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Autosomal Dominant Partial Epilepsy with Auditory Features

Synonyms: ADLTE, ADPEAF, Autosomal Dominant Lateral Temporal Lobe Epilepsy
, PhD
Professor of Epidemiology, Neurology and GH Sergievsky Center
Deputy Director for Research, GH Sergievsky Center
Columbia University
Research Scientist, Epidemiology Division
New York State Psychiatric Institute
New York, New York

Initial Posting: ; Last Update: January 31, 2013.

Summary

Disease characteristics. Autosomal dominant partial epilepsy with auditory features (ADPEAF) is an idiopathic 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 secondarily generalized seizures, usually accompanied by simple partial and complex partial seizures, with auditory symptoms as a major simple partial seizure manifestation. Some persons have seizures precipitated by sounds such as a ringing telephone. Age at onset ranges from four to 50 years but is usually in adolescence or early adulthood. The clinical course of ADPEAF is benign. After initiation of medical therapy, seizures are usually well controlled.

Diagnosis/testing. The diagnosis of ADPEAF is based on clinical findings, family history, and normal brain imaging studies (MRI or CT). Mutations in LGI1 have been identified in approximately one third of affected families (as defined by the presence of two or more family members with idiopathic focal epilepsy with ictal auditory symptoms or receptive aphasia); no other loci have yet been reported.

Management. Treatment of manifestations: Seizure control is usually readily achieved with antiepileptic drugs (AEDs) used routinely in clinical practice (e.g., carbamazepine, phenytoin, valproate).

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

Genetic counseling. ADPEAF is inherited in an autosomal dominant manner. Most individuals with ADPEAF have an affected parent; the proportion of cases caused by de novo gene mutations is believed to be very low. Each child of an individual with ADPEAF has a 50% chance of inheriting the mutation. The chance that the offspring who inherits the mutation will manifest ADPEAF is between 55% and 78%, depending on the penetrance. Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutation in the family is known. However, requests for prenatal testing for conditions which (like ADPEAF) do not affect intellect and are usually easily treated are not common.

Diagnosis

Clinical Diagnosis

The diagnosis of autosomal dominant partial epilepsy with auditory features (ADPEAF), also known as autosomal dominant lateral temporal epilepsy (ADLTE), is based on the following:

  • A clinical history consistent with focal (partial or localization-related) epilepsy from the affected individual and witnesses. Other causes of epilepsy (antecedent illness or injury to the central nervous system, such as severe head trauma, stroke, and brain tumor) must be excluded.
  • Family history consistent with autosomal dominant inheritance (with reduced and age-dependent penetrance).Two or more family members (including the proband) must have a history of focal epilepsy with either ictal auditory symptoms or ictal aphasia; other family members may have different epilepsy types or symptoms.
  • Auditory symptoms must occur in temporal association with seizures (as an aura immediately preceding generalized tonic-clonic convulsions or as a component of simple partial or complex partial seizures).

    Note: Auditory symptoms may be underreported; therefore, specific questions to elicit occurrence of auditory symptoms should be included in the clinical history.
  • Aphasia that accompanies seizure onset may be difficult to distinguish from nonspecific confusion or alteration of consciousness; therefore, specific questions to assess the inability to understand spoken language in the absence of general confusion should be included in the clinical history.

Clinical imaging (MRI or CT) is normal.

The interictal EEG is often normal, although focal epileptiform abnormalities (usually localized to the temporal region) are found in up to two thirds of cases.

Molecular Genetic Testing

Gene. Mutations in the leucine-rich, glioma-inactivated-1 gene (LGI1) have been identified in approximately 33% of families with ADPEAF [Gu et al 2002a, Kalachikov et al 2002, Morante-Redolat et al 2002, Michelucci et al 2003, Ottman et al 2004, Nobile et al 2009].

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Autosomal Dominant Partial Epilepsy with Auditory Features

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
Family History
PositiveNegative
LGI1Sequence analysis Sequence variants 433% 51.9% 6
Deletion/duplication analysis 7Exonic and whole-gene deletions1 family 8Unknown

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. With 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; Ottman, unpublished findings].

6. Germline mutations in LGI1 are rarely found in simplex cases (i.e., individuals with symptoms consistent with ADPEAF who do not have a family history). De novo mutations were identified in two of 104 simplex cases (1.9%) [Bisulli et al 2004a, Bisulli et al 2004b, Flex et al 2005, Michelucci et al 2007, Michelucci et al 2009].

7. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

8. Deletion encompassing first four exons [Fanciulli et al 2012]

Testing Strategy

To confirm/establish the diagnosis in a proband

  • Single gene testing. One strategy for molecular diagnosis of a proband suspected of having ADPEAF is sequence analysis of LGI1 followed by deletion/duplication analysis if a disease-causing mutation is not identified. If the family history is consistent with autosomal dominant inheritance and at least two family members have idiopathic focal epilepsy with ictal auditory symptoms or receptive aphasia, identification of an LGI1 mutation in the proband would provide strong evidence in favor of the diagnosis of ADPEAF in the family. However, absence of a mutation in LGI1 would not rule out the diagnosis because approximately 67% of families who meet diagnostic criteria for ADPEAF do not have a mutation in LGI1.

    In an individual with idiopathic focal epilepsy with auditory symptoms or receptive aphasia who does not have a family history of epilepsy, sequencing of LGI1 may reveal a mutation in fewer than 2% of cases, and in these cases the mutation is very likely to be de novo. Identification of such a mutation would confirm the diagnosis in the individual; however, failure to identify a mutation would be uninformative.
  • Multi-gene panel. Another strategy for molecular diagnosis of a proband suspected of having ADPEAF is use of a multi-gene panel. See Differential Diagnosis. Multi-gene panels may be more cost effective and informative, particularly because the clinical symptoms of different epilepsy syndromes can vary widely enough that interrogation of other epilepsy-causing genes may reveal a diagnosis that was not suspected based on clinical features alone.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

Autosomal dominant partial epilepsy with auditory features (ADPEAF) is characterized by focal epilepsy not caused by a previous illness or injury, with auditory symptoms and/or receptive aphasia as prominent ictal manifestations. Age at onset has ranged from four to 50 years in previously reported families [Winawer et al 2000, Brodtkorb et al 2002, Winawer et al 2002, Michelucci et al 2003], but is usually in adolescence or early adulthood. The prominent auditory symptoms and aphasia are thought to reflect a localization of the epileptogenic zone in the lateral temporal lobe; accordingly ADPEAF is also known as autosomal dominant lateral temporal epilepsy (ADLTE).

Affected individuals have secondarily generalized seizures, usually accompanied by simple partial and complex partial seizures, with auditory symptoms as a major simple partial seizure manifestation. The most common auditory symptoms are simple unformed sounds such as humming, buzzing, or ringing. Less frequently, other types of auditory symptoms occur, including complex sounds (e.g., specific songs or voices) or distortions (e.g., volume changes). Some persons have seizures precipitated by specific sounds, such as a telephone ringing [Michelucci et al 2003, Michelucci et al 2004].

Another distinctive feature is ictal receptive aphasia (i.e., sudden onset of an inability to understand language, in the absence of general confusion). Ictal aphasia was the most prominent symptom in one large Norwegian family with an LGI1 mutation [Brodtkorb et al 2002, Brodtkorb et al 2005a] (although auditory symptoms also occurred) and in a small Japanese family [Kanemoto & Kawasaki 2000]. Aphasia has also been reported in other families with LGI1 mutations [Michelucci et al 2003, Ottman et al 2004, Di Bonaventura et al 2009].

In families with ADPEAF, affected individuals also have other ictal symptoms, either in isolation or accompanying auditory symptoms or aphasia. These occur less frequently than auditory symptoms, and include other sensory symptoms (visual, olfactory, vertiginous, or cephalic) as well as motor, psychic, and autonomic symptoms [Poza et al 1999, Winawer et al 2000, Winawer et al 2002, Michelucci et al 2003, Hedera et al 2004, Ottman et al 2004]. Also, although most individuals in families with ADPEAF have focal epilepsy, idiopathic generalized epilepsy was reported in four individuals with LGI1 mutations in two previously reported families [Ottman et al 2004]. The occurrence of idiopathic generalized epilepsies in these families may be explained either as an effect of LGI1 on risk for idiopathic generalized epilepsy, or by a co-occurring mutation in these families in another (unidentified) gene that influences risk for idiopathic generalized epilepsy specifically.

Febrile seizures do not occur with increased frequency in ADPEAF.

The clinical course of ADPEAF is usually benign. For example, in a series of 34 affected individuals in seven Spanish and Italian families [Michelucci et al 2003], secondarily generalized seizures occurred only once or twice per year. The frequency of simple or complex partial seizures ranged from twice per year to several times per month. After initiation of medical therapy, seizures were well controlled by any of a variety of medications (carbamazepine, phenobarbital, or phenytoin), sometimes at low doses. In the Norwegian family with prominent ictal aphasia [Brodtkorb et al 2002], all individuals had been free from secondarily generalized seizures for two or more years, and simple partial seizures occurred infrequently in most patients. However, two family members with epilepsy died suddenly in their sleep, both at age 28 years; a relationship to seizures was suspected but could not be confirmed. In one other family with an LGI1 mutation [Di Bonaventura et al 2009] an unusual clinical picture was described with high seizure frequency and antiepileptic drug resistance.

EEG. Interictal EEGs may be normal in persons with ADPEAF; however, epileptiform interictal EEG abnormalities are found in up to two thirds of affected individuals [Poza et al 1999, Winawer et al 2000, Brodtkorb et al 2002, Winawer et al 2002, Fertig et al 2003, Michelucci et al 2003, Pizzuti et al 2003, Hedera et al 2004, Ottman et al 2004, Pisano et al 2005].

Ictal EEGs have been reported in three persons [Winawer et al 2002, Brodtkorb et al 2005a, Di Bonaventura et al 2009]. One of these showed left mid- and anterior temporal onset [Winawer et al 2002], and another onset in the left frontotemporal region with bilateral and posterior spreading, documented during a video-recorded aphasic seizure [Brodtkorb et al 2005a]. The third was recorded during a prolonged seizure cluster lasting several hours in a patient with prominent ictal aphasia; the EEG pattern consisted of low-voltage fast activity followed by delta activity and rhythmic sharp waves located in the anterior and middle left temporal regions [Di Bonaventura et al 2009].

Findings from magnetoencephalography (MEG) with auditory stimuli showed significantly delayed peak 2 auditory evoked field latency in individuals with LGI1 mutations [Ottman et al 2008]. Another study using MEG detected significantly large N100m signals in three out of five patients, contralateral to the auditory stimulation [Usui et al 2009].

Neuroimaging. Findings from routine neurologic examination and routine clinical imaging (MRI or CT) are normal.

An interictal single-photon emission computed tomographic (SPECT) scan in one person identified hypoperfusion in the left temporal lobe [Poza et al 1999].

A left lateral temporal lobe malformation was identified through high-resolution MRI in ten individuals in a Brazilian family with an LGI1 mutation [Kobayashi et al 2003]. However, other studies using high-resolution MRI in families with LGI1 mutations have not confirmed this finding [Tessa et al 2007, Ottman et al 2008].

Diffusion tensor imaging identified a region of increased fractional anisotropy in the left temporal lobe in individuals with an LGI1 mutation [Tessa et al 2007].

In functional MRI with an auditory description decision task, persons with epilepsy in families with an LGI1 mutation had significantly less activation than controls [Ottman et al 2008]. These results suggest that individuals with ADPEAF have functional impairment in language processing.

Other investigations. Asymmetry of long-latency auditory evoked potentials (with reduced left N1-P2 amplitudes) was shown in the Norwegian family with aphasic seizures [Brodtkorb et al 2005b]. Abnormal phonologic processing was demonstrated in four persons in a Sardinian family by means of a fused dichotic listening task [Pisano et al 2005]. The above data, though based on a small sample size, seem to suggest the existence of some structural abnormalities in the lateral temporal neuronal network.

Genotype-Phenotype Correlations

A study of 36 published ADPEAF families with LGI1 mutations evaluated mutation clustering within the gene and associations of phenotypic features with both mutation location (N-terminal leucine-rich repeats [LRR] domain and C-terminal epitempin repeat [EPTP] domain) and predicted effect (truncation or missense) [Ho et al 2012]. Mutations clustered significantly in the LRR domain of LGI1. Also, auditory symptoms were less frequent in individuals with truncation mutations in the EPTP domain than in those with other mutation type/domain combinations.

No phenotypic differences have been found between simplex cases who did not have an LGI1 mutation and the published familial cases [Bisulli et al 2004a, Bisulli et al 2004b, Flex et al 2005, Michelucci et al 2007, Michelucci et al 2009].

Penetrance

Penetrance is incomplete. It is estimated at 67% (95% CI 55%-77%) [Rosanoff & Ottman 2008], based on analysis of obligate heterozygotes in 24 published families. In three large families, penetrance was estimated at 71%, 78%, and 60%-80% [Ottman et al 1995, Poza et al 1999]. In a study that attempted to control for ascertainment bias by considering only family members who did not lead to the selection of families for study, penetrance was estimated as 54% (95% confidence interval 34%-71%) [Ottman et al 2004]. An additional study estimated penetrance to be 85% based on a statistical model [Wang et al 2006]. All of these estimates are likely to be inflated by ascertainment bias, since they are based on families selected for study because they contained many affected individuals.

Anticipation

Anticipation has not been found to occur in this syndrome.

Nomenclature

A consensus has not yet been reached regarding the most appropriate term for this syndrome.

Ottman and colleagues have used the term autosomal dominant partial epilepsy with auditory features (ADPEAF) because of its simplicity and utility for identifying families likely to have mutations in LGI1 [Winawer et al 2000].

Poza et al [1999] proposed the term autosomal dominant lateral temporal epilepsy (ADLTE) because the symptoms that they identified in a large Basque family, including both auditory and visual symptoms, strongly suggest a lateral temporal localization of the epileptogenic zone. Both terms are used widely in the literature.

Prevalence

The prevalence of this disorder 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 ADPEAF.

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, ADPEAF may not be rare [Ottman et al 2004]. In that study, 9/48 (19%) of families with two or more individuals with idiopathic focal epilepsy met criteria for ADPEAF (i.e., they contained ≥2 individuals with ictal auditory symptoms).

Differential Diagnosis

See Epilepsy, Familial Temporal Lobe: OMIM Phenotypic Series, a table of similar phenotypes that are genetically diverse.

Epilepsy multi-gene panels may include testing for a number of the genes associated with disorders discussed in this section. Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time; a panel may not include a specific gene of interest.

Tinnitus and other auditory disturbances may be reported as incidental findings in a person with epilepsy; thus, care should be taken in obtaining the medical history to document a consistent temporal association of auditory symptoms with seizure events.

Persons with epilepsy may report the inability to comprehend speech at the onset of seizures as a result of nonspecific confusion or alteration in consciousness; thus, care should be taken in obtaining the medical history to distinguish this confusion from specific symptoms of aphasia (i.e., an inability to understand language in the absence of alteration in consciousness).

The following three other forms of Mendelian focal epilepsy have been identified. Distinguishing among these disorders can be challenging because the symptoms in affected family members are variable and no operational criteria for classification of families are yet available [Picard et al 2000].

  • Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is characterized by clusters of nocturnal motor seizures varying from simple arousals from sleep to dramatic, often bizarre, hyperkinetic events with tonic or dystonic features. A minority of individuals experience daytime seizures. In contrast, the seizures in ADPEAF are most often associated with auditory or other sensory symptoms, and usually occur during the day (although nocturnal seizures have been observed in some cases). The diagnosis of ADNFLE is made on clinical grounds. A detailed history from the affected individual and witnesses, supplemented if necessary by video-EEG monitoring, is the key to diagnosis. Molecular genetic testing reveals mutations in CHRNA4, CHRNB2, or CHRNA2 in approximately 10%-20% of individuals with a positive family history and fewer than 5% of individuals with a negative family history.
  • Familial mesial temporal lobe epilepsy (FMTLE) is characterized by seizures with symptoms suggesting a mesial temporal lobe localization of the epileptogenic zone [Andermann et al 2005], in contrast to ADPEAF, in which symptoms are more suggestive of a lateral temporal localization. In the initial description of the syndrome by Berkovic et al [1996], affected individuals had simple and complex partial seizures, and less commonly, secondarily generalized seizures. The seizure semiology most often involved psychic symptoms, with déjà vu the most common among them. Autonomic or special sensory components were observed in about half of cases; auditory symptoms were found in fewer than 10% of cases.

    As with ADPEAF, age at onset was usually in late adolescence or early adulthood; neuroimaging results were normal; interictal epileptiform EEG abnormalities were found in a minority (~20%) of cases; febrile seizures were not more common than in the general population; and the clinical course was benign, with long remissions and good response to a range of therapies (carbamazepine, phenytoin, or valproate).

    Subsequent studies demonstrated clinical heterogeneity in FMTLE, with some families having hippocampal atrophy and a less benign clinical course [Cendes et al 1998, Kobayashi et al 2001]. Families with temporal lobe epilepsy and prominent febrile seizures have also been described [Baulac et al 2001, Depondt et al 2002]. Because of the similarities between ADPEAF and FMTLE and the great intrafamilial variability of symptoms in both syndromes, differential diagnosis is challenging and relies mainly on the semiology of seizures observed in affected family members. In ADPEAF, auditory symptoms are most common, and autonomic or psychic symptoms occur in fewer than 25% of cases [Ottman et al 2004], whereas in FMTLE, psychic symptoms (particularly déjà vu) are most common, and auditory symptoms are seldom seen. In FMTLE, mutations in LGI1 have not been found [Berkovic et al 2004a], and no genes have yet been identified, although evidence for linkage to several different regions has been reported [Baulac et al 2001, Claes et al 2004, Hedera et al 2007].
  • Familial partial epilepsy with variable foci (FPEVF) is characterized by autosomal dominant inheritance of focal epilepsy, with different localization of the epileptogenic zone (frontal, temporal, or occipital) in different family members [Scheffer et al 1998, Xiong et al 1999, Callenbach et al 2003, Berkovic et al 2004b]. Frontal lobe seizures are the most common type. However, in FPEVF the seizures occur less frequently and more in the daytime than in ADNFLE. Auditory symptoms and aphasia have not been described in families with FPEVF. Linkage to chromosome 22q12 has been found in five families with FPEVF; the involved gene has yet to be identified [Xiong et al 1999, Callenbach et al 2003, Berkovic et al 2004b].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with autosomal dominant partial epilepsy with auditory features (ADPEAF), the following evaluations are recommended:

  • A clinical history from the patient and witnesses to establish seizure types and their frequencies, and symptoms associated with each seizure type
  • Routine interictal EEG
  • Routine clinical imaging to rule out structural abnormalities
  • Medical genetics consultation

Treatment of Manifestations

ADPEAF is a benign syndrome in the great majority of cases. No clinical trials of different antiepileptic medications have been carried out, but most patients have been readily able to achieve seizure control with medications used routinely in clinical practice (e.g., carbamazepine, phenytoin, valproate).

Evaluation of Relatives at Risk

Interview of relatives at risk to identify symptoms possibly related to seizures is advisable so that early treatment may be initiated in those who develop seizures.

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

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

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 partial epilepsy with auditory features (ADPEAF) is inherited in an autosomal dominant manner, with reduced and age-dependent penetrance.

Risk to Family Members

Parents of a proband

  • Most individuals with ADPEAF have an affected parent. However, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of seizures, late onset of the disease in the affected parent, or reduced penetrance.
  • A proband with ADPEAF may have the disorder as the result of a de novo gene mutation; the proportion of cases caused by de novo gene mutations is believed to be very low.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include molecular genetic testing of the parents and a medical history to ascertain a history of seizures.

Sibs of a proband

  • The risk to sibs of a proband depends on the genetic status of the parents.
  • If one parent has clinical characteristics consistent with ADPEAF or has a mutation in LGI1, the likelihood that each sib will inherit the mutant allele is 50%. The chance that a sib who inherits the mutation will manifest ADPEAF ranges from 55% to 78% depending on the assumed penetrance (i.e., using the 95% confidence interval of the most recent penetrance estimate to define the penetrance range).
  • The risk to sibs of a proband whose parents are asymptomatic and do not have an LGI1 mutation is difficult to estimate.

Offspring of a proband

  • Each child of an individual with ADPEAF has a 50% chance of inheriting the mutation.
  • The chance that the offspring who inherits the mutation will manifest ADPEAF ranges from 55% to 78%, depending on the penetrance.

Other family members of a proband. The risk to other family members depends on their genetic relationship to a family member who has phenotypic features consistent with ADPEAF or has a mutation in LGI1. In general, the risk of inheriting the mutation and manifesting symptoms is 50% times the penetrance of 55%-78%, or 28%-39%, for any first-degree relative of a family member who has phenotypic features consistent with ADPEAF or who has a mutation. For example, if one of the proband's parents is affected or has a mutation, the risk to his or her sibs (the aunts and uncles of the proband) of having inherited the mutation and of manifesting symptoms is 28%-39%. The risk to a second-degree relative of a family member who has phenotypic features consistent with ADPEAF or who has a mutation is half of this amount (14%-20%).

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 mutations in individuals with ADPEAF does not have high clinical utility because identification of a mutation would not lead to a change in treatment or patient management [Ottman et al 2010]. However, identification of a mutation has genetic counseling implications, and some individuals may benefit from having a mutation identified because it informs them of the cause of their epilepsy. The utility of presymptomatic testing is limited because penetrance is reduced: approximately one third of those in whom a mutation is identified will remain unaffected. Also, given that the disorder is treatable in most affected individuals and methods for prevention of seizure onset in those with a mutation have not been identified, the benefit from presymptomatic testing or early diagnosis is not likely to be substantial.

In qualitative research on families containing multiple individuals with epilepsy (including families with ADPEAF) most participants said they would choose to have testing if offered. They cited many potential benefits, including learning what caused epilepsy in their family, being better able to care and advocate for children at risk, reducing guilt and blame, providing an increased sense of control, and relieving anxiety. Although respondents believed genetic testing would be useful for informing their reproductive choices, they also expressed fear that it could lead to external pressures to modify these choices. Other concerns about the potential negative impact of genetic information included increased blame and guilt, increased stigma and discrimination in employment and insurance, self-imposed limitations on life goals, and alterations in fundamental conceptions of "what epilepsy is" [Shostak et al 2011].

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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation has been identified or linkage has been established in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions which (like ADPEAF) do not affect intellect and are usually easily treated are not common. Perspectives may vary among affected individuals and families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is advisable.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

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.

  • American Epilepsy Society (AES)
    342 North Main Street
    West Hartford CT 06117-2507
    Phone: 860-586-7505
    Fax: 860-586-7550
    Email: info@aesnet.org
  • Epilepsy Foundation
    8301 Professional Place
    Landover MD 20785-7223
    Phone: 800-332-1000 (toll-free)
    Fax: 301-577-2684
    Email: info@efa.org

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 Partial Epilepsy with Auditory Features: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Autosomal Dominant Partial Epilepsy with Auditory Features (View All in OMIM)

600512EPILEPSY, FAMILIAL TEMPORAL LOBE, 1; ETL1
604619LEUCINE-RICH GENE, GLIOMA-INACTIVATED, 1; LGI1

Normal allelic variants. LGI1 has eight exons. The longest full-length transcript includes all eight exons, a 224-bp 5' untranslated region, a 1674-bp coding region (spanning 225-1898 bp including stop-codon "TGA"), and a 356-bp 3' untranslated region.

LGI1 is a member of a subfamily of leucine-rich repeat (LRR)-encoding genes, denoted LGI1, LGI2, LGI3, and LGI4 [Gu et al 2002b].

Pathogenic allelic variants. Disease-causing mutations have been found throughout the gene, without apparent clustering in any region. Two thirds of the reported pathogenic variants have been missense; the remaining one third are truncating. Three intronic mutations have been reported, in each case leading to protein truncation [Kalachikov et al 2002, Kobayashi et al 2003, Chabrol et al 2007]. Almost all of the identified pathogenic variants have been unique to an individual family. The exceptions were:

In addition, two of the reported missense mutations – p.Cys42Arg (c.124T>C) and p.Cys42Gly (c.124T>G) – affected the same nucleotide [Berkovic et al 2004a, Ottman et al 2004]. See Table 2. For additional pathogenic variants, see Table 3 (pdf).

A microdeletion about 81 kb in size encompassing the first four exons of LGI1 was identified in a family with ADPEAF in which exon sequencing revealed no point mutation [Fanciulli et al 2012]. Families with ADPEAF in which no point mutations are revealed by direct exon sequencing should be screened for possible genomic deletion mutations using CMA analysis.

Table 2. Selected LGI1 Pathogenic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.124T>Cp.Cys42ArgNM_005097​.2
NP_005088​.1
c.124T>Gp.Cys42Gly
c.136T>Cp.Cys46Arg
c.758delCp.Ala253ValfsTer32
c.1420C>Tp.Arg474Ter
Deletion 81,245 bp (including exons 1-4) 1

Note on variant classification: Variants listed in the table have been provided by the author(s). 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 (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Fanciulli et al [2012]

Normal gene product and possible pathogenic mechanism. The main transcription product is predicted to encode a protein, Lgi1, of 557 amino acids, with a structure consisting of an amino-terminal signal peptide sequence and two distinct structural domains, each spanning about half of the protein. The N-terminal half consists of 3.5 leucine-rich repeat (LRR) sequences flanked on both sides by typical cysteine-rich repeat sequence clusters [Kobe & Kajava 2001]. The C-terminal half consists of seven copies of a novel repeat of about 45 residues, named the epitempin (EPT) [Staub et al 2002] or epilepsy-associated repeat (EAR) [Scheel et al 2002] region, which is reminiscent of the beta-propeller structural domain [Paoli 2001]. This domain is shared with the protein encoded by GPR98 (formerly known as MASS1), which is mutated in the Frings mouse model of audiogenic epilepsy [Skradski et al 2001]. The four paralogs of the LGI subfamily all have the same structure of LRRs and EAR domains [Gu et al 2002b, Scheel et al 2002, Staub et al 2002]. LRR and beta-propeller motifs are found in many other proteins and often mediate protein-protein interactions. LGI1 is expressed primarily in the brain, and in situ hybridization studies in mouse showed that expression is predominantly neuronal [Kalachikov et al 2002].

Abnormal gene product. The function of the normal gene product, Lgi1, and the mechanism by which alterations in the protein cause epilepsy remain poorly understood, but there have been several important findings. Based on protein homology, initially Lgi1 was hypothesized to influence risk for epilepsy through a mechanism related to central nervous system development [Kalachikov et al 2002].

A 2006 study showed that Lgi1 interacts with presynaptic Kv1 potassium channels, selectively removing rapid inactivation mediated by the Kvβ1 subunit; truncated proteins encoded by mutations found in humans failed to slow inactivation by Kvβ1 [Schulte et al 2006]. However, another study demonstrated that Lgi1 is secreted and mutations lead to defects in secretion [Senechal et al 2005]. The establishment of Lgi1 secretion is difficult to reconcile with a potassium channel mechanism.

Further evidence shows that there are two protein isoforms, with different expression patterns in human brain [Furlan et al 2006]. The long isoform is secreted, whereas the short isoform is retained in an intracellular pool [Sirerol-Piquer et al 2006]. ADPEAF-related mutants of the long form are defective for secretion, and the normal secreted protein specifically binds to the cell surface of differentiated PC12 cells [Sirerol-Piquer et al 2006].

Another study suggested that Lgi1 may influence risk for epilepsy through a glutamatergic mechanism: Lgi1 binds selectively to ADAM22, a neuronal membrane protein, and this binding facilitates glutamate-AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor-mediated neurotransmission [Fukata et al 2006, Snyder 2006].

Studies in transgenic mice showed that mutations in Lgi1 cause epilepsy by impairing the postnatal development of glutamatergic circuits in the hippocampus [Zhou et al 2009].

In research using a mouse knock-out model, extracellularly secreted Lgi1 was found to link two epilepsy-related receptors – ADAM22 and ADAM23 – in the brain and to organize a transsynaptic protein complex that includes presynaptic potassium channels and postsynaptic AMPA receptor scaffolds. A lack of Lgi1disrupts this synaptic protein connection and selectively reduces AMPA receptor-mediated synaptic transmission in the hippocampus [Fukata et al 2010].

LGI1 expression is absent or significantly downregulated in many high-grade but not low-grade gliomas, suggesting a role for LGI1 in glial tumor progression [Chernova et al 1998, Somerville et al 2000], although no excess of brain tumors or other malignancies has been found in families with ADPEAF.

References

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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: efscu@columbia.edu

Revision History

  • 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 to live Web site
  • 1 February 2007 (ro) Original submission
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