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. Age at onset is usually in adolescence or early adulthood (age 10-30 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 can be established in a proband with characteristic clinical features, normal brain imaging by MRI, and family history consistent with autosomal dominant inheritance. The molecular diagnosis is established in a proband with characteristic clinical features and a heterozygous pathogenic variant in LGI1, MICAL1, or RELN identified by molecular genetic testing.

Management.

Treatment of manifestations: Seizure control is usually readily achieved with standard anti-seizure medications (ASM).

Surveillance: Monitoring of epilepsy as clinically indicated; neurocognitive assessments in individuals suspected to have memory or attention deficits; evaluation by a psychiatrist for any psychiatric comorbidities.

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

Pregnancy management: Discussion of the risks and benefits of using a given ASM during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible.

Genetic counseling.

By definition, ADEAF is inherited in an autosomal dominant manner. Most individuals diagnosed with ADEAF have an affected parent; the proportion of individuals with ADEAF caused by a de novo pathogenic variant is believed to be low. Offspring of an individual with ADEAF who is heterozygous for a pathogenic variant have a 50% chance of inheriting the pathogenic variant; the chance that offspring who inherit the pathogenic variant will manifest ADEAF ranges from 54% to 85% depending on the assumed penetrance. Once the ADEAF-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

ADEAF should be suspected in individuals with the following clinical, neuroimaging, and EEG findings and family history.

Clinical findings. A history consistent with focal epilepsy typically in adolescence/adulthood (age of onset 10-30 years) with no prior history of seizures or developmental delays. Seizure semiology is consistent with focal aware seizures with auditory symptoms and/or receptive aphasia:

• Auditory symptoms can occur in a temporal association with seizures as:
  • An aura immediately preceding a bilateral tonic-clonic seizure;
  • A component of focal aware or focal impaired-awareness seizures;
  • The only ictal symptom.
• 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.

Early development and neurologic examination are typically normal.

Brain imaging is typically normal.

Interictal EEG is often normal. However, focal (temporal) or diffuse epileptiform abnormalities are found in up to two thirds of individuals.

Family history is consistent with autosomal dominant inheritance (with reduced penetrance). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The clinical diagnosis of ADEAF can be established in a proband based on clinical diagnostic criteria [Riney et al 2022]. The molecular diagnosis is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in LGI1, MICAL1, or RELN identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous variant of uncertain significance in one of the genes listed in Table 1 does not establish or rule out the diagnosis.

Clinical Description

Autosomal dominant epilepsy with auditory features (ADEAF) is characterized by adolescence/adulthood onset of focal aware seizures with auditory symptoms and/or receptive aphasia in individuals with normal cognitive and neurologic development [Michelucci et al 2009, Riney et al 2022].

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 4 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 to the Heschl gyrus or Wernicke area. Typically, individuals have normal neurologic examination and intellectual development.

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 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].

Febrile seizures do not appear to 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 affected individuals.

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. Another distinctive feature of ADEAF 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 and RELN pathogenic variants [Michelucci et al 2003, Ottman et al 2004, Di Bonaventura et al 2009, Michelucci et al 2020].

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 of consciousness).

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 occasions 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, depression appeared to be related to either the epilepsy or anti-seizure medication (ASM) [Heiman et al 2010].
• Migraine headaches segregating with occipitotemporal epilepsy resembling ADEAF has been described in one family [Deprez et al 2007].

Prognosis. The clinical course of ADEAF is usually benign. Several studies have reported on variable outcomes, as summarized below.

• In a series of 34 affected individuals from 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 were seizure-free (from focal or 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 ASM resistance was described [Di Bonaventura et al 2009].
• In one family with ADEAF caused by a pathogenic RELN variant, the proband had a long history of refractory focal seizures. Interestingly, brain MRI showed left temporal lobe abnormalities suggestive of focal cortical dysplasia [Michelucci et al 2020].
• In a large retrospective cohort study investigating a heterogeneous group of individuals with epilepsy with auditory features (EAF), prognosis seems to be more variable, ranging from mild to severe intractable epilepsy. However, in this cohort familial cases represented 32% of individuals, with a clear autosomal dominant inheritance pattern of ADEAF identified only in 12% [Bisulli et al 2018]. Furthermore, some of these ADEAF cases were reported to be due to pathogenic DEPDC5 variants and could therefore be better considered to have familial focal epilepsy with variable foci (see DEPDC5-Related Epilepsy).

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, 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 rare cases [Winawer et al 2002, Brodtkorb et al 2005a, DiBonaventura et al 2009, Michelucci et al 2020]. One of these showed left mid- and anterior temporal onset [Winawer et al 2002], and another showed 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]. More recently an ictal EEG in a familial case with a pathogenic RELN variant has been described, showing – at least in the longer seizures (up to 20-30 seconds) – rhythmic focal discharges in the left temporal region [Michelucci et al 2020].

Findings from magnetoencephalography (MEG) with auditory stimuli showed significantly delayed peak 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], suggesting a plausible hyperexcitability in the pathologic temporal cortex in ADEAF.

Neuroimaging. Routine brain imaging studies (MRI or CT) are typically normal.

A left lateral temporal lobe malformation was identified by high-resolution MRI in ten individuals in a Brazilian family with an LGI1 pathogenic variant, but this neuroradiologic finding did not segregate entirely with the genotype [Kobayashi et al 2003]. 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 eight individuals with ADEAF with an LGI1 pathogenic variant [Tessa et al 2007], indicating a link between pathogenic LGI1 variants and a focal structural abnormality that could be epileptogenic.

Using functional MRI with an auditory description decision task, individuals 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.

An interictal single-photon emission computed tomography scan in one person identified hypoperfusion in the left temporal lobe [Poza et al 1999], whereas a left mesial temporal hypometabolism in a F-fluorodeoxyglucose positron emission tomography (FDG-PET) scan was found interictally in an individual with a pathogenic RELN variant [Michelucci et al 2020], suggesting a more complicated epileptogenic network.

In another study, two individuals with ADEAF in the same family underwent stereoelectroencephalography (SEEG) investigation and subsequent SEEG-guided radiofrequency thermocoagulation and in one case surgical resection. Fast activities recorded with deep electrodes originated from the right superior temporal gyrus with rapid spreading to other network's nodes. Despite a normal cerebral MRI, an FDG-PET scan showed hypometabolism in the superior temporal gyrus. Genetic findings were incomplete [Wei et al 2022].

Other investigations. Asymmetry of long-latency auditory evoked potentials (with reduced left N1-P2 amplitudes) was shown in a Norwegian family with aphasic seizures [Brodtkorb et al 2005b]. Abnormal phonologic processing was demonstrated in four individuals 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, 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 epilepsy-associated (epitempin) domain than with other LGI1 pathogenic variant types / domain combinations [Ho et al 2012]. No significant clinical differences were observed between families with an LGI1 pathogenic variant and families without an identified pathogenic variant [Michelucci et al 2013].

Phenotypic features were similar in published familial cases with LGI1, MICAL1, or RELN pathogenic variants [Dazzo et al 2015a, Michelucci et al 2017, Dazzo et al 2018]. Further, no phenotypic differences have been found between simplex cases (i.e., a single occurrence in a family) and published familial cases of epilepsy with auditory features [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 across these studies.

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

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 these estimates are likely to be inflated by ascertainment bias, as they are based on families selected for analysis because they comprised many affected individuals.

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

MICAL1. Penetrance is unknown.

Nomenclature

The term "epilepsy with auditory features (EAF)" refers to all individuals with a diagnosis of EAF, encompassing individuals with a known family history of EAF ("familial EAF [FEAF]") and individuals who appear to represent simplex cases (i.e., the only family known to be affected with EAF). EAF has been proposed to replace the family history-dependent terms – "autosomal dominant lateral temporal lobe epilepsy (ADLTE)" and "autosomal dominant partial epilepsy with auditory features (ADPEAF)" – used previously to refer to the disorder [Furia et al 2022, Riney et al 2022]. However, this terminology change is questionable, since the term "EAF" includes a more heterogeneous group of individuals with variable prognosis and etiology. Indeed, genetic advances in this field have been obtained by studying only clinically defined families with a dominant inheritance pattern.

"Autosomal dominant epilepsy with auditory features (ADEAF)" refers to individuals with EAF whose family history is consistent with autosomal dominant inheritance (e.g., affected family members in multiple generations) and/or individuals with EAF known to be caused by a heterozygous pathogenic variant. (Note: An individual with ADEAF may appear to represent a simplex case due to the possibility of reduced penetrance in asymptomatic, heterozygous family members.) The alternative term of ADLTE may be preferred, since some ictal symptoms of this condition (such as aphasia, vertiginous and complex visual auras, high propensity to generalize) indicate a clear localization over the lateral temporal cortex.

Prevalence

The prevalence of ADEAF is unknown but likely 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. Further, isolated auditory symptoms, especially when simple, might not be adequately recognized as pertaining to a disease and especially epilepsy. Therefore, a precise estimate of the incidence of EAF is currently not available.

Whereas genetic epilepsy syndromes account for a 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].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with autosomal dominant epilepsy with auditory features (ADEAF), the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves care by specialists in relevant fields (see Table 5).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

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 ADEAF-related 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 sensory symptoms (visual, olfactory, vertiginous, or cephalic) and/or motor, psychic, and autonomic symptoms possibly related to seizures.

Note:

• Approximately one third of individuals with an ADEAF-related pathogenic variant will remain unaffected due to reduced penetrance.
• Seizures are treatable in most affected individuals.
• No interventions have been identified to prevent the development or occurrence of seizures in individuals with an ADEAF-related pathogenic.

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 anti-seizure medication (ASM) during pregnancy reduces this risk. However, exposure to ASMs may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which the medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from ASM exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of ASMs to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given ASM 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.

Mode of Inheritance

By definition, autosomal dominant epilepsy with auditory features (ADEAF) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with ADEAF have an affected parent.
• Some individuals diagnosed with ADEAF may have the disorder as the result of a de novo pathogenic variant; the proportion of individuals with ADEAF caused by a de novo pathogenic variant is believed to be low (~1%). De novo pathogenic variants have been reported in individuals with LGI1-related ADEAF [Bisulli et al 2004b, Michelucci et al 2007, Kesim et al 2016] and with MICAL1-related ADEAF [Bonanni et al 2024].
• If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the evaluation of the parents of the proband include a medical history to ascertain a history of seizures and – if a molecular diagnosis has been established in the proband – genetic testing for the pathogenic variant identified in the proband.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicismand will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The family history of some individuals diagnosed with ADEAF 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 (approximately one third of individuals with an ADEAF-related pathogenic variant will remain unaffected due to reduced penetrance). Therefore, an apparently negative family history cannot be confirmed unless a molecular diagnosis has been established in the proband and molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.

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

• If a parent has clinical characteristics consistent with ADEAF and/or has the pathogenic variant identified in the proband, the likelihood that each sib will inherit the pathogenic variant is 50%. The chance that a sib who inherits the pathogenic variant will manifest ADEAF ranges from 54% to 85%, depending on the assumed penetrance (see Penetrance).
• Note: 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].
• If the proband has a known LGI1, MICAL1, or RELN pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental germline mosaicism [Rahbari et al 2016]. To date, parental germline mosaicism has not been reported in ADEAF.
• If the parents are clinically unaffected but their genetic status is unknown, sibs are presumed to be at increased risk for ADEAF because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism.

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

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

Related Genetic Counseling Issues

Predictive testing (i.e., testing of asymptomatic at-risk individuals)

• Predictive testing for at-risk relatives is possible if the ADEAF-related pathogenic variant has been identified in an affected family member.
• Potential consequences of such testing as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives to identify 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).

Family planning

• Discussion of the risks and benefits of using a given anti-seizure medication during pregnancy should ideally take place prior to conception (see Pregnancy Management).
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the ADEAF-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Despite its clinical homogeneity, autosomal dominant epilepsy with auditory features (ADEAF) is genetically heterogeneous. To date, three causative genes have been identified, LGI1, MICAL1, and RELN.

LGI1 encodes leucine-rich glioma inactivated protein 1 (LGI1), a secreted protein [Sirerol-Piquer et al 2006] expressed mainly in glutamatergic neurons, particularly in the neocortex and limbic regions [Kalachikov et al 2002].

Most pathogenic variants of LGI1 cause defective secretion, whereas a few pathogenic variants are secretion competent. Both classes of variants have loss-of-function effects, but secretion-competent pathogenic variants appear to exert their effect extracellularly by decreasing molecular affinity for both ADAM22 and ADAM23 [Sirerol-Piquer et al 2006, Dazzo et al 2016]. Furthermore, one study suggested that LGI1 may influence the risk for epilepsy through a glutamatergic mechanism through its interaction with ADAM22 controlling the synaptic content of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors, and thereby modulating synaptic transmission as well as regulating the maturation of excitatory synapses [Lovero et al 2015].

MICAL1 encodes [F-actin]-monooxygenase MICAL1 (MICAL1), a protein that contains an enzymatically active oxidoreductase activity that induces disassembly of actin filaments, thereby regulating the organization of the actin cytoskeleton in developing and adult neurons as well as other cell types [Vanoni 2017]. Pathogenic variants in MICAL1 reported to date have been shown to significantly increase the oxidoreductase activity of MICAL1 and induce cell contraction in cultured cells, which likely resulted from deregulation of actin cytoskeleton dynamics. MICAL1 oxidoreductase activity is autoinhibited by the C-terminal domain, so that the wild type protein is nearly inactive. Therefore, this gain-of-function effect that induces dysregulation of the actin cytoskeleton dynamics in neurons is a likely mechanism underlying MICAL1-related ADEAF [Dazzo et al 2018].

RELN encodes reelin, a large protein secreted by Cajal-Retzius cells during embryonic development and by GABAergic neurons in the postnatal brain [D'Arcangelo 2014]. Pathogenic variants in RELN are associated with decreased serum levels of reelin, suggesting an inhibitory effect on protein secretion [Dazzo et al 2015a]. Reduced levels of serum reelin are observed in heterozygous reeler mice, which have apparently normal brains but display functional and molecular defects at the synapse [Smalheiser et al 2000, Ventruti et al 2011]. Similar synaptic defects may also be associated with the heterozygous pathogenic variants in RELN in ADEAF giving rise to epilepsy. One study showed that pathogenic RELN variants abolish or significantly reduce secretion of mutated proteins in vitro; the loss-of-function effect results from impaired trafficking of mutated reelin along the secretory pathway; and mutated proteins are degraded by the autophagy system [Dazzo & Nobile 2022].

Most pathogenic variants reported in RELN affected structurally important amino acids or likely protein folding [Dazzo et al 2015a, Michelucci et al 2020].

Mechanism of disease causation

• LGI1. Loss of function (defective secretion or reduced binding to receptors)
• MICAL1. Gain of function
• RELN. Loss of function (defective secretion)

Author Notes

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

Acknowledgements

We are grateful for the research support of the Telethon Foundation, the Genetics Commission of the Italian League Against Epilepsy, and the Fondo di Beneficenza Intesa San Paolo.

Author History

Emanuela Dazzo, PhD (2024-present)
Roberto Michelucci, MD, PhD (2019-present)
Carlo Nobile, PhD; CNR Institute of Neuroscience (2019-2024)
Ruth Ottman, PhD; Columbia University (2007-2019)
Elena Pasini, MD (2024-present)

Revision History

• 9 May 2024 (gm) Comprehensive update posted live
• 10 January 2019 (bp) Comprehensive update posted live
• 27 August 2015 (me) Comprehensive update posted live
• 31 January 2013 (me) Comprehensive update posted live
• 13 July 2010 (me) Comprehensive update posted live
• 20 April 2007 (me) Review posted live
• 1 February 2007 (ro) Original submission

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