Autosomal Dominant Epilepsy With Auditory Features
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 testing 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, 2 | Proportion of ADEAF 3 Attributed to Pathogenic Variants in Gene | Proportion of Pathogenic Variants 4 in Gene Detectable by Method | |
|---|---|---|---|
| Sequence analysis 5 | Gene-targeted deletion/duplication analysis 6 | ||
| LGI1 | 30% 7 | 95% | 5% 8 |
| MICAL1 | 7% 9 | 90%-95% | Unknown |
| RELN | 17%-18% 7 | 90%-95%% 10 | Unknown |
| Unknown 11 | ~50% | NA | |
- 1.
Genes are listed in alphabetic order.
- 2.
See Table A. Genes and Databases for chromosome locus and protein.
- 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. 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.
Michelucci et al [2017]
- 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.
Dazzo et al [2018]
- 10.
Dazzo et al [2015a]
- 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
| Disorder | Gene(s) | MOI | Clinical Features | |||||
|---|---|---|---|---|---|---|---|---|
| Localization of epileptogenic zone | Seizure semiology | Age at onset | Neuroimaging | EEG | Other | |||
| Autosomal dominant epilepsy w/auditory features (ADEAF) | LGI1 MICAL1 RELN | AD | Lateral temporal |
| Usually late adolescence or early adulthood | Normal |
| |
| Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) | CHRNA4 CHRNB2 CHRNA2 KCNT1 DEPDC5 CRH 4 | AD | Frontal lobe (rarely from extrafrontal areas - e.g., temporal, insular, & parietal regions) | Asymmetric tonic/dystonic posturing &/or complex hyperkinetic seizures, mostly during sleep | 1st 2 decades of life in ~80% (mean onset age 10 yrs) | Normal |
|
|
| Familial mesial temporal lobe epilepsy (FMTLE) (OMIM PS600512) | Unknown | AD AR | Mesial temporal lobe 5 |
| Usually late adolescence or early adulthood | Normal | Interictal epileptiform EEG abnormalities in ~20% |
|
| Familial partial epilepsy w/variable foci (FPEVF) (OMIM PS604364) | DEPDC5 NPRL2 NPRL3 | AD |
| Auditory symptoms & aphasia not described in families w/FPEVF | Usually middle childhood to early adulthood | Normal | Interictal & 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. |
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
- 1.
Ottman et al [2004]
- 2.
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]
- 3.
Winawer et al [2002], Brodtkorb et al [2005b], Di Bonaventura et al [2009]
- 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.
Andermann et al [2005]
- 6.
Scheffer et al [1998], Xiong et al [1999], Callenbach et al [2003], Berkovic et al [2004b]
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).
- If the LGI1, MICAL1, 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.
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 EU Clinical Trials Register 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.