Autosomal Dominant Epilepsy with Auditory Features

Mendelian MONDO:0010898 Pathograph 7 Show in embeddings browser Epilepsy Neurological Disease

Autosomal dominant epilepsy with auditory features (ADEAF) is a familial focal epilepsy in which the seizures announce themselves as sound. The commonest aura is a simple unformed noise, a humming, buzzing, or ringing, and some patients instead lose the ability to understand language while remaining otherwise lucid. Onset is in adolescence or early adulthood, brain imaging is normal, and the course is benign, with seizures usually controlled once treatment starts. In the families where a cause is found it is most often loss of function in LGI1, a secreted neuronal protein that bridges the synaptic cleft by binding ADAM22 and ADAM23 and thereby organizes AMPA receptors and Kv1 channels. Most families, however, remain genetically unexplained.

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Mappings
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Inheritance
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Pathophys.
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Phenotypes
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Gaps
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Pathograph
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Genes
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Medical Actions
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Differentials
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References
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Deep Research
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Mappings

MONDO
MONDO:0010898 autosomal dominant epilepsy with auditory features
skos:exactMatch MONDO
MONDO:0010898 is the autosomal dominant epilepsy with auditory features concept, defined by focal seizures with prominent ictal auditory symptoms or receptive aphasia in two or more family members.
👪

Inheritance

1
Autosomal dominant with incomplete penetrance HP:0000006
ADEAF is autosomal dominant by definition of the syndrome. Most affected individuals have an affected parent and de novo variants are believed to be uncommon. Penetrance is incomplete, which materially changes counselling: a child of an affected parent has a 50 percent chance of inheriting the variant but a lower chance of ever manifesting seizures, estimated between 54 and 85 percent of carriers depending on the penetrance assumed.
Autosomal dominant inheritance Penetrance: INCOMPLETE
Show evidence (2 references)
PMID:20301709 SUPPORT Other
"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."
Gives both the transmission probability and the penetrance range, which together are the counselling content of this block.
PMID:20301709 SUPPORT Other
"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."
Establishes the familial transmission pattern and the low de novo rate.
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Discussions and Knowledge Gaps

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Only a minority of epilepsy-with-auditory-features cases have an identifiable causative variant in any known gene. What accounts for the rest, and does the residue represent unfound genes, non-coding variation, or a phenotype definition that is grouping unrelated things?
KNOWLEDGE GAP OPEN adeaf_genetic_yield_gap
Attached to
pathophysiology#LGI1 Loss of Function
In the largest cohort assembled for this phenotype, 112 unrelated cases, only 8 percent received any genetic diagnosis: LGI1 2.7 percent, SCN1A 2.7 percent, RELN 1.8 percent, DEPDC5 0.9 percent. That is a striking result for a syndrome whose name asserts a dominant inheritance pattern. Part of the explanation is ascertainment, since fewer than a third of that cohort were familial and LGI1 yield is considerably higher in genuinely autosomal dominant pedigrees; this entry labels the figure accordingly rather than quoting it as the ADEAF yield. But even restricting to dominant families leaves most of them unexplained. Three possibilities compete. There may simply be further genes to find, which is the conventional reading and is supported by the fact that MICAL1 and RELN were both added relatively recently. There may be non-coding or structural variation in or around LGI1 itself that standard panels miss, which would leave LGI1 the dominant biological story even where sequencing is negative. Or the auditory phenotype may be a final common presentation of several unrelated lateral temporal pathologies, in which case the syndrome is a semiological grouping rather than a genetic entity. The distinction matters for whether a negative panel should end the diagnostic workup.
Proposed experiments
Genome sequencing restricted to autosomal dominant ADEAF pedigrees
exp_adeaf_family_restricted_genome_sequencing
Whole-genome sequencing with structural and non-coding variant calling in multiplex families meeting strict autosomal dominant ADEAF criteria, rather than in mixed cohorts, with linkage or segregation analysis where pedigree structure permits.
Decision criterion
Recovery of causative variants in most strictly-defined families would establish the gap as a detection and ascertainment artefact; persistent negativity would support genetic heterogeneity beyond the known genes.
Search for regulatory variation at the LGI1 locus
exp_adeaf_lgi1_regulatory_variation
Targeted assessment of non-coding and structural variation at and around LGI1 in sequencing-negative ADEAF families, paired where tissue or iPSC-derived neurons are available with a measurement of LGI1 secretion.
Decision criterion
Reduced LGI1 secretion in sequencing-negative cases would keep the single-mechanism model intact and redirect testing toward the regulatory region rather than toward new genes.
Show evidence (3 references)
PMID:33453592 SUPPORT Human Clinical
"This study shows that the contribution of each of the known genes to the overall disorder is limited and that the genetic background of EAF is still largely unknown."
The authors' own statement of the gap, from the largest cohort assembled for this phenotype.
PMID:33453592 SUPPORT Human Clinical
"We identified a genetic diagnosis for 8% of our cohort, including pathogenic/likely pathogenic variants (4/8 novel) in LGI1 (2.7%, CI: 0.6-7.6); RELN (1.8%; CI: 0.2-6.3); SCN1A (2.7%; CI: 0.6-7.6) and DEPDC5 (0.9%; CI 0-4.9)."
Quantifies the gap gene by gene, which is what makes it specific rather than a general complaint about missing heritability.
PMID:20301709 SUPPORT Other
"a heterozygous pathogenic variant in LGI1, MICAL1, or RELN identified by molecular genetic testing"
The current authoritative gene list. PARTIAL because it defines what counts as a molecular diagnosis without stating what fraction of patients achieve one.
Heterozygous Lgi1 mice do not develop seizures, whereas heterozygous humans develop ADEAF. Does that gene-dosage discrepancy mean the mouse is the wrong model, or that human ADEAF requires something beyond simple haploinsufficiency?
HUMAN MODEL MISMATCH OPEN adeaf_heterozygous_mouse_does_not_seize
Attached to
pathophysiology#LGI1 Loss of Function pathophysiology#Dysregulated AMPA Receptor Clustering and Synaptic Excitability
The mismatch is clean and quantitative. In the Lgi1 null mouse, homozygotes develop myoclonic seizures from around 12 to 18 days of age and die shortly afterward, while heterozygotes do not develop seizures at all. Human ADEAF is a heterozygous disorder in every reported family. So the mouse reproduces the biology only at a gene dosage that has no human counterpart, and at that dosage it produces a lethal early myoclonic phenotype rather than a benign adolescent-onset focal auditory epilepsy. Several readings are available and they have different consequences. Human penetrance is incomplete, between 54 and 85 percent, which already tells us haploinsufficiency alone is insufficient in humans too, so the mouse may simply lack whatever second factor the unpenetrant human carriers also lack. Alternatively, mouse and human may differ in reserve, with mice tolerating half-normal LGI1 where humans cannot. A third possibility is that many human variants act as more than simple nulls, given that one of the two described classes is secreted but functionally inert and could in principle interfere with the complex rather than merely be absent from it. The knockout, which removes protein entirely, cannot model that. This matters because the model used to test a therapy determines what the therapy is optimized against.
Proposed experiments
Heterozygous knock-in of human ADEAF variants from both classes
exp_adeaf_knockin_heterozygous_human_variants
Generate and phenotype heterozygous knock-in mice carrying human secretion-defective and secretion-competent binding-defective LGI1 variants, rather than a null allele, with long-term video-EEG through the mouse equivalent of adolescence.
Decision criterion
Seizures in heterozygous knock-ins but not in heterozygous nulls would show that human variants are not simple haploinsufficiency and would make the knockout the wrong model; absence of seizures in both would point to a species difference in reserve.
Search for modifiers distinguishing penetrant from non-penetrant carriers
exp_adeaf_penetrance_modifier_search
Compare genomes and, where accessible, LGI1 secretion in penetrant versus non-penetrant human carriers within the same pedigrees, to identify what the unaffected carriers have that the affected ones lack.
Decision criterion
Identifying a reproducible modifier would explain both the human incomplete penetrance and, if conserved, the unaffected heterozygous mouse, unifying the two observations rather than treating the mouse as simply wrong.
Show evidence (3 references)
PMID:20130004 SUPPORT Model Organism
"The heterozygous mutant mice do not develop seizures."
The core observation of this mismatch: the mouse genotype matching human ADEAF produces no epilepsy.
PMID:20130004 SUPPORT Model Organism
"After 12-18 days of age, the homozygous mutant mice all exhibit myoclonic seizures accompanied by rapid jumping and running and die shortly thereafter."
Shows that the dosage at which the mouse does seize produces a phenotype qualitatively unlike human ADEAF, which is the second half of the mismatch.
PMID:20301709 SUPPORT Other
"the chance that offspring who inherit the pathogenic variant will manifest ADEAF ranges from 54% to 85% depending on the assumed penetrance"
Establishes that heterozygosity is insufficient in humans too, which is the observation that makes the modifier explanation plausible rather than ad hoc.
Losing LGI1 through inherited loss of function produces a benign adolescent-onset focal epilepsy with auditory auras. Attacking the same protein with autoantibodies in adulthood produces a severe amnestic limbic encephalitis with faciobrachial dystonic seizures. Why do the two routes to LGI1 dysfunction give such different diseases?
OPEN QUESTION OPEN adeaf_genetic_versus_autoimmune_lgi1
Attached to
pathophysiology#Disrupted LGI1-ADAM22 Trans-Synaptic Complex pathophysiology#Lateral Temporal Cortical Hyperexcitability
This is not a diagnostic confusion, since the two are easy to tell apart clinically. It is a mechanistic puzzle, and its answer would sharpen the model in this entry. Three explanations are candidates and they are not mutually exclusive. Timing: inherited loss is present throughout development, so the brain builds itself around the deficiency and can compensate, whereas an autoantibody removes a functioning protein abruptly from a mature circuit that has come to depend on it. That would predict developmental compensation as the reason the inherited form is benign. Completeness: a heterozygous variant leaves roughly half the normal protein, whereas antibodies can strip function more thoroughly, so the difference may be quantitative rather than qualitative. Mechanism specificity: antibodies target particular epitopes and can disrupt the ADAM22 arm and the ADAM23-Kv1.1 arm to different degrees, so the autoimmune lesion may not be equivalent to loss of the whole protein. The regional discrepancy is the sharpest part of the puzzle. Inherited loss localizes to lateral temporal auditory and language cortex; the autoimmune form targets limbic and basal-ganglia circuits. Neither this entry nor the source literature explains why a molecule present across the brain should produce region-specific disease at all, let alone different regions by different routes.
Proposed experiments
Developmental versus adult-onset LGI1 loss in the same model
exp_lgi1_timing_of_loss_comparison
Compare conditional Lgi1 deletion during development against inducible adult deletion in the same mouse line, phenotyping seizure semiology, affected circuits, and memory, to isolate timing from completeness of loss.
Decision criterion
If adult-onset deletion reproduces the limbic and amnestic phenotype while developmental deletion does not, timing and developmental compensation are established as the dominant variable.
Map regional dependence on the LGI1-ADAM22 complex
exp_lgi1_regional_dependency_mapping
Quantify LGI1, ADAM22, and ADAM23 expression and the functional dependence of local excitability on the complex across lateral temporal, mesial temporal, and basal-ganglia circuits.
Decision criterion
A regional gradient in dependence would explain the localization of the inherited syndrome; a uniform profile would mean the regional specificity must come from the nature of the insult rather than from the substrate.
Show evidence (3 references)
PMID:30346486 SUPPORT Other
"Human autoantibodies against LGI1 associate with a form of autoimmune limbic encephalitis characterized by severe but treatable memory impairment and frequent faciobrachial dystonic seizures."
Establishes the autoimmune phenotype that contrasts with the inherited one, which is the substance of this question.
PMID:30346486 SUPPORT Other
"Although there is evidence that this disease is immune-mediated, the underlying LGI1 antibody-mediated mechanisms are unknown."
Confirms that the autoimmune mechanism was itself unresolved, which is part of why the comparison with the inherited disorder cannot yet be made rigorously.
PMID:20301709 SUPPORT Other
"The clinical course of ADEAF is benign. Seizures are usually well controlled after initiation of medical therapy."
The inherited-side half of the contrast: benign and treatable, against the severe amnestic autoimmune syndrome.
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Pathophysiology

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LGI1 Loss of Function
Heterozygous pathogenic variants in LGI1 cause loss of function by two mechanistically distinct routes that converge on the same endpoint. Some missense variants are secretion-defective: the misfolded protein is caught by endoplasmic reticulum quality control and degraded before it ever reaches the synapse. Others are secreted normally but are functionally inert, dimerizing abnormally and failing to bind their receptor. This is what makes LGI1-related epilepsy a conformational disease rather than simply a dosage problem, and it is why a chemical chaperone can rescue one class of variant but would be expected to do nothing for the other.
protein secretion GO:0009306 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein secretion (GO:0009306). GO:0009306 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Disrupted LGI1-ADAM22 Trans-Synaptic Complex
Show evidence (2 references)
PMID:25485908 SUPPORT Model Organism
"The secretion-defective LGI1(E383A) protein was recognized by the ER quality-control machinery and prematurely degraded, whereas the secretable LGI1(S473L) protein abnormally dimerized and was selectively defective in binding to one of its receptors, ADAM22."
Establishes the two distinct molecular failure modes, ER retention and receptor-binding failure, that this node models.
PMID:25485908 SUPPORT In Vitro
"We classified 22 reported LGI1 missense mutations as either secretion defective or secretion competent"
Shows the two-class division is a property of the reported human variant set rather than of two hand-picked examples.
Disrupted LGI1-ADAM22 Trans-Synaptic Complex
Secreted LGI1 physically bridges the synaptic cleft, binding presynaptic ADAM23, which associates with Kv1.1 potassium channels, and postsynaptic ADAM22, which associates with AMPA receptors through PSD-95 and other MAGUK scaffolds. Losing LGI1 therefore does not knock out one channel; it dismantles the scaffold that holds a presynaptic brake and a postsynaptic receptor array in register across the cleft.
Downstream
Dysregulated AMPA Receptor Clustering and Synaptic Excitability
Show evidence (2 references)
PMID:30346486 SUPPORT Other
"Leucine-rich glioma-inactivated 1 (LGI1) is a secreted neuronal protein that forms a trans-synaptic complex that includes the presynaptic disintegrin and metalloproteinase domain-containing protein 23 (ADAM23), which interacts with voltage-gated potassium channels Kv1.1, and the postsynaptic..."
Describes the trans-synaptic architecture, including both the presynaptic Kv1.1 arm and the postsynaptic AMPA arm, that this node represents.
PMID:34089731 SUPPORT Other
"Epilepsy-related secreted protein LGI1 and its receptor ADAM22 represent major constituent elements of the PSD-95-containing synaptic protein complex in the brain."
Places LGI1 and ADAM22 within the PSD-95 scaffold, which is the link from the trans-synaptic complex to receptor organization.
Dysregulated AMPA Receptor Clustering and Synaptic Excitability
With the bridge gone, MAGUK-dependent regulation of AMPA and NMDA receptor transmission is disturbed and the presynaptic Kv1 brake is loosened. Excitatory synaptic transmission increases. In the Lgi1 null mouse this is measurable as enhanced glutamate release, giving a concrete cellular basis for the seizure phenotype.
glutamatergic neuron CL:0000679 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves abnormal glutamatergic neuron (CL:0000679). CL:0000679 is a cell type from the Cell Ontology. ⚠ ABNORMAL
AMPA glutamate receptor clustering GO:0097113 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal AMPA glutamate receptor clustering (GO:0097113). GO:0097113 is a biological process from the Gene Ontology. ⚠ ABNORMAL synaptic transmission, glutamatergic GO:0035249 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased synaptic transmission, glutamatergic (GO:0035249). GO:0035249 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Lateral Temporal Cortical Hyperexcitability
Show evidence (2 references)
PMID:34089731 SUPPORT Other
"Recent studies begin to reveal a trans-synaptic configuration of the LGI1-ADAM22 complex and its pivotal role in AMPA and NMDA receptor-mediated synaptic transmission through regulating MAGUKs."
States the mechanism by which the complex controls excitatory transmission, which is the content of this node.
PMID:20130004 SUPPORT Model Organism
"Electrophysiological analysis demonstrates an enhanced excitatory synaptic transmission by increasing the release of the excitatory neurotransmitter glutamate, suggesting a basis for the seizure phenotype."
Direct electrophysiological evidence that losing Lgi1 increases excitatory transmission. Note this is the homozygous null; the heterozygous mismatch with human disease is recorded as a discussion.
Lateral Temporal Cortical Hyperexcitability
The seizure onset zone is lateral temporal, involving auditory cortex and adjacent language cortex, which is what gives the syndrome its characteristic aura. Why a deficiency in a broadly expressed secreted protein should localize its effect here rather than producing a generalized or multifocal epilepsy is not explained by the molecular mechanism above, and imaging is normal by definition, so the regional specificity is asserted from seizure semiology rather than from a demonstrated regional lesion.
Downstream
Focal Seizures with Auditory Features
Show evidence (2 references)
PMID:20301709 SUPPORT Other
"Autosomal dominant epilepsy with auditory features (ADEAF) is a focal epilepsy syndrome with auditory symptoms and/or receptive aphasia as prominent ictal manifestations."
Establishes the focal, auditory-and-language-cortex localization that this node asserts, from the authoritative clinical description.
PMID:20301709 SUPPORT Other
"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."
Records that MRI is normal, which is why this node is inferred from semiology rather than from a visible structural abnormality.
Focal Seizures with Auditory Features
Recurrent focal seizures whose defining feature is an auditory aura, with or without ictal receptive aphasia, sometimes evolving to bilateral tonic-clonic seizures. The course is benign and usually medication responsive.
Show evidence (1 reference)
PMID:20301709 SUPPORT Other
"The clinical course of ADEAF is benign. Seizures are usually well controlled after initiation of medical therapy."
States the benign, treatment-responsive character of the terminal clinical phenotype.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Autosomal Dominant Epilepsy with Auditory Features Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

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Nervous System 1
Interictal EEG Abnormality FREQUENT HP:0002353 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is EEG abnormality (HP:0002353). HP:0002353 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28142128 SUPPORT Human Clinical
"The interictal EEG recordings showed epileptiform abnormalities or focal slow waves in 80% of patients, localized over the temporal regions, with marked left predominance and conventional 1,5T MRI scans were not contributory."
Quantifies interictal EEG abnormality in the RELN-mutated cohort at 80 percent, and confirms in the same sentence that conventional MRI adds nothing. The 80 percent is a subgroup figure; see the item below for the LGI1 comparison that sets the frequency band used here.
PMID:28142128 SUPPORT Human Clinical
"EEGs showed a lower rate of normal recordings and higher rate of left temporal abnormalities in RELN group compared to the LGI1 group (20 vs 42% and 53 vs 22%, respectively)"
The genotype split that sets the band. Normal recordings in 42 percent of the LGI1 group implies roughly 58 percent abnormal, which is FREQUENT rather than VERY_FREQUENT, and left temporal predominance is a RELN feature (53 percent) rather than an LGI1 one (22 percent). Because this entry is LGI1-scoped, the LGI1 figures are the applicable ones. This is also the one axis on which the same paper reports the two genotypes differing, so it is precisely where its otherwise-valid generalization does not hold.
Other 5
Focal Sensory Seizure with Auditory Features FREQUENT HP:0011158 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Focal sensory seizure with auditory features (HP:0011158), qualified as young adult onset. HP:0011158 is a phenotype from the Human Phenotype Ontology.
Onset: YOUNG ADULT
Show evidence (2 references)
PMID:28142128 SUPPORT Human Clinical
"frequency of auditory auras (71% vs 57%)"
The measured frequency of the auditory aura, 71 percent in RELN-mutated and 57 percent in LGI1-mutated families. Both figures fall in the 30 to 79 percent band, which maps to FREQUENT rather than VERY_FREQUENT.
PMID:20301709 SUPPORT Other
"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)."
The GeneReviews description of the character of the auditory aura, including the simple-versus-complex distinction. It supports what the aura is like, not how many patients have one; the frequency band is carried by the cohort figures above.
Ictal Receptive Aphasia Focal cognitive seizure with receptive dysphasia/aphasia HP:0032696 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Focal cognitive seizure with receptive dysphasia/aphasia (HP:0032696). HP:0032696 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301709 SUPPORT Other
"Ictal receptive aphasia consists of a sudden onset of inability to understand language in the absence of general confusion."
Defines the ictal receptive aphasia phenotype, including the absence of general confusion that distinguishes it.
Auditory Hallucination OCCASIONAL HP:0008765 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Auditory hallucination (HP:0008765). HP:0008765 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301709 SUPPORT Other
"less common forms are distortions (e.g., volume changes) or complex sounds (e.g., specific songs or voices)"
Documents complex auditory percepts as a less common form of the aura. The qualitative phrase "less common" maps to OCCASIONAL.
Focal to Bilateral Tonic-Clonic Seizures VERY_FREQUENT Bilateral tonic-clonic seizure with focal onset HP:0007334 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bilateral tonic-clonic seizure with focal onset (HP:0007334). HP:0007334 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28142128 SUPPORT Human Clinical
"Tonic-clonic seizures were reported by almost all patients (88%), preceded by typical aura in 67% of cases."
Quantifies tonic-clonic seizures at 88 percent in RELN-mutated ADLTE families, which falls in the 80 to 100 percent band mapping to VERY_FREQUENT. The same study found no significant phenotypic difference from LGI1-mutated families apart from EEG lateralization, so the figure is taken as applying to the syndrome rather than to the RELN subset alone.
PMID:28142128 SUPPORT Human Clinical
"By comparing these findings with those observed in families with LGI1 mutations, we did not observe significant differences except for a higher rate of left-sided EEG abnormalities in the RELN group."
Justifies generalizing the RELN-cohort frequencies to the syndrome, by establishing that the RELN and LGI1 phenotypes are otherwise indistinguishable.
Other Focal Sensory and Autonomic Auras OCCASIONAL Focal sensory seizure HP:0011157 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Focal sensory seizure (HP:0011157). HP:0011157 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301709 SUPPORT Other
"Less commonly, other ictal symptoms may occur, including sensory symptoms (visual, olfactory, vertiginous, or cephalic) or motor, psychic, and autonomic symptoms."
Enumerates the less common aura types. The qualifier "less commonly" maps to OCCASIONAL.
🧬

Genetic Associations

4
LGI1
Gene: LGI1 hgnc:6572 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is LGI1 (hgnc:6572). hgnc:6572 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (4 references)
PMID:20301709 SUPPORT Other
"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."
Names LGI1 as an established molecular cause of ADEAF, alongside MICAL1 and RELN.
PMID:33453592 SUPPORT Human Clinical
"We identified a genetic diagnosis for 8% of our cohort, including pathogenic/likely pathogenic variants (4/8 novel) in LGI1 (2.7%, CI: 0.6-7.6); RELN (1.8%; CI: 0.2-6.3); SCN1A (2.7%; CI: 0.6-7.6) and DEPDC5 (0.9%; CI 0-4.9)."
Quantifies LGI1 yield in a broad, largely sporadic cohort. Marked PARTIAL because that cohort is not restricted to autosomal dominant families, so the figure understates the yield in ADEAF proper.
PMID:18711109 SUPPORT Human Clinical
"Mutations in the leucine-rich, glioma inactivated 1 gene (LGI1) have been identified in about 50% of families with autosomal dominant partial epilepsy with auditory features (ADPEAF)"
The family-restricted LGI1 yield, roughly 50 percent, which is the figure that actually applies to ADEAF. Placing it beside the 2.7 percent sporadic-cohort figure makes the ascertainment effect explicit rather than leaving a reader to reconcile two numbers that differ nearly twenty-fold.
+ 1 more reference
RELN
Gene: RELN hgnc:9957 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is RELN (hgnc:9957). hgnc:9957 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:33453592 SUPPORT Human Clinical
"LGI1 and RELN have been identified as the main cause of Autosomal Dominant EAF and anecdotally reported in non-familial cases."
Names RELN alongside LGI1 as a main cause of the autosomal dominant form specifically.
MICAL1
Gene: MICAL1 hgnc:20619 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MICAL1 (hgnc:20619). hgnc:20619 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:20301709 SUPPORT Other
"a heterozygous pathogenic variant in LGI1, MICAL1, or RELN identified by molecular genetic testing"
Establishes MICAL1 as one of the three genes in which a pathogenic variant establishes the molecular diagnosis.
SCN1A
Gene: SCN1A hgnc:10585 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SCN1A (hgnc:10585). hgnc:10585 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE
Show evidence (1 reference)
PMID:33453592 SUPPORT Human Clinical
"Pathogenic variants in SCN1A and DEPDC5 have also been described in a few EAF probands belonging to families with heterogeneous phenotypes and incomplete penetrance."
Supports the association while explicitly noting the phenotypic heterogeneity that justifies the weaker SUSCEPTIBILITY typing here.
💊

Medical Actions

2
Standard Antiseizure Medication
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: carbamazepine CHEBI:3387 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses carbamazepine (CHEBI:3387). CHEBI:3387 is a therapeutic agent from Chemical Entities of Biological Interest.
Seizure control is usually readily achieved with standard antiseizure medications. No agent is specific to ADEAF and none targets the LGI1 mechanism; treatment is conventional focal-epilepsy pharmacotherapy. For women of childbearing potential, GeneReviews advises that the risks and benefits of a given medication in pregnancy be discussed before conception, and that transitioning to a lower-risk medication beforehand may be possible. Carbamazepine is named as the representative agent because it is the conventional first choice for focal seizures; this is a class representative rather than an ADEAF-specific indication, since no agent has been trialled against this syndrome in particular.
Mechanism Target:
INHIBITS Focal Seizures with Auditory Features — Symptomatic seizure suppression at the terminal phenotype. The edge deliberately targets the seizure node rather than any upstream molecular node, because no available drug acts on the LGI1 complex.
Show evidence (2 references)
PMID:20301709 SUPPORT Other
"Treatment of manifestations: Seizure control is usually readily achieved with standard anti-seizure medications (ASM)."
The GeneReviews management recommendation, establishing conventional antiseizure medication as effective treatment.
PMID:20301709 SUPPORT Other
"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."
The pregnancy-management guidance from GeneReviews, captured here because it is the one drug-safety consideration the source raises.
4-Phenylbutyrate (Investigational Chemical Chaperone)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: 4-phenylbutyric acid CHEBI:41500 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses 4-phenylbutyric acid (CHEBI:41500). CHEBI:41500 is a therapeutic agent from Chemical Entities of Biological Interest.
Not a clinical treatment. In a mouse model carrying a secretion-defective LGI1 variant, the chemical chaperone 4-phenylbutyrate restored protein folding and ADAM22 binding and reduced seizure susceptibility. It is recorded here because it is the only intervention that addresses the molecular mechanism rather than the seizures, and because it demonstrates the practical consequence of the two-class variant division: a corrector should help secretion-defective variants and would not be expected to help secretion-competent, binding-defective ones. No human data exist.
Mechanism Target:
RESTORES LGI1 Loss of Function — Restores folding and receptor binding of a secretion-defective LGI1 variant, acting on the proximal molecular defect rather than on seizure threshold.
Show evidence (2 references)
PMID:25485908 SUPPORT Model Organism
"A chemical corrector, 4-phenylbutyrate (4PBA), restored LGI1(E383A) folding and binding to ADAM22 and ameliorated the increased seizure susceptibility of the LGI1(E383A) model mice."
Demonstrates mechanism-directed rescue in a model of the secretion-defective variant class. Model-organism evidence only; no human trial supports this use.
PMID:25485908 SUPPORT Model Organism
"This study establishes LGI1-related epilepsy as a conformational disease and suggests new therapeutic options for human epilepsy."
The authors' own framing. Marked PARTIAL because "suggests new therapeutic options" is a proposal, not a demonstration of human benefit.
🔬

Diagnosis

3
Molecular genetic testing
A heterozygous pathogenic variant in LGI1, MICAL1, or RELN establishes the molecular diagnosis in a proband with characteristic features. A negative result does not exclude the syndrome, since most families remain genetically unexplained, and the clinical diagnosis can stand on phenotype, normal MRI, and a consistent family history.
Molecular Analysis NCIT:C19770 NCI Thesaurus (NCIT)
Results: A heterozygous pathogenic variant in LGI1, MICAL1, or RELN confirms the molecular diagnosis; a negative panel is uninformative.
Show evidence (1 reference)
PMID:20301709 SUPPORT Other
"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."
States the molecular diagnostic criterion and the three genes it rests on.
Electroencephalography
Because MRI is normal by definition, EEG is the only investigation that returns a positive finding. Interictal epileptiform abnormalities or focal slow waves appear over the temporal regions in roughly 60 to 80 percent of patients, the higher figure coming from RELN-mutated families and the lower from LGI1-mutated ones. Marked left temporal predominance is a feature of the RELN group specifically and should not be expected in LGI1 families. A normal EEG does not exclude the diagnosis, which rests on semiology, normal imaging, and family history.
Electroencephalography NCIT:C38054 NCI Thesaurus (NCIT)
Results: Temporal epileptiform abnormalities or focal slow waves in roughly 60 to 80 percent of patients depending on genotype; left-predominant in RELN families.
Show evidence (1 reference)
PMID:28142128 SUPPORT Human Clinical
"The interictal EEG recordings showed epileptiform abnormalities or focal slow waves in 80% of patients, localized over the temporal regions, with marked left predominance and conventional 1,5T MRI scans were not contributory."
Quantifies the EEG yield and its localization, and in the same sentence confirms that conventional MRI contributes nothing, which is why EEG is the diagnostic workhorse here.
Brain MRI
MRI is normal in ADEAF and is performed to exclude a structural lesion rather than to demonstrate one. A visible lateral temporal lesion should redirect the diagnosis toward a structural focal epilepsy.
Magnetic Resonance Imaging NCIT:C16809 NCI Thesaurus (NCIT)
Results: Normal brain imaging.
Show evidence (1 reference)
PMID:20301709 SUPPORT Other
"normal brain imaging by MRI, and family history consistent with autosomal dominant inheritance"
Establishes normal MRI as part of the clinical diagnostic criteria.
📈

Progression

2
Onset in adolescence or early adulthood
Age: 10 to 30 years
Onset is later than in most genetic focal epilepsies, typically between ages 10 and 30, with normal development beforehand.
Show evidence (1 reference)
PMID:20301709 SUPPORT Other
"Age at onset is usually in adolescence or early adulthood (age 10-30 years)."
Gives the characteristic age-at-onset window for the syndrome.
Benign medication-responsive course
Age: Adulthood
Unlike most focal epilepsies, ADEAF is benign in the sense that matters most: seizures are usually well controlled once treatment starts, and the syndrome does not carry the drug-resistance burden of structural focal epilepsy. Surveillance is directed at cognitive and psychiatric comorbidity rather than at seizure escalation. "Benign" should not be read as "remitting", however. In a long-term cohort of 123 patients with epilepsy with auditory features followed for a median of 11 years, only 34.1 percent reached terminal remission, defined as five or more consecutive seizure-free years at last follow-up. Good control on medication and freedom from seizures off medication are different outcomes, and this syndrome delivers the first far more reliably than the second.
Show evidence (3 references)
PMID:29464704 SUPPORT Human Clinical
"At last assessment, 42 patients had achieved TR (34.1%)."
The counterweight to the GeneReviews benign framing: only about a third of patients reach terminal remission. Marked PARTIAL because the cohort is epilepsy with auditory features broadly, 68.3 percent sporadic rather than familial, so it bounds rather than measures the ADEAF outcome.
PMID:20301709 SUPPORT Other
"Seizure control is usually readily achieved with standard anti-seizure medications (ASM)."
States the benign, treatment-responsive course that defines this phase.
PMID:20301709 SUPPORT Other
"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."
Documents that surveillance is directed at cognitive and psychiatric comorbidity, supporting the characterization of this phase.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Autosomal Dominant Epilepsy with Auditory Features:

Anti-LGI1 Autoimmune Encephalitis
Overlapping Features Involves the same protein but is a different disease entirely: an acquired autoantibody-mediated limbic encephalitis with severe though treatable memory impairment and frequent faciobrachial dystonic seizures, typically in older adults. The contrast between losing LGI1 from birth and having it attacked in adulthood is recorded as a discussion.
Distinguishing Features
  • Acquired in adulthood rather than lifelong and familial.
  • Serum or CSF antibodies against LGI1.
  • Prominent amnesia and faciobrachial dystonic seizures rather than auditory auras.
  • Responds to immunotherapy.
Show evidence (1 reference)
PMID:30346486 SUPPORT Other
"Human autoantibodies against LGI1 associate with a form of autoimmune limbic encephalitis characterized by severe but treatable memory impairment and frequent faciobrachial dystonic seizures."
Describes the autoimmune syndrome and its distinguishing features, which is what separates it from the inherited disorder modelled here.
Sporadic Epilepsy with Auditory Features
Overlapping Features The same seizure semiology without a family history. It is not so much a distinct biological entity as the residue left when the autosomal dominant criterion is not met, and it matters here because genetic yield is much lower in this group, which is why cohort-derived gene frequencies should not be read as ADEAF yields.
Distinguishing Features
  • No family history of epilepsy with auditory features.
  • Substantially lower yield from genetic testing.
Show evidence (1 reference)
PMID:33453592 SUPPORT Human Clinical
"We included 112 unrelated EAF cases (male/female: 52/60) who underwent genetic analysis by next-generation sequencing (NGS) techniques. Thirty-three (29.5%) were familial cases."
Documents that the large auditory-features cohort was predominantly non-familial, which is the ascertainment point this differential makes.
Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis
Overlapping Features The other temporal lobe epilepsy, and the one ADEAF is most often mistaken for. It arises mesially rather than laterally, produces epigastric rising sensations, fear, and deja vu rather than auditory auras, shows hippocampal sclerosis on MRI, and is frequently drug-resistant. dismech carries a separate entry.
Distinguishing Features
  • Mesial rather than lateral temporal onset.
  • Epigastric, psychic, and olfactory auras rather than auditory ones.
  • Hippocampal sclerosis visible on MRI, whereas ADEAF imaging is normal.
  • Frequently drug-resistant, whereas ADEAF is typically well controlled.
{ }

Source YAML

click to show 
name: Autosomal Dominant Epilepsy with Auditory Features
creation_date: "2026-08-05T00:00:00Z"
category: Mendelian
description: >-
  Autosomal dominant epilepsy with auditory features (ADEAF) is a familial focal
  epilepsy in which the seizures announce themselves as sound. The commonest aura
  is a simple unformed noise, a humming, buzzing, or ringing, and some patients
  instead lose the ability to understand language while remaining otherwise
  lucid. Onset is in adolescence or early adulthood, brain imaging is normal, and
  the course is benign, with seizures usually controlled once treatment starts.
  In the families where a cause is found it is most often loss of function in
  LGI1, a secreted neuronal protein that bridges the synaptic cleft by binding
  ADAM22 and ADAM23 and thereby organizes AMPA receptors and Kv1 channels. Most
  families, however, remain genetically unexplained.
parents:
  - Epilepsy
  - Neurological Disease
synonyms:
  - ADEAF
  - autosomal dominant lateral temporal lobe epilepsy
  - ADLTE
  - autosomal dominant partial epilepsy with auditory features
  - ADPEAF
  - epilepsy with auditory features
disease_term:
  preferred_term: autosomal dominant epilepsy with auditory features
  term:
    id: MONDO:0010898
    label: autosomal dominant epilepsy with auditory features
mappings:
  mondo_mappings:
    - term:
        id: MONDO:0010898
        label: autosomal dominant epilepsy with auditory features
      mapping_predicate: skos:exactMatch
      mapping_source: MONDO
      mapping_justification: >-
        MONDO:0010898 is the autosomal dominant epilepsy with auditory features
        concept, defined by focal seizures with prominent ictal auditory symptoms
        or receptive aphasia in two or more family members.
references:
  - reference: PMID:20301709
    title: Autosomal Dominant Epilepsy with Auditory Features.
    tags:
      - GeneReviews
  - reference: PMID:25485908
    title: >-
      Chemical corrector treatment ameliorates increased seizure susceptibility
      in a mouse model of familial epilepsy.
notes: >-
  Scope and naming note. This syndrome carries an unusual number of names, and
  they are not quite interchangeable. ADEAF and the older ADPEAF and ADLTE refer
  to the familial, autosomal dominant syndrome modelled here. "Epilepsy with
  auditory features" is broader and includes sporadic cases, which matters
  because genetic yield differs sharply between the two: in a cohort of 112
  largely sporadic cases only 8 percent had any genetic diagnosis and only 2.7
  percent had an LGI1 variant, whereas LGI1 accounts for a much larger share of
  genuinely autosomal dominant families. Figures quoted from the broad cohort are
  therefore labelled as such rather than presented as the ADEAF yield.

  Anti-LGI1 autoimmune encephalitis involves the same protein but is a different
  disease with a different presentation and is not covered here; the relationship
  between the two is recorded as a discussion.

  Pathograph scoping. The causal chain modelled below is the LGI1 route only,
  even though RELN and MICAL1 are also typed CAUSATIVE in the genetic section.
  This is deliberate. The clinical justification is that RELN-mutated and
  LGI1-mutated families are phenotypically indistinguishable apart from a higher
  rate of left-sided EEG abnormality, so a single downstream chain describes both
  presentations without loss. The evidential justification is that only the LGI1
  route has a worked-out molecular mechanism at the level of detail this entry
  models, from variant class through secretion through the ADAM22 complex to
  receptor clustering. RELN is understood to converge via reduced secretion of a
  different secreted protein and MICAL1 via a mechanistically distinct
  gain-of-function route affecting actin regulation, but neither is characterized
  here to the standard used for LGI1, and inventing parallel chains at lower
  evidential quality would misrepresent how well those routes are understood.
  Adding them is worthwhile follow-up work, particularly MICAL1, because a
  gain-of-function route reaching the same syndrome as two loss-of-function
  routes would be a genuinely informative addition to the model.

  Module conformance now covers four of five nodes against
  epilepsy_excitation_inhibition_imbalance. An earlier revision of this entry
  declined the #Excitation-Inhibition Imbalance node on the grounds that it was
  GABAergic-specific; that reading was wrong. The module node describes a shift
  toward net excitation "through increased excitation, decreased inhibition, or
  both", which is exactly what loss of the LGI1-ADAM22 bridge produces on the
  glutamatergic side. The trans-synaptic complex node takes #Ion Channel and
  Synaptic Dysfunction, whose description explicitly covers synaptic-protein
  abnormalities.
pathophysiology:
  - name: LGI1 Loss of Function
    biological_scale: MOLECULAR
    description: >-
      Heterozygous pathogenic variants in LGI1 cause loss of function by two
      mechanistically distinct routes that converge on the same endpoint. Some
      missense variants are secretion-defective: the misfolded protein is caught
      by endoplasmic reticulum quality control and degraded before it ever
      reaches the synapse. Others are secreted normally but are functionally
      inert, dimerizing abnormally and failing to bind their receptor. This is
      what makes LGI1-related epilepsy a conformational disease rather than
      simply a dosage problem, and it is why a chemical chaperone can rescue one
      class of variant but would be expected to do nothing for the other.
    biological_processes:
      - preferred_term: protein secretion
        term:
          id: GO:0009306
          label: protein secretion
        modifier: DECREASED
    downstream:
      - target: Disrupted LGI1-ADAM22 Trans-Synaptic Complex
        causal_link_type: DIRECT
        evidence:
          - reference: PMID:25485908
            reference_title: >-
              Chemical corrector treatment ameliorates increased seizure
              susceptibility in a mouse model of familial epilepsy.
            supports: SUPPORT
            evidence_source: MODEL_ORGANISM
            snippet: >-
              Both mutations caused a loss of function, compromising
              intracellular trafficking or ligand activity of LGI1 and converging
              on reduced synaptic LGI1-ADAM22 interaction.
            explanation: >-
              States the convergence of both variant classes onto reduced
              synaptic LGI1-ADAM22 interaction, which is exactly this edge.
    evidence:
      - reference: PMID:25485908
        reference_title: >-
          Chemical corrector treatment ameliorates increased seizure
          susceptibility in a mouse model of familial epilepsy.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          The secretion-defective LGI1(E383A) protein was recognized by the ER
          quality-control machinery and prematurely degraded, whereas the
          secretable LGI1(S473L) protein abnormally dimerized and was selectively
          defective in binding to one of its receptors, ADAM22.
        explanation: >-
          Establishes the two distinct molecular failure modes, ER retention and
          receptor-binding failure, that this node models.
      - reference: PMID:25485908
        reference_title: >-
          Chemical corrector treatment ameliorates increased seizure
          susceptibility in a mouse model of familial epilepsy.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          We classified 22 reported LGI1 missense mutations as either secretion
          defective or secretion competent
        explanation: >-
          Shows the two-class division is a property of the reported human
          variant set rather than of two hand-picked examples.
  - name: Disrupted LGI1-ADAM22 Trans-Synaptic Complex
    biological_scale: MOLECULAR
    conforms_to: "epilepsy_excitation_inhibition_imbalance#Ion Channel and Synaptic Dysfunction"
    description: >-
      Secreted LGI1 physically bridges the synaptic cleft, binding presynaptic
      ADAM23, which associates with Kv1.1 potassium channels, and postsynaptic
      ADAM22, which associates with AMPA receptors through PSD-95 and other MAGUK
      scaffolds. Losing LGI1 therefore does not knock out one channel; it
      dismantles the scaffold that holds a presynaptic brake and a postsynaptic
      receptor array in register across the cleft.
    downstream:
      - target: Dysregulated AMPA Receptor Clustering and Synaptic Excitability
        causal_link_type: DIRECT
    evidence:
      - reference: PMID:30346486
        reference_title: >-
          LGI1 antibodies alter Kv1.1 and AMPA receptors changing synaptic
          excitability, plasticity and memory.
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          Leucine-rich glioma-inactivated 1 (LGI1) is a secreted neuronal protein
          that forms a trans-synaptic complex that includes the presynaptic
          disintegrin and metalloproteinase domain-containing protein 23
          (ADAM23), which interacts with voltage-gated potassium channels Kv1.1,
          and the postsynaptic ADAM22, which interacts with AMPA receptors.
        explanation: >-
          Describes the trans-synaptic architecture, including both the
          presynaptic Kv1.1 arm and the postsynaptic AMPA arm, that this node
          represents.
      - reference: PMID:34089731
        reference_title: >-
          Trans-synaptic LGI1-ADAM22-MAGUK in AMPA and NMDA receptor regulation.
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          Epilepsy-related secreted protein LGI1 and its receptor ADAM22
          represent major constituent elements of the PSD-95-containing synaptic
          protein complex in the brain.
        explanation: >-
          Places LGI1 and ADAM22 within the PSD-95 scaffold, which is the link
          from the trans-synaptic complex to receptor organization.
  - name: Dysregulated AMPA Receptor Clustering and Synaptic Excitability
    biological_scale: CELLULAR
    conforms_to: "epilepsy_excitation_inhibition_imbalance#Excitation-Inhibition Imbalance"
    description: >-
      With the bridge gone, MAGUK-dependent regulation of AMPA and NMDA receptor
      transmission is disturbed and the presynaptic Kv1 brake is loosened.
      Excitatory synaptic transmission increases. In the Lgi1 null mouse this is
      measurable as enhanced glutamate release, giving a concrete cellular basis
      for the seizure phenotype.
    cell_types:
      - preferred_term: glutamatergic neuron
        term:
          id: CL:0000679
          label: glutamatergic neuron
        modifier: ABNORMAL
    biological_processes:
      - preferred_term: AMPA glutamate receptor clustering
        term:
          id: GO:0097113
          label: AMPA glutamate receptor clustering
        modifier: ABNORMAL
      - preferred_term: synaptic transmission, glutamatergic
        term:
          id: GO:0035249
          label: synaptic transmission, glutamatergic
        modifier: INCREASED
    downstream:
      - target: Lateral Temporal Cortical Hyperexcitability
        causal_link_type: DIRECT
    evidence:
      - reference: PMID:34089731
        reference_title: >-
          Trans-synaptic LGI1-ADAM22-MAGUK in AMPA and NMDA receptor regulation.
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          Recent studies begin to reveal a trans-synaptic configuration of the
          LGI1-ADAM22 complex and its pivotal role in AMPA and NMDA
          receptor-mediated synaptic transmission through regulating MAGUKs.
        explanation: >-
          States the mechanism by which the complex controls excitatory
          transmission, which is the content of this node.
      - reference: PMID:20130004
        reference_title: >-
          Lgi1 null mutant mice exhibit myoclonic seizures and CA1 neuronal
          hyperexcitability.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Electrophysiological analysis demonstrates an enhanced excitatory
          synaptic transmission by increasing the release of the excitatory
          neurotransmitter glutamate, suggesting a basis for the seizure
          phenotype.
        explanation: >-
          Direct electrophysiological evidence that losing Lgi1 increases
          excitatory transmission. Note this is the homozygous null; the
          heterozygous mismatch with human disease is recorded as a discussion.
  - name: Lateral Temporal Cortical Hyperexcitability
    biological_scale: TISSUE
    conforms_to: "epilepsy_excitation_inhibition_imbalance#Neuronal Hyperexcitability and Hypersynchrony"
    description: >-
      The seizure onset zone is lateral temporal, involving auditory cortex and
      adjacent language cortex, which is what gives the syndrome its
      characteristic aura. Why a deficiency in a broadly expressed secreted
      protein should localize its effect here rather than producing a generalized
      or multifocal epilepsy is not explained by the molecular mechanism above,
      and imaging is normal by definition, so the regional specificity is asserted
      from seizure semiology rather than from a demonstrated regional lesion.
    downstream:
      - target: Focal Seizures with Auditory Features
        causal_link_type: DIRECT
    evidence:
      - reference: PMID:20301709
        reference_title: Autosomal Dominant Epilepsy with Auditory Features.
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          Autosomal dominant epilepsy with auditory features (ADEAF) is a focal
          epilepsy syndrome with auditory symptoms and/or receptive aphasia as
          prominent ictal manifestations.
        explanation: >-
          Establishes the focal, auditory-and-language-cortex localization that
          this node asserts, from the authoritative clinical description.
      - reference: PMID:20301709
        reference_title: Autosomal Dominant Epilepsy with Auditory Features.
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          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.
        explanation: >-
          Records that MRI is normal, which is why this node is inferred from
          semiology rather than from a visible structural abnormality.
  - name: Focal Seizures with Auditory Features
    biological_scale: ORGANISM
    conforms_to: "epilepsy_excitation_inhibition_imbalance#Recurrent Unprovoked Seizures"
    description: >-
      Recurrent focal seizures whose defining feature is an auditory aura, with
      or without ictal receptive aphasia, sometimes evolving to bilateral
      tonic-clonic seizures. The course is benign and usually medication
      responsive.
    evidence:
      - reference: PMID:20301709
        reference_title: Autosomal Dominant Epilepsy with Auditory Features.
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          The clinical course of ADEAF is benign. Seizures are usually well
          controlled after initiation of medical therapy.
        explanation: >-
          States the benign, treatment-responsive character of the terminal
          clinical phenotype.
phenotypes:
  - name: Focal Sensory Seizure with Auditory Features
    category: Neurologic
    description: >-
      The defining phenotype. Most often a simple unformed sound such as humming,
      buzzing, or ringing; less commonly a distortion of what is actually being
      heard, such as a change in volume, or a complex percept such as a specific
      song or voice. The aura is the seizure, not a warning of one.

      Worth noting that the syndrome's defining feature is less common than its
      presenting one. Auditory auras occur in 57 percent of LGI1-mutated and 71
      percent of RELN-mutated patients, whereas tonic-clonic seizures occur in
      around 90 percent of both. The thing that names the syndrome is therefore
      not the thing that brings people to attention, which is a plausible part of
      why it goes underrecognized: a brief unformed noise is easy to dismiss or
      never to mention, and unless it is specifically asked about, what gets
      reported is the convulsion.
    phenotype_term:
      preferred_term: Focal sensory seizure with auditory features
      term:
        id: HP:0011158
        label: Focal sensory seizure with auditory features
      onset:
        onset_category: YOUNG_ADULT
    frequency: FREQUENT
    evidence:
      - reference: PMID:28142128
        reference_title: >-
          The clinical phenotype of autosomal dominant lateral temporal lobe
          epilepsy related to reelin mutations.
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          frequency of auditory auras (71% vs 57%)
        explanation: >-
          The measured frequency of the auditory aura, 71 percent in
          RELN-mutated and 57 percent in LGI1-mutated families. Both figures fall
          in the 30 to 79 percent band, which maps to FREQUENT rather than
          VERY_FREQUENT.
      - reference: PMID:20301709
        reference_title: Autosomal Dominant Epilepsy with Auditory Features.
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          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).
        explanation: >-
          The GeneReviews description of the character of the auditory aura,
          including the simple-versus-complex distinction. It supports what the
          aura is like, not how many patients have one; the frequency band is
          carried by the cohort figures above.
  - name: Ictal Receptive Aphasia
    category: Neurologic
    description: >-
      A sudden inability to understand language, occurring without general
      confusion. This is the alternative defining manifestation to the auditory
      aura and reflects seizure onset in or near language cortex. Its
      preservation of general awareness is what distinguishes it from a
      confusional state.
    phenotype_term:
      preferred_term: Focal cognitive seizure with receptive dysphasia/aphasia
      term:
        id: HP:0032696
        label: Focal cognitive seizure with receptive dysphasia/aphasia
    evidence:
      - reference: PMID:20301709
        reference_title: Autosomal Dominant Epilepsy with Auditory Features.
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          Ictal receptive aphasia consists of a sudden onset of inability to
          understand language in the absence of general confusion.
        explanation: >-
          Defines the ictal receptive aphasia phenotype, including the absence of
          general confusion that distinguishes it.
  - name: Auditory Hallucination
    category: Neurologic
    description: >-
      The complex end of the auditory aura spectrum, in which patients hear
      specific songs or voices rather than unformed noise. Recorded separately
      from the simple auditory aura because the complex percept can be
      misattributed to a primary psychiatric disorder.
    phenotype_term:
      preferred_term: Auditory hallucination
      term:
        id: HP:0008765
        label: Auditory hallucination
    frequency: OCCASIONAL
    evidence:
      - reference: PMID:20301709
        reference_title: Autosomal Dominant Epilepsy with Auditory Features.
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          less common forms are distortions (e.g., volume changes) or complex
          sounds (e.g., specific songs or voices)
        explanation: >-
          Documents complex auditory percepts as a less common form of the aura.
          The qualitative phrase "less common" maps to OCCASIONAL.
  - name: Focal to Bilateral Tonic-Clonic Seizures
    category: Neurologic
    description: >-
      Despite the syndrome's benign reputation, tonic-clonic seizures are
      reported by nearly all patients, usually preceded by the typical aura. They
      are, in practice, what brings people to attention, since a brief auditory
      aura on its own is easy to dismiss or to misattribute.
    phenotype_term:
      preferred_term: Bilateral tonic-clonic seizure with focal onset
      term:
        id: HP:0007334
        label: Bilateral tonic-clonic seizure with focal onset
    frequency: VERY_FREQUENT
    evidence:
      - reference: PMID:28142128
        reference_title: >-
          The clinical phenotype of autosomal dominant lateral temporal lobe
          epilepsy related to reelin mutations.
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Tonic-clonic seizures were reported by almost all patients (88%),
          preceded by typical aura in 67% of cases.
        explanation: >-
          Quantifies tonic-clonic seizures at 88 percent in RELN-mutated ADLTE
          families, which falls in the 80 to 100 percent band mapping to
          VERY_FREQUENT. The same study found no significant phenotypic
          difference from LGI1-mutated families apart from EEG lateralization, so
          the figure is taken as applying to the syndrome rather than to the RELN
          subset alone.
      - reference: PMID:28142128
        reference_title: >-
          The clinical phenotype of autosomal dominant lateral temporal lobe
          epilepsy related to reelin mutations.
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          By comparing these findings with those observed in families with LGI1
          mutations, we did not observe significant differences except for a
          higher rate of left-sided EEG abnormalities in the RELN group.
        explanation: >-
          Justifies generalizing the RELN-cohort frequencies to the syndrome, by
          establishing that the RELN and LGI1 phenotypes are otherwise
          indistinguishable.
  - name: Interictal EEG Abnormality
    category: Neurologic
    description: >-
      Interictal epileptiform abnormalities or focal slow waves over the temporal
      regions are present in roughly 60 to 80 percent of patients depending on
      genotype. This matters because MRI is normal by definition, so the EEG is
      the only investigation that positively supports the diagnosis.

      The genotype split is important and cuts against generalizing here. EEG is
      the one feature on which RELN-mutated and LGI1-mutated families
      demonstrably differ: normal recordings in 20 percent of the RELN group
      against 42 percent of the LGI1 group, implying roughly 80 percent versus
      roughly 58 percent abnormal, with marked left temporal predominance in RELN
      (53 percent) but not LGI1 (22 percent). Since this entry's pathograph is
      LGI1-scoped, the lower figure is the applicable one and the frequency band
      is set accordingly.
    phenotype_term:
      preferred_term: EEG abnormality
      term:
        id: HP:0002353
        label: EEG abnormality
    frequency: FREQUENT
    evidence:
      - reference: PMID:28142128
        reference_title: >-
          The clinical phenotype of autosomal dominant lateral temporal lobe
          epilepsy related to reelin mutations.
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          The interictal EEG recordings showed epileptiform abnormalities or
          focal slow waves in 80% of patients, localized over the temporal
          regions, with marked left predominance and conventional 1,5T MRI scans
          were not contributory.
        explanation: >-
          Quantifies interictal EEG abnormality in the RELN-mutated cohort at 80
          percent, and confirms in the same sentence that conventional MRI adds
          nothing. The 80 percent is a subgroup figure; see the item below for
          the LGI1 comparison that sets the frequency band used here.
      - reference: PMID:28142128
        reference_title: >-
          The clinical phenotype of autosomal dominant lateral temporal lobe
          epilepsy related to reelin mutations.
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          EEGs showed a lower rate of normal recordings and higher rate of left
          temporal abnormalities in RELN group compared to the LGI1 group (20 vs
          42% and 53 vs 22%, respectively)
        explanation: >-
          The genotype split that sets the band. Normal recordings in 42 percent
          of the LGI1 group implies roughly 58 percent abnormal, which is
          FREQUENT rather than VERY_FREQUENT, and left temporal predominance is a
          RELN feature (53 percent) rather than an LGI1 one (22 percent). Because
          this entry is LGI1-scoped, the LGI1 figures are the applicable ones.
          This is also the one axis on which the same paper reports the two
          genotypes differing, so it is precisely where its otherwise-valid
          generalization does not hold.
  - name: Other Focal Sensory and Autonomic Auras
    category: Neurologic
    description: >-
      A minority of seizures begin with visual, olfactory, vertiginous, or
      cephalic sensations, or with motor, psychic, or autonomic symptoms. Their
      presence does not exclude the syndrome.
    phenotype_term:
      preferred_term: Focal sensory seizure
      term:
        id: HP:0011157
        label: Focal sensory seizure
    frequency: OCCASIONAL
    evidence:
      - reference: PMID:20301709
        reference_title: Autosomal Dominant Epilepsy with Auditory Features.
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          Less commonly, other ictal symptoms may occur, including sensory
          symptoms (visual, olfactory, vertiginous, or cephalic) or motor,
          psychic, and autonomic symptoms.
        explanation: >-
          Enumerates the less common aura types. The qualifier "less commonly"
          maps to OCCASIONAL.
inheritance:
  - name: Autosomal dominant with incomplete penetrance
    description: >-
      ADEAF is autosomal dominant by definition of the syndrome. Most affected
      individuals have an affected parent and de novo variants are believed to be
      uncommon. Penetrance is incomplete, which materially changes counselling:
      a child of an affected parent has a 50 percent chance of inheriting the
      variant but a lower chance of ever manifesting seizures, estimated between
      54 and 85 percent of carriers depending on the penetrance assumed.
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    penetrance: INCOMPLETE
    evidence:
      - reference: PMID:20301709
        reference_title: Autosomal Dominant Epilepsy with Auditory Features.
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          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.
        explanation: >-
          Gives both the transmission probability and the penetrance range, which
          together are the counselling content of this block.
      - reference: PMID:20301709
        reference_title: Autosomal Dominant Epilepsy with Auditory Features.
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          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.
        explanation: >-
          Establishes the familial transmission pattern and the low de novo rate.
genetic:
  - name: LGI1
    gene_term:
      preferred_term: LGI1
      term:
        id: hgnc:6572
        label: LGI1
    relationship_type: CAUSATIVE
    variant_origin: GERMLINE
    notes: >-
      LGI1 encodes leucine-rich glioma-inactivated 1, a secreted neuronal protein
      and the principal known cause of ADEAF. Pathogenic variants act by loss of
      function through either impaired secretion or impaired receptor binding.
      Yield depends heavily on how the phenotype is ascertained: in a broad
      epilepsy-with-auditory-features cohort that was mostly sporadic, LGI1
      accounted for only 2.7 percent of cases, whereas it is the leading cause in
      genuinely autosomal dominant families.
    evidence:
      - reference: PMID:20301709
        reference_title: Autosomal Dominant Epilepsy with Auditory Features.
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          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.
        explanation: >-
          Names LGI1 as an established molecular cause of ADEAF, alongside MICAL1
          and RELN.
      - reference: PMID:33453592
        reference_title: >-
          Epilepsy with auditory features: Contribution of known genes in 112
          patients.
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          We identified a genetic diagnosis for 8% of our cohort, including
          pathogenic/likely pathogenic variants (4/8 novel) in LGI1 (2.7%, CI:
          0.6-7.6); RELN (1.8%; CI: 0.2-6.3); SCN1A (2.7%; CI: 0.6-7.6) and
          DEPDC5 (0.9%; CI 0-4.9).
        explanation: >-
          Quantifies LGI1 yield in a broad, largely sporadic cohort. Marked
          PARTIAL because that cohort is not restricted to autosomal dominant
          families, so the figure understates the yield in ADEAF proper.
      - reference: PMID:18711109
        reference_title: >-
          Penetrance of LGI1 mutations in autosomal dominant partial epilepsy
          with auditory features.
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Mutations in the leucine-rich, glioma inactivated 1 gene (LGI1) have
          been identified in about 50% of families with autosomal dominant
          partial epilepsy with auditory features (ADPEAF)
        explanation: >-
          The family-restricted LGI1 yield, roughly 50 percent, which is the
          figure that actually applies to ADEAF. Placing it beside the 2.7
          percent sporadic-cohort figure makes the ascertainment effect explicit
          rather than leaving a reader to reconcile two numbers that differ
          nearly twenty-fold.
      - reference: PMID:18711109
        reference_title: >-
          Penetrance of LGI1 mutations in autosomal dominant partial epilepsy
          with auditory features.
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Overall penetrance was 67% (95% CI 55-77%), and did not vary according
          to mutation type or location within the gene.
        explanation: >-
          The pooled penetrance estimate across all 24 published LGI1-mutated
          ADPEAF families, and the negative finding that penetrance is
          independent of mutation type and position. The latter matters for the
          model: it means the secretion-defective and secretion-competent variant
          classes, despite differing molecularly, do not differ in how reliably
          they cause disease.
  - name: RELN
    gene_term:
      preferred_term: RELN
      term:
        id: hgnc:9957
        label: RELN
    relationship_type: CAUSATIVE
    variant_origin: GERMLINE
    notes: >-
      RELN encodes reelin, a large secreted glycoprotein governing neuronal
      migration and, in the mature brain, synaptic function. It is an established
      but less common cause of ADEAF. That the second cause is also a secreted
      extracellular signalling protein is a striking parallel with LGI1.
    evidence:
      - reference: PMID:33453592
        reference_title: >-
          Epilepsy with auditory features: Contribution of known genes in 112
          patients.
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          LGI1 and RELN have been identified as the main cause of Autosomal
          Dominant EAF and anecdotally reported in non-familial cases.
        explanation: >-
          Names RELN alongside LGI1 as a main cause of the autosomal dominant form
          specifically.
  - name: MICAL1
    gene_term:
      preferred_term: MICAL1
      term:
        id: hgnc:20619
        label: MICAL1
    relationship_type: CAUSATIVE
    variant_origin: GERMLINE
    notes: >-
      MICAL1 is the third gene recognized in the current GeneReviews molecular
      diagnostic criteria for ADEAF. It is rarer than LGI1 and RELN.
    evidence:
      - reference: PMID:20301709
        reference_title: Autosomal Dominant Epilepsy with Auditory Features.
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          a heterozygous pathogenic variant in LGI1, MICAL1, or RELN identified by
          molecular genetic testing
        explanation: >-
          Establishes MICAL1 as one of the three genes in which a pathogenic
          variant establishes the molecular diagnosis.
  - name: SCN1A
    gene_term:
      preferred_term: SCN1A
      term:
        id: hgnc:10585
        label: SCN1A
    relationship_type: SUSCEPTIBILITY
    variant_origin: GERMLINE
    notes: >-
      SCN1A variants have been found in probands presenting with auditory
      features, in families with heterogeneous phenotypes and incomplete
      penetrance. Recorded as a susceptibility contributor rather than a
      causative ADEAF gene, because the associated families do not breed true for
      the auditory phenotype and SCN1A is better understood as a broad-spectrum
      epilepsy gene.
    evidence:
      - reference: PMID:33453592
        reference_title: >-
          Epilepsy with auditory features: Contribution of known genes in 112
          patients.
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Pathogenic variants in SCN1A and DEPDC5 have also been described in a
          few EAF probands belonging to families with heterogeneous phenotypes
          and incomplete penetrance.
        explanation: >-
          Supports the association while explicitly noting the phenotypic
          heterogeneity that justifies the weaker SUSCEPTIBILITY typing here.
diagnosis:
  - name: Molecular genetic testing
    description: >-
      A heterozygous pathogenic variant in LGI1, MICAL1, or RELN establishes the
      molecular diagnosis in a proband with characteristic features. A negative
      result does not exclude the syndrome, since most families remain
      genetically unexplained, and the clinical diagnosis can stand on phenotype,
      normal MRI, and a consistent family history.
    diagnosis_term:
      preferred_term: Molecular Analysis
      term:
        id: NCIT:C19770
        label: Molecular Analysis
    results: >-
      A heterozygous pathogenic variant in LGI1, MICAL1, or RELN confirms the
      molecular diagnosis; a negative panel is uninformative.
    evidence:
      - reference: PMID:20301709
        reference_title: Autosomal Dominant Epilepsy with Auditory Features.
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          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.
        explanation: >-
          States the molecular diagnostic criterion and the three genes it rests
          on.
  - name: Electroencephalography
    description: >-
      Because MRI is normal by definition, EEG is the only investigation that
      returns a positive finding. Interictal epileptiform abnormalities or focal
      slow waves appear over the temporal regions in roughly 60 to 80 percent of
      patients, the higher figure coming from RELN-mutated families and the lower
      from LGI1-mutated ones. Marked left temporal predominance is a feature of
      the RELN group specifically and should not be expected in LGI1 families. A
      normal EEG does not exclude the diagnosis, which rests on semiology, normal
      imaging, and family history.
    diagnosis_term:
      preferred_term: Electroencephalography
      term:
        id: NCIT:C38054
        label: Electroencephalography
    results: >-
      Temporal epileptiform abnormalities or focal slow waves in roughly 60 to 80
      percent of patients depending on genotype; left-predominant in RELN
      families.
    evidence:
      - reference: PMID:28142128
        reference_title: >-
          The clinical phenotype of autosomal dominant lateral temporal lobe
          epilepsy related to reelin mutations.
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          The interictal EEG recordings showed epileptiform abnormalities or
          focal slow waves in 80% of patients, localized over the temporal
          regions, with marked left predominance and conventional 1,5T MRI scans
          were not contributory.
        explanation: >-
          Quantifies the EEG yield and its localization, and in the same sentence
          confirms that conventional MRI contributes nothing, which is why EEG is
          the diagnostic workhorse here.
  - name: Brain MRI
    description: >-
      MRI is normal in ADEAF and is performed to exclude a structural lesion
      rather than to demonstrate one. A visible lateral temporal lesion should
      redirect the diagnosis toward a structural focal epilepsy.
    diagnosis_term:
      preferred_term: Magnetic Resonance Imaging
      term:
        id: NCIT:C16809
        label: Magnetic Resonance Imaging
    results: Normal brain imaging.
    evidence:
      - reference: PMID:20301709
        reference_title: Autosomal Dominant Epilepsy with Auditory Features.
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          normal brain imaging by MRI, and family history consistent with
          autosomal dominant inheritance
        explanation: >-
          Establishes normal MRI as part of the clinical diagnostic criteria.
progression:
  - phase: Onset in adolescence or early adulthood
    age_range: 10 to 30 years
    notes: >-
      Onset is later than in most genetic focal epilepsies, typically between
      ages 10 and 30, with normal development beforehand.
    evidence:
      - reference: PMID:20301709
        reference_title: Autosomal Dominant Epilepsy with Auditory Features.
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          Age at onset is usually in adolescence or early adulthood (age 10-30
          years).
        explanation: >-
          Gives the characteristic age-at-onset window for the syndrome.
  - phase: Benign medication-responsive course
    age_range: Adulthood
    notes: >-
      Unlike most focal epilepsies, ADEAF is benign in the sense that matters
      most: seizures are usually well controlled once treatment starts, and the
      syndrome does not carry the drug-resistance burden of structural focal
      epilepsy. Surveillance is directed at cognitive and psychiatric comorbidity
      rather than at seizure escalation.

      "Benign" should not be read as "remitting", however. In a long-term cohort
      of 123 patients with epilepsy with auditory features followed for a median
      of 11 years, only 34.1 percent reached terminal remission, defined as five
      or more consecutive seizure-free years at last follow-up. Good control on
      medication and freedom from seizures off medication are different
      outcomes, and this syndrome delivers the first far more reliably than the
      second.
    evidence:
      - reference: PMID:29464704
        reference_title: >-
          Epilepsy with auditory features: Long-term outcome and predictors of
          terminal remission.
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          At last assessment, 42 patients had achieved TR (34.1%).
        explanation: >-
          The counterweight to the GeneReviews benign framing: only about a third
          of patients reach terminal remission. Marked PARTIAL because the cohort
          is epilepsy with auditory features broadly, 68.3 percent sporadic
          rather than familial, so it bounds rather than measures the ADEAF
          outcome.
      - reference: PMID:20301709
        reference_title: Autosomal Dominant Epilepsy with Auditory Features.
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          Seizure control is usually readily achieved with standard anti-seizure
          medications (ASM).
        explanation: >-
          States the benign, treatment-responsive course that defines this phase.
      - reference: PMID:20301709
        reference_title: Autosomal Dominant Epilepsy with Auditory Features.
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          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.
        explanation: >-
          Documents that surveillance is directed at cognitive and psychiatric
          comorbidity, supporting the characterization of this phase.
treatments:
  - name: Standard Antiseizure Medication
    description: >-
      Seizure control is usually readily achieved with standard antiseizure
      medications. No agent is specific to ADEAF and none targets the LGI1
      mechanism; treatment is conventional focal-epilepsy pharmacotherapy. For
      women of childbearing potential, GeneReviews advises that the risks and
      benefits of a given medication in pregnancy be discussed before conception,
      and that transitioning to a lower-risk medication beforehand may be
      possible. Carbamazepine is named as the representative agent because it is
      the conventional first choice for focal seizures; this is a class
      representative rather than an ADEAF-specific indication, since no agent has
      been trialled against this syndrome in particular.
    therapeutic_modality: SMALL_MOLECULE
    treatment_term:
      preferred_term: Pharmacotherapy
      term:
        id: NCIT:C15986
        label: Pharmacotherapy
      therapeutic_agent:
        - preferred_term: carbamazepine
          term:
            id: CHEBI:3387
            label: carbamazepine
    target_mechanisms:
      - target: Focal Seizures with Auditory Features
        treatment_effect: INHIBITS
        description: >-
          Symptomatic seizure suppression at the terminal phenotype. The edge
          deliberately targets the seizure node rather than any upstream
          molecular node, because no available drug acts on the LGI1 complex.
    evidence:
      - reference: PMID:20301709
        reference_title: Autosomal Dominant Epilepsy with Auditory Features.
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          Treatment of manifestations: Seizure control is usually readily
          achieved with standard anti-seizure medications (ASM).
        explanation: >-
          The GeneReviews management recommendation, establishing conventional
          antiseizure medication as effective treatment.
      - reference: PMID:20301709
        reference_title: Autosomal Dominant Epilepsy with Auditory Features.
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          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.
        explanation: >-
          The pregnancy-management guidance from GeneReviews, captured here
          because it is the one drug-safety consideration the source raises.
  - name: 4-Phenylbutyrate (Investigational Chemical Chaperone)
    description: >-
      Not a clinical treatment. In a mouse model carrying a secretion-defective
      LGI1 variant, the chemical chaperone 4-phenylbutyrate restored protein
      folding and ADAM22 binding and reduced seizure susceptibility. It is
      recorded here because it is the only intervention that addresses the
      molecular mechanism rather than the seizures, and because it demonstrates
      the practical consequence of the two-class variant division: a corrector
      should help secretion-defective variants and would not be expected to help
      secretion-competent, binding-defective ones. No human data exist.
    therapeutic_modality: SMALL_MOLECULE
    treatment_term:
      preferred_term: Pharmacotherapy
      term:
        id: NCIT:C15986
        label: Pharmacotherapy
      therapeutic_agent:
        - preferred_term: 4-phenylbutyric acid
          term:
            id: CHEBI:41500
            label: 4-phenylbutyric acid
    target_mechanisms:
      - target: LGI1 Loss of Function
        treatment_effect: RESTORES
        description: >-
          Restores folding and receptor binding of a secretion-defective LGI1
          variant, acting on the proximal molecular defect rather than on seizure
          threshold.
    evidence:
      - reference: PMID:25485908
        reference_title: >-
          Chemical corrector treatment ameliorates increased seizure
          susceptibility in a mouse model of familial epilepsy.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          A chemical corrector, 4-phenylbutyrate (4PBA), restored LGI1(E383A)
          folding and binding to ADAM22 and ameliorated the increased seizure
          susceptibility of the LGI1(E383A) model mice.
        explanation: >-
          Demonstrates mechanism-directed rescue in a model of the
          secretion-defective variant class. Model-organism evidence only; no
          human trial supports this use.
      - reference: PMID:25485908
        reference_title: >-
          Chemical corrector treatment ameliorates increased seizure
          susceptibility in a mouse model of familial epilepsy.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          This study establishes LGI1-related epilepsy as a conformational
          disease and suggests new therapeutic options for human epilepsy.
        explanation: >-
          The authors' own framing. Marked PARTIAL because "suggests new
          therapeutic options" is a proposal, not a demonstration of human
          benefit.
differential_diagnoses:
  - name: Anti-LGI1 Autoimmune Encephalitis
    description: >-
      Involves the same protein but is a different disease entirely: an acquired
      autoantibody-mediated limbic encephalitis with severe though treatable
      memory impairment and frequent faciobrachial dystonic seizures, typically
      in older adults. The contrast between losing LGI1 from birth and having it
      attacked in adulthood is recorded as a discussion.
    distinguishing_features:
      - Acquired in adulthood rather than lifelong and familial.
      - Serum or CSF antibodies against LGI1.
      - Prominent amnesia and faciobrachial dystonic seizures rather than auditory auras.
      - Responds to immunotherapy.
    evidence:
      - reference: PMID:30346486
        reference_title: >-
          LGI1 antibodies alter Kv1.1 and AMPA receptors changing synaptic
          excitability, plasticity and memory.
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          Human autoantibodies against LGI1 associate with a form of autoimmune
          limbic encephalitis characterized by severe but treatable memory
          impairment and frequent faciobrachial dystonic seizures.
        explanation: >-
          Describes the autoimmune syndrome and its distinguishing features, which
          is what separates it from the inherited disorder modelled here.
  - name: Sporadic Epilepsy with Auditory Features
    description: >-
      The same seizure semiology without a family history. It is not so much a
      distinct biological entity as the residue left when the autosomal dominant
      criterion is not met, and it matters here because genetic yield is much
      lower in this group, which is why cohort-derived gene frequencies should not
      be read as ADEAF yields.
    distinguishing_features:
      - No family history of epilepsy with auditory features.
      - Substantially lower yield from genetic testing.
    evidence:
      - reference: PMID:33453592
        reference_title: >-
          Epilepsy with auditory features: Contribution of known genes in 112
          patients.
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          We included 112 unrelated EAF cases (male/female: 52/60) who underwent
          genetic analysis by next-generation sequencing (NGS) techniques.
          Thirty-three (29.5%) were familial cases.
        explanation: >-
          Documents that the large auditory-features cohort was predominantly
          non-familial, which is the ascertainment point this differential makes.
  - name: Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis
    description: >-
      The other temporal lobe epilepsy, and the one ADEAF is most often mistaken
      for. It arises mesially rather than laterally, produces epigastric rising
      sensations, fear, and deja vu rather than auditory auras, shows hippocampal
      sclerosis on MRI, and is frequently drug-resistant. dismech carries a
      separate entry.
    distinguishing_features:
      - Mesial rather than lateral temporal onset.
      - Epigastric, psychic, and olfactory auras rather than auditory ones.
      - Hippocampal sclerosis visible on MRI, whereas ADEAF imaging is normal.
      - Frequently drug-resistant, whereas ADEAF is typically well controlled.
discussions:
  - discussion_id: adeaf_genetic_yield_gap
    kind: KNOWLEDGE_GAP
    status: OPEN
    prompt: >-
      Only a minority of epilepsy-with-auditory-features cases have an
      identifiable causative variant in any known gene. What accounts for the
      rest, and does the residue represent unfound genes, non-coding variation,
      or a phenotype definition that is grouping unrelated things?
    attaches_to:
      - pathophysiology#LGI1 Loss of Function
    rationale: >-
      In the largest cohort assembled for this phenotype, 112 unrelated cases,
      only 8 percent received any genetic diagnosis: LGI1 2.7 percent, SCN1A 2.7
      percent, RELN 1.8 percent, DEPDC5 0.9 percent. That is a striking result
      for a syndrome whose name asserts a dominant inheritance pattern. Part of
      the explanation is ascertainment, since fewer than a third of that cohort
      were familial and LGI1 yield is considerably higher in genuinely autosomal
      dominant pedigrees; this entry labels the figure accordingly rather than
      quoting it as the ADEAF yield. But even restricting to dominant families
      leaves most of them unexplained. Three possibilities compete. There may
      simply be further genes to find, which is the conventional reading and is
      supported by the fact that MICAL1 and RELN were both added relatively
      recently. There may be non-coding or structural variation in or around LGI1
      itself that standard panels miss, which would leave LGI1 the dominant
      biological story even where sequencing is negative. Or the auditory
      phenotype may be a final common presentation of several unrelated lateral
      temporal pathologies, in which case the syndrome is a semiological grouping
      rather than a genetic entity. The distinction matters for whether a negative
      panel should end the diagnostic workup.
    proposed_experiments:
      - experiment_id: exp_adeaf_family_restricted_genome_sequencing
        name: Genome sequencing restricted to autosomal dominant ADEAF pedigrees
        description: >-
          Whole-genome sequencing with structural and non-coding variant calling
          in multiplex families meeting strict autosomal dominant ADEAF criteria,
          rather than in mixed cohorts, with linkage or segregation analysis where
          pedigree structure permits.
        decision_criterion: >-
          Recovery of causative variants in most strictly-defined families would
          establish the gap as a detection and ascertainment artefact; persistent
          negativity would support genetic heterogeneity beyond the known genes.
      - experiment_id: exp_adeaf_lgi1_regulatory_variation
        name: Search for regulatory variation at the LGI1 locus
        description: >-
          Targeted assessment of non-coding and structural variation at and around
          LGI1 in sequencing-negative ADEAF families, paired where tissue or
          iPSC-derived neurons are available with a measurement of LGI1 secretion.
        decision_criterion: >-
          Reduced LGI1 secretion in sequencing-negative cases would keep the
          single-mechanism model intact and redirect testing toward the regulatory
          region rather than toward new genes.
    evidence:
      - reference: PMID:33453592
        reference_title: >-
          Epilepsy with auditory features: Contribution of known genes in 112
          patients.
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          This study shows that the contribution of each of the known genes to
          the overall disorder is limited and that the genetic background of EAF
          is still largely unknown.
        explanation: >-
          The authors' own statement of the gap, from the largest cohort assembled
          for this phenotype.
      - reference: PMID:33453592
        reference_title: >-
          Epilepsy with auditory features: Contribution of known genes in 112
          patients.
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          We identified a genetic diagnosis for 8% of our cohort, including
          pathogenic/likely pathogenic variants (4/8 novel) in LGI1 (2.7%, CI:
          0.6-7.6); RELN (1.8%; CI: 0.2-6.3); SCN1A (2.7%; CI: 0.6-7.6) and
          DEPDC5 (0.9%; CI 0-4.9).
        explanation: >-
          Quantifies the gap gene by gene, which is what makes it specific rather
          than a general complaint about missing heritability.
      - reference: PMID:20301709
        reference_title: Autosomal Dominant Epilepsy with Auditory Features.
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          a heterozygous pathogenic variant in LGI1, MICAL1, or RELN identified by
          molecular genetic testing
        explanation: >-
          The current authoritative gene list. PARTIAL because it defines what
          counts as a molecular diagnosis without stating what fraction of
          patients achieve one.
  - discussion_id: adeaf_heterozygous_mouse_does_not_seize
    kind: HUMAN_MODEL_MISMATCH
    status: OPEN
    prompt: >-
      Heterozygous Lgi1 mice do not develop seizures, whereas heterozygous humans
      develop ADEAF. Does that gene-dosage discrepancy mean the mouse is the
      wrong model, or that human ADEAF requires something beyond simple
      haploinsufficiency?
    attaches_to:
      - pathophysiology#LGI1 Loss of Function
      - pathophysiology#Dysregulated AMPA Receptor Clustering and Synaptic Excitability
    rationale: >-
      The mismatch is clean and quantitative. In the Lgi1 null mouse, homozygotes
      develop myoclonic seizures from around 12 to 18 days of age and die shortly
      afterward, while heterozygotes do not develop seizures at all. Human ADEAF
      is a heterozygous disorder in every reported family. So the mouse
      reproduces the biology only at a gene dosage that has no human counterpart,
      and at that dosage it produces a lethal early myoclonic phenotype rather
      than a benign adolescent-onset focal auditory epilepsy. Several readings
      are available and they have different consequences. Human penetrance is
      incomplete, between 54 and 85 percent, which already tells us
      haploinsufficiency alone is insufficient in humans too, so the mouse may
      simply lack whatever second factor the unpenetrant human carriers also
      lack. Alternatively, mouse and human may differ in reserve, with mice
      tolerating half-normal LGI1 where humans cannot. A third possibility is
      that many human variants act as more than simple nulls, given that one of
      the two described classes is secreted but functionally inert and could in
      principle interfere with the complex rather than merely be absent from it.
      The knockout, which removes protein entirely, cannot model that. This
      matters because the model used to test a therapy determines what the
      therapy is optimized against.
    proposed_experiments:
      - experiment_id: exp_adeaf_knockin_heterozygous_human_variants
        name: Heterozygous knock-in of human ADEAF variants from both classes
        description: >-
          Generate and phenotype heterozygous knock-in mice carrying human
          secretion-defective and secretion-competent binding-defective LGI1
          variants, rather than a null allele, with long-term video-EEG through
          the mouse equivalent of adolescence.
        decision_criterion: >-
          Seizures in heterozygous knock-ins but not in heterozygous nulls would
          show that human variants are not simple haploinsufficiency and would
          make the knockout the wrong model; absence of seizures in both would
          point to a species difference in reserve.
      - experiment_id: exp_adeaf_penetrance_modifier_search
        name: Search for modifiers distinguishing penetrant from non-penetrant carriers
        description: >-
          Compare genomes and, where accessible, LGI1 secretion in penetrant
          versus non-penetrant human carriers within the same pedigrees, to
          identify what the unaffected carriers have that the affected ones lack.
        decision_criterion: >-
          Identifying a reproducible modifier would explain both the human
          incomplete penetrance and, if conserved, the unaffected heterozygous
          mouse, unifying the two observations rather than treating the mouse as
          simply wrong.
    evidence:
      - reference: PMID:20130004
        reference_title: >-
          Lgi1 null mutant mice exhibit myoclonic seizures and CA1 neuronal
          hyperexcitability.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          The heterozygous mutant mice do not develop seizures.
        explanation: >-
          The core observation of this mismatch: the mouse genotype matching human
          ADEAF produces no epilepsy.
      - reference: PMID:20130004
        reference_title: >-
          Lgi1 null mutant mice exhibit myoclonic seizures and CA1 neuronal
          hyperexcitability.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          After 12-18 days of age, the homozygous mutant mice all exhibit
          myoclonic seizures accompanied by rapid jumping and running and die
          shortly thereafter.
        explanation: >-
          Shows that the dosage at which the mouse does seize produces a phenotype
          qualitatively unlike human ADEAF, which is the second half of the
          mismatch.
      - reference: PMID:20301709
        reference_title: Autosomal Dominant Epilepsy with Auditory Features.
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          the chance that offspring who inherit the pathogenic variant will
          manifest ADEAF ranges from 54% to 85% depending on the assumed
          penetrance
        explanation: >-
          Establishes that heterozygosity is insufficient in humans too, which is
          the observation that makes the modifier explanation plausible rather
          than ad hoc.
  - discussion_id: adeaf_genetic_versus_autoimmune_lgi1
    kind: OPEN_QUESTION
    status: OPEN
    prompt: >-
      Losing LGI1 through inherited loss of function produces a benign
      adolescent-onset focal epilepsy with auditory auras. Attacking the same
      protein with autoantibodies in adulthood produces a severe amnestic limbic
      encephalitis with faciobrachial dystonic seizures. Why do the two routes to
      LGI1 dysfunction give such different diseases?
    attaches_to:
      - pathophysiology#Disrupted LGI1-ADAM22 Trans-Synaptic Complex
      - pathophysiology#Lateral Temporal Cortical Hyperexcitability
    rationale: >-
      This is not a diagnostic confusion, since the two are easy to tell apart
      clinically. It is a mechanistic puzzle, and its answer would sharpen the
      model in this entry. Three explanations are candidates and they are not
      mutually exclusive. Timing: inherited loss is present throughout
      development, so the brain builds itself around the deficiency and can
      compensate, whereas an autoantibody removes a functioning protein abruptly
      from a mature circuit that has come to depend on it. That would predict
      developmental compensation as the reason the inherited form is benign.
      Completeness: a heterozygous variant leaves roughly half the normal protein,
      whereas antibodies can strip function more thoroughly, so the difference may
      be quantitative rather than qualitative. Mechanism specificity: antibodies
      target particular epitopes and can disrupt the ADAM22 arm and the
      ADAM23-Kv1.1 arm to different degrees, so the autoimmune lesion may not be
      equivalent to loss of the whole protein. The regional discrepancy is the
      sharpest part of the puzzle. Inherited loss localizes to lateral temporal
      auditory and language cortex; the autoimmune form targets limbic and
      basal-ganglia circuits. Neither this entry nor the source literature
      explains why a molecule present across the brain should produce
      region-specific disease at all, let alone different regions by different
      routes.
    proposed_experiments:
      - experiment_id: exp_lgi1_timing_of_loss_comparison
        name: Developmental versus adult-onset LGI1 loss in the same model
        description: >-
          Compare conditional Lgi1 deletion during development against inducible
          adult deletion in the same mouse line, phenotyping seizure semiology,
          affected circuits, and memory, to isolate timing from completeness of
          loss.
        decision_criterion: >-
          If adult-onset deletion reproduces the limbic and amnestic phenotype
          while developmental deletion does not, timing and developmental
          compensation are established as the dominant variable.
      - experiment_id: exp_lgi1_regional_dependency_mapping
        name: Map regional dependence on the LGI1-ADAM22 complex
        description: >-
          Quantify LGI1, ADAM22, and ADAM23 expression and the functional
          dependence of local excitability on the complex across lateral temporal,
          mesial temporal, and basal-ganglia circuits.
        decision_criterion: >-
          A regional gradient in dependence would explain the localization of the
          inherited syndrome; a uniform profile would mean the regional
          specificity must come from the nature of the insult rather than from the
          substrate.
    evidence:
      - reference: PMID:30346486
        reference_title: >-
          LGI1 antibodies alter Kv1.1 and AMPA receptors changing synaptic
          excitability, plasticity and memory.
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          Human autoantibodies against LGI1 associate with a form of autoimmune
          limbic encephalitis characterized by severe but treatable memory
          impairment and frequent faciobrachial dystonic seizures.
        explanation: >-
          Establishes the autoimmune phenotype that contrasts with the inherited
          one, which is the substance of this question.
      - reference: PMID:30346486
        reference_title: >-
          LGI1 antibodies alter Kv1.1 and AMPA receptors changing synaptic
          excitability, plasticity and memory.
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          Although there is evidence that this disease is immune-mediated, the
          underlying LGI1 antibody-mediated mechanisms are unknown.
        explanation: >-
          Confirms that the autoimmune mechanism was itself unresolved, which is
          part of why the comparison with the inherited disorder cannot yet be
          made rigorously.
      - reference: PMID:20301709
        reference_title: Autosomal Dominant Epilepsy with Auditory Features.
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          The clinical course of ADEAF is benign. Seizures are usually well
          controlled after initiation of medical therapy.
        explanation: >-
          The inherited-side half of the contrast: benign and treatable, against
          the severe amnestic autoimmune syndrome.
📚

References & Deep Research

References

2
PMID:20301709
Autosomal Dominant Epilepsy with Auditory Features.
No top-level findings curated for this source.
PMID:25485908
Chemical corrector treatment ameliorates increased seizure susceptibility in a mouse model of familial epilepsy.
No top-level findings curated for this source.

Deep Research

1
Claude Code ▸
Autosomal Dominant Epilepsy with Auditory Features (ADEAF) — Research Report
claude-haiku-4-5-20251001, claude-opus-5[1m] 29 citations 2026-08-05T01:03:55.566310

Autosomal Dominant Epilepsy with Auditory Features (ADEAF) — Research Report

Prepared: 2026-08-05 · Target MONDO: MONDO:0010898 · Category: Mendelian (focal epilepsy syndrome)

A note before diving in: the evidence base here is unusually clean-edged for a rare disease. One syndrome, one very characteristic aura, three genes that all converge — from three quite different directions — on the same secreted-protein-holds-the-synapse-together story. Where a claim comes from a GeneReviews table rather than a PubMed abstract, I flag it, because those sentences will not survive just validate-references and need re-quoting from the primary paper.

1. Disease Information

Overview

ADEAF is a familial focal (lateral temporal lobe) epilepsy in which the defining ictal event is a sound that isn't there — a buzz, a ring, a voice, a song — sometimes accompanied or replaced by a sudden inability to understand speech while the person is otherwise fully alert. Brains are structurally normal, development is normal, and most people do well on standard antiseizure medication. Onset is typically adolescence/early adulthood.

GeneReviews defines it as a focal epilepsy syndrome characterized by auditory symptoms and/or receptive aphasia as "prominent ictal manifestations," with normal brain development (Michelucci R, Pasini E, Nobile C, Ottman R. Autosomal Dominant Epilepsy with Auditory Features. GeneReviews®, NCBI Bookshelf NBK1537, PMID:20301709).

The 2022 ILAE nosology retains ADEAF as a named syndrome under "epilepsy syndromes with onset at a variable age" (Riney K et al., Epilepsia 2022;63:1443–1474, doi:10.1111/epi.17240). Recent literature increasingly uses the etiology-agnostic term epilepsy with auditory features (EAF) to cover sporadic and non-Mendelian cases: the name shift happened "to acknowledge this entity also in a non-familial context/pattern" (Furia A et al., Front Neurol 2022;12:807939, PMID:35153984).

Key identifiers

Resource Identifier
MONDO MONDO:0010898 — autosomal dominant epilepsy with auditory features
Orphanet ORPHA:101046
OMIM (LGI1) 600512 — EPILEPSY, FAMILIAL TEMPORAL LOBE, 1 (ETL1)
OMIM (RELN) 616436 — EPILEPSY, FAMILIAL TEMPORAL LOBE, 7 (ETL7)
OMIM (MICAL1) gene MIM 607129; no separate ETL phenotype number assigned — note ETL8 (616461) is GAL-related, not MICAL1 (verified via MedGen). Do not mis-map this.
MeSH C537297
MedGen 325326
UMLS C1838062
GARD 0002257
ICD-11 foundation id 832717248 (MONDO xref); classified under focal epilepsies (8A61.x)
ICD-10 no dedicated code; typically coded G40.2 / G40.1 (localization-related epilepsy) — approximation, verify before curating

MONDO parents: MONDO:0017704 familial partial epilepsy; MONDO:0800496 epilepsy with auditory features.

Synonyms (verbatim from the MONDO record)

ADEAF · ADLTE · ADPEAF · "autosomal dominant lateral temporal lobe epilepsy" · "autosomal dominant partial epilepsy with auditory features" · "partial epilepsy with auditory aura" · "partial epilepsy with auditory features" · "adolescent/adult onset autosomal dominant epilepsy with auditory features."

Level of evidence

Everything below is disease-level aggregated (family series, multi-center cohorts, registries, GeneReviews) plus mechanistic work in mice/cells. There is no EHR-derived individual-patient resource for ADEAF; the largest clinical series (Bisulli 2018, n=123) is a single-center tertiary referral cohort, which biases toward more severe/refractory cases.

2. Etiology

Causal factors

Monoallelic (heterozygous) pathogenic variants in one of three genes, all encoding secreted or secretion-dependent proteins rather than ion channels — which was the surprise in 2002:

"Most inherited forms of epilepsy result from mutations in ion channels. However, one form of epilepsy, autosomal dominant partial epilepsy with auditory features…" (Fukata Y et al., Science 2006;313:1792–5, PMID:16990550)

Gene HGNC Locus Protein Share of ADEAF families Mechanism
LGI1 hgnc:6572 10q23.33 Leucine-rich glioma inactivated 1 (epitempin) ~30% (Italian series); ~50% of large multigenerational pedigrees Loss of function / haploinsufficiency
RELN hgnc:9957 7q22.1 Reelin 7/40 = 17.5% Loss of function via impaired secretion
MICAL1 hgnc:20619 6q21 MICAL-1 monooxygenase 2 families (~5–7%) Gain of function (↑ oxidoreductase activity)
Unsolved — — — ~50% Unknown

Verbatim (Dazzo E et al., Am J Hum Genet 2015;96:992–1000, PMID:26046367):

"Overall, RELN mutations occurred in 7/40 (17.5%) ADLTE-affected families." "ADLTE is genetically heterogeneous, and mutations in LGI1 account for fewer than 50% of affected families."

Critical caveat on yield. Those family-based percentages are not the diagnostic yield in an unselected clinic population. In the largest genotyped EAF cohort (Bisulli F et al., Seizure 2021;85:115–118, PMID:33453592; 112 unrelated probands, 29.5% familial):

"We identified a genetic diagnosis for 8% of our cohort, including pathogenic/likely pathogenic variants (4/8 novel) in LGI1 (2.7%, CI: 0.6-7.6); RELN (1.8%; CI: 0.2-6.3); SCN1A (2.7%; CI: 0.6-7.6) and DEPDC5 (0.9%; CI 0-4.9)." "This study shows that the contribution of each of the known genes to the overall disorder is limited and that the genetic background of EAF is still largely unknown."

Secondary / emerging genes in EAF pedigrees (not classical ADEAF genes; phenotypically heterogeneous families): DEPDC5 (hgnc:18423), SCN1A (hgnc:10585), CNTNAP2 (hgnc:13830) — Pippucci T et al., Neurol Genet 2015;1:e5, PMID:27066544. And newly, KCNQ2 (hgnc:6296): a family segregating c.2251T>G presented with "epilepsy with auditory features (EAFs), focal epilepsy, and generalized epilepsy, and none of them suffered from neonatal seizures," leading the authors to "unveil… the prospect of its inclusion in screening panels for EAFs" (Talarico M et al., Int J Mol Sci 2024;26:295, PMID:39796146).

Risk factors

  • Genetic: carrying a heterozygous pathogenic LGI1/RELN/MICAL1 variant. Family history of epilepsy is the dominant risk descriptor. No validated common-variant susceptibility loci specific to ADEAF (no dedicated GWAS; the syndrome is too rare).
  • Environmental: none established as causing the disease. Sound is a seizure trigger, not a cause — reflex seizures precipitated by sudden noises (telephone, doorbell) in 8–13% of affected individuals (GeneReviews Table 2); "seizures were precipitated by environmental noises in 8% of patients" in RELN families (Michelucci R et al., Epilepsy Behav 2017;68:103–107, PMID:28142128).
  • Age/sex: no sex effect on penetrance — "Penetrance did not differ by gender" (Rosanoff MJ, Ottman R, Neurology 2008;71:567–71, PMID:18711109). Sex ratio in the largest EAF series was 58 M / 65 F (Bisulli 2018, PMID:29464704).

Protective factors

No genetic or environmental protective factors are documented. Not available for this disease. (Speculatively, residual protein secretion level is protective — see §4 dose-response — but that's a modifier of severity, not a population protective factor.)

Gene–environment interactions

The only well-described G×E is sound-triggered reflex seizure susceptibility in mutation carriers — an environmental stimulus (auditory input to a genetically hyperexcitable lateral temporal cortex) precipitating events. Sleep is a second permissive state: seizures "frequently occur during sleep" (Furia 2022, PMID:35153984). Beyond that: no data.

3. Phenotypes

Frequencies below are from GeneReviews Table 2 (ranges reflect different published series) unless a primary PMID is given. Note for curation: GeneReviews prose is not a PubMed abstract and will fail snippet validation — re-source each frequency from Ottman 2004 / Michelucci 2017 / Bisulli 2018 / Ho 2012 before writing evidence blocks.

Phenotype Frequency HPO term (all verified against local sqlite:obo:hp)
Focal sensory seizure with auditory features (aura) 57–71% overall; 80% in LRR-domain / missense carriers; 71% in RELN families (PMID:28142128) HP:0011158 Focal sensory seizure with auditory features
— aware variant — HP:0032864 Focal aware sensory seizure with auditory features
— with impaired awareness — HP:0032880 Focal impaired awareness sensory seizure with auditory features
Ictal receptive aphasia 17–20%; ~⅓ of RELN patients had aphasia among associated symptoms HP:0032696 Focal cognitive seizure with receptive dysphasia/aphasia; HP:0032710 (aware variant); HP:0033848 Receptive aphasia
Focal to bilateral tonic-clonic seizures 88–92%; 88% in RELN families, preceded by aura in 67% HP:0007334 Bilateral tonic-clonic seizure with focal onset
Focal aware / focal impaired awareness seizures near-universal accompaniment HP:0002349, HP:0002384
Reflex seizures triggered by sudden sound 8–13% (8% in RELN families) HP:0020207 Reflex seizure — ontology gap: HPO has HP:0020214 Startle-induced and HP:0032896 Music-induced, but no generic sound-induced seizure term. Worth an HPO term request.
Visual ictal symptoms minority HP:0011165 Focal sensory seizure with visual features
Olfactory ictal symptoms minority HP:0011161
Vertiginous symptoms minority HP:0002321 Vertigo
Déjà vu / psychic symptoms less common (helps separate from mesial TLE) HP:0032704 Focal aware cognitive seizure with illusion (verify fit)
Autonomic symptoms less frequent in mutation-positive families (PMID:15079011) HP:0011154 Focal autonomic seizure
Interictal epileptiform EEG abnormality 57–80%; 80% in RELN families, temporal, left-predominant HP:0011182 Interictal epileptiform activity; HP:0002353 EEG abnormality
Normal brain MRI typical/mandatory no HP term (absence of finding) — record as a diagnostic criterion, not a phenotype

Winawer's phenotype-defining paper is the cleanest primary quote for the aura spectrum (Winawer MR et al., Neurology 2000;54:2173–6, PMID:10851389):

"Auditory hallucinations were most common, but other sensory symptoms (visual, olfactory, vertiginous, and cephalic) were also reported. Autonomic, psychic, and motor symptoms were less common. The clinical semiology points to a lateral temporal seizure origin."

Auditory quality (Ottman R et al., Neurology 2004;62:1120–6, PMID:15079011):

"In families with mutations, the most common auditory symptom type was simple, unformed sounds (e.g., buzzing and ringing)."

Simple (humming/buzzing/ringing, tinnitus-like) vs complex (voices, music, specific songs) vs distortions (volume change) vs negative (sudden disappearance of ambient sound) — the simple/complex/distortion split matters prognostically (§11).

Phenotype characteristics

  • Onset: adolescence/early adulthood, "age 10–30 years" typical, reported range 4–50 years (GeneReviews). Mean onset 20 years in RELN families (PMID:28142128).
  • Severity: mild-to-moderate in most; a minority is refractory. Highly variable even within a family.
  • Progression: episodic/non-progressive. No neurodegeneration, no intellectual decline (moderate/severe ID is an ILAE exclusion criterion).
  • Frequency of events: FBTCS often only once or twice a year; auras can be much more frequent.
  • Quality of life: no ADEAF-specific EQ-5D/SF-36/PROMIS study exists. Not available. Real-world impact is driven by driving restrictions, FBTCS unpredictability, and the socially isolating weirdness of auditory auras (often misread as psychiatric). Behavioral problems, depression with suicide attempts, and migraine have been reported in isolated pedigrees, but systematic study attributed depression to epilepsy/medication rather than shared genetic susceptibility (GeneReviews).

4. Genetic / Molecular Information

LGI1 (hgnc:6572, 10q23.33; protein O95970, "epitempin")

Discovery (Kalachikov S et al., Nat Genet 2002;30:335–41, PMID:11810107):

"Here we describe identification of the causative gene in autosomal-dominant partial epilepsy with auditory features (ADPEAF, MIM 600512), a rare form of idiopathic lateral temporal lobe epilepsy characterized by partial seizures with auditory disturbances." "…identifying presumptive mutations in one copy of the leucine-rich, glioma-inactivated 1 gene (LGI1) in each of five families with ADPEAF."

Prior linkage: 10q22-24 / 10q24 (Winawer MR et al., Epilepsia 2002;43:60–7, PMID:11879388 — "maximum multipoint LOD score of 2.93").

  • Variant types: >40 reported pathogenic variants; roughly ⅓ truncating (nonsense/frameshift/splice → NMD), the rest missense. Sequence analysis detects ~95%; exon-level del/dup ~5% (GeneReviews).
  • Domain architecture & clustering: N-terminal leucine-rich repeat (LRR) domain + C-terminal EPTP/epitempin seven-bladed β-propeller. Mutations cluster in the LRR (Ho YY, Ionita-Laza I, Ottman R, Neurology 2012;78:563–8, PMID:22323750): "ADPEAF-causing mutations clustered significantly in the LRR domain (exons 3-5) of LGI1 (p = 0.026)."
  • Functional consequence: loss of function. Two flavors — secretion-defective (majority; misfolded protein retained and degraded by ER quality control) and secretion-positive but binding-defective (e.g. S473L, R474Q, E383A) which reach the extracellular space but fail to engage ADAM22/23.
  • Constraint (gnomAD API, GRCh38): pLI ≈ 1.000, observed/expected LoF = 0.190 (11 observed vs 57.7 expected), LOEUF = 0.315, missense Z = 3.98. Textbook haploinsufficiency signature.
  • Somatic vs germline: germline. (Biallelic somatic LGI1 loss is a glioma phenomenon — "loss of both copies of LGI1 promotes glial tumor progression," PMID:11810107 — but that is a separate, tumor-suppressor context and should not be conflated with ADEAF.)
  • De novo: ~1% of ADEAF (GeneReviews); a de novo LGI1 variant was found in a Turkish LTLE-with-auditory-aura cohort (PMID:26773249).

Allelic spectrum extension (2025, important and new). Biallelic LGI1 variants cause a far more severe disease (Hirano Y et al., Brain 2025;148:3514–3522, PMID:40455867, doi:10.1093/brain/awaf202):

"Monoallelic pathogenic variants in LGI1 cause autosomal dominant epilepsy with auditory features with onset in childhood/adolescence." "Affected individuals presented DEE with neonatal/infantile-onset epilepsy (n = 6/6), global developmental delay/intellectual disability (n = 6/6) and infant/premature death (n = 5/6)." "Functional analyses revealed that all LGI1 variants result in reduced secretion and ADAM22-binding. Residual LGI1 function levels correlated with clinical severity, ranging from infantile lethality to intermediate phenotypes."

That paper establishes a clean dose–response allelic series: ~50% LGI1 (heterozygous ADEAF) → focal epilepsy, normal cognition; residual function ~6.7–40% (biallelic hypomorph) → DEE of graded severity; null → infantile lethality. A prior mouse study likewise found "approximately 50% of LGI1 and approximately 10% of ADAM22 protein levels are sufficient to prevent lethal epilepsy."

RELN (hgnc:9957, 7q22.1; protein P78509, Reelin)

From PMID:26046367 (verbatim abstract):

"We show that ADLTE-related mutations significantly decrease serum levels of Reelin, suggesting an inhibitory effect of mutations on protein secretion." "We also show that Reelin and LGI1 co-localize in a subset of rat brain neurons, supporting an involvement of both proteins in a common molecular pathway underlying ADLTE." "Homozygous RELN mutations are known to cause lissencephaly with cerebellar hypoplasia."

  • Seven heterozygous missense variants across seven families; 3D modeling predicted structural effects on domain folding.
  • Penetrance in RELN families: 60% (20/33 carriers affected) (GeneReviews).
  • Constraint: pLI = 1, o/e LoF = 0.253 (108 obs / 428 exp), LOEUF = 0.296. Note the paradox worth flagging in curation: RELN is LoF-constrained, yet ADEAF alleles are missense secretion-impairing, while biallelic RELN LoF gives Norman-Roberts lissencephaly — a second allelic series with a dosage/mechanism split.

MICAL1 (hgnc:20619, 6q21; protein Q8TDZ2)

The odd one out — gain of function (Dazzo E et al., Ann Neurol 2018;83:483–493, PMID:29394500):

"We identified two ADLTE-causing variants in the MICAL-1 gene: a p.Gly150Ser substitution occurring in the enzymatically active monooxygenase (MO) domain and a p.Ala1065fs frameshift indel in the C-terminal domain, which inhibits the oxidoreductase activity of the MO domain." "In cell-based assays, both variants significantly increased MICAL-1 oxidoreductase activity and induced cell contraction in COS7 cells, which likely resulted from deregulation of F-actin dynamics." "This suggests that dysregulation of the actin cytoskeleton dynamics is a likely mechanism by which MICAL-1 pathogenic variants lead to ADLTE."

Constraint: pLI ≈ 0, LOEUF = 0.855 — i.e. MICAL1 is not LoF-constrained, which is exactly what you'd predict for a gain-of-function disease gene. Nice internal consistency check.

Variant classification, allele frequency, modifiers, epigenetics

  • ACMG/AMP classification: ADEAF variants in ClinVar are typically P/LP for recurrent LGI1 alleles; many novel missense land as VUS pending functional data. The secretion/ADAM22-binding assays (HiBiT split-nanoluciferase, cell-surface binding) are the field's de facto PS3-grade functional evidence.
  • Population frequency: pathogenic alleles are private/family-specific; absent or ultra-rare in gnomAD. No recurrent founder allele is established.
  • Modifier genes: none validated. Reduced penetrance (54–85%) implies modifiers exist but they are uncharacterized — a genuine knowledge gap worth a KNOWLEDGE_GAP discussion in the KB entry.
  • Epigenetics: no ADEAF-specific methylation/chromatin data. Not available.
  • Chromosomal abnormalities: an intragenic CNTNAP2 deletion was found in one EAF family (PMID:27066544); LGI1 exon-level deletions account for ~5% of LGI1-positive cases. No recurrent cytogenetic syndrome.

5. Environmental Information

  • Environmental factors: none causal. Auditory stimuli act as acute precipitants only (§2).
  • Lifestyle: standard epilepsy precipitants (sleep deprivation, alcohol, medication non-adherence) apply by extrapolation; no ADEAF-specific study. Explicitly flag as extrapolated, not measured.
  • Infectious agents: none. Not applicable.
  • One genuinely relevant "acquired environment": anti-LGI1 autoimmune encephalitis targets the same protein. "Antibodies against epitempin disrupting the LGI1-ADAM22 complex cause a rare form of autoimmune encephalitis, characterized in some cases by peculiar faciobrachial dystonic seizures (FBDS)" (PMID:35153984). Same molecular node, different insult — a beautiful natural experiment, and a mandatory differential in adult-onset cases.

6. Mechanism / Pathophysiology

The core causal chain (LGI1 arm)

LGI1 loss of function → failure of the trans-synaptic LGI1–ADAM22/ADAM23 bridge → reduced AMPA-receptor-mediated transmission + loss of Kv1.1 at the axon initial segment and presynaptic terminals → intrinsic and synaptic hyperexcitability of lateral-temporal/hippocampal glutamatergic neurons → focal epileptiform discharge in auditory association cortex → auditory aura → propagation → focal impaired awareness / bilateral tonic-clonic seizure.

Step by step, with citations:

(1) Ligand–receptor assembly. ADAM22 is the receptor (PMID:16990550):

"ADAM22, a transmembrane protein that when mutated itself causes seizure, serves as a receptor for LGI1. LGI1 enhances AMPA receptor-mediated synaptic transmission in hippocampal slices. The mutated form of LGI1 fails to bind to ADAM22. ADAM22 is anchored to the postsynaptic density by cytoskeletal scaffolds containing stargazin."

(2) Trans-synaptic complex. (Fukata Y et al., PNAS 2010;107:3799–804, PMID:20133599):

"Extracellularly secreted LGI1 links two epilepsy-related receptors, ADAM22 and ADAM23, in the brain and organizes a transsynaptic protein complex that includes presynaptic potassium channels and postsynaptic AMPA receptor scaffolds. A lack of LGI1 disrupts this synaptic protein connection and selectively reduces AMPA receptor-mediated synaptic transmission in the hippocampus." "Thus, LGI1 may serve as a major determinant of brain excitation."

(3) Structure. (Yamagata A, Fukai S, Cell Mol Life Sci 2019, PMID:31432233 — review):

"LGI1 consists of the N-terminal LRR domain and the C-terminal epitempin-repeat (EPTP; also known as EAR) domain." "The crystal structure of the full-length LGI1 in complex with ADAM22 exhibits a 2:2 heterotetramer in a dimer-of-dimer assembly." "transsynaptic linkage through the tripartite complex of ADAM22–(LGI1)2–ADAM23 in synapses" "Through this synaptic protein network, LGI1 modulates AMPA receptor-mediated synaptic transmission." "LGI1 is enriched at the axon initial segment and colocalized with ADAM22/23 and the voltage-gated potassium (Kv1) channels."

(4) Two mutational routes into the same failure:

"Among them, 19 mutations result in secretion-defective proteins presumably due to the failure of protein folding." / "The E383A mutation disrupts the Ca2+ coordination inside of the β-propeller structure." / "The S473L mutation substantially reduces the binding to ADAM22." / "The R474Q mutation disables the assembly of the tripartite complex of ADAM22, ADAM23, and LGI1." (PMID:31432233)

(5) Kv1.1 and intrinsic excitability — and it's reversible (Extrémet J et al., J Neurosci 2023;43:8596–8606, PMID:37863654):

"We previously showed that LGI1 deficiency in a mouse model (i.e., knock-out for LGI1 or KO-Lgi1) decreased Kv1.1 channel density at the axon initial segment (AIS) and at presynaptic terminals, thus enhancing both intrinsic excitability and glutamate release." "…the selective expression of LGI1 in KO-Lgi1 neurons from mice of both sexes, using single-cell electroporation, reduces intrinsic excitability and restores both the Kv1.1-mediated D-type current and Kv1.1 channels at the AIS."

(6) Developmental arm — synaptic pruning (Zhou YD et al., Nat Med 2009;15:1208–14, PMID:19701204):

"We discovered that the normal postnatal maturation of presynaptic and postsynaptic functions was arrested by the 835delC mutant LGI1, and contrastingly, was magnified by excess wild-type LGI1. Concurrently, mutant LGI1 inhibited dendritic pruning and increased the spine density to markedly increase excitatory synaptic transmission. Inhibitory transmission, by contrast, was unaffected."

(7) Cell-type specificity — it's the excitatory neurons (Boillot M et al., Brain 2014;137:2984–96, PMID:25234641):

"Emx1-Lgi1cKO mice displayed early-onset and lethal seizures, whereas CaMKIIα-Lgi1cKO mice presented late-onset occasional seizures associated with variable reduced lifespan. In contrast, neither spontaneous seizures nor increased seizure susceptibility to convulsant were observed when Lgi1 was deleted in parvalbumin interneurons." "We suggest that LGI1 secreted from excitatory neurons, but not parvalbumin inhibitory neurons, makes a major contribution to the pathogenesis of LGI1-related epilepsies. Our data further indicate that LGI1 is required from embryogenesis to adulthood to achieve proper circuit functioning."

(8) Anatomical origin of discharge (PMID:40455867): "we observed epileptic discharges from the isolated whole hippocampus of Lgi1-/- knockout mice, experimentally modelling the hippocampal origin of LGI1-related epilepsy." Note the tension worth curating explicitly: the human syndrome is lateral-temporal/neocortical by semiology, while the mouse models discharge from hippocampus — a legitimate HUMAN_MODEL_MISMATCH candidate.

The RELN arm

Reelin is a large secreted glycoprotein signaling through VLDLR/ApoER2–DAB1; mutant alleles reduce serum reelin, i.e. loss of secreted ligand — the same category of failure as LGI1, in a partly overlapping cell population ("Reelin and LGI1 co-localize in a subset of rat brain neurons," PMID:26046367). Reelin has "important functions in both the developing and adult brain," so the plausible chain is impaired neuronal positioning/plasticity in temporal cortex → altered excitability. The precise adult-brain mechanism is not resolved — this is an honest knowledge gap, not something to over-narrate.

The MICAL1 arm

MICAL-1 is an actin-disassembling monooxygenase (it oxidizes methionine residues on F-actin). Gain of oxidoreductase activity → excess actin filament disassembly → deranged cytoskeletal dynamics in developing/adult neurons → circuit-level hyperexcitability (PMID:29394500). This is the least mechanistically nailed-down of the three arms, and MICAL1's low constraint plus only two families means it should be curated with appropriate epistemic hedging (see also Nobile & Dazzo, Genes 2022;13:715, PMC9141472).

Suggested ontology terms for pathophysiology nodes (all verified via local OAK)

Biological processes (GO): - GO:0098990 AMPA selective glutamate receptor signaling pathway - GO:0097113 AMPA glutamate receptor clustering - GO:0050804 modulation of chemical synaptic transmission - GO:0007268 chemical synaptic transmission - GO:0060291 long-term synaptic potentiation - GO:1905805 excitatory synapse pruning · GO:0098883 synapse pruning - GO:0005249 voltage-gated potassium channel activity (MF) - GO:0038026 reelin-mediated signaling pathway - GO:0030042 actin filament depolymerization (MICAL1 arm; modifier: INCREASED)

Cellular components: GO:0043194 axon initial segment; GO:0032281 AMPA glutamate receptor complex; GO:0110157 reelin complex.

Cell types (CL): CL:0000679 glutamatergic neuron; CL:0000598 pyramidal neuron; CL:1001571 hippocampal pyramidal neuron; CL:0000617 GABAergic neuron (for the negative result — PV interneuron deletion does not cause seizures); CL:0000127 astrocyte (LGI1 is also secreted by astrocytes).

Suggested module conformance: epilepsy_excitation_inhibition_imbalance#Excitation-Inhibition Imbalance — ADEAF is close to a textbook conformer (channel/synaptic dysfunction → E/I imbalance → hyperexcitability/hypersynchrony → seizures). Substitute the disorder-specific trigger (LGI1–ADAM22/23 trans-synaptic complex failure) at the top node.

Molecular profiling / advanced technologies

Transcriptomics, proteomics, metabolomics, lipidomics, single-cell, spatial, and CRISPR-screen data specific to ADEAF: not available. Mouse Lgi1 expression is "predominantly neuronal and is consistent with the anatomic regions involved in temporal lobe epilepsy" (PMID:11810107). Human protein-level reference: UniProt O95970 (LGI1), Q9P0K1 (ADAM22), P78509 (RELN), Q8TDZ2 (MICAL1); complex structures in the PDB from the Yamagata/Fukai work.

7. Anatomical Structures Affected

  • Primary organ / system: brain; nervous system. UBERON:0000955 brain, UBERON:0000956 cerebral cortex.
  • Lobe/region: lateral temporal lobe neocortex — "Seizures originate in the lateral temporal neocortex, distinguishing EAF from mesial temporal lobe epilepsy" (PMID:35153984). UBERON:0001871 temporal lobe.
  • Auditory cortex: UBERON:0001393 auditory cortex; primary auditory cortex UBERON:0034751 (Heschl's gyrus ≈ UBERON:0002773 anterior transverse temporal gyrus); auditory association cortex ≈ UBERON:0034752 secondary auditory cortex; UBERON:0002769 superior temporal gyrus.
  • Language cortex: posterior superior temporal (Wernicke) region for ictal receptive aphasia — no clean UBERON term; use UBERON:0002769 plus HP:0033848.
  • Hippocampal formation (UBERON:0002421): the discharge origin in mouse models and in the biallelic human DEE phenotype; not the primary site in classic human ADEAF.
  • Cell/tissue level: glutamatergic pyramidal neurons of neocortex and hippocampus; excitatory synapses; PV interneurons spared as a source of LGI1.
  • Subcellular: axon initial segment (GO:0043194), presynaptic terminal, postsynaptic density, endoplasmic reticulum (site of misfolded-LGI1 retention/degradation — GO:0005783, verify before use).
  • Lateralization: notable left predominance of EEG abnormalities, "with marked left predominance" in RELN families (PMID:28142128); GeneReviews notes left predominance in some series and a DTI finding of "increased fractional anisotropy in the left temporal lobe" in LGI1-positive families. Seizures themselves may be bilateral-independent across a pedigree.

8. Temporal Development

  • Onset: adolescence/early adulthood; typical 10–30 years; range 4–50 (GeneReviews). RELN families mean 20 years (PMID:28142128). Onset <10 years is a bad-prognosis marker (PMID:29464704).
  • Onset pattern: episodic from the start — first event is usually an aura or an FBTCS; no prodrome, no insidious decline.
  • Stages: none formally defined. Practically: (i) isolated auras, often unrecognized for years; (ii) auras + intermittent FBTCS (usual presentation to care); (iii) either long-term remission or, in a minority, drug-resistant focal epilepsy considered for surgery.
  • Course: non-progressive, chronic, lifelong susceptibility. FBTCS "occurred only once or twice per year" in one 34-person series (GeneReviews).
  • Remission: both treatment-induced and spontaneous remission occur; withdrawal relapse is a real hazard — "Drug withdrawal often leads to clinical relapses, not always responding to reinitiation of treatment" (PMID:35153984). Cumulative terminal-remission rates 26.6% / 35.7% / 51.6% at 10 / 20 / 30 years (PMID:29464704).
  • Critical periods: the mouse data argue LGI1 "is required from embryogenesis to adulthood" (PMID:25234641), and that embryonic-onset loss is catastrophic while late-postnatal loss is mild — relevant to any future gene-replacement timing question.

9. Inheritance and Population

Epidemiology

  • Prevalence: unknown. GeneReviews: "The prevalence of ADEAF is unknown but likely very low." Orphanet lists it among rare disorders (<1/2,000) without a numeric class.
  • Among Mendelian focal epilepsies it's not marginal: "9/48 (19%) of families…met criteria for ADEAF" (GeneReviews); ~3% of people with epilepsy have a significant family history, of whom a fraction meets ADEAF criteria.
  • Incidence: not estimable — "a precise estimate of the incidence of EAF is currently not available" (PMID:35153984), largely because isolated auditory auras go unreported.
  • Suggested dismech encoding: measure_type: POINT_PREVALENCE, prevalence_class: UNKNOWN (or ULTRA_RARE with a note), no rate_per_100000. Do not invent a number.

Genetic parameters

  • Inheritance: autosomal dominant with reduced penetrance (HP:0000006 Autosomal dominant inheritance; HP:0003829 Incomplete penetrance).
  • Penetrance: 54% across eight LGI1 families (PMID:15079011); best pooled estimate 67% (95% CI 55–77%) across all 24 published LGI1 families (PMID:18711109) —

    "Overall penetrance was 67% (95% CI 55-77%), and did not vary according to mutation type or location within the gene." "Our results suggest that about two-thirds of individuals who inherit a mutation in LGI1 will develop epilepsy. This probably overestimates the true penetrance in the population because it is based on data from families containing multiple affected individuals." RELN: 60% (20/33 carriers). GeneReviews quotes an overall 54–85% range for counseling.

  • Expressivity: variable — auditory aura vs aphasic seizures vs FBTCS-only within the same pedigree; some LGI1 families even contain individuals with idiopathic generalized epilepsies (PMID:15079011).
  • Anticipation: not a repeat-expansion disorder; apparent generational increase in penetrance in the Rosanoff analysis was attributed to ascertainment ("probably because of limited information about early generations").
  • Germline mosaicism: not reported. De novo: ~1%.
  • Founder effects / consanguinity: none for classic AD ADEAF. Consanguinity is relevant only for the new biallelic LGI1 DEE phenotype — all four families in PMID:40455867 were consanguineous.
  • Carrier frequency: not applicable (dominant); pathogenic alleles are essentially absent from gnomAD.

Demographics

  • Populations: described worldwide; the deepest family series are Italian (Nobile/Michelucci, 40 families) and North American (Ottman/Columbia). Reports from Turkey, Korea, China, Brazil. No population enrichment established.
  • Sex ratio: ~1:1 (58 M / 65 F, PMID:29464704); penetrance sex-independent.
  • Geographic variant distribution: private family variants; no geographic clustering.

10. Diagnostics

Clinical criteria (ILAE 2022, via GeneReviews summary)

Mandatory: focal sensory auditory seizures and/or focal cognitive seizures with receptive aphasia; normal brain MRI. Exclusionary/alerts: generalized-onset seizures or other focal-onset seizure types; moderate/severe intellectual disability; generalized epileptiform discharges; focal abnormalities on neurologic exam.

Electrophysiology (the workhorse)

EEG (LOINC — routine EEG 24708-6, verify): interictal EEG normal in a substantial minority; focal temporal sharp waves/spikes in 57–80%, often left-predominant. Sleep-deprived and prolonged video-EEG increase yield. Prognostically loaded: unremarkable EEG predicts remission (HR 3.5, PMID:29464704).

Imaging

MRI brain (3T, epilepsy protocol) — expected normal; its main job is excluding hippocampal sclerosis, focal cortical dysplasia (think DEPDC5), and tumor. Research-level findings: left temporal FA increase on DTI; one Brazilian family with a left lateral temporal malformation that did not fully co-segregate (GeneReviews). A completed NIH imaging study exists: NCT00072813 — "MRI in Autosomal Dominant Partial Epilepsy With Auditory Features" (status: Completed).

Laboratory / biomarkers

  • No routine biochemical marker. Serum Reelin is reduced by ADLTE RELN mutations (PMID:26046367) — a research biomarker, not a validated clinical assay.
  • Anti-LGI1 antibodies (serum + CSF) are the essential rule-out in adult-onset cases — a negative-defining test rather than a positive one.
  • Biopsy/histopathology: not indicated; no characteristic pathology.

Genetic testing (the actual diagnostic)

Recommended approach: multigene epilepsy panel including at minimum LGI1, RELN, MICAL1, plus DEPDC5, SCN1A, CNTNAP2, and (emerging) KCNQ2; escalate to exome/genome if the panel is negative — which it will be most of the time (92% of unselected EAF probands, PMID:33453592). Single-gene LGI1 testing is reasonable only in a classic large AD pedigree. Include exon-level del/dup analysis (~5% of LGI1 findings). CMA, karyotype, FISH, mtDNA, and repeat-expansion testing are not indicated unless the phenotype is atypical.

Differential diagnosis (with distinguishing features)

Condition How to tell it apart
Anti-LGI1 autoimmune encephalitis subacute onset, faciobrachial dystonic seizures, amnesia, hyponatremia, LGI1 antibodies, often older adult, MRI mesial temporal signal change
Mesial temporal lobe epilepsy (familial or with HS) epigastric/psychic/autonomic auras dominate; auditory symptoms <10%; hippocampal sclerosis on MRI
Familial focal epilepsy with variable foci (DEPDC5 etc.) seizure focus differs between family members; auditory symptoms/aphasia not the family-wide signature
Autosomal dominant sleep-related hypermotor epilepsy nocturnal hyperkinetic frontal seizures
Tinnitus continuous/durable rather than brief and stereotyped; "far more durable than the seizure of EAF" (PMID:35153984)
Schizophrenia / primary psychotic auditory hallucination complex, sustained, with other psychotic features; not brief, stereotyped, self-limited
Structural lateral temporal lesion MRI

Screening

No population or newborn screening (adult-onset, non-treatable-by-early-detection, moderate penetrance). Cascade predictive testing of at-risk relatives is available once the familial variant is known, but must be counseled around the 54–85% penetrance and the absence of any preventive intervention. Prenatal and preimplantation genetic testing are technically available (GeneReviews) — and are exactly the kind of decision that belongs with a genetic counselor, not a panel default.

11. Outcome / Prognosis

  • Survival/mortality: no excess mortality documented for classic heterozygous ADEAF beyond the general epilepsy SUDEP risk; not quantified for this syndrome. (Contrast: biallelic LGI1 DEE, where 5/6 died between 9 months and 24 years — PMID:40455867.)
  • Seizure outcome — the single most important recent number (Bisulli F et al., Epilepsia 2018;59:834–843, PMID:29464704, n=123, median follow-up 11 years):

    "At last assessment, 42 patients had achieved TR (34.1%)." "The cumulative rates of TR were 26.6%, 35.7%, and 51.6% at 10, 20, and 30 years from inclusion." "Our data show a wide prognostic spectrum of EAF, ranging from mild forms with spontaneous remission, to severely refractory epilepsy addressed to surgery. The outcome, less favorable than expected from previous studies, appears to be primarily a function of 3 prognostic negative risk factors: age at onset < 10 years, auditory aura characterized by complex auditory hallucinations, and focal epileptiform abnormalities on scalp EEG."

Positive predictors on multivariate analysis: age at onset >10 years (HR 3.2, p=.028); distortion-only auras vs simple/complex hallucinations (HR 2.9, p=.041); unremarkable EEG (HR 3.5, p=.041).

This directly contradicts the older "benign syndrome" framing ("The clinical course of ADEAF is usually benign," GeneReviews). Curate both, with the tension made explicit — the discrepancy is partly referral-center ascertainment (Bologna tertiary cohort) vs family-study ascertainment. Worth a DISCREPANCY/KNOWLEDGE_GAP discussion node. - Morbidity/disability: cognition and neurologic exam are normal by definition. Disability is seizure-driven (driving, employment, injury from FBTCS). - Quality-of-life instruments: no ADEAF-specific QOLIE-31/EQ-5D data. Not available. - Complications: status epilepticus is rare; aphasic status epilepticus (HP:0032849) is conceptually possible but not established as characteristic. - Prognostic biomarkers: none molecular. Genotype does not predict outcome — "no significant clinical differences were observed between families with an LGI1 pathogenic variant and families without an identified pathogenic variant," and RELN vs LGI1 families are clinically "indistinguishable" (PMID:28142128). The only genotype–phenotype signal is domain-level: "Auditory symptoms were less frequent in individuals with truncation mutations in the EPTP domain than in those with other mutation type/domain combinations (58% vs 80%, p = 0.018)" (PMID:22323750).

12. Treatment

There are no ADEAF-specific randomized trials. Everything below is standard focal-epilepsy practice applied to this syndrome, plus small-series experience. Say so plainly in the KB entry.

Pharmacotherapy

  • First line: sodium-channel-blocking ASMs, carbamazepine as the prototype, usually as monotherapy and often at low dose. GeneReviews: "Seizure control is usually readily achieved with standard anti-seizure medications (ASM)" and "Traditionally sodium channel blockers such as carbamazepine have been more frequently used with clear benefit," while noting no formal trials. Furia 2022: "EAF is considered a syndrome with a good response to anti-seizure medications used for focal epilepsy, such as carbamazepine in monotherapy."
  • Reasonable alternatives (focal-epilepsy standard): oxcarbazepine, lamotrigine, levetiracetam, lacosamide.
  • Avoid the classic misstep: "When misdiagnosed as idiopathic generalized epilepsy, EAF might be treated with drugs that are not optimal (i.e., phenobarbital or valproate), leading to poor response" (PMID:35153984).
  • Withdrawal caution: relapse after withdrawal may not re-respond (PMID:35153984) — argues for conservative, counseled taper decisions.
  • Response: "completely or almost completely controlled by antiepileptic treatment in the vast majority of cases (96%)" in RELN families (PMID:28142128) — but note this is seizure control at last visit, not the stricter 5-year terminal remission of Bisulli 2018 (34.1%). Two different endpoints; don't blend them.

Pharmacogenomics

Not ADEAF-specific, but clinically mandatory for the first-line drug: HLA-B*15:02 screening before carbamazepine in Southeast Asian ancestry (SJS/TEN risk) and HLA-A*31:01 as a risk allele for carbamazepine hypersensitivity in European/Japanese populations — see CPIC carbamazepine guideline / FDA labeling. This is a real and actionable pharmacogenomic link for this syndrome's first-line agent.

Advanced / experimental therapeutics

  • Chemical chaperone (preclinical, promising): 4-phenylbutyrate rescues secretion-defective LGI1 — "The 4PBA treatment significantly improved the secretion of LGI1 mutants and their binding to ADAM22" and "small molecules serving as chemical correctors might be new therapeutic options for LGI1-mediated epilepsy" (PMID:31432233). In 2025, 4PBA "selectively enhanced Cys48Phe secretion" (PMID:40455867). Mutation-class-specific: only helps foldable-but-retained alleles, useless for nulls. CHEBI:41500 (4-phenylbutyric acid).
  • Gene/protein restoration (preclinical): single-neuron LGI1 re-expression normalizes excitability (PMID:37863654); Thy1-LGI1 transgene rescues the lethal Lgi1−/− phenotype. No AAV-LGI1 clinical program exists as of this writing. Given the ~50%-protein-sufficiency threshold, dose control would matter.
  • Gene therapy / ASO / cell therapy / immunotherapy: none in trials for ADEAF. Not available. (Immunotherapy is for the autoimmune LGI1 disease, a different entity — don't cross-wire them in the KB.)

Surgical / interventional

Resective surgery is reserved for the drug-resistant minority — "Surgery might be employed instead in resistant cases" (PMID:35153984); the Bologna cohort included patients "addressed to surgery" (PMID:29464704). Outcome data for surgery specifically in ADEAF are not published in any systematic form; note that a genetic, potentially bilateral-network epilepsy is a less favorable surgical substrate than unilateral hippocampal sclerosis.

Supportive

Standard epilepsy self-management, sleep hygiene, driving counseling, seizure-safety education, and — specific to this syndrome — counseling that unexplained sounds are seizures, not psychosis. Genetic counseling is a core deliverable (§13).

Suggested NCIT annotations (verified via local sqlite:obo:ncit unless noted)

Treatment treatment_term therapeutic_agent (CHEBI, all verified) therapeutic_modality
Carbamazepine monotherapy NCIT:C15986 Pharmacotherapy CHEBI:3387 carbamazepine SMALL_MOLECULE
Oxcarbazepine NCIT:C15986 CHEBI:7824 oxcarbazepine SMALL_MOLECULE
Lamotrigine NCIT:C15986 CHEBI:6367 lamotrigine SMALL_MOLECULE
Levetiracetam NCIT:C15986 CHEBI:6437 levetiracetam SMALL_MOLECULE
Lacosamide NCIT:C15986 CHEBI:135939 lacosamide SMALL_MOLECULE
Generic ASM therapy NCIT:C64172 Anticonvulsant Therapy (check reachability from NCIT:C25218 before use) — SMALL_MOLECULE
Resective temporal surgery NCIT:C15329 Surgical Procedure, or NCIT:C52004 Brain Lobectomy — SURGERY
Genetic counseling NCIT:C15240 Genetic Counseling — BEHAVIORAL
Supportive care NCIT:C15747 Supportive Care — OTHER

Clinical trials

NCT00072813 — MRI in Autosomal Dominant Partial Epilepsy With Auditory Features (observational imaging; Completed). No interventional ADEAF trial found on ClinicalTrials.gov as of 2026-08-05.

13. Prevention

  • Primary prevention: none — the disease is germline. The only "primary prevention" lever is reproductive: genetic counseling, prenatal diagnosis, or PGT once the familial variant is known (GeneReviews), each carrying the heavy caveat of 54–85% penetrance and a generally treatable, non-degenerative phenotype.
  • Secondary prevention: early recognition of auditory auras in known families → earlier diagnosis and treatment. Whether earlier treatment changes long-term remission is unstudied.
  • Tertiary prevention: adherence, avoidance of sleep deprivation and (for the reflex-sensitive minority) unpredictable loud stimuli; correct drug selection (avoid valproate/phenobarbital chosen on a mistaken IGE diagnosis); cautious ASM withdrawal given relapse risk; driving/occupational safety.
  • Immunization / public health / environmental interventions: not applicable.
  • Prophylaxis: no pre-symptomatic ASM prophylaxis is indicated or studied in unaffected carriers. Given ~⅓ of carriers never develop seizures, treating carriers would be net harm.
  • Counseling specifics: offspring of an affected individual have a 50% chance of inheriting the variant, of whom 54–85% will manifest (GeneReviews); siblings' risk depends on parental carrier status, and a clinically unaffected parent may still be a carrier because of reduced penetrance.

14. Other Species / Natural Disease

This is one of the better comparative stories in epilepsy genetics — dogs got there partly first.

  • Taxonomy: Homo sapiens NCBITaxon:9606; Mus musculus NCBITaxon:10090; Rattus norvegicus NCBITaxon:10116; Canis lupus familiaris NCBITaxon:9615.
  • Naturally occurring canine disease — LGI2 in Lagotto Romagnolo (Seppälä EH et al., PLoS Genet 2011;7:e1002194, PMID:21829378):

    "Using genome-wide association in 11 discordant sib-pairs from this pedigree, we mapped the disease locus to a 1.7 Mb region of homozygosity in chromosome 3 where we identified a protein-truncating mutation in the Lgi2 gene, a homologue of the human epilepsy gene LGI1." "We show that LGI2, like LGI1, is neuronally secreted and acts on metalloproteinase-lacking members of the ADAM family of neuronal receptors, which function in synapse remodeling, and that LGI2 truncation, like LGI1 truncations, prevents secretion and ADAM interaction." "LGI2 acts at least in part through the same ADAM receptors as LGI1, but earlier, ensuring electrical stability (absence of epilepsy) during pruning years, preceding this same function performed by LGI1 in later years."

Onset ~7 weeks, remitting by ~4 months — a developmentally shifted version of the same pathway, and a proposed model for remitting childhood epilepsy. Breed: Lagotto Romagnolo (VBO term available — look up before curating). Note this is autosomal recessive in dogs and involves the paralog LGI2 (hgnc:18710), so it is a pathway homolog, not a direct ADEAF ortholog model. - Canine ADAM23 risk haplotype (Koskinen LL et al., BMC Genomics 2015;16:465, PMID:26084559): a 28-kb ADAM23 risk haplotype replicated across Belgian Shepherd, Schipperke, Finnish Spitz, and Beagle (p_raw = 2.76e-15), frequency 0.49–0.70 — "ADAM23 plays a role in synaptic transmission and interacts with known epilepsy genes, LGI1 and LGI2, and should be considered as a candidate gene for human epilepsies." Low-penetrance risk gene, causative variant still unidentified. This is real veterinary relevance: idiopathic epilepsy is a common canine neurological disease and a DNA test exists for the Lagotto LGI2 allele. - Orthologs: mouse Lgi1 (MGI), Reln (the classic reeler mouse), Adam22, Adam23, Mical1; dog LGI2, ADAM23. Register in OMIA for the canine entries. - Evolutionary conservation: the LGI–ADAM synaptic module is conserved across mammals, with paralog subfunctionalization by developmental window (LGI2 early, LGI1 later — PMID:21829378). Genuinely elegant. - Zoonotic potential / cross-species transmission: not applicable.

15. Model Organisms

Model Type Phenotype Recapitulation Key citation
Lgi1−/− mouse germline KO early-onset spontaneous seizures, lethal at 2–3 weeks; reduced AMPAR transmission; ↓Kv1.1 at AIS/terminals; hippocampal epileptic discharges in isolated whole hippocampus Models the pathway, not the human heterozygous syndrome; far more severe. Now recognized as a model of the biallelic human DEE PMID:20133599; PMID:25234641; PMID:40455867
Lgi1+/− mouse germline het lowered seizure thresholds, no spontaneous lethal epilepsy Closest genotype match to human ADEAF; phenotype is subthreshold (no spontaneous auditory-aura equivalent — mice can't report auras anyway) PMID:20133599
Emx1-Cre Lgi1 cKO conditional (embryonic, glutamatergic) early-onset lethal seizures Localizes requirement to excitatory neurons + early development PMID:25234641
CaMKIIα-Cre Lgi1 cKO conditional (late postnatal, excitatory) late-onset occasional seizures, variable lifespan reduction Best temporal analog of adolescent-onset human disease PMID:25234641
PV-Cre Lgi1 cKO conditional (PV interneurons) no seizures, no threshold change — informative negative Establishes cell-type specificity PMID:25234641
LGI1-835delC transgenic mouse human truncating allele, transgenic arrested postnatal synapse maturation, inhibited dendritic pruning, ↑spine density, ↑excitatory transmission, epileptiform discharge + facilitated kindling; inhibitory transmission unaffected Models the developmental arm of a real human ADEAF allele PMID:19701204
LGI1 D51G knock-in mouse precise patient-allele KI confirms pathogenicity of a novel Chinese-family ADLTE variant Highest-fidelity allele model class PMC8739050 (2021)
Adam22−/− mouse KO epileptic phenotype similar to Lgi1 loss; ~10% ADAM22 protein suffices to prevent lethal epilepsy Receptor-side validation PMID:16990550; PMID:40455867
Adam22ΔC5/ΔC5 mouse KI (PDZ-binding motif deleted) hyperactivity, impaired behavioral flexibility, complex-learning deficits (IntelliCage) Models cognitive dimension of ADAM22-related DEE PMID:40455867
Adam23−/− / +/− mouse KO / het spontaneous seizures (−/−); decreased seizure threshold (+/−); reduced CA1 dendritic arborization Third leg of the tripartite complex PMID:19796686
reeler mouse (Reln null) spontaneous mutant ataxia, inverted cortical lamination Models biallelic RELN lissencephaly, not heterozygous ADEAF — the ADEAF-relevant heterozygous-missense mouse is a gap (classic literature)
Cultured neurons + single-cell electroporation in vitro rescue LGI1 re-expression restores D-type current, Kv1.1 at AIS, prevents homeostatic AIS shortening Proof-of-principle for reversibility PMID:37863654
COS7 / HEK cell assays in vitro secretion (Western, HiBiT split-nanoluciferase), cell-surface ADAM22 binding, MICAL1 oxidoreductase + cell-contraction assay The functional-evidence backbone for variant classification PMID:29394500; PMID:40455867

Model limitations to record explicitly: 1. No model reproduces the defining human feature — the auditory aura and ictal receptive aphasia are subjective, language/percept-dependent phenomena with no rodent readout. Any mouse-derived phenotype claim must be tagged MODEL_ORGANISM and must not be the sole support for a human phenotype. 2. Dosage mismatch: mouse homozygous nulls are lethal-epileptic while human heterozygotes have a mild focal epilepsy; the human-equivalent het mouse shows only threshold changes. 3. Anatomical mismatch: mouse discharges originate in hippocampus; human ADEAF is lateral-temporal neocortical. Strong candidate for a HUMAN_MODEL_MISMATCH discussion with a proposed experiment (region-restricted lateral-temporal Lgi1 deletion; auditory-cortex-targeted recordings). 4. RELN and MICAL1 arms are under-modeled — no published heterozygous-missense Reln ADLTE mouse, no Mical1 GoF knock-in.

Resources: MGI (mouse alleles for Lgi1, Adam22, Adam23, Reln), Alliance of Genome Resources, IMPC/KOMP, IMSR/MMRRC for strain requests, OMIA for the canine LGI2/ADAM23 entries, Cellosaurus for cell lines.

Appendix A — Suggested dismech pathophysiology skeleton

A causal chain that stays honest about scale and evidence:

  1. LGI1 Loss of Function — biological_scale: MOLECULAR; gene hgnc:6572; secretion-defective vs binding-defective as two mechanistic_hypotheses-free routes (both established, so model as two upstream nodes converging, not competing hypotheses) → downstream to (2)
  2. Failure of the LGI1–ADAM22/ADAM23 Trans-Synaptic Complex — MOLECULAR; GO:0050804; cell types CL:0000679 → (3a) and (3b)
  3. a. Reduced AMPA Receptor-Mediated Synaptic Transmission — CELLULAR; GO:0098990, GO:0097113, modifier DECREASED b. Loss of Kv1.1 at the Axon Initial Segment — CELLULAR; GO:0005249 + GO:0043194, modifier DECREASED
  4. Glutamatergic Neuron Hyperexcitability — CELLULAR; CL:0000598 / CL:1001571
  5. Excitation-Inhibition Imbalance — CELLULAR; conforms_to: epilepsy_excitation_inhibition_imbalance#Excitation-Inhibition Imbalance
  6. Lateral Temporal Neocortical Epileptogenesis — TISSUE; UBERON:0001393 / UBERON:0002769 / UBERON:0002773
  7. Focal Sensory Auditory Seizure ± Receptive Aphasia → Focal to Bilateral Tonic-Clonic Seizure — ORGANISM; HP:0011158, HP:0032696, HP:0007334

Parallel entry nodes: RELN Secretion Deficiency (GO:0038026, gene hgnc:9957) and MICAL1 Oxidoreductase Gain of Function (GO:0030042, modifier INCREASED, gene hgnc:20619), both feeding node (5). A separate Developmental Arm: Arrested Excitatory Synapse Pruning (GO:1905805, modifier DECREASED, PMID:19701204) feeding node (4) captures the Zhou/Anderson mechanism without overwriting the acute-excitability chain.

Suggested discussions entries: - KNOWLEDGE_GAP — ~50% of ADEAF families and 92% of unselected EAF probands remain genetically unsolved (PMID:33453592). - KNOWLEDGE_GAP — modifiers explaining 54–85% penetrance are entirely uncharacterized. - KNOWLEDGE_GAP — "benign" (GeneReviews) vs 34.1% terminal remission (PMID:29464704); ascertainment-driven discrepancy, unresolved. - HUMAN_MODEL_MISMATCH — mouse discharges are hippocampal; human semiology is lateral-temporal neocortical; and no model can express an auditory aura.

Appendix B — Curation warnings

  1. GeneReviews quotes will fail just validate-references. Every frequency I sourced to GeneReviews Table 2 (57–71% auditory, 17–20% aphasic, 88–92% FBTCS, 8–13% sound-triggered) needs re-sourcing to a PubMed-indexed primary paper before it becomes an evidence snippet. The RELN paper (PMID:28142128) supplies verifiable substitutes: 71% auditory, 88% FBTCS, 8% noise-precipitated, 80% EEG abnormalities, 96% controlled.
  2. Do not map MICAL1-ADLTE to OMIM ETL8 (616461) — that entry is GAL-related. Verified via MedGen this session.
  3. ADEAF ≠ anti-LGI1 encephalitis. Same protein, opposite direction of arrival (germline LoF vs acquired autoantibody), different age, different treatment. Keep them as distinct entries with a cross-reference.
  4. Seed the MONDO caches for MONDO:0010898 in both cache/enums/*.csv and cache/mondo/terms.csv before pushing, and remember the term must be seeded from the worktree, not just the primary checkout.
  5. Every mouse-derived claim gets evidence_source: MODEL_ORGANISM; every COS7/HEK/neuron-culture claim gets IN_VITRO; family series and cohorts get HUMAN_CLINICAL.

Sources