING, 1; MICAL1
616436EPILEPSY, FAMILIAL TEMPORAL LOBE, 7; ETL7

Molecular Genetic Pathogenesis

The proteins reelin and Lgi1 colocalize in a subset of rat brain neurons, supporting a common molecular pathway underlying ADEAF [Dazzo et al 2015a]. Reelin serves a dual purpose in mammalian brain with critical roles both during embryonic development [D'Arcangelo et al 1995, Lambert de Rouvroit & Goffinet 1998] and postnatally [Niu et al 2004, Beffert et al 2005]. Work on conditional knockout mice suggests that Lgi1, like reelin, could serve different functions during brain development and in adulthood [Boillot et al 2014]. Thus, a functional interplay between the two proteins may be necessary for proper regulation of various neuronal processes during development and in adult life.

The protein MICAL1 has an enzymatic oxidoreductase activity that induces disassembly of actin filaments, thereby regulating the organization of the actin cytoskeleton in developing and adult neurons and in other cell types. Dysregulation of the actin cytoskeleton dynamics in neurons is a likely mechanism underlying MICAL1-related ADEAF [Dazzo et al 2018].

LGI1

Gene structure. The longest LGI1 transcript variant (NM_005097.2) has eight exons. LGI1 is a member of a subfamily of leucine-rich repeat (LRR)-encoding genes, denoted LGI1, LGI2, LGI3, and LGI4 [Gu et al 2002b]. See Table A, Gene for a detailed summary of gene and protein information.

Pathogenic variants. Pathogenic variants have been found throughout the gene; they were found to cluster in the LRR domain (exons 3-5) [Ho et al 2012].

Of the reported pathogenic variants, two thirds are missense variants and one third are frameshift variants that predict premature translation termination leading to unstable mRNA or truncated protein. Three intronic pathogenic variants have been reported, each predicting protein truncation [Kalachikov et al 2002, Kobayashi et al 2003, Chabrol et al 2007]. Almost all of the identified pathogenic variants have been unique to an individual family. The exceptions:

In addition, two of the reported pathogenic missense variants, c.124T>C and c.124T>G, changed the same nucleotide [Berkovic et al 2004a, Ottman et al 2004].

Deletions encompassing one or more exons of LGI1 were identified in families with ADEAF in which exon sequencing revealed no pathogenic variant [Fanciulli et al 2012, Dazzo et al 2015b].

Table 3.

LGI1 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.124T>Cp.Cys42ArgNM_005097​.2
NP_005088​.1
c.124T>Gp.Cys42Gly
c.136T>Cp.Cys46Arg
c.758delCp.Ala253ValfsTer32
c.1418C>Tp.Ser473Leu
c.1420C>Tp.Arg474Ter
Deletion of ~81 kb 1

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Deletes exons 1-4 and maps between rs11187602 and rs7099034 [Fanciulli et al 2012]

Normal gene product. The longest transcript NM_005097.2 is predicted to encode the longest isoform, the 557-amino-acid leucine-rich glioma-inactivated protein 1 (Lgi1) (NP_005088.1) [Nobile at al 2009]. See Molecular Genetic Pathogenesis.

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; multiple lines of evidence have been investigated.

Interestingly, there are two protein isoforms, with different expression patterns in human brain [Furlan et al 2006]. The long isoform (NP_005088.1) is secreted [Sirerol-Piquer et al 2006]. Most pathogenic variants are defective for secretion, whereas a few pathogenic variants allow protein secretion but reduce the binding ability of the Lgi1 long form to its neuronal receptors ADAM22 and ADAM23 [Sirerol-Piquer et al 2006, Dazzo et al 2016].

One study suggested that Lgi1 may influence the risk for epilepsy through a glutamatergic mechanism: through its interaction with ADAM22, Lgi1 controls the synaptic content of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors, thereby modulating synaptic transmission as well as regulating the maturation of excitatory synapses [Lovero et al 2015].

Studies in transgenic mice showed that overexpression of an Lgi1 pathogenic variant, homologous to one known to cause ADEAF in humans, causes epilepsy by impairing the postnatal development of glutamatergic circuits in the hippocampus [Zhou et al 2009].

Cancer and benign tumors. Cancerous tissues obtained from normal individuals show that 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 ADEAF.

MICAL1

Gene structure. The main MICAL1 transcript has 25 exons (NM_022765.4). MICAL1 is a member of a family of genes that includes two more human genes: MICAL2 and MICAL3. See Table A, Gene for a detailed summary of gene and protein information.

Pathogenic variants. Two pathogenic variants have been identified in two families with ADEAF [Dazzo et al 2018]. A missense variant, p.Gly150Ser, was found in the enzymatically active oxidoreductase domain, and a two-base pair frameshift deletion, p.Ala1065fs, in the C-terminal domain, resulting in truncation of the terminal portion of the protein.

Table 4.

MICAL1 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.448G>Ap.Gly150SerNM_022765​.4
c.3189_3190delp.Ala1065fsNP_073602​.3

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. MICAL1 encodes [F-actin]-monooxygenase MICAL1, a protein of 1,067 amino acids (NP_073602.3) that contains an enzymatically active oxidoreductase domain and three other domains that mediate protein-protein interactions. For a review see Vanoni [2017].

Abnormal gene product. Both pathogenic variants were shown to significantly increase the oxidoreductase activity of MICAL1 and induce cell contraction in cultured cells, which likely resulted from deregulation of actin cytoskeleton dynamics. MICAL1 oxidoreductase activity is autoinhibited by the C-terminal domain, so that the wild type protein is nearly inactive. A small deletion like p.Ala1065fs that alters the structure of the C-terminal domain reduces its ability to suppress the oxidoreductase activity, which is therefore increased (gain of function). The p.Gly150Ser variant affects a highly conserved glycine residue, the substitution of which with a polar serine may result in a local perturbation of domain conformation that partially releases inhibition by the C-terminal domain.

RELN

Gene structure. The longest RELN transcript has 65 exons and is primarily expressed in the brain [Dazzo et al 2015a]. Two transcript variants encoding distinct isoforms have been identified for this gene. Other transcript variants have been described but their full length nature has not been determined. See Table A, Gene for a detailed summary of gene and protein information.

Pathogenic variants. Seven pathogenic variants have been identified in seven Italian families with ADEAF [Dazzo et al 2015a]. All were missense variants that affected structurally important amino acids or likely affected protein folding. Four pathogenic variants – p.Asp763Gly, p.His798Asn, p.Gly2783Cys, and p.Glu3176Lys – were shown to reduce serum levels of reelin, suggesting a loss-of-function effect due to impaired protein secretion [Dazzo et al 2015a].

Table 5.

RELN Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.2015C>Tp.Pro672LeuNM_005045​.3
NP_005036​.2
c.2168A>Gp.Tyr723Cys
c.2288A>Gp.Asp763Gly
c.2392C>Ap.His798Asn
c.2531C>Tp.Pro844Leu
c.8347G>Tp.Gly2783Cys
c.9526G>Ap.Glu3176Lys

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. RELN encodes reelin, a very large secreted protein of 3,460 amino acids. See Molecular Genetic Pathogenesis and D'Arcangelo [2014] for a review.

Abnormal gene product. Pathogenic variants in RELN were associated with decreased serum levels of reelin, suggesting an inhibitory effect on protein secretion [Dazzo et al 2015a]. Reduced levels of serum reelin are observed in heterozygous reeler mice [Smalheiser et al 2000], which have apparently normal brains but display functional and molecular defects at the synapse [Ventruti et al 2011]. Similar synaptic defects may also be associated with the heterozygous pathogenic variants in RELN in ADEAF, eventually giving rise to epilepsy.

In humans, homozygous RELN pathogenic variants cause autosomal recessive lissencephaly with cerebellar hypoplasia (LCH) (OMIM 257320) [Hong et al 2000]. In three small consanguineous families with LCH reported, clinically normal heterozygotes (carriers of one RELN pathogenic variant) exhibited reduced serum reelin [Hong et al 2000, Zaki et al 2007]. The apparently normal carrier phenotype is consistent with the relatively low penetrance of RELN pathogenic variants in families with ADEAF. Thus, as in other genetic epilepsy syndromes, RELN-related disorders may be genetically and clinically heterogeneous, with pathogenic variants resulting in ADEAF in heterozygotes and the more severe LCH in homozygotes.

References

Literature Cited

  • Andermann F, Kobayashi E, Andermann E. Genetic focal epilepsies: state of the art and paths to the future. Epilepsia. 2005;46 Suppl 10:61–7. [PubMed: 16359475]
  • Beffert U, Weeber EJ, Durudas A, Qiu S, Masiulis I, Sweatt JD, Li WP, Adelmann G, Frotscher M, Hammer RE, Herz J. Modulation of synaptic plasticity and memory by Reelin involves differential splicing of the lipoprotein receptor Apoer2. Neuron. 2005;47:567–79. [PubMed: 16102539]
  • Berkovic SF, Izzillo P, McMahon JM, Harkin LA, McIntosh AM, Phillips HA, Briellmann RS, Wallace RH, Mazarib A, Neufeld MY, Korczyn AD, Scheffer IE, Mulley JC. LGI1 mutations in temporal lobe epilepsies. Neurology. 2004a;62:1115–9. [PubMed: 15079010]
  • Berkovic SF, Serratosa JM, Phillips HA, Xiong L, Andermann E, Díaz-Otero F, Gómez-Garre P, Martín M, Fernández-Bullido Y, Andermann F, Lopes-Cendes I, Dubeau F, Desbiens R, Scheffer IE, Wallace RH, Mulley JC, Pandolfo M. Familial partial epilepsy with variable foci: clinical features and linkage to chromosome 22q12. Epilepsia. 2004b;45:1054–60. [PubMed: 15329069]
  • Bisulli F, Naldi I, Baldassari S, Magini P, Licchetta L, Castegnaro G, Fabbri M, Stipa C, Ferrari S, Seri M, Goncalves Silva GE, Tinuper P, Pippucci T. Autosomal dominant partial epilepsy with auditory features: a new locus on chromosome 19q13.11-q13.31. Epilepsia. 2014;55:841–8. [PubMed: 24579982]
  • Bisulli F, Tinuper P, Avoni P, Striano P, Striano S, d'Orsi G, Vignatelli L, Bagattin A, Scudellaro E, Florindo I, Nobile C, Tassinari CA, Baruzzi A, Michelucci R. Idiopathic partial epilepsy with auditory features (IPEAF): a clinical and genetic study of 53 sporadic cases. Brain. 2004a;127:1343–52. [PubMed: 15090473]
  • Bisulli F, Tinuper P, Scudellaro E, Naldi I, Bagattin A, Avoni P, Michelucci R, Nobile C. A de novo LGI1 mutation in sporadic partial epilepsy with auditory features. Ann Neurol. 2004b;56:455–6. [PubMed: 15349881]
  • Boillot M, Huneau C, Marsan E, Lehongre K, Navarro V, Ishida S, Dufresnois B, Ozkaynak E, Garrigue J, Miles R, Martin B, Leguern E, Anderson MP, Baulac S. Glutamatergic neuron-targeted loss of LGI1 epilepsy gene results in seizures. Brain. 2014;137:2984–96. [PMC free article: PMC4208469] [PubMed: 25234641]
  • 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;43:228–35. [PubMed: 11906506]
  • Brodtkorb E, Michler RP, Gu W, Steinlein OK. Speech-induced aphasic seizures in epilepsy caused by LGI1 mutation. Epilepsia. 2005a;46:963–6. [PubMed: 15946341]
  • Brodtkorb E, Steinlein OK, Sand T. Asymmetry of long-latency auditory evoked potentials in LGI1-related autosomal dominant lateral temporal lobe epilepsy. Epilepsia. 2005b;46:1692–4. [PubMed: 16190946]
  • Callenbach PM, van den Maagdenberg AM, Hottenga JJ, van den Boogerd EH, de Coo RF, Lindhout D, Frants RR, Sandkuijl LA, Brouwer OF. Familial partial epilepsy with variable foci in a Dutch family: clinical characteristics and confirmation of linkage to chromosome 22q. Epilepsia. 2003;44:1298–305. [PubMed: 14510823]
  • Chabrol E, Popescu C, Gourfinkel-An I, Trouillard O, Depienne C, Senechal K, Baulac M, LeGuern E, Baulac S. Two novel epilepsy-linked mutations leading to a loss of function of LGI1. Arch Neurol. 2007;64:217–22. [PubMed: 17296837]
  • Chernova OB, Somerville RP, Cowell JK. A novel gene, LGI1, from 10q24 is rearranged and downregulated in malignant brain tumors. Oncogene. 1998;17:2873–81. [PubMed: 9879993]
  • D'Arcangelo G. Reelin in the years: controlling neuronal migration and maturation in the mammalian brain. Advances in Neuroscience. 2014. Available online.
  • D'Arcangelo G, Miao GG, Chen SC, Soares HD, Morgan JI, Curran T. A protein related to extracellular matrix proteins deleted in the mouse mutant reeler. Nature. 1995;374:719–23. [PubMed: 7715726]
  • Dazzo E, Fanciulli M, Serioli E, Minervini G, Pulitano P, Binelli S, Di Bonaventura C, Luisi C, Pasini E, Striano S, Striano P, Coppola G, Chiavegato A, Radovic S, Spadotto A, Uzzau S, La Neve A, Giallonardo AT, Mecarelli O, Tosatto SC, Ottman R, Michelucci R, Nobile C. Heterozygous reelin mutations cause autosomal-dominant lateral temporal epilepsy. Am J Hum Genet. 2015a;96:992–1000. [PMC free article: PMC4457960] [PubMed: 26046367]
  • Dazzo E, Leonardi E, Belluzzi E, Malacrida S, Vitiello L, Greggio E, Tosatto SC, Nobile C. Secretion-positive LGI1 mutations linked to lateral temporal epilepsy impair binding to ADAM22 and ADAM23 receptors. PLoS Genet. 2016;12:e1006376. [PMC free article: PMC5070869] [PubMed: 27760137]
  • Dazzo E, Rehberg K, Michelucci R, Passarelli D, Boniver C, Vianello Dri V, Striano P, Striano S, Pasterkamp RJ, Nobile C. Mutations in MICAL-1 cause autosomal-dominant lateral temporal epilepsy. Ann Neurol. 2018;83:483–93. [PubMed: 29394500]
  • Dazzo E, Santulli L, Posar A, Fattouch J, Conti S, Loden-van Straaten M, Mijalkovic J, De Bortoli M, Rosa M, Millino C, Pacchioni B, Di Bonaventura C, Giallonardo AT, Striano S, Striano P, Parmeggiani A, Nobile C. Autosomal dominant lateral temporal epilepsy (ADLTE): novel structural and single-nucleotide LGI1 mutations in families with predominant visual auras. Epilepsy Res. 2015b;110:132–8. [PubMed: 25616465]
  • Deprez L, Peeters K, Van Paesschen W, Claeys KG, Claes LR, Suls A, Audenaert D, Van Dyck T, Goossens D, Del-Favero J, De Jonghe P. Familial occipitotemporal lobe epilepsy and migraine with visual aura – linkage to chromosome 9q. Neurology. 2007;68:1995–2002. [PubMed: 17460155]
  • Di Bonaventura C, Carni M, Diani E, Fattouch J, Vaudano EA, Egeo G, Pantano P, Maraviglia B, Bozzao L, Manfredi M, Prencipe M, Giallonardo TA, Nobile C. Drug resistant ADLTE and recurrent partial status epilepticus with dysphasic features in a family with a novel LGI1 mutation: electroclinical, genetic, and EEG/fMRI findings. Epilepsia. 2009;50:2481–6. [PubMed: 19552651]
  • Dibbens LM, de Vries B, Donatello S, Heron SE, Hodgson BL, Chintawar S, Crompton DE, Hughes JN, Bellows ST, Klein KM, Callenbach PM, Corbett MA, Gardner AE, Kivity S, Iona X, Regan BM, Weller CM, Crimmins D, O'Brien TJ, Guerrero-Lopez R, Mulley JC, Dubeau F, Licchetta L, Bisulli F, Cossette P, Thomas PQ, Gecz J, Serratosa J, Brouwer OF, Andermann F, Andermann E, van den Maagdenberg AM, Pandolfo M, Berkovic SF, Scheffer IE. Mutations in DEPDC5 cause familial focal epilepsy with variable foci. Nat Genet. 2013;45:546–51. [PubMed: 23542697]
  • Fanciulli M, Pasini E, Malacrida S, Striano P, Striano S, Michelucci R, Ottman R, Nobile C. Copy number variations and susceptibility to lateral temporal epilepsy: a study of 21 pedigrees. Epilepsia. 2014;55:1651–8. [PubMed: 25243798]
  • Fanciulli M, Santulli L, Errichiello L, Barozzi C, Tomasi L, Rigon L, Cubeddu T, de Falco A, Rampazzo A, Michelucci R, Uzzau S, Striano S, de Falco FA, Striano P, Nobile C. LGI1 microdeletion in autosomal dominant lateral temporal epilepsy. Neurology. 2012;78:1299–303. [PMC free article: PMC3335451] [PubMed: 22496201]
  • 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. [PubMed: 12771268]
  • Flex E, Pizzuti A, Di Bonaventura C, Douzgou S, Egeo G, Fattouch J, Manfredi M, Dallapiccola B, Giallonardo AT. LGI1 gene mutation screening in sporadic partial epilepsy with auditory features. J Neurol. 2005;252:62–6. [PubMed: 15654555]
  • Furlan S, Roncaroli F, Forner F, Vitiello L, Calabria E, Piquer-Sirerol S, Valle G, Perez-Tur J, Michelucci R, Nobile C. The LGI1/epitempin gene encodes two protein isoforms differentially expressed in human brain. J Neurochem. 2006;98:985–91. [PubMed: 16787412]
  • Gu W, Brodtkorb E, Steinlein OK. LGI1 is mutated in familial temporal lobe epilepsy characterized by aphasic seizures. Ann Neurol. 2002a;52:364–7. [PubMed: 12205652]
  • Gu W, Wevers A, Schröder H, Grzeschik KH, Derst C, Brodtkorb E, de Vos R, Steinlein OK. The LGI1 gene involved in lateral temporal lobe epilepsy belongs to a new subfamily of leucine-rich repeat proteins. FEBS Lett. 2002b;519:71–6. [PubMed: 12023020]
  • 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. [PubMed: 15009222]
  • Heiman GA, Kamberakis K, Gill R, Kalachikov S, Pedley TA, Hauser WA, Ottman R. Evaluation of depression risk in LGI1 mutation carriers. Epilepsia. 2010;51:1685–90. [PMC free article: PMC2939248] [PubMed: 20659151]
  • Ho YY, Ionita-Laza I, Ottman R. Domain-dependent clustering and genotype-phenotype analysis of LGI1 mutations in ADPEAF. Neurology. 2012;78:563–8. [PMC free article: PMC3280014] [PubMed: 22323750]
  • Hong SE, Shugart YY, Huang DT, Shahwan SA, Grant PE, Hourihane JO, Martin ND, Walsh CA. Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nat Genet. 2000;26:93–6. [PubMed: 10973257]
  • Kalachikov S, Evgrafov O, Ross B, Winawer M, Barker-Cummings C, Martinelli Boneschi F, Choi C, Morozov P, Das K, Teplitskaya E, Yu A, Cayanis E, Penchaszadeh G, Kottmann AH, Pedley TA, Hauser WA, Ottman R, Gilliam TC. Mutations in LGI1 cause autosomal-dominant partial epilepsy with auditory features. Nat Genet. 2002;30:335–41. [PMC free article: PMC2606053] [PubMed: 11810107]
  • Kanemoto K, Kawasaki J. Familial aphasic episodes: another variant of partial epilepsy with simple inheritance? Epilepsia. 2000;41:1036–8. [PubMed: 10961632]
  • Kawamata J, Ikeda A, Fujita Y, Usui K, Shimohama S, Takahashi R. Mutations in LGI1 gene in Japanese families with autosomal dominant lateral temporal lobe epilepsy: the first report from Asian families. Epilepsia. 2010;51:690–3. [PubMed: 19780791]
  • Kesim YF, Uzun GA, Yucesan E, Tuncer FN, Ozdemir O, Bebek N, Ozbek U, Iseri SA, Baykan B. Screening LGI1 in a cohort of 26 lateral temporal lobe epilepsy patients with auditory aura from Turkey detects a novel de novo mutation. Epilepsy Res. 2016;120:73–8. [PubMed: 26773249]
  • Kobayashi E, Santos NF, Torres FR, Secolin R, Sardinha LA, Lopez-Cendes I, Cendes F. Magnetic resonance imaging abnormalities in familial temporal lobe epilepsy with auditory auras. Arch Neurol. 2003;60:1546–51. [PubMed: 14623726]
  • Lambert de Rouvroit C, Goffinet AM. The reeler mouse as a model of brain development. Adv Anat Embryol Cell Biol. 1998;150:1–106. [PubMed: 9816727]
  • Lovero KL, Fukata Y, Granger AJ, Fukata M, Nicoll RA. The LGI1-ADAM22 protein complex directs synapse maturation through regulation of PSD-95 function. Proc Natl Acad Sci U S A. 2015;112:E4129–37. [PMC free article: PMC4522810] [PubMed: 26178195]
  • Magini P, Bisulli F, Baldassari S, Stipa C, Naldi I, Licchetta L, Menghi V, Tinuper P, Seri M, Pippucci T. LGI1 microdeletions are not a frequent cause of partial epilepsy with auditory features (PEAF). Epilepsy Res. 2014;108:972–7. [PubMed: 24721199]
  • Manna I, Mumoli L, Labate A, Citrigno L, Ferlazzo E, Aguglia U, Quattrone A, Gambardella A. Autosomal dominant lateral temporal epilepsy (ADLTE): absence of chromosomal rearrangements in LGI1 gene. Epilepsy Res. 2014;108:597–9. [PubMed: 24315022]
  • Michelucci R, Gardella E, de Haan GJ, Bisulli F, Zaniboni A, Cantalupo G, Alberto Tassinari C, Tinuper P, Nobile C, Nichelli P, Kasteleijn-Nolst Trenité DG. Telephone-induced seizures: a new type of reflex epilepsy. Epilepsia. 2004;45:280–3. [PubMed: 15009231]
  • Michelucci R, Mecarelli O, Bovo G, Bisulli F, Testoni S, Striano P, Striano S, Tinuper P, Nobile C. A de novo LGI1 mutation causing idiopathic partial epilepsy with telephone-induced seizures. Neurology. 2007;68:2150–1. [PubMed: 17562837]
  • Michelucci R, Pasini E, Malacrida S, Striano P, Bonaventura CD, Pulitano P, Bisulli F, Egeo G, Santulli L, Sofia V, Gambardella A, Elia M, de Falco A, Neve A, Banfi P, Coppola G, Avoni P, Binelli S, Boniver C, Pisano T, Marchini M, Dazzo E, Fanciulli M, Bartolini Y, Riguzzi P, Volpi L, de Falco FA, Giallonardo AT, Mecarelli O, Striano S, Tinuper P, Nobile C. Low penetrance of autosomal dominant lateral temporal epilepsy in Italian families without LGI1 mutations. Epilepsia. 2013;54:1288–97. [PubMed: 23621105]
  • Michelucci R, Pasini E, Nobile C. Lateral temporal lobe epilepsies: clinical and genetic features. Epilepsia. 2009;50 Suppl 5:52–4. [PubMed: 19469848]
  • Michelucci R, Poza JJ, Sofia V, de Feo MR, Binelli S, Bisulli F, Scudellaro E, Simionati B, Zimbello R, D'Orsi G, Passarelli D, Avoni P, Avanzini G, Tinuper P, Biondi R, Valle G, Mautner VF, Stephani U, Tassinari CA, Moschonas NK, Siebert R, Lopez de Munain A, Perez-Tur J, Nobile C. Autosomal dominant lateral temporal epilepsy: clinical spectrum, new epitempin mutations, and genetic heterogeneity in seven European families. Epilepsia. 2003;44:1289–97. [PubMed: 14510822]
  • Michelucci R, Pulitano P, Di Bonaventura C, Binelli S, Luisi C, Pasini E, Striano S, Striano P, Coppola G, La Neve A, Giallonardo AT, Mecarelli O, Serioli E, Dazzo E, Fanciulli M, Nobile C. The clinical phenotype of autosomal dominant lateral temporal lobe epilepsy related to reelin mutations. Epilepsy Behav. 2017;68:103–7. [PMC free article: PMC5378904] [PubMed: 28142128]
  • Morante-Redolat JM, Gorostidi-Pagola A, Piquer-Sirerol S, Sáenz A, Poza JJ, Galán J, Gesk S, Sarafidou T, Mautner VF, Binelli S, Staub E, Hinzmann B, French L, Prud'homme JF, Passarelli D, Scannapieco P, Tassinari CA, Avanzini G, Martí-Massó JF, Kluwe L, Deloukas P, Moschonas NK, Michelucci R, Siebert R, Nobile C, Pérez-Tur J, López de Munain A. Mutations in the LGI1/Epitempin gene on 10q24 cause autosomal dominant lateral temporal epilepsy. Hum Mol Genet. 2002;11:1119–28. [PubMed: 11978770]
  • Niu S, Renfro A, Quattrocchi CC, Sheldon M, D'Arcangelo G. Reelin promotes hippocampal dendrite development through the VLDLR/ApoER2-Dab1 pathway. Neuron. 2004;41:71–84. [PubMed: 14715136]
  • 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;30:530–6. [PubMed: 19191227]
  • Ottman R, Hirose S, Jain S, Lerche H, Lopes-Cendes I, Noebels JL, Serratosa J, Zara F, Scheffer IE. Genetic testing in the epilepsies—report of the ILAE Genetics Commission. Epilepsia. 2010;51:655–70. [PMC free article: PMC2855784] [PubMed: 20100225]
  • Ottman R, Risch N, Hauser WA, Pedley TA, Lee JH, Barker-Cummings C, Lustenberger A, Nagle KJ, Lee KS, Scheuer ML, Neystat M, Susser M, Wilhelmsen K. Localization of a gene for partial epilepsy to chromosome 10q. Nat Genet. 1995;10:56–60. [PMC free article: PMC2823475] [PubMed: 7647791]
  • Ottman R, Rosenberger L, Bagic A, Kamberakis K, Ritzl EK, Wohlschlager AM, Shamim S, Sato S, Liew C, Gaillard WD, Wiggs E, Berl MM, Reeves-Tyer P, Baker EH, Butman JA, Theodore WH. Altered language processing in autosomal dominant partial epilepsy with auditory features. Neurology. 2008;71:1973–80. [PMC free article: PMC2654241] [PubMed: 19064878]
  • Ottman R, Winawer MR, Kalachikov S, Barker-Cummings C, Gilliam TC, Pedley TA, Hauser WA. LGI1 mutations in autosomal dominant partial epilepsy with auditory features. Neurology. 2004;62:1120–6. [PMC free article: PMC1361770] [PubMed: 15079011]
  • Picard F, Baulac S, Kahane P, Hirsch E, Sebastianelli R, Thomas P, Vigevano F, Genton P, Guerrini R, Gericke CA, An I, Rudolf G, Herman A, Brice A, Marescaux C, LeGuern E. Dominant partial epilepsies. A clinical, electrophysiological and genetic study of 19 European families. Brain. 2000;123:1247–62. [PubMed: 10825362]
  • Pisano T, Marini C, Brovedani P, Brizzolara D, Pruna D, Mei D, Moro F, Cianchetti C, Guerrini R. Abnormal phonologic processing in familial lateral temporal lobe epilepsy due to a new LGI1 mutation. Epilepsia. 2005;46:118–23. [PubMed: 15660777]
  • Pizzuti A, Flex E, Di Bonaventura C, Dottorini T, Egeo G, Manfredi M, Dallapiccola B, Giallonardo AT. Epilepsy with auditory features: a LGI1 gene mutation suggests a loss-of-function mechanism. Ann Neurol. 2003;53:396–9. [PubMed: 12601709]
  • Pizzuti A, Giallonardo AT. Epilepsy with auditory features: a LGI1 gene mutation suggests a loss-of-function mechanism. Ann Neurol. 2003;53:396–9. Errata. [PubMed: 12601709]
  • Poduri A. DEPDC5 does it all: shared genetics for diverse epilepsy syndromes. Ann Neurol. 2014;75:631–3. [PubMed: 24753000]
  • Poza JJ, Sáenz A, Martínez-Gil A, Cheron N, Cobo AM, Urtasun M, Martí-Massó JF, Grid D, Beckmann JS, Prud'homme JF, López de Munain A. Autosomal dominant lateral temporal epilepsy: clinical and genetic study of a large Basque pedigree linked to chromosome 10q. Ann Neurol. 1999;45:182–8. [PubMed: 9989620]
  • Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126–33. [PMC free article: PMC4731925] [PubMed: 26656846]
  • Rosanoff MJ, Ottman R. Penetrance of LGI1 mutations in autosomal dominant partial epilepsy with auditory features. Neurology. 2008;71:567–71. [PMC free article: PMC2652575] [PubMed: 18711109]
  • Sarma AK, Khandker N, Kurczewski L, Brophy GM. Medical management of epileptic seizures: challenges and solutions. Neuropsychiatr Dis Treat. 2016;12:467–85. [PMC free article: PMC4771397] [PubMed: 26966367]
  • Scheffer IE, Phillips HA, O'Brien CE, Saling MM, Wrennall JA, Wallace RH, Mulley JC, Berkovic SF. Familial partial epilepsy with variable foci: a new partial epilepsy syndrome with suggestion of linkage to chromosome 2. Ann Neurol. 1998;44:890–9. [PubMed: 9851433]
  • Sirerol-Piquer MS, Ayerdi-Izquierdo A, Morante-Redolat JM, Herranz-Pérez V, Favell K, Barker PA, Pérez-Tur J. The epilepsy gene LGI1 encodes a secreted glycoprotein that binds to the cell surface. Hum Mol Genet. 2006;15:3436–45. [PubMed: 17067999]
  • Smalheiser NR, Costa E, Guidotti A, Impagnatiello F, Auta J, Lacor P, Kriho V, Pappas GD. Expression of reelin in adult mammalian blood, liver, pituitary pars intermedia, and adrenal chromaffin cells. Proc Natl Acad Sci U S A. 2000;97:1281–6. [PMC free article: PMC15597] [PubMed: 10655522]
  • Somerville RP, Chernova O, Liu S, Shoshan Y, Cowell JK. Identification of the promoter, genomic structure, and mouse ortholog of LGI1. Mamm Genome. 2000;11:622–7. [PubMed: 10920229]
  • Tessa C, Michelucci R, Nobile C, Giannelli M, Della Nave R, Testoni S, Bianucci D, Tinuper P, Bisulli F, Sofia V, De Feo MR, Giallonardo AT, Tassinari CA, Mascalchi M. Structural anomaly of left lateral temporal lobe in epilepsy due to mutated LGI1. Neurology. 2007;69:1298–300. [PubMed: 17875918]
  • Usui K, Ikeda A, Nagamine T, Matsubayashi J, Matsumoto R, Hiraumi H, Kawamata J, Matsuhashi M, Takahashi R, Fukuyama H. Abnormal auditory cortex with giant N100m signal in patients with autosomal dominant lateral temporal lobe epilepsy. Clin Neurophysiol. 2009;120:1923–6. [PubMed: 19793676]
  • Vanoni MA. Structure-function studies of MICAL, the unusual multidomain flavoenzyme involved in actin cytoskeleton dynamics. Arch Biochem Biophys. 2017;632:118–41. [PubMed: 28602956]
  • Ventruti A, Kazdoba TM, Niu S, D'Arcangelo G. Reelin deficiency causes specific defects in the molecular composition of the synapses in the adult brain. Neuroscience. 2011;189:32–42. [PubMed: 21664258]
  • Wang Y, Ottman R, Rabinowitz D. A method for estimating penetrance from families sampled for linkage analysis. Biometrics. 2006;62:1081–8. [PMC free article: PMC1839037] [PubMed: 17156282]
  • Winawer MR, Martinelli Boneschi F, Barker-Cummings C, Lee JH, Liu J, Mekios C, Gilliam TC, Pedley TA, Hauser WA, Ottman R. Four new families with autosomal dominant partial epilepsy with auditory features: clinical description and linkage to chromosome 10q24. Epilepsia. 2002;43:60–7. [PMC free article: PMC2707111] [PubMed: 11879388]
  • Winawer MR, Ottman R, Hauser WA, Pedley TA. Autosomal dominant partial epilepsy with auditory features: defining the phenotype. Neurology. 2000;54:2173–6. [PMC free article: PMC2659636] [PubMed: 10851389]
  • Xiong L, Labuda M, Li DS, Hudson TJ, Desbiens R, Patry G, Verret S, Langevin P, Mercho S, Seni MH, Scheffer I, Dubeau F, Berkovic SF, Andermann F, Andermann E, Pandolfo M. Mapping of a gene determining familial partial epilepsy with variable foci to chromosome 22q11-q12. Am J Hum Genet. 1999;65:1698–710. [PMC free article: PMC1288381] [PubMed: 10577924]
  • Zaki M, Shehab M, El-Aleem AA, Abdel-Salam G, Koeller HB, Ilkin Y, Ross ME, Dobyns WB, Gleeson JG. Identification of a novel recessive RELN mutation using a homozygous balanced reciprocal translocation. Am J Med Genet A. 2007;143A:939–44. [PubMed: 17431900]
  • 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;15:1208–14. [PMC free article: PMC2759408] [PubMed: 19701204]

Chapter Notes

Author Notes

To volunteer for research, please contact:

Project Coordinator, Epilepsy Family Study of Columbia University
Columbia University
Tel: 212-305-9188
Email: ude.aibmuloc@ucsfe

Author History

Roberto Michelucci, MD, PhD (2019-present)
Carlo Nobile, PhD (2019-present)
Ruth Ottman, PhD; Columbia University (2007-2019)

Revision History

  • 10 January 2019 (bp) Comprehensive update posted live
  • 27 August 2015 (me) Comprehensive update posted live
  • 31 January 2013 (me) Comprehensive update posted live
  • 13 July 2010 (me) Comprehensive update posted live
  • 26 September 2007 (cd) Revision: sequence analysis available on a clinical basis; prenatal diagnosis available
  • 20 April 2007 (me) Review posted live
  • 1 February 2007 (ro) Original submission
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Bookshelf ID: NBK1537PMID: 20301709

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