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Autosomal Dominant Partial Epilepsy with Auditory Features

Synonyms: ADEAF, ADLTE, ADPEAF, Autosomal Dominant Lateral Temporal Lobe Epilepsy
, PhD
Professor of Epidemiology, Department of 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: August 27, 2015.

Summary

Clinical 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. Seizures are usually well controlled after initiation of medical therapy.

Diagnosis/testing.

The diagnosis of ADPEAF is established by clinical findings, family history, and normal brain imaging studies (MRI or CT). A pathogenic variant in LGI1 has been identified in approximately one third of affected families. A pathogenic variant in RELN has been identified in seven affected families.

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 a de novo pathogenic variant is believed to be very low. Each child of an individual with ADPEAF has a 50% chance of inheriting the pathogenic variant. The chance that the offspring who inherits the pathogenic variant will manifest ADPEAF is between 55% and 78%, depending on the penetrance. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant 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

Suggestive Findings

Autosomal dominant partial epilepsy with auditory features (ADPEAF) should be suspected in individuals with:

  • A clinical history consistent with focal (partial or localization-related) 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.
  • 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 that 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. 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.
  • Normal brain imaging (MRI or CT)
  • Interictal EEG that is often normal. However, focal epileptiform abnormalities (usually localized to the temporal region) are found in up to two thirds of individuals.

Establishing the Diagnosis

The diagnosis of ADPEAF is established in a proband with the above clinical features and family history consistent with autosomal dominant inheritance. Identification of a heterozygous LGI1 or RELN pathogenic variant on molecular genetic testing (Table 1) establishes the diagnosis if clinical features are inconclusive.

Molecular testing approaches can include single-gene testing, use of a multi-gene panel, and genomic testing.

  • Single-gene testing. Sequence analysis of LGI1 is performed first followed by sequence analysis of RELN. Gene-targeted deletion/duplication analysis of LGI1 can be performed if no pathogenic variant is found on sequence analysis.
  • A multi-gene panel that includes LGI, RELN and other genes of interest (see Differential Diagnosis) may also be considered. Note: The genes included and sensitivity of multi-gene panels vary by laboratory and over time.
  • Genomic testing may be considered if serial single-gene testing (and/or use of a multi-gene panel) has not confirmed a diagnosis in an individual with features of ADPEAF. Such testing may include whole-exome sequencing (WES), whole-genome sequencing (WGS), and whole mitochondrial sequencing (WMitoSeq).

    For issues to consider in interpretation of genomic test results, click here.

Table 1.

Molecular Genetic Testing Used in Autosomal Dominant Partial Epilepsy with Auditory Features

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
Positive Family HistoryNegative Family History
LGI1Sequence analysis 333% 41% 5
Gene-targeted deletion/duplication analysis 62 families 7None reported 8
RELNSequence analysis 37 families 9Unknown
Unknown 10NA
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

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.

4.

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, Michelucci et al 2013].

5.

Heterozygous pathogenic variants have been identified in three (1%) of 230 simplex cases [Bisulli et al 2004a, Bisulli et al 2004b, Flex et al 2005, Michelucci et al 2007, Dazzo et al 2015b]. Two of these variants were found to be de novo [Bisulli et al 2004b, Michelucci et al 2007]; the origin of the third could not be determined [Dazzo et al 2015b].

6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used 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.

A deletion encompassing the first four exons 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 through MLPA analysis of 43 other families [Magini et al 2014, Manna et al 2014, Dazzo et al 2015b].

8.

No structural variants were identified through MLPA analysis of 197 simplex cases [Magini et al 2014, Manna et al 2014, Dazzo et al 2015b].

9.

Heterozygous missense pathogenic variants in RELN were identified in seven of 40 (17.5%) families with ADPEAF [Dazzo et al 2015a].

10.

A locus on 19q13.11-q13.31 likely to harbor a gene associated with ADPEAF was identified in a large Brazilian family [Bisulli et al 2014]. In 21 families with ADPEAF, 12 rare CNVs were identified by genome-wide SNP microarray analysis that segregated with ADPEAF 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].

Clinical Characteristics

Clinical Description

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).

Epilepsy. 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 individuals have seizures precipitated by specific sounds, such as a telephone ringing [Michelucci et al 2003, Michelucci et al 2004]. Although most individuals in families with ADPEAF 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 mutation in these families of another (unidentified) gene that specifically influences risk for idiopathic generalized epilepsy.

Febrile seizures do not occur with increased frequency in ADPEAF.

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).

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 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, Dazzo et al 2015b].

The clinical course of ADPEAF is usually benign. For example, in a series of 34 affected individuals in seven Spanish and Italian families, 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 [Michelucci et al 2003]. In the Norwegian family with prominent ictal aphasia, all individuals had been free from secondarily generalized seizures for two or more years, and simple partial 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 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 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 out 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 (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 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 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, would appear to suggest the existence of some structural abnormalities in the lateral temporal neuronal network.

Genotype-Phenotype Correlations

A study of 36 published families with ADPEAF and LGI1 pathogenic variants evaluated mutation clustering within the gene and associations of phenotypic features with both pathogenic variant 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]. Pathogenic variants clustered significantly in the LRR domain of LGI1. Also, auditory symptoms were less frequent in individuals with pathogenic truncation variants in the EPTP domain than in those with other pathogenic variant type/domain combinations.

Phenotypic features are the same in published familial cases with LGI1 and RELN pathogenic variants [Dazzo et al 2015a]. No phenotypic differences have been found between simplex cases 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. Penetrance of LGI1 pathogenic variants 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 at 54% (95% confidence interval 34%-71%) [Ottman et al 2004]. An additional study estimated penetrance of LGI1 pathogenic variants to be 85% based on a statistical model [Wang et al 2006]. In seven families with pathogenic variants in RELN, 20/33 (60%) of variant carriers had epilepsy [Dazzo et al 2015a]. Similarly, in 33 families with ADPEAF, penetrance was estimated at 61% in ten families with an LGI1 pathogenic variant, but only 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 contained many affected individuals.

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

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]. 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 containing 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 ADPEAF.

  • Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is characterized by clusters of nocturnal motor seizures, which are often stereotyped and brief (5 seconds to 5 minutes). They vary from simple arousals from sleep to dramatic, often bizarre, hyperkinetic events with tonic or dystonic features. Affected individuals may experience aura. Retained awareness during seizures is common. A minority of individuals experience daytime seizures. Onset ranges from infancy to adulthood. About 80% of individuals develop ADNFLE in the first two decades of life; mean age of onset is ten years. Clinical neurologic examination is normal and intellect is usually preserved, but psychiatric comorbidity or cognitive deficits may occur. Within a family, the manifestations of the disorder may vary considerably. ADNFLE is lifelong but not progressive. As an individual reaches middle age, attacks may become milder and less frequent. 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 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.
  • Familial mesial temporal lobe epilepsy (FMTLE) (OMIM 600512, 608096, 611630, 611631, 614417, 615697, 616461) 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 individuals; auditory symptoms were found in fewer than 10% of individuals.

    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 individuals; 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 individuals [Ottman et al 2004], whereas in FMTLE, psychic symptoms (particularly déjà vu) are most common, and auditory symptoms are seldom seen. In FMTLE, pathogenic variants in LGI1 have not been found [Berkovic et al 2004a]. Evidence for linkage to several different regions has been reported [Baulac et al 2001, Claes et al 2004, Hedera et al 2007, Baulac 2014]. Pathogenic variants in DEPDC5 have been identified in some families with FMTLE [Ishida et al 2013].
  • Familial partial epilepsy with variable foci (FPEVF) (OMIM 604364) 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 was found in several families with FPEVF [Xiong et al 1999, Callenbach et al 2003, Berkovic et al 2004b], and the mutated gene in that region was identified as DEPDC5 [Dibbens et al 2013].

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

Management

Evaluations Following Initial Diagnosis

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

  • A clinical history from the individual 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
  • Consultation with a medical geneticist and/or genetic counselor

Treatment of Manifestations

ADPEAF is a benign syndrome in the great majority of individuals. No clinical trials of different antiepileptic medications have been carried out, but most individuals 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

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).

  • If the LGI1 or RELN pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives.
  • If the pathogenic variant in the family is not known, interview of relatives at risk may identify symptoms possibly related to 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.
  • A proband with ADPEAF may have the disorder as the result of a de novo LGI1 or RELN pathogenic variant; the proportion of cases caused by a de novo pathogenic variant is believed to be low (~1%).
  • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo pathogenic variant in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include molecular genetic testing of the parents and a medical history to ascertain a history of seizures.
  • The family history of some individuals diagnosed with ADPEAF 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. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations (e.g., molecular genetic testing and/or clinical history) have been performed on the parents of the proband.

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 pathogenic variant in LGI1 or RELN, the likelihood that each sib will inherit the pathogenic variant is 50%.
    • The chance that a sib who inherits the pathogenic variant 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 who does not have an identified LGI1 or RELN pathogenic variant and whose parents are asymptomatic is difficult to estimate. However, such sibs are still at increased risk for ADPEAF because of the possibility of reduced penetrance in a parent.
  • If the LGI1 or RELN pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband

  • Each child of an individual with ADPEAF has a 50% chance of inheriting the pathogenic variant.
  • The chance that the offspring who inherits the pathogenic variant 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 pathogenic variant in LGI1 or RELN. If an individual inherits the pathogenic variant, the risk of manifesting symptoms is 55%-78%.

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 or RELN pathogenic variants in individuals with ADPEAF does not have high clinical utility because identification of a pathogenic variant would not lead to a change in treatment or management [Ottman et al 2010]. However, identification of a pathogenic variant has genetic counseling implications, and some individuals may benefit from having a pathogenic variant 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 pathogenic variant 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 pathogenic variant 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the LGI1 or RELN pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of the relevant gene or custom prenatal testing.

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 LGI1 or RELN pathogenic variant 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)
  • Epilepsy Foundation
    8301 Professional Place East
    Suite 200
    Landover MD 20785-7223
    Phone: 800-332-1000 (toll-free)
    Email: ContactUs@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 from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein 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
600514REELIN; RELN
604619LEUCINE-RICH GENE, GLIOMA-INACTIVATED, 1; LGI1
616436EPILEPSY, FAMILIAL TEMPORAL LOBE, 7; ETL7

LGI1

Gene structure. 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. Pathogenic variants have been found throughout the gene. Pathogenic variants were found to cluster in the LRR domain (exons 3-5) [Ho et al 2012]. Two thirds of the reported pathogenic variants have been missense; the remaining one third are truncating. Three intronic pathogenic variants have been reported, each 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:

In addition, two of the reported pathogenic missense variants – c.124T>C and c.124T>G – affected the same nucleotide [Berkovic et al 2004a, Ottman et al 2004]. See Table 2.

Microdeletions encompassing one or more exons of LGI1 were identified in families with ADPEAF in which exon sequencing revealed no pathogenic variant [Fanciulli et al 2012, Dazzo et al 2015b]. Families with ADPEAF in which no SNVs are revealed by direct exon sequencing should be screened for possible genomic deletions 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.1418C>Tp.Ser473Leu
c.1420C>Tp.Arg474Ter
Deletion ~81 kb 1

Note on variant classification: Variants listed in the table have been provided by the author. 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.

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

Normal gene product and possible pathogenic mechanism. The main transcription product is predicted to encode the 557-amino acid leucine-rich glioma-inactivated protein 1(Lgi1) which has 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]. 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 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 pathogenic variants found in humans failed to slow inactivation by Kvβ1 [Schulte et al 2006]. However, another study demonstrated that Lgi1 is secreted and pathogenic variants 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 pathogenic variants 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.

RELN

Gene structure. RELN 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.

Pathogenic allelic variants. Seven pathogenic variants have been identified in seven Italian families with ADPEAF [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 3.

RELN Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid Change
(Alias 1)
Reference Sequences
c.2015C>T(Pro672Leu)NM​_005045
NM​_173054
c.2168A>G(Tyr723Cys)
c.2288A>G(Asp763Gly)
c.2392C>A(His798Asn)
c.2531C>T(Pro844Leu)
c.8347G>T(Gly2783Cys)
c.9526G>A(Glu3176Lys)

Note on variant classification: Variants listed in the table have been provided by the author. 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.

Variant designation that does not conform to current naming conventions

Normal gene product. RELN encodes reelin, a very large secreted protein of 3,460 amino acids, which consists of an N-terminal signal peptide, an F-spondin-like domain, a unique region, and eight tandem repeats of 350-390 residues termed “reelin repeats.” Each reelin repeat comprises a central epidermal growth factor (EGF or EGF-like) module flanked by two subrepeats (A and B), each containing a 14-amino acid Asp-box (BNR) motif. Both the EGF-like and Asp-box modules support the compact, “horseshoe-like” structural arrangement of each reelin repeat [Dazzo et al 2015a].

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]. RELN was first identified in the homozygous null mutant reeler mouse strain [D’Arcangelo et al 1995]. 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 ADPEAF, 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 individuals heterozygous for pathogenic RELN variants 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 pathogenic RELN variants in families with ADPEAF. Thus, as in other genetic epilepsy syndromes, RELN-related disorders may be genetically and clinically heterogeneous, with pathogenic variants resulting in ADPEAF in heterozygotes and the more severe LCH in homozygotes.

Reelin and Lgi1 proteins were found to colocalize in a subset of rat brain neurons, supporting a common molecular pathway underlying ADPEAF [Dazzo et al 2015a]. Reelin serves a dual purpose in mammalian brain, playing 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]. Recent work on conditional knockout mice suggests that Lgi1, like reelin, could serve different functions during brain development and 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.

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: ude.aibmuloc@ucsfe

Revision History

  • 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 to live Web site
  • 1 February 2007 (ro) Original submission
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Bookshelf ID: NBK1537PMID: 20301709

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