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MONDO

MONDO:0010898 autosomal dominant epilepsy with auditory features

Exact disease concept for the autosomal dominant syndrome characterized by auditory seizures or receptive aphasia; molecular diagnosis can be established even when family history is absent.

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Inheritance

1

Autosomal dominant with incomplete penetrance HP:0000006

Heterozygous pathogenic variants cause dominant disease with incomplete penetrance. A variant carrier has a 50% transmission probability per pregnancy, distinct from the probability that an inheriting child develops epilepsy. Family estimates vary by gene and ascertainment; de novo variants can occur and MICAL1 penetrance is not established.

Autosomal dominant inheritance Penetrance: INCOMPLETE

Show evidence (2 references)

PMID:20301709 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"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 DIRECT REVIEW SYNTHESIS Human Clinical

"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

4

How do distinct LGI1 physiological effects produce the human focal epilepsy phenotype?

INTERPRETATION OPEN adeaf_preparation_specific_physiology

AMPA-mediated responses decrease in one null preparation and increase in another; baseline intrinsic properties can be unchanged in acute or intact hippocampus while cultured CA3 neurons show a Kv1-related deficit. Regional, developmental, allele and preparation differences matter. A compensatory AMPA-loss-to-hyperexcitability cascade is a hypothesis rather than a demonstrated common sequence. The cultured restoration study explicitly did not test synaptic rescue.

Show evidence (5 references)

PMID:20133599 SUPPORT DIRECT PRIMARY RESULT In Vitro

"A lack of LGI1 disrupts this synaptic protein connection and selectively reduces AMPA receptor-mediated synaptic transmission in the hippocampus."

Abstract-level mouse hippocampal observation; physiological readout is ex vivo and differs from other preparations.

PMID:20130004 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Remarkably, however, the frequency of mEPSCs was dramatically increased in the mutant mice"

Mouse hippocampal slice readout; mEPSC frequency is not a direct extracellular glutamate-concentration measurement.

PMID:20130004 SUPPORT DIRECT PRIMARY RESULT In Vitro

"These results indicate that Lgi1 mutation did not change the intrinsic properties of pyramidal neurons in the hippocampal CA1 region."

Baseline intrinsic firing, membrane potential and input resistance were unchanged in this acute-slice preparation.

+ 2 more references

How much does developmental circuit maturation contribute relative to continuing LGI1 function?

KNOWLEDGE GAP OPEN adeaf_developmental_and_later_requirements

The 835delC transgene supports altered postnatal dendritic maturation, while conditional deletion at later postnatal stages still produces seizures and culture restoration changes intrinsic physiology. These studies do not establish a single irreversible developmental lesion or a requirement for a second hit. The dog LGI2 epilepsy and a proposed LGI2-to-LGI1 developmental handover concern a paralog and cannot establish a human ADEAF mechanism.

Show evidence (4 references)

PMID:19701204 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Concurrently, mutant LGI1 inhibited dendritic pruning and increased the spine density to markedly increase excitatory synaptic transmission."

835delC BAC transgene model supports a developmental synaptic branch; it is not a heterozygous knock-in or a universal patient finding.

PMID:25234641 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Emx1-Lgi1cKO mice displayed early-onset and lethal seizures, whereas CaMKIIα-Lgi1cKO mice presented late-onset occasional seizures associated with variable reduced lifespan."

Conditional deletion separates embryonic from later postnatal glutamatergic-neuron perturbations; details beyond the abstract are not inferred.

PMID:37863654 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Here, we show that 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."

Restoration in organotypic mouse hippocampal neurons supports a Kv1-related excitability mechanism; this is not a human treatment.

+ 1 more reference

Do LGI1, RELN and MICAL1 defects converge on the same neuronal pathway?

KNOWLEDGE GAP OPEN adeaf_gene_convergence

Human clinical overlap does not demonstrate molecular convergence. Reelin serum and secretion findings, MICAL1 lysate activity and LGI1 synaptic-channel studies measure different compartments and endpoints. MICAL1-to-actin-to-network and reelin-to-human-epilepsy intermediates remain unresolved; direct patient-neuron studies and allele-aware rescue would be informative.

Show evidence (4 references)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC4457960/ SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In total, we identified seven ... mutations, each in a different ADLTE-affected family."

Selected-family genetic evidence supports the RELN association.

PMID:34508592 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Using a cell-based secretion assay, we show that pathogenic RELN mutations abolish or significantly reduce secretion of mutant proteins and that this secretion defect results from impaired trafficking of mutant Reelin along the secretory pathway."

Direct cell-assay result reported in an abstract-only source; precise constructs and culture conditions were not recoverable.

PMID:38654463 SUPPORT DIRECT PRIMARY RESULT In Vitro

"We found that the oxidoreductase activities of human (hMICAL‐1Arg915Cys) and mouse (mMICAL‐1Arg902Cys) mutants were significantly increased"

Variant-dependent activity increase in transfected-cell lysates.

+ 1 more reference

Which LGI1 alleles and experimental corrections translate to dominant ADEAF?

HUMAN MODEL MISMATCH OPEN adeaf_allelic_translation

Biallelic LGI1 encephalopathy is a distinct human phenotype, so severe null mice are not simply evidence of an unsupported human condition. The six-person biallelic series had heterogeneous survival and is not representative of dominant ADEAF. Cell 4PBA responses differ across alleles; organotypic LGI1 restoration does not establish delivery, durability, seizure reduction or clinical benefit in heterozygous patients.

Show evidence (3 references)

PMID:40455867 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The clinical features available of six patients (Patients P1A–C, P2, P3 and P4) with LGI1 variants identified from four consanguineous families"

Separate biallelic clinical series.

PMID:40455867 SUPPORT DIRECT PRIMARY RESULT In Vitro

"We found that treatment with 4PBA (5 mM) for 72 h significantly increased the secretion of LGI1 Cys48Phe as well as WT, whereas it reduced the secretion of Ser524Pro and Ter558GlyextTer23 (Supplementary Fig. 4B)."

Opposite 4PBA secretion responses across alleles preclude class-wide rescue prediction.

PMID:37863654 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The effect of LGI1 rescue on synaptic function has not been tested in the present study."

The current study measures intrinsic electrophysiology, not synaptic or network-seizure rescue.

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Pathophysiology

19

Heterozygous LGI1 Variants

Pathogenic heterozygous LGI1 variants cause a reduced-penetrance dominant epilepsy. Experimental allele classes include impaired secretion and impaired ligand interaction; gene dosage, altered mutant protein and complete knockout preparations are not interchangeable.

Downstream

Reduced LGI1 Secretion Selected variants produce cellular secretion defects; the effect is allele dependent.

Reduced LGI1-ADAM22 Binding Selected secretion-competent variants have altered ligand interaction.

Reduced Axon Initial Segment Kv1.1 Density Null-neuron restoration supports an experimental model for LGI1-related channel localization; transfer to heterozygous patient variants is indirect.

Shortened Axon Initial Segment A structural response in deficient cultured neurons provides an experimental hypothesis, not a documented patient lesion.

Impaired Postnatal Dendritic Pruning The 835delC transgene supports one allele/model-specific developmental branch; generic dominant-negative action across LGI1 alleles is not established.

Show evidence (1 reference)

PMID:20301709 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"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."

Human genetic diagnosis establishes a disease association; downstream allele-specific mechanisms are assessed separately.

Reduced LGI1 Secretion

Selected pathogenic LGI1 variants reduce extracellular availability through abnormal folding, intracellular retention or degradation. E383A is one experimentally characterized example; secretion-competent pathogenic variants also occur.

protein secretion GO:0009306 ↓ DECREASED

Experimental models

LGI1 variant secretion and receptor-binding cell assays CELL LINE Cell-medium protein assays quantify reduced secretion for selected constructs.

Downstream

Disrupted LGI1-Linked Synaptic Complex Reduced ligand availability or function can disrupt synaptic complex organization; exact in vivo intermediates vary by allele.

Show evidence (1 reference)

PMID:25485908 SUPPORT DIRECT PRIMARY RESULT In Vitro

"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."

The abstract reports distinct cellular defects for two variants; neither mechanism is assumed universal.

Reduced LGI1-ADAM22 Binding

Some secreted variants impair interaction with ADAM22. The S473L dimerization/binding result is distinct from secretion failure and does not define every pathogenic allele.

Experimental models

LGI1 variant secretion and receptor-binding cell assays CELL LINE The S473L construct shows an interaction defect distinct from secretion failure.

Downstream

Disrupted LGI1-Linked Synaptic Complex Reduced ligand availability or function can disrupt synaptic complex organization; exact in vivo intermediates vary by allele.

Show evidence (1 reference)

PMID:25485908 SUPPORT DIRECT PRIMARY RESULT In Vitro

"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."

The abstract reports distinct cellular defects for two variants; neither mechanism is assumed universal.

Disrupted LGI1-Linked Synaptic Complex

LGI1 supports an extracellular complex involving ADAM22, ADAM23 and associated synaptic scaffolds. Loss of available or functional ligand can disrupt this organization. Receptor association does not make every downstream ion-channel response direct or identical across preparations.

Downstream

Reduced AMPA Receptor-Mediated Transmission The experimental loss condition associates complex disruption with reduced AMPA-mediated transmission; this does not resolve every scaffolding intermediate.

Show evidence (2 references)

PMID:20133599 SUPPORT DIRECT PRIMARY RESULT Model Organism

"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."

Mouse/biochemical study supports organization of the synaptic complex; only the abstract was recoverable.

PMID:20133599 SUPPORT DIRECT PRIMARY RESULT In Vitro

"A lack of LGI1 disrupts this synaptic protein connection and selectively reduces AMPA receptor-mediated synaptic transmission in the hippocampus."

Abstract-level mouse hippocampal observation; physiological readout is ex vivo and differs from other preparations.

Reduced AMPA Receptor-Mediated Transmission

Reduced AMPA receptor-mediated transmission is observed in one LGI1-null hippocampal preparation. Other genetic or antibody preparations show increased evoked excitation. This node records a preparation-specific phenotype and is not linked as a proven driver of hyperexcitability.

Show evidence (1 reference)

PMID:20133599 SUPPORT DIRECT PRIMARY RESULT In Vitro

"A lack of LGI1 disrupts this synaptic protein connection and selectively reduces AMPA receptor-mediated synaptic transmission in the hippocampus."

Abstract-level mouse hippocampal observation; physiological readout is ex vivo and differs from other preparations.

Reduced Axon Initial Segment Kv1.1 Density

LGI1-deficient CA3 neurons in organotypic mouse hippocampal slices show reduced AIS Kv1.1 immunostaining, reversed by local LGI1 expression. Localization and electrical current are measured separately.

Experimental models

Local LGI1 restoration in organotypic hippocampal culture OTHER AIS Kv1.1 immunostaining recovers in expressing neurons; significant density rescue was not demonstrated in neighboring neurons.

Downstream

Reduced Kv1-Mediated D-Type Current Density and current recover together after LGI1 restoration; localization-specific mediation is not isolated from other LGI1 effects.

Show evidence (1 reference)

PMID:37863654 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Here, we show that 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."

Restoration in organotypic mouse hippocampal neurons supports a Kv1-related excitability mechanism; this is not a human treatment.

Reduced Kv1-Mediated D-Type Current

A slowly inactivating potassium-current deficit is measured in LGI1-deficient cultured mouse CA3 neurons. LGI1 restoration and Kv1 blockade support its contribution to altered excitability in this preparation.

Experimental models

Local LGI1 restoration in organotypic hippocampal culture OTHER Local LGI1 expression restores the DTx-K-sensitive conductance; toxin reapplication supports a channel contribution to intrinsic rescue.

Downstream

Increased Intrinsic Neuronal Excitability Restoration and blocker experiments support a Kv1 contribution to firing control in the cultured CA3 preparation.

Show evidence (1 reference)

PMID:37863654 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Here, we show that 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."

Restoration in organotypic mouse hippocampal neurons supports a Kv1-related excitability mechanism; this is not a human treatment.

Increased Intrinsic Neuronal Excitability

LGI1-deficient CA3 neurons in organotypic culture can fire more readily, with local LGI1 restoration reducing excitability. This is not universal across cell types or preparations: other knockout studies found unchanged baseline intrinsic properties.

Experimental models

Lgi1-null acute hippocampal slices OTHER Measured CA1 intrinsic properties are unchanged in this preparation.

Local LGI1 restoration in organotypic hippocampal culture OTHER Current-evoked excitability decreases after local expression in deficient CA3 cells.

Excised intact Lgi1-null hippocampus OTHER The baseline intrinsic properties sampled in this intact preparation were not different.

Downstream

Epileptic Network Activity These experimental cellular phenotypes plausibly contribute to network instability, but their individual necessity and weighting in human disease are unresolved.

Show evidence (1 reference)

PMID:37863654 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Here, we show that 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."

Restoration in organotypic mouse hippocampal neurons supports a Kv1-related excitability mechanism; this is not a human treatment.

Shortened Axon Initial Segment

AIS shortening accompanies LGI1 deficiency in cultured CA3 neurons and is partly reversed by local restoration. A compensatory homeostatic role is proposed, without proof that shortening causes the increased excitability.

Experimental models

Local LGI1 restoration in organotypic hippocampal culture OTHER AIS length recovers partially, without evidence that shortening causes the firing phenotype.

Show evidence (1 reference)

PMID:37863654 SUPPORT DIRECT PRIMARY RESULT In Vitro

"We show that rescuing the Lgi1 expression in LGI1-deficient neurons was sufficient to partially suppress the AIS length shortening"

AIS structural rescue is partial and distinct from the current and firing endpoints.

Impaired Postnatal Dendritic Pruning

In the 835delC BAC transgene model, dentate granule-cell dendritic maturation is perturbed during postnatal development. The model retains endogenous alleles and is not evidence that every human variant acts through a fixed developmental lesion.

Animal models

LGI1 835delC BAC transgenic mice Mouse measures Dentate granule-cell dendritic arbors retain immature branching patterns; cell maturation and synaptic changes are separable readouts.

Downstream

Increased Excitatory Synaptic Transmission Morphological and electrophysiological changes co-occur in the transgenic model; pruning was not independently manipulated to prove sole mediation.

Show evidence (1 reference)

PMID:19701204 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Concurrently, mutant LGI1 inhibited dendritic pruning and increased the spine density to markedly increase excitatory synaptic transmission."

835delC BAC transgene model supports a developmental synaptic branch; it is not a heterozygous knock-in or a universal patient finding.

Increased Excitatory Synaptic Transmission

In selected null and 835delC transgenic preparations, excitatory synaptic currents or miniature-event frequency increase while measured inhibitory currents remain similar. This observation is distinct from intrinsic excitability and from the reduced AMPA response in other preparations.

Experimental models

Lgi1-null acute hippocampal slices OTHER mEPSC frequency increases without a significant amplitude change; this is not a direct glutamate-concentration assay.

Downstream

Epileptic Network Activity These experimental cellular phenotypes plausibly contribute to network instability, but their individual necessity and weighting in human disease are unresolved.

Show evidence (2 references)

PMID:19701204 SUPPORT DIRECT PRIMARY RESULT In Vitro

"the amplitude of evoked AMPA and NMDA receptor-mediated EPSCs (Fig. 4a–d) and the frequency of miniature EPSCs (mEPSCs) (Fig. 4e,f) were increased in mature mLGI1 compared to wild-type."

Acute-slice synaptic recordings in the transgenic model, distinct from the in-vivo dendritic morphology and kindling outcomes.

PMID:20130004 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Remarkably, however, the frequency of mEPSCs was dramatically increased in the mutant mice"

Mouse hippocampal slice readout; mEPSC frequency is not a direct extracellular glutamate-concentration measurement.

Epileptic Network Activity

LGI1 perturbations can support hypersynchronous epileptic activity in animal and isolated hippocampal preparations. Which cellular changes are necessary for human auditory-feature epilepsy, and why the human symptoms preferentially involve auditory/language networks, remain unresolved.

Experimental models

Lgi1-null acute hippocampal slices OTHER Burst frequency increases under modified proconvulsant ACSF.

Excised intact Lgi1-null hippocampus OTHER The isolated preparation supports an intrahippocampal source of the observed abnormal discharges.

Animal models

Constitutive Lgi1-null mice Mouse partially recapitulates Null animals exhibit lethal epilepsy, without modeling a subjective auditory aura.

LGI1 835delC BAC transgenic mice Mouse partially recapitulates Mutant transgene enhances susceptibility under the reported chemical-kindling protocol.

Glutamatergic-neuron conditional Lgi1 knockout mice Mouse partially recapitulates Loss restricted to the studied excitatory-neuron populations is sufficient for seizures with timing-dependent severity.

Parvalbumin-neuron conditional Lgi1 knockout mice Mouse fails to recapitulate The reported seizure endpoints were not increased in the PV-targeted conditional model.

Downstream

Focal Seizures with Auditory Features Human genetics and electroclinical features support epileptogenesis, but the bridge from experimental hippocampal activity to the auditory/language phenotype is indirect.

Interictal EEG Abnormality Interictal discharges or slowing can accompany the disorder; a normal EEG remains possible.

Show evidence (1 reference)

PMID:20133599 SUPPORT DIRECT PRIMARY RESULT Model Organism

"We find that loss of LGI1 in mice (LGI1(-/-)) causes lethal epilepsy, which is specifically rescued by the neuronal expression of LGI1 transgene, but not LGI3."

Severe null mouse phenotype and genetic rescue establish experimental seizure relevance; they do not reproduce typical heterozygous human severity.

Focal Seizures with Auditory Features

Human focal seizures engage auditory or language-related networks and may impair awareness or spread to bilateral convulsive seizures. Clinical semiology suggests lateral temporal involvement; mouse hippocampal findings do not directly establish the human site or subjective experience.

Downstream

Focal Sensory Seizure with Auditory Features This is a clinically documented manifestation of focal seizure activity; symptom-specific network intermediates are not established by the cited experimental models.

Ictal Receptive Aphasia This is a clinically documented manifestation of focal seizure activity; symptom-specific network intermediates are not established by the cited experimental models.

Auditory Hallucination This is a clinically documented manifestation of focal seizure activity; symptom-specific network intermediates are not established by the cited experimental models.

Focal to Bilateral Tonic-Clonic Seizures This is a clinically documented manifestation of focal seizure activity; symptom-specific network intermediates are not established by the cited experimental models.

Focal Visual Seizures This is a clinically documented manifestation of focal seizure activity; symptom-specific network intermediates are not established by the cited experimental models.

Focal Olfactory Seizures This is a clinically documented manifestation of focal seizure activity; symptom-specific network intermediates are not established by the cited experimental models.

Focal Vestibular Seizures This is a clinically documented manifestation of focal seizure activity; symptom-specific network intermediates are not established by the cited experimental models.

Focal Autonomic Seizures This is a clinically documented manifestation of focal seizure activity; symptom-specific network intermediates are not established by the cited experimental models.

Focal Impaired Awareness Seizures This is a clinically documented manifestation of focal seizure activity; symptom-specific network intermediates are not established by the cited experimental models.

Noise-Triggered Reflex Seizures This is a clinically documented manifestation of focal seizure activity; symptom-specific network intermediates are not established by the cited experimental models.

Show evidence (1 reference)

PMID:28142128 SUPPORT DIRECT BACKGROUND Human Clinical

"Autosomal dominant lateral temporal epilepsy (ADLTE) otherwise known as autosomal dominant partial epilepsy with auditory features (ADPEAF) is a genetic focal epileptic syndrome characterized by the onset at any age, but with preponderance in young adults, of focal seizures, either with or..."

Clinical syndrome description, not an experimental localization study.

Heterozygous RELN Variants

Heterozygous pathogenic RELN variants cause a reduced-penetrance ADEAF form. Clinical similarity to LGI1 disease does not demonstrate a common molecular route.

Downstream

Reduced Reelin Secretion Variant expression produces a secretion defect in the studied cell assay.

Increased Mutant Reelin Autophagic Processing Overexpressed mutant proteins increase LC3 flux in the studied cells.

Show evidence (1 reference)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC4457960/ SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In total, we identified seven ... mutations, each in a different ADLTE-affected family."

Selected-family genetic evidence supports the RELN association.

Reduced Reelin Secretion

Selected epilepsy-associated mutant reelin proteins show impaired trafficking and reduced secretion in transfected-cell assays. A loss of extracellular function is a proposed epileptogenic mechanism, without direct measurement of the corresponding patient brain pathway.

protein secretion GO:0009306 ↓ DECREASED

Experimental models

Mutant reelin trafficking and autophagy cell assays CELL LINE Mutant-protein secretion is reduced in the reported assay.

Downstream

Reduced Circulating Reelin Cellular secretion results provide a plausible explanation for reduced circulating protein, but the patients and source tissues were not experimentally manipulated.

Epileptic Network Activity Reduced extracellular reelin function is a candidate link between the familial variants and epilepsy; developmental versus adult synaptic intermediates remain unproven.

Show evidence (1 reference)

PMID:34508592 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Using a cell-based secretion assay, we show that pathogenic RELN mutations abolish or significantly reduce secretion of mutant proteins and that this secretion defect results from impaired trafficking of mutant Reelin along the secretory pathway."

Direct cell-assay result reported in an abstract-only source; precise constructs and culture conditions were not recoverable.

Increased Mutant Reelin Autophagic Processing

Mutant reelin overexpression is associated with autophagy-marker accumulation and increased LC3 flux in a cell model. The experiment does not establish that autophagy is the sole cause of reduced secretion or a clinical treatment target.

Experimental models

Mutant reelin trafficking and autophagy cell assays CELL LINE LC3 immunoblotting reports increased flux under mutant overexpression.

Show evidence (1 reference)

PMID:34508592 SUPPORT DIRECT PRIMARY RESULT In Vitro

"In addition, LC3 immunoblotting shows a significant increase of autophagy flux due to mutant overexpression."

Reported LC3 flux response in transfected cells, not a patient neuronal measurement.

Reduced Circulating Reelin

Immunoblotting in four variant carriers showed reduced serum 310-kDa reelin relative to controls, with four assay experiments. Brain secretion and signaling were not directly measured; a serum concentration is not equivalent to a neuronal mechanism.

Show evidence (1 reference)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC4457960/ SUPPORT DIRECT PRIMARY RESULT Human Clinical

"the amount of the 310-kDa Reelin isoform was remarkably ... lower in the sera from these affected individuals than in ... the sera from control individuals"

Patient serum protein observation; largely liver-derived circulating protein is not a direct brain secretion assay.

Heterozygous MICAL1 Variants

Selected heterozygous MICAL1 variants are associated with familial or de novo auditory-feature epilepsy. Functional gain-of-function support is variant specific; rare variants with normal assays remain uncertain.

Downstream

Increased MICAL1 Oxidoreductase Activity Selected variant constructs increase the measured enzyme-activity proxy in cell assays.

Show evidence (2 references)

url:https://dspace.library.uu.nl/bitstreams/27d672f3-83aa-4bb8-9ef7-6eed404b9335/download SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We found two pathogenic MICAL-1 variants in 28 families (7%) diagnosed with ADLTE."

Selected familial genetic result, with preliminary yield and one co-segregating GRIN2A variant caveat.

PMID:20301709 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"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."

MICAL1 is included among recognized molecular diagnostic genes.

Increased MICAL1 Oxidoreductase Activity

Selected variants increase NADPH-dependent H2O2 production in transfected-cell lysate assays. COS7 cell contraction provides a separate morphology proxy. These findings support altered MICAL1 regulation without directly demonstrating neuronal actin oxidation, axon guidance or patient synaptic dysfunction.

Experimental models

MICAL1 transfected-cell activity and morphology assays CELL LINE Selected variant constructs increase an indirect oxidoreductase-activity readout.

Downstream

Epileptic Network Activity A contribution through altered cytoskeletal regulation is proposed; actin, circuit and clinical intermediates have not been causally resolved.

Show evidence (2 references)

PMID:38654463 SUPPORT DIRECT PRIMARY RESULT In Vitro

"To determine the effects of the p.Arg915Cys variant on MICAL‐1 redox activity, we used an indirect enzyme‐linked assay that measures H2O2 production."

HEK293T lysate H2O2 production is an enzyme-activity proxy, not a direct neuronal F-actin assay.

PMID:38654463 SUPPORT DIRECT PRIMARY RESULT In Vitro

"We found that the oxidoreductase activities of human (hMICAL‐1Arg915Cys) and mouse (mMICAL‐1Arg902Cys) mutants were significantly increased"

Variant-dependent activity increase in transfected-cell lysates.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

11

Head and Neck 1

Focal Olfactory Seizures Focal sensory seizure with olfactory features HP:0011161

Show evidence (1 reference)

PMID:20301709 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Less commonly, other ictal symptoms may occur, including sensory symptoms (visual, olfactory, vertiginous, or cephalic) or motor, psychic, and autonomic symptoms."

GeneReviews includes this ictal symptom class; no quantitative frequency is inferred.

Nervous System 10

Focal Sensory Seizure with Auditory Features HP:0011158

Show evidence (1 reference)

PMID:20301709 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"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)."

Defines the auditory seizure spectrum without assigning a frequency band.

Ictal Receptive Aphasia Focal cognitive seizure with receptive dysphasia/aphasia HP:0032696

Show evidence (1 reference)

PMID:20301709 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Ictal receptive aphasia consists of a sudden onset of inability to understand language in the absence of general confusion."

Defines the receptive-language ictal phenotype.

Auditory Hallucination HP:0008765

Show evidence (1 reference)

PMID:20301709 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"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)."

Complex songs or voices are included in the clinical auditory spectrum; “less common” does not define a numeric frequency.

Focal to Bilateral Tonic-Clonic Seizures Bilateral tonic-clonic seizure with focal onset HP:0007334

Show evidence (1 reference)

PMID:28142128 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Overall, focal seizures without impairment of consciousness were reported by 10 patients (41%), focal seizures with impairment of consciousness by 6 patients (25%) and focal seizures evolving to tonic–clonic seizures by 16 patients (67%)."

Directly documented focal evolution in the selected 24-person RELN clinical series, not the broader convulsion total.

Focal Visual Seizures Focal sensory seizure with visual features HP:0011165

Show evidence (1 reference)

PMID:20301709 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Less commonly, other ictal symptoms may occur, including sensory symptoms (visual, olfactory, vertiginous, or cephalic) or motor, psychic, and autonomic symptoms."

GeneReviews includes this ictal symptom class; no quantitative frequency is inferred.

Focal Vestibular Seizures Focal sensory seizure with vestibular features HP:0032759

Show evidence (1 reference)

PMID:20301709 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Less commonly, other ictal symptoms may occur, including sensory symptoms (visual, olfactory, vertiginous, or cephalic) or motor, psychic, and autonomic symptoms."

GeneReviews includes this ictal symptom class; no quantitative frequency is inferred.

Focal Autonomic Seizures HP:0011154

Show evidence (1 reference)

PMID:20301709 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Less commonly, other ictal symptoms may occur, including sensory symptoms (visual, olfactory, vertiginous, or cephalic) or motor, psychic, and autonomic symptoms."

GeneReviews includes this ictal symptom class; no quantitative frequency is inferred.

Interictal EEG Abnormality HP:0002353

Show evidence (1 reference)

PMID:28142128 SUPPORT DIRECT PRIMARY RESULT 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."

The reported percentage concerns the 15 available RELN recordings, not all carriers or an umbrella frequency.

Focal Impaired Awareness Seizures HP:0002384

Show evidence (1 reference)

PMID:28142128 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"focal seizures with impairment of consciousness by 6 patients (25%)"

Direct category count in the selected RELN clinical cohort.

Noise-Triggered Reflex Seizures HP:0020207

Show evidence (1 reference)

PMID:28142128 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Sudden noises and noisy environments could precipitate the seizures in 2 cases (8%) belonging to 2 families."

Selected RELN family observations support sound-triggered seizures without a disease-wide band.

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Genetic Associations

3

LGI1

Gene: LGI1 hgnc:6572 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:20301709 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"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 the established molecular diagnostic genes.

PMID:18711109 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Overall penetrance was 67% (95% CI 55-77%), and did not vary according to mutation type or location within the gene."

Selected pedigree penetrance analysis; null comparisons do not establish equivalence or secretion-class-specific effects.

RELN

Gene: RELN hgnc:9957 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC4457960/ SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In total, we identified seven ... mutations, each in a different ADLTE-affected family."

Familial genetic evidence in a selected discovery cohort.

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC4457960/ SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In the families we studied, 20/33 (60%) of individuals carrying one of these mutations have epilepsy"

Selected-family carrier observation, not population penetrance.

MICAL1

Gene: MICAL1 hgnc:20619 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:20301709 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"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."

GeneReviews recognizes MICAL1 as a molecular cause.

url:https://dspace.library.uu.nl/bitstreams/27d672f3-83aa-4bb8-9ef7-6eed404b9335/download SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We found two pathogenic MICAL-1 variants in 28 families (7%) diagnosed with ADLTE."

Preliminary yield in a selected LGI1/RELN-negative familial cohort, with functional and segregation caveats retained.

PMID:38654463 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Here, we describe a de novo MICAL-1 pathogenic variant, p.Arg915Cys, in a sporadic case, an affected 21-year-old Italian man with no family history of epilepsy."

A later single de novo case expands the reported allelic series.

💊

Medical Actions

7

Standard Antiseizure Medication

Action: Pharmacotherapy NCIT:C15986

Agent: carbamazepine CHEBI:3387

Platform: Small molecule

Treat focal seizures with an antiseizure medication selected by an experienced neurologist for seizure type, comorbidity, interactions and reproductive considerations. Carbamazepine has historically been used with benefit, but comparative ADEAF-specific trials do not establish a uniquely preferred drug. Many patients respond to monotherapy; persistent seizures and withdrawal decisions require reassessment.

Mechanism Target:

INHIBITS Focal Seizures with Auditory Features — Symptomatic seizure suppression; no correction of the inherited molecular defect is implied.

Show evidence (1 reference)

PMID:20301709 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Seizure control is usually readily achieved with standard anti-seizure medications (ASM)."

Clinical treatment-response synthesis supports symptomatic seizure suppression.

Show evidence (3 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1537/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Standardized treatment w/ASM by epileptologist or experienced neurologist"

GeneReviews clinical recommendation based on author experience.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1537/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Traditionally sodium channel blockers such as carbamazepine have been more frequently used with clear benefit."

Historical clinical use, not a head-to-head efficacy ranking.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1537/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"However, no clinical trials of different anti-seizure medications have been carried out"

The chapter reports no comparative ADEAF-specific antiseizure medication trial.

4-Phenylbutyrate (Investigational Chemical Chaperone)

Action: Pharmacotherapy NCIT:C15986

Agent: 4-phenylbutyric acid CHEBI:41500

Platform: Small molecule

Preclinical, allele-specific chemical-corrector research, not established clinical care. Earlier experiments reported 4PBA rescue of LGI1 E383A folding/binding and mouse seizure susceptibility. In a later biallelic-LGI1 study, 5 mM/72 h 4PBA increased secretion of C48F and wild type but reduced secretion of S524P and a terminal-extension variant in HEK293T cells. No human treatment or seizure-rescue outcome was measured in that later study; a secretion-defective label alone does not predict benefit.

Mechanism Target:

RESTORES Reduced LGI1 Secretion — Partial rescue of secretion is demonstrated only for selected alleles and preparations; other alleles worsen.

Show evidence (1 reference)

PMID:25485908 SUPPORT DIRECT PRIMARY RESULT 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."

Allele-specific preclinical intervention; the abstract combines cellular correction and mouse seizure susceptibility.

Show evidence (2 references)

PMID:25485908 SUPPORT DIRECT PRIMARY RESULT 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."

Allele-specific preclinical intervention; the abstract combines cellular correction and mouse seizure susceptibility.

PMID:40455867 SUPPORT DIRECT PRIMARY RESULT In Vitro

"We found that treatment with 4PBA (5 mM) for 72 h significantly increased the secretion of LGI1 Cys48Phe as well as WT, whereas it reduced the secretion of Ser524Pro and Ter558GlyextTer23 (Supplementary Fig. 4B)."

Later HEK293T experiments show opposite responses across alleles, without human efficacy evidence.

Seizure and neurocognitive surveillance

Action: Supportive Care NCIT:C15747

Platform: Behavioral / lifestyle

Monitor seizure control and medication effects at clinical visits, with assessment of memory, attention, development or psychiatric symptoms when indicated. Surveillance detects evolving needs and does not itself modify a molecular mechanism.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1537/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"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."

Clinical surveillance guidance, including ongoing seizure monitoring.

Seizure education and safety planning

Action: Supportive Care NCIT:C15747

Platform: Behavioral / lifestyle

Teach patients and caregivers to recognize focal and convulsive seizures, provide appropriate first aid and plan individualized precautions for activities that could cause injury during a seizure.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1537/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Education of parents/caregivers regarding common seizure presentations is appropriate."

GeneReviews recommends seizure-recognition education; safety advice is individualized.

Genetic counseling and family evaluation

Action: Supportive Care NCIT:C15747

Platform: Behavioral / lifestyle

Explain dominant transmission, reduced penetrance, variant uncertainty and reproductive options; offer family-specific molecular evaluation when the causal variant is established. A positive predictive test does not determine age at onset or severity.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1537/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"To inform affected persons & their families re nature, MOI, & implications of ADEAF to facilitate medical & personal decision making"

Genetics-professional counseling recommendation.

Preconception antiseizure medication review

Action: Supportive Care NCIT:C15747

Platform: Behavioral / lifestyle

Discuss medication benefits and reproductive risks before pregnancy and consider an appropriate lower-risk regimen when feasible. Decisions remain individualized; seizure control should be maintained with specialist input.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1537/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"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."

GeneReviews preconception risk-benefit guidance.

Psychiatric and family support

Action: Supportive Care NCIT:C15747

Platform: Behavioral / lifestyle

Assess psychiatric comorbidity and provide standard treatment when needed; arrange family resources, care coordination and transition planning. These are needs-based services, not universal manifestations.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1537/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Ensure appropriate social work involvement to connect families w/local resources& support."

GeneReviews family-support recommendation.

🔬

Biochemical Markers

1

Circulating reelin (DECREASED)

Context: Reduced serum 310-kDa reelin was measured in four variant carriers compared with controls, with repeated assay experiments. Circulating reelin largely reflects liver production. This small research assay is not a validated diagnostic, prognostic or brain-function biomarker.

Pathograph Readouts

Readout Of Reduced Circulating Reelin

A lower band measurement reflects the circulating-protein observation, not a direct brain secretion measurement.

Show evidence (1 reference)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC4457960/ SUPPORT DIRECT PRIMARY RESULT Human Clinical

"the amount of the 310-kDa Reelin isoform was remarkably ... lower in the sera from these affected individuals than in ... the sera from control individuals"

Patient serum protein observation; largely liver-derived circulating protein is not a direct brain secretion assay.

Show evidence (1 reference)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC4457960/ SUPPORT DIRECT PRIMARY RESULT Human Clinical

"the amount of the 310-kDa Reelin isoform was remarkably ... lower in the sera from these affected individuals than in ... the sera from control individuals"

Patient serum protein observation; largely liver-derived circulating protein is not a direct brain secretion assay.

🔬

Diagnosis

4

Electroclinical history and pedigree assessment

Ask specifically about brief stereotyped auditory experiences, sudden receptive-language failure, impaired awareness, convulsions, triggers and family history. Interview apparently unaffected relatives when appropriate, because subtle focal seizures may be overlooked. History, EEG, imaging and molecular testing are interpreted together.

Diagnostic Procedure NCIT:C18020

Show evidence (2 references)

PMID:20301709 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"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)."

Characterizes the sensory symptoms that require specific questioning.

PMID:20301709 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Ictal receptive aphasia consists of a sudden onset of inability to understand language in the absence of general confusion."

Distinguishes receptive aphasia from nonspecific confusion.

Molecular genetic testing

Use a phenotype-informed epilepsy panel including LGI1, RELN and MICAL1, with deletion/duplication or exome/genome testing as appropriate. A heterozygous pathogenic or likely pathogenic variant concordant with the phenotype can establish the molecular diagnosis. A VUS is not diagnostic; a negative result does not exclude a clinically defined syndrome. Absent family history can reflect reduced penetrance or a de novo variant.

Molecular Analysis NCIT:C19770

Results: A phenotype-concordant pathogenic or likely pathogenic variant; negative or uncertain results require clinical interpretation.

Show evidence (1 reference)

PMID:20301709 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"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

EEG can demonstrate temporal epileptiform abnormalities or focal slowing. Normal interictal EEG does not exclude ADEAF. Small selected genotype comparisons do not justify a stable RELN-left/LGI1-other rule or imply that EEG is the only informative investigation.

Electroencephalography NCIT:C38054

Results: Temporal epileptiform discharges, focal slowing or a normal recording.

Show evidence (1 reference)

PMID:28142128 SUPPORT DIRECT PRIMARY RESULT 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."

Available-recording result in a selected RELN family cohort, not an umbrella diagnostic sensitivity estimate.

Brain MRI

High-resolution MRI evaluates structural causes of focal epilepsy. A normal MRI is part of consensus clinical criteria and is usual in ADEAF, but reported genetically affected individuals can have imaging abnormalities. A detected lesion requires assessment of its clinical relevance rather than an automatic exclusion of genetic disease.

Magnetic Resonance Imaging NCIT:C16809

Results: Often normal; evaluate any lesion in the electroclinical and genetic context.

Show evidence (1 reference)

PMID:20301709 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"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 usually between 10 and 30 years, with wider ages documented in selected families. Typical dominant disease has preserved prior development; neonatal developmental encephalopathy should prompt a broader or allelic differential.

Show evidence (1 reference)

PMID:20301709 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Age at onset is usually in adolescence or early adulthood (age 10-30 years)."

Gives the characteristic age-at-onset window for the syndrome.

Variable seizure control and remission

Many affected individuals respond to standard medication, but drug resistance and relapse after withdrawal occur. A broader EAF cohort of 123 patients (68.3% sporadic), followed a median 11 years, reported 42/123 with terminal remission. Its definition was at least five consecutive seizure-free years at last follow-up, not necessarily off medication; this is not an ADEAF-specific prognosis estimate.

Show evidence (2 references)

PMID:20301709 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Seizure control is usually readily achieved with standard anti-seizure medications (ASM)."

Clinical review describes typical treatment response without guaranteeing it.

PMID:29464704 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"At last assessment, 42 patients had achieved TR (34.1%)."

Broader EAF cohort outcome, not medication-free remission or familial-only prognosis.

📊

Prevalence

1

Worldwide

Population prevalence is not established. Brief unrecognized auditory seizures and incomplete penetrance complicate ascertainment.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1537/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The prevalence of ADEAF is unknown but likely very low."

GeneReviews explicitly reports unknown prevalence; no numerical population rate is inferred.

🔀

Differential Diagnoses

4

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

Anti-LGI1 Autoimmune Encephalitis

Overlapping Features Acquired LGI1-antibody limbic encephalitis is distinct from inherited ADEAF. Prominent subacute memory impairment, faciobrachial dystonic seizures, hyponatremia and antibodies support this differential; the usual response to immunotherapy does not justify immunotherapy for inherited ADEAF.

Distinguishing Features

Acquired, usually subacute presentation rather than a Mendelian syndrome; absent family history alone is not discriminating.
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 DIRECT BACKGROUND Human Clinical

"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.

Other Epilepsies with Auditory Features

Overlapping Features Broad EAF includes nonfamilial, structural and other genetic focal epilepsies. SCN1A and DEPDC5 findings in heterogeneous families, and one proposed KCNQ2-associated EAF case, do not establish the same narrow familial ADEAF syndrome or a shared LGI1 mechanism. Conversely, de novo variants and reduced penetrance allow molecular ADEAF without an affected parent.

Distinguishing Features

Interpret electroclinical and imaging findings with the gene-specific phenotype.
A negative family history or panel does not by itself classify an individual outside ADEAF.

Show evidence (2 references)

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.

PMID:39796146 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The phenotypes observed in the affected members of family 1, which shared the c.2251T>G variant, were epilepsy with auditory features (EAFs), focal epilepsy, and generalized epilepsy, and none of them suffered from neonatal seizures."

One proposed KCNQ2-associated EAF proband in a phenotypically heterogeneous family; no channel functional assay establishes a shared ADEAF mechanism.

Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis

Overlapping Features Mesial temporal lobe epilepsy can produce experiential, autonomic or olfactory symptoms and may be associated with hippocampal sclerosis. Auditory symptoms favor a lateral temporal network but are not an infallible anatomical discriminator.

Distinguishing Features

Mesial experiential or epigastric symptoms may predominate.
High-resolution MRI may demonstrate hippocampal sclerosis.
Clinical localization and treatment response require individual evaluation.

Show evidence (1 reference)

PMID:35153984 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"EAF phenotype is characterized by seizures with auditory symptoms or aphasia, suggesting a lateral temporal lobe involvement."

Review localizes the characteristic auditory/language phenotype, while other focal syndromes require differential assessment.

Biallelic LGI1 Developmental and Epileptic Encephalopathy

Overlapping Features A separate recessive allelic disorder was reported in six individuals from four families, with early seizures and developmental impairment. Severe homozygous mouse phenotypes therefore have a human allelic counterpart, but this does not make neonatal encephalopathy typical of dominant ADEAF.

Distinguishing Features

Biallelic rather than heterozygous LGI1 variants.
Early infantile seizures and developmental impairment.

Show evidence (1 reference)

PMID:40455867 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The clinical features available of six patients (Patients P1A–C, P2, P3 and P4) with LGI1 variants identified from four consanguineous families"

Six-person biallelic series, distinct from the usual dominant clinical syndrome.

📊

Related Datasets

1

Expression data from homozygous deletion of the Lgi1 gene in murine neural precursor-like cells geo:GSE49145

Gene-expression microarray resource comparing Large-T-antigen-immortalized neural precursor-like cultures from E13.5 Lgi1-null and wild-type mice. It is a complete-loss developmental cell model, not a patient cohort or a direct auditory-seizure assay.

Mus musculus MICROARRAY n=6 Affymetrix GeneChip Mouse Gene 1.0 ST Array

Accession, organism and six-sample metadata verified against GEO on 2026-09-21 through the sanctioned reference fetcher. The dataset summary proposes migration and synapse effects; those are not promoted into an established human causal branch without primary experimental adjudication.

Show evidence (1 reference)

GEO:GSE49145 SUPPORT DIRECT BACKGROUND In Vitro

"we first generated and immortalized neural precursor-like cells (NPC), isolated from Lgi1 null and wild type mice at E13.5 stage using Large-T antigen."

Repository description identifies the biological material and perturbation; no patient phenotype or causal migration result is inferred.

🔬

Clinical Trials

1

clinicaltrials:NCT00072813 NOT_APPLICABLE COMPLETED

Observational MRI study of familial auditory-feature epilepsy, including affected participants, unaffected relatives and healthy volunteers. Structural and functional imaging were planned; this is not a treatment trial and no clinical efficacy result is inferred from the registry summary.

Show evidence (1 reference)

clinicaltrials:NCT00072813 SUPPORT DIRECT BACKGROUND Human Clinical

"This study will examine the possible structural and functional abnormalities in patients with an inherited form of epilepsy. It will use magnetic resonance imaging (MRI)."

Registry study identity and planned imaging scope; completed status was checked separately in the live API.

🧫

Experimental Models

6

Lgi1-null acute hippocampal slices OTHER

P14–18 null and wild-type mouse hippocampal slices were studied with CA1 recordings. Miniature-event frequency and evoked AMPA/NMDA responses increased, while measured inhibitory currents and baseline intrinsic properties were similar. Enhanced spontaneous bursts were recorded in magnesium-free, low-calcium, high-potassium ACSF, which is a proconvulsant condition.

Pathograph links

Increased Excitatory Synaptic Transmission measures fidelity: unknown mEPSC frequency increases without a significant amplitude change; this is not a direct glutamate-concentration assay.

Readouts

mEPSC frequency

Direction: INCREASED

Interpretation: mEPSC frequency increases without a significant amplitude change; this is not a direct glutamate-concentration assay.

Show evidence (1 reference)

PMID:20130004 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Remarkably, however, the frequency of mEPSCs was dramatically increased in the mutant mice"

Mouse hippocampal slice readout; mEPSC frequency is not a direct extracellular glutamate-concentration measurement.

Show evidence (1 reference)

PMID:20130004 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Remarkably, however, the frequency of mEPSCs was dramatically increased in the mutant mice"

Mouse hippocampal slice readout; mEPSC frequency is not a direct extracellular glutamate-concentration measurement.

Epileptic Network Activity measures fidelity: unknown Burst frequency increases under modified proconvulsant ACSF.

Readouts

Epileptiform burst frequency

Direction: INCREASED

Interpretation: Burst frequency increases under modified proconvulsant ACSF.

Show evidence (1 reference)

PMID:20130004 SUPPORT DIRECT PRIMARY RESULT In Vitro

"the spontaneous burst discharge frequency was significantly increased in the Lgi1-mutant mice"

In this sentence the observation is in excised slices exposed to modified proconvulsant ACSF, not unprovoked whole-animal EEG.

Show evidence (1 reference)

PMID:20130004 SUPPORT DIRECT PRIMARY RESULT In Vitro

"the spontaneous burst discharge frequency was significantly increased in the Lgi1-mutant mice"

In this sentence the observation is in excised slices exposed to modified proconvulsant ACSF, not unprovoked whole-animal EEG.

Increased Intrinsic Neuronal Excitability fails to recapitulate fidelity: unknown Measured CA1 intrinsic properties are unchanged in this preparation.

Limitations: Cell region, developmental stage and preparation differ from cultured CA3 restoration experiments.

Readouts

Baseline intrinsic firing properties

Direction: UNCHANGED

Interpretation: Measured CA1 intrinsic properties are unchanged in this preparation.

Show evidence (1 reference)

PMID:20130004 SUPPORT DIRECT PRIMARY RESULT In Vitro

"These results indicate that Lgi1 mutation did not change the intrinsic properties of pyramidal neurons in the hippocampal CA1 region."

Baseline intrinsic firing, membrane potential and input resistance were unchanged in this acute-slice preparation.

Show evidence (1 reference)

PMID:20130004 SUPPORT DIRECT PRIMARY RESULT In Vitro

"These results indicate that Lgi1 mutation did not change the intrinsic properties of pyramidal neurons in the hippocampal CA1 region."

Baseline intrinsic firing, membrane potential and input resistance were unchanged in this acute-slice preparation.

Show evidence (3 references)

PMID:20130004 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Remarkably, however, the frequency of mEPSCs was dramatically increased in the mutant mice"

Mouse hippocampal slice readout; mEPSC frequency is not a direct extracellular glutamate-concentration measurement.

PMID:20130004 SUPPORT DIRECT PRIMARY RESULT In Vitro

"the spontaneous burst discharge frequency was significantly increased in the Lgi1-mutant mice"

In this sentence the observation is in excised slices exposed to modified proconvulsant ACSF, not unprovoked whole-animal EEG.

PMID:20130004 SUPPORT DIRECT PRIMARY RESULT In Vitro

"These results indicate that Lgi1 mutation did not change the intrinsic properties of pyramidal neurons in the hippocampal CA1 region."

Baseline intrinsic firing, membrane potential and input resistance were unchanged in this acute-slice preparation.

Local LGI1 restoration in organotypic hippocampal culture OTHER

Organotypic slices from P7–10 homozygous-null mice of both sexes underwent single-cell electroporation of 8–10 selected neurons per slice. Inducible LGI1 expression was assessed with CA3 recordings after three days; extracellular tagged-protein visualization used a separate six-day interval. Intrinsic recordings blocked ionotropic glutamate and GABA receptors. Current, firing and AIS Kv1.1 rescue were measured in expressing cells; nearby rheobase improved, but nearby Kv1.1 staining was not significantly increased.

Pathograph links

Reduced Kv1-Mediated D-Type Current rescues fidelity: unknown Local LGI1 expression restores the DTx-K-sensitive conductance; toxin reapplication supports a channel contribution to intrinsic rescue.

Readouts

DTx-K-sensitive conductance

Direction: RESTORED

Interpretation: Local LGI1 expression restores the DTx-K-sensitive conductance; toxin reapplication supports a channel contribution to intrinsic rescue.

Show evidence (2 references)

PMID:37863654 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Here, we show that 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."

Restoration in organotypic mouse hippocampal neurons supports a Kv1-related excitability mechanism; this is not a human treatment.

+ 1 more reference

Show evidence (2 references)

PMID:37863654 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Here, we show that 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."

Restoration in organotypic mouse hippocampal neurons supports a Kv1-related excitability mechanism; this is not a human treatment.

+ 1 more reference

Reduced Axon Initial Segment Kv1.1 Density rescues fidelity: unknown AIS Kv1.1 immunostaining recovers in expressing neurons; significant density rescue was not demonstrated in neighboring neurons.

Readouts

AIS Kv1.1 staining

Direction: RESTORED

Interpretation: AIS Kv1.1 immunostaining recovers in expressing neurons; significant density rescue was not demonstrated in neighboring neurons.

Show evidence (1 reference)

PMID:37863654 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Here, we show that 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."

Restoration in organotypic mouse hippocampal neurons supports a Kv1-related excitability mechanism; this is not a human treatment.

Show evidence (1 reference)

PMID:37863654 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Here, we show that 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."

Restoration in organotypic mouse hippocampal neurons supports a Kv1-related excitability mechanism; this is not a human treatment.

Increased Intrinsic Neuronal Excitability rescues fidelity: unknown Current-evoked excitability decreases after local expression in deficient CA3 cells.

Readouts

Intrinsic neuronal firing

Direction: DECREASED

Interpretation: Current-evoked excitability decreases after local expression in deficient CA3 cells.

Show evidence (1 reference)

PMID:37863654 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Here, we show that 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."

Restoration in organotypic mouse hippocampal neurons supports a Kv1-related excitability mechanism; this is not a human treatment.

Show evidence (1 reference)

PMID:37863654 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Here, we show that 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."

Restoration in organotypic mouse hippocampal neurons supports a Kv1-related excitability mechanism; this is not a human treatment.

Shortened Axon Initial Segment rescues fidelity: unknown AIS length recovers partially, without evidence that shortening causes the firing phenotype.

Readouts

AIS length

Direction: INCREASED

Interpretation: AIS length recovers partially, without evidence that shortening causes the firing phenotype.

Show evidence (1 reference)

PMID:37863654 SUPPORT DIRECT PRIMARY RESULT In Vitro

"We show that rescuing the Lgi1 expression in LGI1-deficient neurons was sufficient to partially suppress the AIS length shortening"

AIS structural rescue is partial and distinct from the current and firing endpoints.

Show evidence (1 reference)

PMID:37863654 SUPPORT DIRECT PRIMARY RESULT In Vitro

"We show that rescuing the Lgi1 expression in LGI1-deficient neurons was sufficient to partially suppress the AIS length shortening"

AIS structural rescue is partial and distinct from the current and firing endpoints.

Counts generally represent neurons or AIS objects; animal/slice hierarchy is not explicit for each comparison. No human allele, patient-derived cell, selective secretion blockade, ADAM22 mediation experiment, living-animal seizure reduction or clinical efficacy was tested. Paracrine spread is supported but autocrine versus intracellular contributions remain unresolved.

Show evidence (3 references)

PMID:37863654 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Here, we show that 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."

Restoration in organotypic mouse hippocampal neurons supports a Kv1-related excitability mechanism; this is not a human treatment.

PMID:37863654 SUPPORT DIRECT PRIMARY RESULT In Vitro

"We show that rescuing the Lgi1 expression in LGI1-deficient neurons was sufficient to partially suppress the AIS length shortening"

AIS structural rescue is partial and distinct from the current and firing endpoints.

PMID:37863654 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The effect of LGI1 rescue on synaptic function has not been tested in the present study."

The current study measures intrinsic electrophysiology, not synaptic or network-seizure rescue.

LGI1 variant secretion and receptor-binding cell assays CELL_LINE

Transfected-cell assays distinguish secretion-defective E383A from secretion-competent S473L with altered ADAM22 interaction. Later HEK293T secretion and COS7 binding assays studied biallelic-encephalopathy variants: C48F, S524P and a terminal extension. All had reduced net binding, while inferred relative binding differed; these assays did not determine an equilibrium affinity constant. Four-phenylbutyrate responses were allele dependent and were not human treatment outcomes.

Pathograph links

Reduced LGI1 Secretion measures fidelity: unknown Cell-medium protein assays quantify reduced secretion for selected constructs.

Readouts

Secreted LGI1

Direction: DECREASED

Interpretation: Cell-medium protein assays quantify reduced secretion for selected constructs.

Show evidence (2 references)

PMID:25485908 SUPPORT DIRECT PRIMARY RESULT In Vitro

"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."

The abstract reports distinct cellular defects for two variants; neither mechanism is assumed universal.

+ 1 more reference

Show evidence (2 references)

PMID:25485908 SUPPORT DIRECT PRIMARY RESULT In Vitro

"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."

The abstract reports distinct cellular defects for two variants; neither mechanism is assumed universal.

+ 1 more reference

Reduced LGI1-ADAM22 Binding measures fidelity: unknown The S473L construct shows an interaction defect distinct from secretion failure.

Readouts

LGI1-ADAM22 interaction

Direction: DECREASED

Interpretation: The S473L construct shows an interaction defect distinct from secretion failure.

Show evidence (1 reference)

PMID:25485908 SUPPORT DIRECT PRIMARY RESULT In Vitro

"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."

The abstract reports distinct cellular defects for two variants; neither mechanism is assumed universal.

Show evidence (1 reference)

PMID:25485908 SUPPORT DIRECT PRIMARY RESULT In Vitro

"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."

The abstract reports distinct cellular defects for two variants; neither mechanism is assumed universal.

Heterologous overexpression and distinct dominant versus biallelic alleles limit direct translation. Five mM 4PBA for 72 hours increased C48F and wild-type secretion but reduced S524P and terminal-extension secretion in the later study.

Show evidence (3 references)

PMID:25485908 SUPPORT DIRECT PRIMARY RESULT In Vitro

"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."

The abstract reports distinct cellular defects for two variants; neither mechanism is assumed universal.

PMID:40455867 SUPPORT DIRECT PRIMARY RESULT In Vitro

"We found differently reduced secretion levels of Cys48Phe, Ser524Pro and Ter558GlyextTer23 variants ∼6.7%, 0.5% and 40% (median, compared to LGI1 WT), respectively (Fig. 1E)."

HEK293T conditioned-medium assay measures variant-specific secretion, not neuronal firing.

PMID:40455867 SUPPORT DIRECT PRIMARY RESULT In Vitro

"We found that treatment with 4PBA (5 mM) for 72 h significantly increased the secretion of LGI1 Cys48Phe as well as WT, whereas it reduced the secretion of Ser524Pro and Ter558GlyextTer23 (Supplementary Fig. 4B)."

Opposite 4PBA secretion responses across alleles preclude class-wide rescue prediction.

Excised intact Lgi1-null hippocampus OTHER

Whole hippocampi from P16–18 homozygous-null mice were studied with CA3 patch and local-field recordings. Abnormal network barrages and oscillations occurred in an isolated preparation without afferents from other brain regions. Baseline spontaneous EPSC/IPSC distributions and sampled intrinsic membrane properties were unchanged. The separate Adam22 mutant behavioral arm of this paper is not an Lgi1 behavioral-rescue experiment.

Pathograph links

Epileptic Network Activity measures fidelity: unknown The isolated preparation supports an intrahippocampal source of the observed abnormal discharges.

Readouts

Epileptic network discharges

Direction: INCREASED

Interpretation: The isolated preparation supports an intrahippocampal source of the observed abnormal discharges.

Show evidence (1 reference)

PMID:40455867 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Because this recording was obtained from a whole hippocampus without afferents from other brain regions, this suggests that epileptic discharges originate in the hippocampus in Lgi1−/− mice."

Excised whole-hippocampus recordings localize abnormal network activity within that preparation.

Show evidence (1 reference)

PMID:40455867 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Because this recording was obtained from a whole hippocampus without afferents from other brain regions, this suggests that epileptic discharges originate in the hippocampus in Lgi1−/− mice."

Excised whole-hippocampus recordings localize abnormal network activity within that preparation.

Increased Intrinsic Neuronal Excitability fails to recapitulate fidelity: unknown The baseline intrinsic properties sampled in this intact preparation were not different.

Limitations: This is not equivalent to every evoked-current test and differs from organotypic culture; absence of a baseline difference does not negate network abnormalities.

Readouts

Baseline intrinsic membrane properties

Direction: UNCHANGED

Interpretation: The baseline intrinsic properties sampled in this intact preparation were not different.

Show evidence (1 reference)

PMID:40455867 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The intrinsic electrical properties of CA3 neurons, such as membrane capacitance, input resistance, resting membrane potential and membrane time constant (Tau) were not different between genotypes (Supplementary Table 3)."

Baseline intrinsic membrane properties did not differ in the sampled CA3 neurons.

Show evidence (1 reference)

PMID:40455867 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The intrinsic electrical properties of CA3 neurons, such as membrane capacitance, input resistance, resting membrane potential and membrane time constant (Tau) were not different between genotypes (Supplementary Table 3)."

Baseline intrinsic membrane properties did not differ in the sampled CA3 neurons.

Show evidence (3 references)

PMID:40455867 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Because this recording was obtained from a whole hippocampus without afferents from other brain regions, this suggests that epileptic discharges originate in the hippocampus in Lgi1−/− mice."

Excised whole-hippocampus recordings localize abnormal network activity within that preparation.

PMID:40455867 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The cumulative frequency distribution of amplitude and inter-event interval (IEI) in sEPSCs and sIPSCs showed no significant difference between WT and Lgi1−/− mice (Fig. 2B)."

Baseline spontaneous excitatory and inhibitory events were not significantly different between genotypes.

PMID:40455867 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The intrinsic electrical properties of CA3 neurons, such as membrane capacitance, input resistance, resting membrane potential and membrane time constant (Tau) were not different between genotypes (Supplementary Table 3)."

Baseline intrinsic membrane properties did not differ in the sampled CA3 neurons.

Mutant reelin trafficking and autophagy cell assays CELL_LINE

A cell-based overexpression study reported impaired mutant trafficking and secretion with increased LC3 autophagy flux. Partial pharmacologic rescue of secretion was reported, but the available abstract does not establish the precise culture, constructs, compounds or a neuronal-seizure rescue. No mandatory autophagy-to-secretion causal sequence is imposed.

Pathograph links

Reduced Reelin Secretion measures fidelity: unknown Mutant-protein secretion is reduced in the reported assay.

Readouts

Secreted mutant reelin

Direction: DECREASED

Interpretation: Mutant-protein secretion is reduced in the reported assay.

Show evidence (1 reference)

PMID:34508592 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Using a cell-based secretion assay, we show that pathogenic RELN mutations abolish or significantly reduce secretion of mutant proteins and that this secretion defect results from impaired trafficking of mutant Reelin along the secretory pathway."

Direct cell-assay result reported in an abstract-only source; precise constructs and culture conditions were not recoverable.

Show evidence (1 reference)

PMID:34508592 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Using a cell-based secretion assay, we show that pathogenic RELN mutations abolish or significantly reduce secretion of mutant proteins and that this secretion defect results from impaired trafficking of mutant Reelin along the secretory pathway."

Direct cell-assay result reported in an abstract-only source; precise constructs and culture conditions were not recoverable.

Increased Mutant Reelin Autophagic Processing measures fidelity: unknown LC3 immunoblotting reports increased flux under mutant overexpression.

Readouts

LC3 autophagy flux

Direction: INCREASED

Interpretation: LC3 immunoblotting reports increased flux under mutant overexpression.

Show evidence (1 reference)

PMID:34508592 SUPPORT DIRECT PRIMARY RESULT In Vitro

"In addition, LC3 immunoblotting shows a significant increase of autophagy flux due to mutant overexpression."

Reported LC3 flux response in transfected cells, not a patient neuronal measurement.

Show evidence (1 reference)

PMID:34508592 SUPPORT DIRECT PRIMARY RESULT In Vitro

"In addition, LC3 immunoblotting shows a significant increase of autophagy flux due to mutant overexpression."

Reported LC3 flux response in transfected cells, not a patient neuronal measurement.

Show evidence (2 references)

PMID:34508592 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Using a cell-based secretion assay, we show that pathogenic RELN mutations abolish or significantly reduce secretion of mutant proteins and that this secretion defect results from impaired trafficking of mutant Reelin along the secretory pathway."

Direct cell-assay result reported in an abstract-only source; precise constructs and culture conditions were not recoverable.

PMID:34508592 SUPPORT DIRECT PRIMARY RESULT In Vitro

"In addition, LC3 immunoblotting shows a significant increase of autophagy flux due to mutant overexpression."

Reported LC3 flux response in transfected cells, not a patient neuronal measurement.

MICAL1 transfected-cell activity and morphology assays CELL_LINE

HEK293T cell-lysate Amplex assays measured NADPH-dependent H2O2 generation for selected MICAL1 variants, with separate COS7 contraction assays in the original study. G150S and the C-terminal extension increased activity, whereas R646Q was a VUS without increased activity. A later R915C assay increased the human and homologous mouse activity proxies. No neuronal actin oxidation, synapse measurement, human rescue or clinical treatment was tested.

Pathograph links

Increased MICAL1 Oxidoreductase Activity measures fidelity: unknown Selected variant constructs increase an indirect oxidoreductase-activity readout.

Readouts

Cell-lysate H2O2 production

Direction: INCREASED

Interpretation: Selected variant constructs increase an indirect oxidoreductase-activity readout.

Show evidence (2 references)

PMID:38654463 SUPPORT DIRECT PRIMARY RESULT In Vitro

"To determine the effects of the p.Arg915Cys variant on MICAL‐1 redox activity, we used an indirect enzyme‐linked assay that measures H2O2 production."

HEK293T lysate H2O2 production is an enzyme-activity proxy, not a direct neuronal F-actin assay.

+ 1 more reference

Show evidence (2 references)

PMID:38654463 SUPPORT DIRECT PRIMARY RESULT In Vitro

"To determine the effects of the p.Arg915Cys variant on MICAL‐1 redox activity, we used an indirect enzyme‐linked assay that measures H2O2 production."

HEK293T lysate H2O2 production is an enzyme-activity proxy, not a direct neuronal F-actin assay.

+ 1 more reference

The original C-terminal extension changes the final three residues and adds a novel tail; it is not deletion of the entire coiled-coil domain. One familial variant co-segregated with an unexcluded GRIN2A variant. Cell contraction is a morphology proxy, not a direct neuronal actin measurement.

Show evidence (2 references)

PMID:38654463 SUPPORT DIRECT PRIMARY RESULT In Vitro

"To determine the effects of the p.Arg915Cys variant on MICAL‐1 redox activity, we used an indirect enzyme‐linked assay that measures H2O2 production."

HEK293T lysate H2O2 production is an enzyme-activity proxy, not a direct neuronal F-actin assay.

PMID:38654463 SUPPORT DIRECT PRIMARY RESULT In Vitro

"We found that the oxidoreductase activities of human (hMICAL‐1Arg915Cys) and mouse (mMICAL‐1Arg902Cys) mutants were significantly increased"

Variant-dependent activity increase in transfected-cell lysates.

🐁

Animal Models

4

Constitutive Lgi1-null mice

Constitutive null mice develop severe early spontaneous seizures and premature death. Neuronal LGI1 transgenic expression, but not LGI3, rescued lethal epilepsy in one abstract-level study. This complete-loss model differs from reduced-penetrance heterozygous ADEAF and should not determine its usual onset or severity.

Species

Mouse

Genotype

Homozygous Lgi1 loss

Pathograph links

Epileptic Network Activity partially recapitulates fidelity: unknown Null animals exhibit lethal epilepsy, without modeling a subjective auditory aura.

Limitations: Complete knockout, early lethality and mouse circuitry differ from typical heterozygous human disease.

Readouts

Spontaneous epilepsy

Direction: INCREASED

Interpretation: Null animals exhibit lethal epilepsy, without modeling a subjective auditory aura.

Show evidence (1 reference)

PMID:20133599 SUPPORT DIRECT PRIMARY RESULT Model Organism

"We find that loss of LGI1 in mice (LGI1(-/-)) causes lethal epilepsy, which is specifically rescued by the neuronal expression of LGI1 transgene, but not LGI3."

Severe null mouse phenotype and genetic rescue establish experimental seizure relevance; they do not reproduce typical heterozygous human severity.

Show evidence (1 reference)

PMID:20133599 SUPPORT DIRECT PRIMARY RESULT Model Organism

"We find that loss of LGI1 in mice (LGI1(-/-)) causes lethal epilepsy, which is specifically rescued by the neuronal expression of LGI1 transgene, but not LGI3."

Severe null mouse phenotype and genetic rescue establish experimental seizure relevance; they do not reproduce typical heterozygous human severity.

Show evidence (1 reference)

PMID:20133599 SUPPORT DIRECT PRIMARY RESULT Model Organism

"We find that loss of LGI1 in mice (LGI1(-/-)) causes lethal epilepsy, which is specifically rescued by the neuronal expression of LGI1 transgene, but not LGI3."

Severe null mouse phenotype and genetic rescue establish experimental seizure relevance; they do not reproduce typical heterozygous human severity.

LGI1 835delC BAC transgenic mice

BAC transgenic mice expressing a patient-derived truncation were compared with wild type and a separate wild-type LGI1-overexpression line. Dentate dendritic maturation, synaptic properties and pentylenetetrazole kindling were examined. This is transgene expression, not a heterozygous knock-in; the seizure result is challenged kindling rather than demonstrated spontaneous auditory-feature epilepsy.

Species

Mouse

Genotype

Truncated 835delC transgene with endogenous Lgi1 retained

Pathograph links

Impaired Postnatal Dendritic Pruning measures fidelity: unknown Dentate granule-cell dendritic arbors retain immature branching patterns; cell maturation and synaptic changes are separable readouts.

Readouts

Persistence of dendritic branching

Direction: INCREASED

Interpretation: Dentate granule-cell dendritic arbors retain immature branching patterns; cell maturation and synaptic changes are separable readouts.

Show evidence (1 reference)

PMID:19701204 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Concurrently, mutant LGI1 inhibited dendritic pruning and increased the spine density to markedly increase excitatory synaptic transmission."

835delC BAC transgene model supports a developmental synaptic branch; it is not a heterozygous knock-in or a universal patient finding.

Show evidence (1 reference)

PMID:19701204 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Concurrently, mutant LGI1 inhibited dendritic pruning and increased the spine density to markedly increase excitatory synaptic transmission."

835delC BAC transgene model supports a developmental synaptic branch; it is not a heterozygous knock-in or a universal patient finding.

Epileptic Network Activity partially recapitulates fidelity: unknown Mutant transgene enhances susceptibility under the reported chemical-kindling protocol.

Limitations: Chemical challenge and altered transgene dosage limit transfer to spontaneous heterozygous human seizures.

Readouts

Kindling epileptogenesis

Direction: INCREASED

Interpretation: Mutant transgene enhances susceptibility under the reported chemical-kindling protocol.

Show evidence (1 reference)

PMID:19701204 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Furthermore, mutant LGI1 promoted epileptiform discharge in vitro and kindling epileptogenesis in vivo with partial gamma-aminobutyric acid(A) (GABA(A)) receptor blockade."

The paper separates slice epileptiform activity from chemically challenged in-vivo kindling.

Show evidence (1 reference)

PMID:19701204 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Furthermore, mutant LGI1 promoted epileptiform discharge in vitro and kindling epileptogenesis in vivo with partial gamma-aminobutyric acid(A) (GABA(A)) receptor blockade."

The paper separates slice epileptiform activity from chemically challenged in-vivo kindling.

Show evidence (2 references)

PMID:19701204 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Concurrently, mutant LGI1 inhibited dendritic pruning and increased the spine density to markedly increase excitatory synaptic transmission."

835delC BAC transgene model supports a developmental synaptic branch; it is not a heterozygous knock-in or a universal patient finding.

PMID:19701204 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Furthermore, mutant LGI1 promoted epileptiform discharge in vitro and kindling epileptogenesis in vivo with partial gamma-aminobutyric acid(A) (GABA(A)) receptor blockade."

The paper separates slice epileptiform activity from chemically challenged in-vivo kindling.

Glutamatergic-neuron conditional Lgi1 knockout mice

Embryonic Emx1-targeted deletion produced early lethal seizures, whereas later CaMKIIα-targeted deletion produced occasional later seizures with variable lifespan. These models support both developmental and later requirements; they do not show that a single early pruning lesion explains all disease.

Species

Mouse

Genotype

Emx1-Lgi1cKO or CaMKIIα-Lgi1cKO

Pathograph links

Epileptic Network Activity partially recapitulates fidelity: unknown Loss restricted to the studied excitatory-neuron populations is sufficient for seizures with timing-dependent severity.

Limitations: Abstract-only recovery; precise recombination completeness, strain and human-allele correspondence were not established here.

Readouts

Spontaneous seizure occurrence

Direction: INCREASED

Interpretation: Loss restricted to the studied excitatory-neuron populations is sufficient for seizures with timing-dependent severity.

Show evidence (1 reference)

PMID:25234641 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Emx1-Lgi1cKO mice displayed early-onset and lethal seizures, whereas CaMKIIα-Lgi1cKO mice presented late-onset occasional seizures associated with variable reduced lifespan."

Conditional deletion separates embryonic from later postnatal glutamatergic-neuron perturbations; details beyond the abstract are not inferred.

Show evidence (1 reference)

PMID:25234641 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Emx1-Lgi1cKO mice displayed early-onset and lethal seizures, whereas CaMKIIα-Lgi1cKO mice presented late-onset occasional seizures associated with variable reduced lifespan."

Conditional deletion separates embryonic from later postnatal glutamatergic-neuron perturbations; details beyond the abstract are not inferred.

Show evidence (1 reference)

PMID:25234641 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Emx1-Lgi1cKO mice displayed early-onset and lethal seizures, whereas CaMKIIα-Lgi1cKO mice presented late-onset occasional seizures associated with variable reduced lifespan."

Conditional deletion separates embryonic from later postnatal glutamatergic-neuron perturbations; details beyond the abstract are not inferred.

Parvalbumin-neuron conditional Lgi1 knockout mice

The tested PV-targeted deletion did not produce observed spontaneous seizures or increased convulsant susceptibility. This cell-population and protocol-specific negative result cannot exclude roles for other inhibitory neurons or assay conditions.

Species

Mouse

Genotype

PV-Lgi1cKO

Pathograph links

Epileptic Network Activity fails to recapitulate fidelity: unknown The reported seizure endpoints were not increased in the PV-targeted conditional model.

Limitations: Negative result is restricted to the targeted PV population and the reported tests; source available only as an abstract.

Readouts

Seizure susceptibility

Direction: UNCHANGED

Interpretation: The reported seizure endpoints were not increased in the PV-targeted conditional model.

Show evidence (1 reference)

PMID:25234641 SUPPORT DIRECT PRIMARY RESULT Model Organism

"In contrast, neither spontaneous seizures nor increased seizure susceptibility to convulsant were observed when Lgi1 was deleted in parvalbumin interneurons."

Negative result in the specific PV-targeted conditional model, not every inhibitory cell population.

Show evidence (1 reference)

PMID:25234641 SUPPORT DIRECT PRIMARY RESULT Model Organism

"In contrast, neither spontaneous seizures nor increased seizure susceptibility to convulsant were observed when Lgi1 was deleted in parvalbumin interneurons."

Negative result in the specific PV-targeted conditional model, not every inhibitory cell population.

Show evidence (1 reference)

PMID:25234641 SUPPORT DIRECT PRIMARY RESULT Model Organism

"In contrast, neither spontaneous seizures nor increased seizure susceptibility to convulsant were observed when Lgi1 was deleted in parvalbumin interneurons."

Negative result in the specific PV-targeted conditional model, not every inhibitory cell population.

{ }

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 focal epilepsy characterized by auditory seizures or ictal receptive aphasia, often beginning in adolescence or early adulthood. Seizures may impair awareness or evolve to bilateral tonic-clonic seizures. Neurologic examination and conventional MRI are usually normal, and many patients respond to standard antiseizure medication, although drug resistance and relapse after withdrawal occur. Heterozygous pathogenic variants in LGI1, RELN or MICAL1 establish recognized molecular forms; reduced penetrance and de novo variants can obscure family history. These genes affect distinct extracellular signaling or intracellular regulatory processes, and their downstream human epileptogenic mechanisms are incompletely resolved.
parents:
- Epilepsy
- Neurological Disease
synonyms:
- ADEAF
- autosomal dominant lateral temporal lobe epilepsy
- ADLTE
- autosomal dominant partial epilepsy with auditory features
- ADPEAF
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: Exact disease concept for the autosomal dominant syndrome characterized by auditory seizures or receptive aphasia; molecular diagnosis can be established even when family history is absent.
references:
- reference: GEO:GSE49145
title: Expression data from homozygous deletion of the Lgi1 gene in murine neural precursor-like cells
- reference: PMID:18711109
title: Penetrance of LGI1 mutations in autosomal dominant partial epilepsy with auditory features.
- reference: PMID:19701204
title: Arrested maturation of excitatory synapses in autosomal dominant lateral temporal lobe epilepsy.
- reference: PMID:20130004
title: Lgi1 null mutant mice exhibit myoclonic seizures and CA1 neuronal hyperexcitability.
- reference: PMID:20133599
title: Disruption of LGI1-linked synaptic complex causes abnormal synaptic transmission and epilepsy.
- reference: PMID:20301709
title: Autosomal Dominant Epilepsy with Auditory Features.
tags:
- GeneReviews
- reference: PMID:21829378
title: LGI2 truncation causes a remitting focal epilepsy in dogs.
- reference: PMID:25234641
title: Glutamatergic neuron-targeted loss of LGI1 epilepsy gene results in seizures.
- reference: PMID:25485908
title: Chemical corrector treatment ameliorates increased seizure susceptibility in a mouse model of familial epilepsy.
- reference: PMID:28142128
title: The clinical phenotype of autosomal dominant lateral temporal lobe epilepsy related to reelin mutations.
- reference: PMID:29464704
title: 'Epilepsy with auditory features: Long-term outcome and predictors of terminal remission.'
- reference: PMID:30346486
title: LGI1 antibodies alter Kv1.1 and AMPA receptors changing synaptic excitability, plasticity and memory.
- reference: PMID:33453592
title: 'Epilepsy with auditory features: Contribution of known genes in 112 patients.'
- reference: PMID:34508592
title: Epilepsy-causing Reelin mutations result in impaired secretion and intracellular degradation of mutant proteins.
- reference: PMID:35153984
title: 'Epilepsy With Auditory Features: From Etiology to Treatment.'
- reference: PMID:37863654
title: Rescue of Normal Excitability in LGI1-Deficient Epileptic Neurons.
- reference: PMID:38654463
title: A de novo pathogenic variant in MICAL-1 causes epilepsy with auditory features.
- reference: PMID:39796146
title: Novel KCNQ2 Variants Related to a Variable Phenotypic Spectrum Ranging from Epilepsy with Auditory Features to Severe Developmental and Epileptic Encephalopathies.
- reference: PMID:40455867
title: Biallelic LGI1 and ADAM23 variants cause hippocampal epileptic encephalopathy via the LGI1-ADAM22/23 pathway.
- reference: clinicaltrials:NCT00072813
title: MRI in Autosomal Dominant Partial Epilepsy With Auditory Features
- reference: url:https://dspace.library.uu.nl/bitstreams/27d672f3-83aa-4bb8-9ef7-6eed404b9335/download
title: https://dspace.library.uu.nl/bitstreams/27d672f3-83aa-4bb8-9ef7-6eed404b9335/download
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC4457960/
title: Heterozygous Reelin Mutations Cause Autosomal-Dominant Lateral Temporal Epilepsy - PMC
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1537/
title: Autosomal Dominant Epilepsy with Auditory Features - GeneReviews® - NCBI Bookshelf
tags:
- GeneReviews
notes: Broad epilepsy with auditory features (EAF) includes nonfamilial and structural epilepsies and is not an exact synonym for ADEAF. Conversely, absent family history does not exclude a molecular diagnosis because penetrance is incomplete and de novo variants occur. Frequencies and genetic yields from selected families, incompletely assessed cohorts and broadly ascertained EAF series are retained only with their denominators and are not converted into disease-wide phenotype bands. The 2015 RELN primary (PMID:26046367) and 2018 MICAL1 primary (PMID:29394500) are cited through generated full-text URLs; canonical PMID records are abstract-only. GeneReviews was updated in May 2024 and predates the biallelic LGI1 encephalopathy report. Experimental findings differ by allele, developmental stage, preparation and perturbation; decreased AMPA transmission is not modeled as a demonstrated cause of hyperexcitability.
pathophysiology:
- name: Heterozygous LGI1 Variants
biological_scale: MOLECULAR
description: Pathogenic heterozygous LGI1 variants cause a reduced-penetrance dominant epilepsy. Experimental allele classes include impaired secretion and impaired ligand interaction; gene dosage, altered mutant protein and complete knockout preparations are not interchangeable.
evidence:
- reference: PMID:20301709
reference_title: Autosomal Dominant Epilepsy with Auditory Features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
quote_role: REVIEW_SYNTHESIS
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: Human genetic diagnosis establishes a disease association; downstream allele-specific mechanisms are assessed separately.
downstream:
- target: Reduced LGI1 Secretion
description: Selected variants produce cellular secretion defects; the effect is allele dependent.
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: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
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: The abstract reports distinct cellular defects for two variants; neither mechanism is assumed universal.
- target: Reduced LGI1-ADAM22 Binding
description: Selected secretion-competent variants have altered ligand interaction.
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: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
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: The abstract reports distinct cellular defects for two variants; neither mechanism is assumed universal.
- target: Reduced Axon Initial Segment Kv1.1 Density
description: Null-neuron restoration supports an experimental model for LGI1-related channel localization; transfer to heterozygous patient variants is indirect.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:37863654
reference_title: Rescue of Normal Excitability in LGI1-Deficient Epileptic Neurons.
supports: SUPPORT
evidence_source: IN_VITRO
directness: INDIRECT
quote_role: PRIMARY_RESULT
snippet: Here, we show that 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.
explanation: Restoration in organotypic mouse hippocampal neurons supports a Kv1-related excitability mechanism; this is not a human treatment.
- target: Shortened Axon Initial Segment
description: A structural response in deficient cultured neurons provides an experimental hypothesis, not a documented patient lesion.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:37863654
reference_title: Rescue of Normal Excitability in LGI1-Deficient Epileptic Neurons.
supports: SUPPORT
evidence_source: IN_VITRO
directness: INDIRECT
quote_role: PRIMARY_RESULT
snippet: We show that rescuing the Lgi1 expression in LGI1-deficient neurons was sufficient to partially suppress the AIS length shortening
explanation: AIS structural rescue is partial and distinct from the current and firing endpoints.
- target: Impaired Postnatal Dendritic Pruning
description: The 835delC transgene supports one allele/model-specific developmental branch; generic dominant-negative action across LGI1 alleles is not established.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:19701204
reference_title: Arrested maturation of excitatory synapses in autosomal dominant lateral temporal lobe epilepsy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: INDIRECT
quote_role: PRIMARY_RESULT
snippet: Concurrently, mutant LGI1 inhibited dendritic pruning and increased the spine density to markedly increase excitatory synaptic transmission.
explanation: 835delC BAC transgene model supports a developmental synaptic branch; it is not a heterozygous knock-in or a universal patient finding.
- name: Reduced LGI1 Secretion
biological_scale: MOLECULAR
description: Selected pathogenic LGI1 variants reduce extracellular availability through abnormal folding, intracellular retention or degradation. E383A is one experimentally characterized example; secretion-competent pathogenic variants also occur.
evidence:
- &id001
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
directness: DIRECT
quote_role: PRIMARY_RESULT
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: The abstract reports distinct cellular defects for two variants; neither mechanism is assumed universal.
biological_processes:
- preferred_term: protein secretion
term:
id: GO:0009306
label: protein secretion
modifier: DECREASED
downstream:
- target: Disrupted LGI1-Linked Synaptic Complex
description: Reduced ligand availability or function can disrupt synaptic complex organization; exact in vivo intermediates vary by allele.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- 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
directness: INDIRECT
quote_role: PRIMARY_RESULT
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: The abstract reports distinct cellular defects for two variants; neither mechanism is assumed universal.
- reference: PMID:20133599
reference_title: Disruption of LGI1-linked synaptic complex causes abnormal synaptic transmission and epilepsy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: INDIRECT
quote_role: PRIMARY_RESULT
snippet: 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.
explanation: Mouse/biochemical study supports organization of the synaptic complex; only the abstract was recoverable.
- name: Reduced LGI1-ADAM22 Binding
biological_scale: MOLECULAR
description: Some secreted variants impair interaction with ADAM22. The S473L dimerization/binding result is distinct from secretion failure and does not define every pathogenic allele.
evidence:
- *id001
downstream:
- target: Disrupted LGI1-Linked Synaptic Complex
description: Reduced ligand availability or function can disrupt synaptic complex organization; exact in vivo intermediates vary by allele.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- 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
directness: INDIRECT
quote_role: PRIMARY_RESULT
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: The abstract reports distinct cellular defects for two variants; neither mechanism is assumed universal.
- reference: PMID:20133599
reference_title: Disruption of LGI1-linked synaptic complex causes abnormal synaptic transmission and epilepsy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: INDIRECT
quote_role: PRIMARY_RESULT
snippet: 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.
explanation: Mouse/biochemical study supports organization of the synaptic complex; only the abstract was recoverable.
- name: Disrupted LGI1-Linked Synaptic Complex
biological_scale: CELLULAR
description: LGI1 supports an extracellular complex involving ADAM22, ADAM23 and associated synaptic scaffolds. Loss of available or functional ligand can disrupt this organization. Receptor association does not make every downstream ion-channel response direct or identical across preparations.
evidence:
- &id009
reference: PMID:20133599
reference_title: Disruption of LGI1-linked synaptic complex causes abnormal synaptic transmission and epilepsy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: 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.
explanation: Mouse/biochemical study supports organization of the synaptic complex; only the abstract was recoverable.
- &id002
reference: PMID:20133599
reference_title: Disruption of LGI1-linked synaptic complex causes abnormal synaptic transmission and epilepsy.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: A lack of LGI1 disrupts this synaptic protein connection and selectively reduces AMPA receptor-mediated synaptic transmission in the hippocampus.
explanation: Abstract-level mouse hippocampal observation; physiological readout is ex vivo and differs from other preparations.
downstream:
- target: Reduced AMPA Receptor-Mediated Transmission
description: The experimental loss condition associates complex disruption with reduced AMPA-mediated transmission; this does not resolve every scaffolding intermediate.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:20133599
reference_title: Disruption of LGI1-linked synaptic complex causes abnormal synaptic transmission and epilepsy.
supports: SUPPORT
evidence_source: IN_VITRO
directness: INDIRECT
quote_role: PRIMARY_RESULT
snippet: A lack of LGI1 disrupts this synaptic protein connection and selectively reduces AMPA receptor-mediated synaptic transmission in the hippocampus.
explanation: Abstract-level mouse hippocampal observation; physiological readout is ex vivo and differs from other preparations.
- name: Reduced AMPA Receptor-Mediated Transmission
biological_scale: CELLULAR
description: Reduced AMPA receptor-mediated transmission is observed in one LGI1-null hippocampal preparation. Other genetic or antibody preparations show increased evoked excitation. This node records a preparation-specific phenotype and is not linked as a proven driver of hyperexcitability.
evidence:
- *id002
- name: Reduced Axon Initial Segment Kv1.1 Density
biological_scale: CELLULAR
description: LGI1-deficient CA3 neurons in organotypic mouse hippocampal slices show reduced AIS Kv1.1 immunostaining, reversed by local LGI1 expression. Localization and electrical current are measured separately.
evidence:
- &id003
reference: PMID:37863654
reference_title: Rescue of Normal Excitability in LGI1-Deficient Epileptic Neurons.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: Here, we show that 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.
explanation: Restoration in organotypic mouse hippocampal neurons supports a Kv1-related excitability mechanism; this is not a human treatment.
downstream:
- target: Reduced Kv1-Mediated D-Type Current
description: Density and current recover together after LGI1 restoration; localization-specific mediation is not isolated from other LGI1 effects.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:37863654
reference_title: Rescue of Normal Excitability in LGI1-Deficient Epileptic Neurons.
supports: SUPPORT
evidence_source: IN_VITRO
directness: INDIRECT
quote_role: PRIMARY_RESULT
snippet: Here, we show that 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.
explanation: Restoration in organotypic mouse hippocampal neurons supports a Kv1-related excitability mechanism; this is not a human treatment.
- name: Reduced Kv1-Mediated D-Type Current
biological_scale: CELLULAR
description: A slowly inactivating potassium-current deficit is measured in LGI1-deficient cultured mouse CA3 neurons. LGI1 restoration and Kv1 blockade support its contribution to altered excitability in this preparation.
evidence:
- *id003
downstream:
- target: Increased Intrinsic Neuronal Excitability
description: Restoration and blocker experiments support a Kv1 contribution to firing control in the cultured CA3 preparation.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:37863654
reference_title: Rescue of Normal Excitability in LGI1-Deficient Epileptic Neurons.
supports: SUPPORT
evidence_source: IN_VITRO
directness: INDIRECT
quote_role: PRIMARY_RESULT
snippet: Here, we show that 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.
explanation: Restoration in organotypic mouse hippocampal neurons supports a Kv1-related excitability mechanism; this is not a human treatment.
- reference: PMID:37863654
reference_title: Rescue of Normal Excitability in LGI1-Deficient Epileptic Neurons.
supports: SUPPORT
evidence_source: IN_VITRO
directness: INDIRECT
quote_role: PRIMARY_RESULT
snippet: However, in KO/Lgi1 neurons, bath application of DTx-k induced a loss of the ramp-and-delay phenotype (Fig. 3C) and a significant decrease of the latency to the first spike
explanation: DTx-K reverses a rescued intrinsic firing feature, supporting a Kv1 contribution without establishing human seizure mediation.
- name: Increased Intrinsic Neuronal Excitability
biological_scale: CELLULAR
description: 'LGI1-deficient CA3 neurons in organotypic culture can fire more readily, with local LGI1 restoration reducing excitability. This is not universal across cell types or preparations: other knockout studies found unchanged baseline intrinsic properties.'
evidence:
- *id003
downstream:
- target: Epileptic Network Activity
description: These experimental cellular phenotypes plausibly contribute to network instability, but their individual necessity and weighting in human disease are unresolved.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:37863654
reference_title: Rescue of Normal Excitability in LGI1-Deficient Epileptic Neurons.
supports: SUPPORT
evidence_source: IN_VITRO
directness: INDIRECT
quote_role: PRIMARY_RESULT
snippet: Here, we show that 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.
explanation: Restoration in organotypic mouse hippocampal neurons supports a Kv1-related excitability mechanism; this is not a human treatment.
- reference: PMID:20133599
reference_title: Disruption of LGI1-linked synaptic complex causes abnormal synaptic transmission and epilepsy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: INDIRECT
quote_role: PRIMARY_RESULT
snippet: We find that loss of LGI1 in mice (LGI1(-/-)) causes lethal epilepsy, which is specifically rescued by the neuronal expression of LGI1 transgene, but not LGI3.
explanation: Severe null mouse phenotype and genetic rescue establish experimental seizure relevance; they do not reproduce typical heterozygous human severity.
- name: Shortened Axon Initial Segment
biological_scale: CELLULAR
description: AIS shortening accompanies LGI1 deficiency in cultured CA3 neurons and is partly reversed by local restoration. A compensatory homeostatic role is proposed, without proof that shortening causes the increased excitability.
evidence:
- &id014
reference: PMID:37863654
reference_title: Rescue of Normal Excitability in LGI1-Deficient Epileptic Neurons.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: We show that rescuing the Lgi1 expression in LGI1-deficient neurons was sufficient to partially suppress the AIS length shortening
explanation: AIS structural rescue is partial and distinct from the current and firing endpoints.
- name: Impaired Postnatal Dendritic Pruning
biological_scale: CELLULAR
description: In the 835delC BAC transgene model, dentate granule-cell dendritic maturation is perturbed during postnatal development. The model retains endogenous alleles and is not evidence that every human variant acts through a fixed developmental lesion.
evidence:
- &id005
reference: PMID:19701204
reference_title: Arrested maturation of excitatory synapses in autosomal dominant lateral temporal lobe epilepsy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: Concurrently, mutant LGI1 inhibited dendritic pruning and increased the spine density to markedly increase excitatory synaptic transmission.
explanation: 835delC BAC transgene model supports a developmental synaptic branch; it is not a heterozygous knock-in or a universal patient finding.
downstream:
- target: Increased Excitatory Synaptic Transmission
description: Morphological and electrophysiological changes co-occur in the transgenic model; pruning was not independently manipulated to prove sole mediation.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:19701204
reference_title: Arrested maturation of excitatory synapses in autosomal dominant lateral temporal lobe epilepsy.
supports: SUPPORT
evidence_source: IN_VITRO
directness: INDIRECT
quote_role: PRIMARY_RESULT
snippet: the amplitude of evoked AMPA and NMDA receptor-mediated EPSCs (Fig. 4a–d) and the frequency of miniature EPSCs (mEPSCs) (Fig. 4e,f) were increased in mature mLGI1 compared to wild-type.
explanation: Acute-slice synaptic recordings in the transgenic model, distinct from the in-vivo dendritic morphology and kindling outcomes.
- name: Increased Excitatory Synaptic Transmission
biological_scale: CELLULAR
description: In selected null and 835delC transgenic preparations, excitatory synaptic currents or miniature-event frequency increase while measured inhibitory currents remain similar. This observation is distinct from intrinsic excitability and from the reduced AMPA response in other preparations.
evidence:
- reference: PMID:19701204
reference_title: Arrested maturation of excitatory synapses in autosomal dominant lateral temporal lobe epilepsy.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: the amplitude of evoked AMPA and NMDA receptor-mediated EPSCs (Fig. 4a–d) and the frequency of miniature EPSCs (mEPSCs) (Fig. 4e,f) were increased in mature mLGI1 compared to wild-type.
explanation: Acute-slice synaptic recordings in the transgenic model, distinct from the in-vivo dendritic morphology and kindling outcomes.
- &id004
reference: PMID:20130004
reference_title: Lgi1 null mutant mice exhibit myoclonic seizures and CA1 neuronal hyperexcitability.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: Remarkably, however, the frequency of mEPSCs was dramatically increased in the mutant mice
explanation: Mouse hippocampal slice readout; mEPSC frequency is not a direct extracellular glutamate-concentration measurement.
downstream:
- target: Epileptic Network Activity
description: These experimental cellular phenotypes plausibly contribute to network instability, but their individual necessity and weighting in human disease are unresolved.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:19701204
reference_title: Arrested maturation of excitatory synapses in autosomal dominant lateral temporal lobe epilepsy.
supports: SUPPORT
evidence_source: IN_VITRO
directness: INDIRECT
quote_role: PRIMARY_RESULT
snippet: the amplitude of evoked AMPA and NMDA receptor-mediated EPSCs (Fig. 4a–d) and the frequency of miniature EPSCs (mEPSCs) (Fig. 4e,f) were increased in mature mLGI1 compared to wild-type.
explanation: Acute-slice synaptic recordings in the transgenic model, distinct from the in-vivo dendritic morphology and kindling outcomes.
- reference: PMID:20133599
reference_title: Disruption of LGI1-linked synaptic complex causes abnormal synaptic transmission and epilepsy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: INDIRECT
quote_role: PRIMARY_RESULT
snippet: We find that loss of LGI1 in mice (LGI1(-/-)) causes lethal epilepsy, which is specifically rescued by the neuronal expression of LGI1 transgene, but not LGI3.
explanation: Severe null mouse phenotype and genetic rescue establish experimental seizure relevance; they do not reproduce typical heterozygous human severity.
- name: Epileptic Network Activity
biological_scale: TISSUE
description: LGI1 perturbations can support hypersynchronous epileptic activity in animal and isolated hippocampal preparations. Which cellular changes are necessary for human auditory-feature epilepsy, and why the human symptoms preferentially involve auditory/language networks, remain unresolved.
evidence:
- &id011
reference: PMID:20133599
reference_title: Disruption of LGI1-linked synaptic complex causes abnormal synaptic transmission and epilepsy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: We find that loss of LGI1 in mice (LGI1(-/-)) causes lethal epilepsy, which is specifically rescued by the neuronal expression of LGI1 transgene, but not LGI3.
explanation: Severe null mouse phenotype and genetic rescue establish experimental seizure relevance; they do not reproduce typical heterozygous human severity.
downstream:
- target: Focal Seizures with Auditory Features
description: Human genetics and electroclinical features support epileptogenesis, but the bridge from experimental hippocampal activity to the auditory/language phenotype is indirect.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:20301709
reference_title: Autosomal Dominant Epilepsy with Auditory Features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
quote_role: REVIEW_SYNTHESIS
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: Human genetic diagnosis establishes a disease association; downstream allele-specific mechanisms are assessed separately.
- target: Interictal EEG Abnormality
description: Interictal discharges or slowing can accompany the disorder; a normal EEG remains possible.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
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
directness: INDIRECT
quote_role: PRIMARY_RESULT
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: The reported percentage concerns the 15 available RELN recordings, not all carriers or an umbrella frequency.
- name: Focal Seizures with Auditory Features
biological_scale: TISSUE
description: Human focal seizures engage auditory or language-related networks and may impair awareness or spread to bilateral convulsive seizures. Clinical semiology suggests lateral temporal involvement; mouse hippocampal findings do not directly establish the human site or subjective experience.
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
directness: DIRECT
quote_role: BACKGROUND
snippet: Autosomal dominant lateral temporal epilepsy (ADLTE) otherwise known as autosomal dominant partial epilepsy with auditory features (ADPEAF) is a genetic focal epileptic syndrome characterized by the onset at any age, but with preponderance in young adults, of focal seizures, either with or without impairment of consciousness or evolving to tonic–clonic seizures, with prominent auditory features or other symptoms, such as aphasia, suggesting a lateral temporal onset
explanation: Clinical syndrome description, not an experimental localization study.
downstream:
- target: Focal Sensory Seizure with Auditory Features
description: This is a clinically documented manifestation of focal seizure activity; symptom-specific network intermediates are not established by the cited experimental models.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:20301709
reference_title: Autosomal Dominant Epilepsy with Auditory Features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
quote_role: REVIEW_SYNTHESIS
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: Defines the auditory seizure spectrum without assigning a frequency band.
- target: Ictal Receptive Aphasia
description: This is a clinically documented manifestation of focal seizure activity; symptom-specific network intermediates are not established by the cited experimental models.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:20301709
reference_title: Autosomal Dominant Epilepsy with Auditory Features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
quote_role: REVIEW_SYNTHESIS
snippet: Ictal receptive aphasia consists of a sudden onset of inability to understand language in the absence of general confusion.
explanation: Defines the receptive-language ictal phenotype.
- target: Auditory Hallucination
description: This is a clinically documented manifestation of focal seizure activity; symptom-specific network intermediates are not established by the cited experimental models.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:20301709
reference_title: Autosomal Dominant Epilepsy with Auditory Features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
quote_role: REVIEW_SYNTHESIS
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: Complex songs or voices are included in the clinical auditory spectrum; “less common” does not define a numeric frequency.
- target: Focal to Bilateral Tonic-Clonic Seizures
description: This is a clinically documented manifestation of focal seizure activity; symptom-specific network intermediates are not established by the cited experimental models.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
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
directness: INDIRECT
quote_role: PRIMARY_RESULT
snippet: Overall, focal seizures without impairment of consciousness were reported by 10 patients (41%), focal seizures with impairment of consciousness by 6 patients (25%) and focal seizures evolving to tonic–clonic seizures by 16 patients (67%).
explanation: Directly documented focal evolution in the selected 24-person RELN clinical series, not the broader convulsion total.
- target: Focal Visual Seizures
description: This is a clinically documented manifestation of focal seizure activity; symptom-specific network intermediates are not established by the cited experimental models.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:20301709
reference_title: Autosomal Dominant Epilepsy with Auditory Features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
quote_role: REVIEW_SYNTHESIS
snippet: Less commonly, other ictal symptoms may occur, including sensory symptoms (visual, olfactory, vertiginous, or cephalic) or motor, psychic, and autonomic symptoms.
explanation: GeneReviews includes this ictal symptom class; no quantitative frequency is inferred.
- target: Focal Olfactory Seizures
description: This is a clinically documented manifestation of focal seizure activity; symptom-specific network intermediates are not established by the cited experimental models.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:20301709
reference_title: Autosomal Dominant Epilepsy with Auditory Features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
quote_role: REVIEW_SYNTHESIS
snippet: Less commonly, other ictal symptoms may occur, including sensory symptoms (visual, olfactory, vertiginous, or cephalic) or motor, psychic, and autonomic symptoms.
explanation: GeneReviews includes this ictal symptom class; no quantitative frequency is inferred.
- target: Focal Vestibular Seizures
description: This is a clinically documented manifestation of focal seizure activity; symptom-specific network intermediates are not established by the cited experimental models.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:20301709
reference_title: Autosomal Dominant Epilepsy with Auditory Features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
quote_role: REVIEW_SYNTHESIS
snippet: Less commonly, other ictal symptoms may occur, including sensory symptoms (visual, olfactory, vertiginous, or cephalic) or motor, psychic, and autonomic symptoms.
explanation: GeneReviews includes this ictal symptom class; no quantitative frequency is inferred.
- target: Focal Autonomic Seizures
description: This is a clinically documented manifestation of focal seizure activity; symptom-specific network intermediates are not established by the cited experimental models.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:20301709
reference_title: Autosomal Dominant Epilepsy with Auditory Features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
quote_role: REVIEW_SYNTHESIS
snippet: Less commonly, other ictal symptoms may occur, including sensory symptoms (visual, olfactory, vertiginous, or cephalic) or motor, psychic, and autonomic symptoms.
explanation: GeneReviews includes this ictal symptom class; no quantitative frequency is inferred.
- target: Focal Impaired Awareness Seizures
description: This is a clinically documented manifestation of focal seizure activity; symptom-specific network intermediates are not established by the cited experimental models.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
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
directness: INDIRECT
quote_role: PRIMARY_RESULT
snippet: focal seizures with impairment of consciousness by 6 patients (25%)
explanation: Direct category count in the selected RELN clinical cohort.
- target: Noise-Triggered Reflex Seizures
description: This is a clinically documented manifestation of focal seizure activity; symptom-specific network intermediates are not established by the cited experimental models.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
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
directness: INDIRECT
quote_role: PRIMARY_RESULT
snippet: Sudden noises and noisy environments could precipitate the seizures in 2 cases (8%) belonging to 2 families.
explanation: Selected RELN family observations support sound-triggered seizures without a disease-wide band.
- name: Heterozygous RELN Variants
biological_scale: MOLECULAR
description: Heterozygous pathogenic RELN variants cause a reduced-penetrance ADEAF form. Clinical similarity to LGI1 disease does not demonstrate a common molecular route.
evidence:
- &id006
reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC4457960/
reference_title: Heterozygous Reelin Mutations Cause Autosomal-Dominant Lateral Temporal Epilepsy - PMC
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: In total, we identified seven ... mutations, each in a different ADLTE-affected family.
explanation: Selected-family genetic evidence supports the RELN association.
downstream:
- target: Reduced Reelin Secretion
description: Variant expression produces a secretion defect in the studied cell assay.
causal_link_type: DIRECT
evidence:
- reference: PMID:34508592
reference_title: Epilepsy-causing Reelin mutations result in impaired secretion and intracellular degradation of mutant proteins.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: Using a cell-based secretion assay, we show that pathogenic RELN mutations abolish or significantly reduce secretion of mutant proteins and that this secretion defect results from impaired trafficking of mutant Reelin along the secretory pathway.
explanation: Direct cell-assay result reported in an abstract-only source; precise constructs and culture conditions were not recoverable.
- target: Increased Mutant Reelin Autophagic Processing
description: Overexpressed mutant proteins increase LC3 flux in the studied cells.
causal_link_type: DIRECT
evidence:
- reference: PMID:34508592
reference_title: Epilepsy-causing Reelin mutations result in impaired secretion and intracellular degradation of mutant proteins.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: In addition, LC3 immunoblotting shows a significant increase of autophagy flux due to mutant overexpression.
explanation: Reported LC3 flux response in transfected cells, not a patient neuronal measurement.
- name: Reduced Reelin Secretion
biological_scale: MOLECULAR
description: Selected epilepsy-associated mutant reelin proteins show impaired trafficking and reduced secretion in transfected-cell assays. A loss of extracellular function is a proposed epileptogenic mechanism, without direct measurement of the corresponding patient brain pathway.
evidence:
- &id007
reference: PMID:34508592
reference_title: Epilepsy-causing Reelin mutations result in impaired secretion and intracellular degradation of mutant proteins.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: Using a cell-based secretion assay, we show that pathogenic RELN mutations abolish or significantly reduce secretion of mutant proteins and that this secretion defect results from impaired trafficking of mutant Reelin along the secretory pathway.
explanation: Direct cell-assay result reported in an abstract-only source; precise constructs and culture conditions were not recoverable.
biological_processes:
- preferred_term: protein secretion
term:
id: GO:0009306
label: protein secretion
modifier: DECREASED
downstream:
- target: Reduced Circulating Reelin
description: Cellular secretion results provide a plausible explanation for reduced circulating protein, but the patients and source tissues were not experimentally manipulated.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:34508592
reference_title: Epilepsy-causing Reelin mutations result in impaired secretion and intracellular degradation of mutant proteins.
supports: SUPPORT
evidence_source: IN_VITRO
directness: INDIRECT
quote_role: PRIMARY_RESULT
snippet: Using a cell-based secretion assay, we show that pathogenic RELN mutations abolish or significantly reduce secretion of mutant proteins and that this secretion defect results from impaired trafficking of mutant Reelin along the secretory pathway.
explanation: Direct cell-assay result reported in an abstract-only source; precise constructs and culture conditions were not recoverable.
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC4457960/
reference_title: Heterozygous Reelin Mutations Cause Autosomal-Dominant Lateral Temporal Epilepsy - PMC
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
quote_role: PRIMARY_RESULT
snippet: the amount of the 310-kDa Reelin isoform was remarkably ... lower in the sera from these affected individuals than in ... the sera from control individuals
explanation: Patient serum protein observation; largely liver-derived circulating protein is not a direct brain secretion assay.
- target: Epileptic Network Activity
description: Reduced extracellular reelin function is a candidate link between the familial variants and epilepsy; developmental versus adult synaptic intermediates remain unproven.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC4457960/
reference_title: Heterozygous Reelin Mutations Cause Autosomal-Dominant Lateral Temporal Epilepsy - PMC
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
quote_role: PRIMARY_RESULT
snippet: In total, we identified seven ... mutations, each in a different ADLTE-affected family.
explanation: Selected-family genetic evidence supports the RELN association.
- reference: PMID:34508592
reference_title: Epilepsy-causing Reelin mutations result in impaired secretion and intracellular degradation of mutant proteins.
supports: SUPPORT
evidence_source: IN_VITRO
directness: INDIRECT
quote_role: PRIMARY_RESULT
snippet: Using a cell-based secretion assay, we show that pathogenic RELN mutations abolish or significantly reduce secretion of mutant proteins and that this secretion defect results from impaired trafficking of mutant Reelin along the secretory pathway.
explanation: Direct cell-assay result reported in an abstract-only source; precise constructs and culture conditions were not recoverable.
- name: Increased Mutant Reelin Autophagic Processing
biological_scale: CELLULAR
description: Mutant reelin overexpression is associated with autophagy-marker accumulation and increased LC3 flux in a cell model. The experiment does not establish that autophagy is the sole cause of reduced secretion or a clinical treatment target.
evidence:
- &id017
reference: PMID:34508592
reference_title: Epilepsy-causing Reelin mutations result in impaired secretion and intracellular degradation of mutant proteins.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: In addition, LC3 immunoblotting shows a significant increase of autophagy flux due to mutant overexpression.
explanation: Reported LC3 flux response in transfected cells, not a patient neuronal measurement.
- name: Reduced Circulating Reelin
biological_scale: MOLECULAR
description: Immunoblotting in four variant carriers showed reduced serum 310-kDa reelin relative to controls, with four assay experiments. Brain secretion and signaling were not directly measured; a serum concentration is not equivalent to a neuronal mechanism.
evidence:
- &id019
reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC4457960/
reference_title: Heterozygous Reelin Mutations Cause Autosomal-Dominant Lateral Temporal Epilepsy - PMC
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: the amount of the 310-kDa Reelin isoform was remarkably ... lower in the sera from these affected individuals than in ... the sera from control individuals
explanation: Patient serum protein observation; largely liver-derived circulating protein is not a direct brain secretion assay.
- name: Heterozygous MICAL1 Variants
biological_scale: MOLECULAR
description: Selected heterozygous MICAL1 variants are associated with familial or de novo auditory-feature epilepsy. Functional gain-of-function support is variant specific; rare variants with normal assays remain uncertain.
evidence:
- reference: url:https://dspace.library.uu.nl/bitstreams/27d672f3-83aa-4bb8-9ef7-6eed404b9335/download
reference_title: https://dspace.library.uu.nl/bitstreams/27d672f3-83aa-4bb8-9ef7-6eed404b9335/download
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: We found two pathogenic MICAL-1 variants in 28 families (7%) diagnosed with ADLTE.
explanation: Selected familial genetic result, with preliminary yield and one co-segregating GRIN2A variant caveat.
- reference: PMID:20301709
reference_title: Autosomal Dominant Epilepsy with Auditory Features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
quote_role: REVIEW_SYNTHESIS
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: MICAL1 is included among recognized molecular diagnostic genes.
downstream:
- target: Increased MICAL1 Oxidoreductase Activity
description: Selected variant constructs increase the measured enzyme-activity proxy in cell assays.
causal_link_type: DIRECT
evidence:
- reference: PMID:38654463
reference_title: A de novo pathogenic variant in MICAL-1 causes epilepsy with auditory features.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: To determine the effects of the p.Arg915Cys variant on MICAL‐1 redox activity, we used an indirect enzyme‐linked assay that measures H2O2 production.
explanation: HEK293T lysate H2O2 production is an enzyme-activity proxy, not a direct neuronal F-actin assay.
- reference: PMID:38654463
reference_title: A de novo pathogenic variant in MICAL-1 causes epilepsy with auditory features.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: We found that the oxidoreductase activities of human (hMICAL‐1Arg915Cys) and mouse (mMICAL‐1Arg902Cys) mutants were significantly increased
explanation: Variant-dependent activity increase in transfected-cell lysates.
- name: Increased MICAL1 Oxidoreductase Activity
biological_scale: MOLECULAR
description: Selected variants increase NADPH-dependent H2O2 production in transfected-cell lysate assays. COS7 cell contraction provides a separate morphology proxy. These findings support altered MICAL1 regulation without directly demonstrating neuronal actin oxidation, axon guidance or patient synaptic dysfunction.
evidence:
- &id018
reference: PMID:38654463
reference_title: A de novo pathogenic variant in MICAL-1 causes epilepsy with auditory features.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: To determine the effects of the p.Arg915Cys variant on MICAL‐1 redox activity, we used an indirect enzyme‐linked assay that measures H2O2 production.
explanation: HEK293T lysate H2O2 production is an enzyme-activity proxy, not a direct neuronal F-actin assay.
- &id008
reference: PMID:38654463
reference_title: A de novo pathogenic variant in MICAL-1 causes epilepsy with auditory features.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: We found that the oxidoreductase activities of human (hMICAL‐1Arg915Cys) and mouse (mMICAL‐1Arg902Cys) mutants were significantly increased
explanation: Variant-dependent activity increase in transfected-cell lysates.
downstream:
- target: Epileptic Network Activity
description: A contribution through altered cytoskeletal regulation is proposed; actin, circuit and clinical intermediates have not been causally resolved.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: url:https://dspace.library.uu.nl/bitstreams/27d672f3-83aa-4bb8-9ef7-6eed404b9335/download
reference_title: https://dspace.library.uu.nl/bitstreams/27d672f3-83aa-4bb8-9ef7-6eed404b9335/download
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
quote_role: PRIMARY_RESULT
snippet: We found two pathogenic MICAL-1 variants in 28 families (7%) diagnosed with ADLTE.
explanation: Selected familial genetic result, with preliminary yield and one co-segregating GRIN2A variant caveat.
- reference: PMID:38654463
reference_title: A de novo pathogenic variant in MICAL-1 causes epilepsy with auditory features.
supports: SUPPORT
evidence_source: IN_VITRO
directness: INDIRECT
quote_role: PRIMARY_RESULT
snippet: We found that the oxidoreductase activities of human (hMICAL‐1Arg915Cys) and mouse (mMICAL‐1Arg902Cys) mutants were significantly increased
explanation: Variant-dependent activity increase in transfected-cell lysates.
phenotypes:
- name: Focal Sensory Seizure with Auditory Features
category: Neurologic
description: Brief stereotyped simple sounds, altered sound perception or complex auditory experiences are characteristic focal ictal symptoms. They are seizures themselves and may be overlooked before a convulsion. In one selected cohort, auditory symptoms were documented in 17/24 RELN and 29/51 LGI1 cases; these are ascertainment-dependent observations.
phenotype_term:
preferred_term: Focal sensory seizure with auditory features
term:
id: HP:0011158
label: Focal sensory seizure with auditory features
evidence:
- reference: PMID:20301709
reference_title: Autosomal Dominant Epilepsy with Auditory Features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
quote_role: REVIEW_SYNTHESIS
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: Defines the auditory seizure spectrum without assigning a frequency band.
- name: Ictal Receptive Aphasia
category: Neurologic
description: Sudden inability to understand language without general confusion is an alternative characteristic ictal symptom and can occur with or without an auditory aura.
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: HUMAN_CLINICAL
directness: DIRECT
quote_role: REVIEW_SYNTHESIS
snippet: Ictal receptive aphasia consists of a sudden onset of inability to understand language in the absence of general confusion.
explanation: Defines the receptive-language ictal phenotype.
- name: Auditory Hallucination
category: Neurologic
description: Complex ictal percepts can include voices, music or specific songs. Their brief stereotyped occurrence should be distinguished from persistent psychiatric hallucinations.
phenotype_term:
preferred_term: Auditory hallucination
term:
id: HP:0008765
label: Auditory hallucination
evidence:
- reference: PMID:20301709
reference_title: Autosomal Dominant Epilepsy with Auditory Features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
quote_role: REVIEW_SYNTHESIS
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: Complex songs or voices are included in the clinical auditory spectrum; “less common” does not define a numeric frequency.
- name: Focal to Bilateral Tonic-Clonic Seizures
category: Neurologic
description: Focal seizures may evolve to bilateral tonic-clonic seizures. The selected RELN series documented focal evolution in 16/24 clinically assessed patients; its 21/24 any-convulsion total also included five cases with unknown onset and cannot be treated as 21 focal-to-bilateral cases.
phenotype_term:
preferred_term: Bilateral tonic-clonic seizure with focal onset
term:
id: HP:0007334
label: Bilateral tonic-clonic seizure with focal onset
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
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: Overall, focal seizures without impairment of consciousness were reported by 10 patients (41%), focal seizures with impairment of consciousness by 6 patients (25%) and focal seizures evolving to tonic–clonic seizures by 16 patients (67%).
explanation: Directly documented focal evolution in the selected 24-person RELN clinical series, not the broader convulsion total.
- name: Focal Visual Seizures
category: Neurologic
description: Visual ictal phenomena occur in some patients and do not exclude the auditory-feature syndrome.
phenotype_term:
preferred_term: Focal sensory seizure with visual features
term:
id: HP:0011165
label: Focal sensory seizure with visual features
evidence:
- reference: PMID:20301709
reference_title: Autosomal Dominant Epilepsy with Auditory Features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
quote_role: REVIEW_SYNTHESIS
snippet: Less commonly, other ictal symptoms may occur, including sensory symptoms (visual, olfactory, vertiginous, or cephalic) or motor, psychic, and autonomic symptoms.
explanation: GeneReviews includes this ictal symptom class; no quantitative frequency is inferred.
- name: Focal Olfactory Seizures
category: Neurologic
description: Olfactory ictal sensations are reported within the less common seizure spectrum.
phenotype_term:
preferred_term: Focal sensory seizure with olfactory features
term:
id: HP:0011161
label: Focal sensory seizure with olfactory features
evidence:
- reference: PMID:20301709
reference_title: Autosomal Dominant Epilepsy with Auditory Features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
quote_role: REVIEW_SYNTHESIS
snippet: Less commonly, other ictal symptoms may occur, including sensory symptoms (visual, olfactory, vertiginous, or cephalic) or motor, psychic, and autonomic symptoms.
explanation: GeneReviews includes this ictal symptom class; no quantitative frequency is inferred.
- name: Focal Vestibular Seizures
category: Neurologic
description: Vertiginous sensations can occur as focal ictal symptoms; nonspecific dizziness alone is not sufficient to classify a seizure.
phenotype_term:
preferred_term: Focal sensory seizure with vestibular features
term:
id: HP:0032759
label: Focal sensory seizure with vestibular features
evidence:
- reference: PMID:20301709
reference_title: Autosomal Dominant Epilepsy with Auditory Features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
quote_role: REVIEW_SYNTHESIS
snippet: Less commonly, other ictal symptoms may occur, including sensory symptoms (visual, olfactory, vertiginous, or cephalic) or motor, psychic, and autonomic symptoms.
explanation: GeneReviews includes this ictal symptom class; no quantitative frequency is inferred.
- name: Focal Autonomic Seizures
category: Neurologic
description: Autonomic symptoms can accompany focal seizures in the syndrome, without a specified population frequency.
phenotype_term:
preferred_term: Focal autonomic seizure
term:
id: HP:0011154
label: Focal autonomic seizure
evidence:
- reference: PMID:20301709
reference_title: Autosomal Dominant Epilepsy with Auditory Features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
quote_role: REVIEW_SYNTHESIS
snippet: Less commonly, other ictal symptoms may occur, including sensory symptoms (visual, olfactory, vertiginous, or cephalic) or motor, psychic, and autonomic symptoms.
explanation: GeneReviews includes this ictal symptom class; no quantitative frequency is inferred.
- name: Interictal EEG Abnormality
category: Neurologic
description: Interictal temporal epileptiform discharges or focal slowing may be present, but a normal recording does not exclude ADEAF. In the selected comparison, recordings were available for 15 RELN and 31 LGI1 patients. Small-sample lateralization differences are not established genotype signatures.
phenotype_term:
preferred_term: EEG abnormality
term:
id: HP:0002353
label: EEG abnormality
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
directness: DIRECT
quote_role: PRIMARY_RESULT
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: The reported percentage concerns the 15 available RELN recordings, not all carriers or an umbrella frequency.
- name: Focal Impaired Awareness Seizures
category: Neurologic
description: Some focal seizures impair awareness. Six of 24 assessed RELN cases had this seizure category in the selected family series; the denominator is not a population frequency.
phenotype_term:
preferred_term: Focal impaired awareness seizure
term:
id: HP:0002384
label: Focal impaired awareness seizure
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
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: focal seizures with impairment of consciousness by 6 patients (25%)
explanation: Direct category count in the selected RELN clinical cohort.
- name: Noise-Triggered Reflex Seizures
category: Neurologic
description: Sudden noise or noisy environments can precipitate seizures in a subset. Two of 24 assessed RELN cases and seven of 51 LGI1 cases had reported sound triggers. Noise is a seizure precipitant, not the cause of the inherited disorder.
phenotype_term:
preferred_term: Reflex seizure
term:
id: HP:0020207
label: Reflex seizure
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
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: Sudden noises and noisy environments could precipitate the seizures in 2 cases (8%) belonging to 2 families.
explanation: Selected RELN family observations support sound-triggered seizures without a disease-wide band.
inheritance:
- name: Autosomal dominant with incomplete penetrance
description: Heterozygous pathogenic variants cause dominant disease with incomplete penetrance. A variant carrier has a 50% transmission probability per pregnancy, distinct from the probability that an inheriting child develops epilepsy. Family estimates vary by gene and ascertainment; de novo variants can occur and MICAL1 penetrance is not established.
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: HUMAN_CLINICAL
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.
quote_role: REVIEW_SYNTHESIS
directness: DIRECT
- reference: PMID:20301709
reference_title: Autosomal Dominant Epilepsy with Auditory Features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
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.
quote_role: REVIEW_SYNTHESIS
directness: DIRECT
genetic:
- name: LGI1
gene_term:
preferred_term: LGI1
term:
id: hgnc:6572
label: LGI1
relationship_type: CAUSATIVE
variant_origin: GERMLINE
notes: Heterozygous pathogenic LGI1 variants affect secretion or ligand function, with allele-specific experimental results. In 24 selected published multiplex families, 58/87 inferred obligate carriers had epilepsy (67%, CI 55–77%); ascertainment can inflate population penetrance. No detected truncating-versus-missense difference is not proof of equivalent secretion-class penetrance. Biallelic LGI1 developmental and epileptic encephalopathy is a separate allelic phenotype.
evidence:
- reference: PMID:20301709
reference_title: Autosomal Dominant Epilepsy with Auditory Features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
quote_role: REVIEW_SYNTHESIS
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 the established molecular diagnostic genes.
- reference: PMID:18711109
reference_title: Penetrance of LGI1 mutations in autosomal dominant partial epilepsy with auditory features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: Overall penetrance was 67% (95% CI 55-77%), and did not vary according to mutation type or location within the gene.
explanation: Selected pedigree penetrance analysis; null comparisons do not establish equivalence or secretion-class-specific effects.
- name: RELN
gene_term:
preferred_term: RELN
term:
id: hgnc:9957
label: RELN
relationship_type: CAUSATIVE
variant_origin: GERMLINE
notes: Heterozygous RELN variants are associated with ADEAF; the initial selected Italian cohort found variants in 7/40 families and epilepsy in 20/33 carriers. Four tested variant carriers had reduced circulating reelin. Serum findings largely reflect liver-derived protein and do not directly measure brain secretion or establish a neuronal migration defect in dominant disease. Biallelic lissencephaly with cerebellar hypoplasia is distinct.
evidence:
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC4457960/
reference_title: Heterozygous Reelin Mutations Cause Autosomal-Dominant Lateral Temporal Epilepsy - PMC
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: In total, we identified seven ... mutations, each in a different ADLTE-affected family.
explanation: Familial genetic evidence in a selected discovery cohort.
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC4457960/
reference_title: Heterozygous Reelin Mutations Cause Autosomal-Dominant Lateral Temporal Epilepsy - PMC
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: In the families we studied, 20/33 (60%) of individuals carrying one of these mutations have epilepsy
explanation: Selected-family carrier observation, not population penetrance.
- name: MICAL1
gene_term:
preferred_term: MICAL1
term:
id: hgnc:20619
label: MICAL1
relationship_type: CAUSATIVE
variant_origin: GERMLINE
notes: MICAL1 is an established ADEAF gene with gain-of-function activity in selected variant cell assays. The original study supported two variants among 28 LGI1/RELN-negative families; its third R646Q variant was explicitly a VUS with no detectable activity increase. One family also carried an unexcluded GRIN2A variant. A later de novo R915C case broadens the allelic series. Increased cell-lysate H2O2 production and COS7 contraction do not directly establish patient neuronal actin dynamics.
evidence:
- reference: PMID:20301709
reference_title: Autosomal Dominant Epilepsy with Auditory Features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
quote_role: REVIEW_SYNTHESIS
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: GeneReviews recognizes MICAL1 as a molecular cause.
- reference: url:https://dspace.library.uu.nl/bitstreams/27d672f3-83aa-4bb8-9ef7-6eed404b9335/download
reference_title: https://dspace.library.uu.nl/bitstreams/27d672f3-83aa-4bb8-9ef7-6eed404b9335/download
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: We found two pathogenic MICAL-1 variants in 28 families (7%) diagnosed with ADLTE.
explanation: Preliminary yield in a selected LGI1/RELN-negative familial cohort, with functional and segregation caveats retained.
- reference: PMID:38654463
reference_title: A de novo pathogenic variant in MICAL-1 causes epilepsy with auditory features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: Here, we describe a de novo MICAL-1 pathogenic variant, p.Arg915Cys, in a sporadic case, an affected 21-year-old Italian man with no family history of epilepsy.
explanation: A later single de novo case expands the reported allelic series.
diagnosis:
- name: Electroclinical history and pedigree assessment
diagnosis_term:
preferred_term: Diagnostic Procedure
term:
id: NCIT:C18020
label: Diagnostic Procedure
description: Ask specifically about brief stereotyped auditory experiences, sudden receptive-language failure, impaired awareness, convulsions, triggers and family history. Interview apparently unaffected relatives when appropriate, because subtle focal seizures may be overlooked. History, EEG, imaging and molecular testing are interpreted together.
evidence:
- reference: PMID:20301709
reference_title: Autosomal Dominant Epilepsy with Auditory Features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
quote_role: REVIEW_SYNTHESIS
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: Characterizes the sensory symptoms that require specific questioning.
- reference: PMID:20301709
reference_title: Autosomal Dominant Epilepsy with Auditory Features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
quote_role: REVIEW_SYNTHESIS
snippet: Ictal receptive aphasia consists of a sudden onset of inability to understand language in the absence of general confusion.
explanation: Distinguishes receptive aphasia from nonspecific confusion.
- name: Molecular genetic testing
description: Use a phenotype-informed epilepsy panel including LGI1, RELN and MICAL1, with deletion/duplication or exome/genome testing as appropriate. A heterozygous pathogenic or likely pathogenic variant concordant with the phenotype can establish the molecular diagnosis. A VUS is not diagnostic; a negative result does not exclude a clinically defined syndrome. Absent family history can reflect reduced penetrance or a de novo variant.
diagnosis_term:
preferred_term: Molecular Analysis
term:
id: NCIT:C19770
label: Molecular Analysis
results: A phenotype-concordant pathogenic or likely pathogenic variant; negative or uncertain results require clinical interpretation.
evidence:
- reference: PMID:20301709
reference_title: Autosomal Dominant Epilepsy with Auditory Features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
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.
quote_role: REVIEW_SYNTHESIS
directness: DIRECT
- name: Electroencephalography
description: EEG can demonstrate temporal epileptiform abnormalities or focal slowing. Normal interictal EEG does not exclude ADEAF. Small selected genotype comparisons do not justify a stable RELN-left/LGI1-other rule or imply that EEG is the only informative investigation.
diagnosis_term:
preferred_term: Electroencephalography
term:
id: NCIT:C38054
label: Electroencephalography
results: Temporal epileptiform discharges, focal slowing or a normal recording.
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: Available-recording result in a selected RELN family cohort, not an umbrella diagnostic sensitivity estimate.
quote_role: PRIMARY_RESULT
directness: DIRECT
- name: Brain MRI
description: High-resolution MRI evaluates structural causes of focal epilepsy. A normal MRI is part of consensus clinical criteria and is usual in ADEAF, but reported genetically affected individuals can have imaging abnormalities. A detected lesion requires assessment of its clinical relevance rather than an automatic exclusion of genetic disease.
diagnosis_term:
preferred_term: Magnetic Resonance Imaging
term:
id: NCIT:C16809
label: Magnetic Resonance Imaging
results: Often normal; evaluate any lesion in the electroclinical and genetic context.
evidence:
- reference: PMID:20301709
reference_title: Autosomal Dominant Epilepsy with Auditory Features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
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.
quote_role: REVIEW_SYNTHESIS
directness: DIRECT
progression:
- phase: Onset in adolescence or early adulthood
age_range: 10 to 30 years
notes: Onset is usually between 10 and 30 years, with wider ages documented in selected families. Typical dominant disease has preserved prior development; neonatal developmental encephalopathy should prompt a broader or allelic differential.
evidence:
- reference: PMID:20301709
reference_title: Autosomal Dominant Epilepsy with Auditory Features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
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.
quote_role: REVIEW_SYNTHESIS
directness: DIRECT
- phase: Variable seizure control and remission
notes: Many affected individuals respond to standard medication, but drug resistance and relapse after withdrawal occur. A broader EAF cohort of 123 patients (68.3% sporadic), followed a median 11 years, reported 42/123 with terminal remission. Its definition was at least five consecutive seizure-free years at last follow-up, not necessarily off medication; this is not an ADEAF-specific prognosis estimate.
evidence:
- reference: PMID:20301709
reference_title: Autosomal Dominant Epilepsy with Auditory Features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
quote_role: REVIEW_SYNTHESIS
snippet: Seizure control is usually readily achieved with standard anti-seizure medications (ASM).
explanation: Clinical review describes typical treatment response without guaranteeing it.
- reference: PMID:29464704
reference_title: 'Epilepsy with auditory features: Long-term outcome and predictors of terminal remission.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: At last assessment, 42 patients had achieved TR (34.1%).
explanation: Broader EAF cohort outcome, not medication-free remission or familial-only prognosis.
treatments:
- name: Standard Antiseizure Medication
description: Treat focal seizures with an antiseizure medication selected by an experienced neurologist for seizure type, comorbidity, interactions and reproductive considerations. Carbamazepine has historically been used with benefit, but comparative ADEAF-specific trials do not establish a uniquely preferred drug. Many patients respond to monotherapy; persistent seizures and withdrawal decisions require reassessment.
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; no correction of the inherited molecular defect is implied.
evidence:
- reference: PMID:20301709
reference_title: Autosomal Dominant Epilepsy with Auditory Features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
quote_role: REVIEW_SYNTHESIS
snippet: Seizure control is usually readily achieved with standard anti-seizure medications (ASM).
explanation: Clinical treatment-response synthesis supports symptomatic seizure suppression.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1537/
reference_title: Autosomal Dominant Epilepsy with Auditory Features - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
quote_role: REVIEW_SYNTHESIS
snippet: Standardized treatment w/ASM by epileptologist or experienced neurologist
explanation: GeneReviews clinical recommendation based on author experience.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1537/
reference_title: Autosomal Dominant Epilepsy with Auditory Features - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
quote_role: REVIEW_SYNTHESIS
snippet: Traditionally sodium channel blockers such as carbamazepine have been more frequently used with clear benefit.
explanation: Historical clinical use, not a head-to-head efficacy ranking.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1537/
reference_title: Autosomal Dominant Epilepsy with Auditory Features - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
quote_role: REVIEW_SYNTHESIS
snippet: However, no clinical trials of different anti-seizure medications have been carried out
explanation: The chapter reports no comparative ADEAF-specific antiseizure medication trial.
- name: 4-Phenylbutyrate (Investigational Chemical Chaperone)
description: Preclinical, allele-specific chemical-corrector research, not established clinical care. Earlier experiments reported 4PBA rescue of LGI1 E383A folding/binding and mouse seizure susceptibility. In a later biallelic-LGI1 study, 5 mM/72 h 4PBA increased secretion of C48F and wild type but reduced secretion of S524P and a terminal-extension variant in HEK293T cells. No human treatment or seizure-rescue outcome was measured in that later study; a secretion-defective label alone does not predict benefit.
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: Reduced LGI1 Secretion
treatment_effect: RESTORES
description: Partial rescue of secretion is demonstrated only for selected alleles and preparations; other alleles worsen.
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
directness: DIRECT
quote_role: PRIMARY_RESULT
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: Allele-specific preclinical intervention; the abstract combines cellular correction and mouse seizure susceptibility.
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
directness: DIRECT
quote_role: PRIMARY_RESULT
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: Allele-specific preclinical intervention; the abstract combines cellular correction and mouse seizure susceptibility.
- reference: PMID:40455867
reference_title: Biallelic LGI1 and ADAM23 variants cause hippocampal epileptic encephalopathy via the LGI1-ADAM22/23 pathway.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: We found that treatment with 4PBA (5 mM) for 72 h significantly increased the secretion of LGI1 Cys48Phe as well as WT, whereas it reduced the secretion of Ser524Pro and Ter558GlyextTer23 (Supplementary Fig. 4B).
explanation: Later HEK293T experiments show opposite responses across alleles, without human efficacy evidence.
- name: Seizure and neurocognitive surveillance
description: Monitor seizure control and medication effects at clinical visits, with assessment of memory, attention, development or psychiatric symptoms when indicated. Surveillance detects evolving needs and does not itself modify a molecular mechanism.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: Supportive Care
term:
id: NCIT:C15747
label: Supportive Care
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1537/
reference_title: Autosomal Dominant Epilepsy with Auditory Features - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
quote_role: REVIEW_SYNTHESIS
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: Clinical surveillance guidance, including ongoing seizure monitoring.
- name: Seizure education and safety planning
description: Teach patients and caregivers to recognize focal and convulsive seizures, provide appropriate first aid and plan individualized precautions for activities that could cause injury during a seizure.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: Supportive Care
term:
id: NCIT:C15747
label: Supportive Care
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1537/
reference_title: Autosomal Dominant Epilepsy with Auditory Features - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
quote_role: REVIEW_SYNTHESIS
snippet: Education of parents/caregivers regarding common seizure presentations is appropriate.
explanation: GeneReviews recommends seizure-recognition education; safety advice is individualized.
- name: Genetic counseling and family evaluation
description: Explain dominant transmission, reduced penetrance, variant uncertainty and reproductive options; offer family-specific molecular evaluation when the causal variant is established. A positive predictive test does not determine age at onset or severity.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: Supportive Care
term:
id: NCIT:C15747
label: Supportive Care
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1537/
reference_title: Autosomal Dominant Epilepsy with Auditory Features - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
quote_role: REVIEW_SYNTHESIS
snippet: To inform affected persons &#x00026; their families re nature, MOI, &#x00026; implications of ADEAF to facilitate medical &#x00026; personal decision making
explanation: Genetics-professional counseling recommendation.
- name: Preconception antiseizure medication review
description: Discuss medication benefits and reproductive risks before pregnancy and consider an appropriate lower-risk regimen when feasible. Decisions remain individualized; seizure control should be maintained with specialist input.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: Supportive Care
term:
id: NCIT:C15747
label: Supportive Care
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1537/
reference_title: Autosomal Dominant Epilepsy with Auditory Features - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
quote_role: REVIEW_SYNTHESIS
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: GeneReviews preconception risk-benefit guidance.
- name: Psychiatric and family support
description: Assess psychiatric comorbidity and provide standard treatment when needed; arrange family resources, care coordination and transition planning. These are needs-based services, not universal manifestations.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: Supportive Care
term:
id: NCIT:C15747
label: Supportive Care
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1537/
reference_title: Autosomal Dominant Epilepsy with Auditory Features - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
quote_role: REVIEW_SYNTHESIS
snippet: Ensure appropriate social work involvement to connect families w/local resources&#x00026; support.
explanation: GeneReviews family-support recommendation.
differential_diagnoses:
- name: Anti-LGI1 Autoimmune Encephalitis
description: Acquired LGI1-antibody limbic encephalitis is distinct from inherited ADEAF. Prominent subacute memory impairment, faciobrachial dystonic seizures, hyponatremia and antibodies support this differential; the usual response to immunotherapy does not justify immunotherapy for inherited ADEAF.
distinguishing_features:
- Acquired, usually subacute presentation rather than a Mendelian syndrome; absent family history alone is not discriminating.
- 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: HUMAN_CLINICAL
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.
quote_role: BACKGROUND
directness: DIRECT
- name: Other Epilepsies with Auditory Features
description: Broad EAF includes nonfamilial, structural and other genetic focal epilepsies. SCN1A and DEPDC5 findings in heterogeneous families, and one proposed KCNQ2-associated EAF case, do not establish the same narrow familial ADEAF syndrome or a shared LGI1 mechanism. Conversely, de novo variants and reduced penetrance allow molecular ADEAF without an affected parent.
distinguishing_features:
- Interpret electroclinical and imaging findings with the gene-specific phenotype.
- A negative family history or panel does not by itself classify an individual outside ADEAF.
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.
- reference: PMID:39796146
reference_title: Novel KCNQ2 Variants Related to a Variable Phenotypic Spectrum Ranging from Epilepsy with Auditory Features to Severe Developmental and Epileptic Encephalopathies.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: The phenotypes observed in the affected members of family 1, which shared the c.2251T>G variant, were epilepsy with auditory features (EAFs), focal epilepsy, and generalized epilepsy, and none of them suffered from neonatal seizures.
explanation: One proposed KCNQ2-associated EAF proband in a phenotypically heterogeneous family; no channel functional assay establishes a shared ADEAF mechanism.
- name: Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis
description: Mesial temporal lobe epilepsy can produce experiential, autonomic or olfactory symptoms and may be associated with hippocampal sclerosis. Auditory symptoms favor a lateral temporal network but are not an infallible anatomical discriminator.
distinguishing_features:
- Mesial experiential or epigastric symptoms may predominate.
- High-resolution MRI may demonstrate hippocampal sclerosis.
- Clinical localization and treatment response require individual evaluation.
evidence:
- reference: PMID:35153984
reference_title: 'Epilepsy With Auditory Features: From Etiology to Treatment.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
quote_role: REVIEW_SYNTHESIS
snippet: EAF phenotype is characterized by seizures with auditory symptoms or aphasia, suggesting a lateral temporal lobe involvement.
explanation: Review localizes the characteristic auditory/language phenotype, while other focal syndromes require differential assessment.
- name: Biallelic LGI1 Developmental and Epileptic Encephalopathy
description: A separate recessive allelic disorder was reported in six individuals from four families, with early seizures and developmental impairment. Severe homozygous mouse phenotypes therefore have a human allelic counterpart, but this does not make neonatal encephalopathy typical of dominant ADEAF.
distinguishing_features:
- Biallelic rather than heterozygous LGI1 variants.
- Early infantile seizures and developmental impairment.
evidence:
- reference: PMID:40455867
reference_title: Biallelic LGI1 and ADAM23 variants cause hippocampal epileptic encephalopathy via the LGI1-ADAM22/23 pathway.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: The clinical features available of six patients (Patients P1A–C, P2, P3 and P4) with LGI1 variants identified from four consanguineous families
explanation: Six-person biallelic series, distinct from the usual dominant clinical syndrome.
discussions:
- discussion_id: adeaf_preparation_specific_physiology
prompt: How do distinct LGI1 physiological effects produce the human focal epilepsy phenotype?
kind: INTERPRETATION
status: OPEN
rationale: AMPA-mediated responses decrease in one null preparation and increase in another; baseline intrinsic properties can be unchanged in acute or intact hippocampus while cultured CA3 neurons show a Kv1-related deficit. Regional, developmental, allele and preparation differences matter. A compensatory AMPA-loss-to-hyperexcitability cascade is a hypothesis rather than a demonstrated common sequence. The cultured restoration study explicitly did not test synaptic rescue.
evidence:
- *id002
- *id004
- &id013
reference: PMID:20130004
reference_title: Lgi1 null mutant mice exhibit myoclonic seizures and CA1 neuronal hyperexcitability.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: These results indicate that Lgi1 mutation did not change the intrinsic properties of pyramidal neurons in the hippocampal CA1 region.
explanation: Baseline intrinsic firing, membrane potential and input resistance were unchanged in this acute-slice preparation.
- &id016
reference: PMID:40455867
reference_title: Biallelic LGI1 and ADAM23 variants cause hippocampal epileptic encephalopathy via the LGI1-ADAM22/23 pathway.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: The intrinsic electrical properties of CA3 neurons, such as membrane capacitance, input resistance, resting membrane potential and membrane time constant (Tau) were not different between genotypes (Supplementary Table 3).
explanation: Baseline intrinsic membrane properties did not differ in the sampled CA3 neurons.
- &id010
reference: PMID:37863654
reference_title: Rescue of Normal Excitability in LGI1-Deficient Epileptic Neurons.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: The effect of LGI1 rescue on synaptic function has not been tested in the present study.
explanation: The current study measures intrinsic electrophysiology, not synaptic or network-seizure rescue.
- discussion_id: adeaf_developmental_and_later_requirements
prompt: How much does developmental circuit maturation contribute relative to continuing LGI1 function?
kind: KNOWLEDGE_GAP
status: OPEN
rationale: The 835delC transgene supports altered postnatal dendritic maturation, while conditional deletion at later postnatal stages still produces seizures and culture restoration changes intrinsic physiology. These studies do not establish a single irreversible developmental lesion or a requirement for a second hit. The dog LGI2 epilepsy and a proposed LGI2-to-LGI1 developmental handover concern a paralog and cannot establish a human ADEAF mechanism.
evidence:
- *id005
- &id012
reference: PMID:25234641
reference_title: Glutamatergic neuron-targeted loss of LGI1 epilepsy gene results in seizures.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: Emx1-Lgi1cKO mice displayed early-onset and lethal seizures, whereas CaMKIIα-Lgi1cKO mice presented late-onset occasional seizures associated with variable reduced lifespan.
explanation: Conditional deletion separates embryonic from later postnatal glutamatergic-neuron perturbations; details beyond the abstract are not inferred.
- *id003
- reference: PMID:21829378
reference_title: LGI2 truncation causes a remitting focal epilepsy in dogs.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: We report functional and expression studies of LGI2, which, combined with previous LGI1 studies, suggest a novel concept of the basis of remission common in childhood epilepsy.
explanation: Paralog dog-model comparison; developmental handover is a proposed interpretation.
- discussion_id: adeaf_gene_convergence
prompt: Do LGI1, RELN and MICAL1 defects converge on the same neuronal pathway?
kind: KNOWLEDGE_GAP
status: OPEN
rationale: Human clinical overlap does not demonstrate molecular convergence. Reelin serum and secretion findings, MICAL1 lysate activity and LGI1 synaptic-channel studies measure different compartments and endpoints. MICAL1-to-actin-to-network and reelin-to-human-epilepsy intermediates remain unresolved; direct patient-neuron studies and allele-aware rescue would be informative.
evidence:
- *id006
- *id007
- *id008
- *id009
- discussion_id: adeaf_allelic_translation
prompt: Which LGI1 alleles and experimental corrections translate to dominant ADEAF?
kind: HUMAN_MODEL_MISMATCH
status: OPEN
rationale: Biallelic LGI1 encephalopathy is a distinct human phenotype, so severe null mice are not simply evidence of an unsupported human condition. The six-person biallelic series had heterogeneous survival and is not representative of dominant ADEAF. Cell 4PBA responses differ across alleles; organotypic LGI1 restoration does not establish delivery, durability, seizure reduction or clinical benefit in heterozygous patients.
evidence:
- reference: PMID:40455867
reference_title: Biallelic LGI1 and ADAM23 variants cause hippocampal epileptic encephalopathy via the LGI1-ADAM22/23 pathway.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: The clinical features available of six patients (Patients P1A–C, P2, P3 and P4) with LGI1 variants identified from four consanguineous families
explanation: Separate biallelic clinical series.
- &id015
reference: PMID:40455867
reference_title: Biallelic LGI1 and ADAM23 variants cause hippocampal epileptic encephalopathy via the LGI1-ADAM22/23 pathway.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: We found that treatment with 4PBA (5 mM) for 72 h significantly increased the secretion of LGI1 Cys48Phe as well as WT, whereas it reduced the secretion of Ser524Pro and Ter558GlyextTer23 (Supplementary Fig. 4B).
explanation: Opposite 4PBA secretion responses across alleles preclude class-wide rescue prediction.
- *id010
prevalence:
- population: Worldwide
notes: Population prevalence is not established. Brief unrecognized auditory seizures and incomplete penetrance complicate ascertainment.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1537/
reference_title: Autosomal Dominant Epilepsy with Auditory Features - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
quote_role: REVIEW_SYNTHESIS
snippet: The prevalence of ADEAF is unknown but likely very low.
explanation: GeneReviews explicitly reports unknown prevalence; no numerical population rate is inferred.
clinical_trials:
- name: clinicaltrials:NCT00072813
status: COMPLETED
phase: NOT_APPLICABLE
description: Observational MRI study of familial auditory-feature epilepsy, including affected participants, unaffected relatives and healthy volunteers. Structural and functional imaging were planned; this is not a treatment trial and no clinical efficacy result is inferred from the registry summary.
notes: Live ClinicalTrials.gov API status and observational design checked on 2026-09-21. The registry summary alone does not establish an imaging biomarker or report outcome results.
evidence:
- reference: clinicaltrials:NCT00072813
reference_title: MRI in Autosomal Dominant Partial Epilepsy With Auditory Features
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
quote_role: BACKGROUND
snippet: This study will examine the possible structural and functional abnormalities in patients with an inherited form of epilepsy. It will use magnetic resonance imaging (MRI).
explanation: Registry study identity and planned imaging scope; completed status was checked separately in the live API.
animal_models:
- name: Constitutive Lgi1-null mice
species: Mouse
genotype: Homozygous Lgi1 loss
description: Constitutive null mice develop severe early spontaneous seizures and premature death. Neuronal LGI1 transgenic expression, but not LGI3, rescued lethal epilepsy in one abstract-level study. This complete-loss model differs from reduced-penetrance heterozygous ADEAF and should not determine its usual onset or severity.
evidence:
- *id011
modeled_mechanisms:
- target: Epileptic Network Activity
relationship: PARTIALLY_RECAPITULATES
description: Null animals exhibit lethal epilepsy, without modeling a subjective auditory aura.
fidelity: UNKNOWN
evidence:
- reference: PMID:20133599
reference_title: Disruption of LGI1-linked synaptic complex causes abnormal synaptic transmission and epilepsy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: We find that loss of LGI1 in mice (LGI1(-/-)) causes lethal epilepsy, which is specifically rescued by the neuronal expression of LGI1 transgene, but not LGI3.
explanation: Severe null mouse phenotype and genetic rescue establish experimental seizure relevance; they do not reproduce typical heterozygous human severity.
limitations: Complete knockout, early lethality and mouse circuitry differ from typical heterozygous human disease.
readouts:
- name: Spontaneous epilepsy
target: Epileptic Network Activity
direction: INCREASED
interpretation: Null animals exhibit lethal epilepsy, without modeling a subjective auditory aura.
evidence:
- reference: PMID:20133599
reference_title: Disruption of LGI1-linked synaptic complex causes abnormal synaptic transmission and epilepsy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: We find that loss of LGI1 in mice (LGI1(-/-)) causes lethal epilepsy, which is specifically rescued by the neuronal expression of LGI1 transgene, but not LGI3.
explanation: Severe null mouse phenotype and genetic rescue establish experimental seizure relevance; they do not reproduce typical heterozygous human severity.
- name: LGI1 835delC BAC transgenic mice
species: Mouse
genotype: Truncated 835delC transgene with endogenous Lgi1 retained
description: BAC transgenic mice expressing a patient-derived truncation were compared with wild type and a separate wild-type LGI1-overexpression line. Dentate dendritic maturation, synaptic properties and pentylenetetrazole kindling were examined. This is transgene expression, not a heterozygous knock-in; the seizure result is challenged kindling rather than demonstrated spontaneous auditory-feature epilepsy.
evidence:
- *id005
- reference: PMID:19701204
reference_title: Arrested maturation of excitatory synapses in autosomal dominant lateral temporal lobe epilepsy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: Furthermore, mutant LGI1 promoted epileptiform discharge in vitro and kindling epileptogenesis in vivo with partial gamma-aminobutyric acid(A) (GABA(A)) receptor blockade.
explanation: The paper separates slice epileptiform activity from chemically challenged in-vivo kindling.
modeled_mechanisms:
- target: Impaired Postnatal Dendritic Pruning
relationship: MEASURES
description: Dentate granule-cell dendritic arbors retain immature branching patterns; cell maturation and synaptic changes are separable readouts.
fidelity: UNKNOWN
evidence:
- reference: PMID:19701204
reference_title: Arrested maturation of excitatory synapses in autosomal dominant lateral temporal lobe epilepsy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: Concurrently, mutant LGI1 inhibited dendritic pruning and increased the spine density to markedly increase excitatory synaptic transmission.
explanation: 835delC BAC transgene model supports a developmental synaptic branch; it is not a heterozygous knock-in or a universal patient finding.
readouts:
- name: Persistence of dendritic branching
target: Impaired Postnatal Dendritic Pruning
direction: INCREASED
interpretation: Dentate granule-cell dendritic arbors retain immature branching patterns; cell maturation and synaptic changes are separable readouts.
evidence:
- reference: PMID:19701204
reference_title: Arrested maturation of excitatory synapses in autosomal dominant lateral temporal lobe epilepsy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: Concurrently, mutant LGI1 inhibited dendritic pruning and increased the spine density to markedly increase excitatory synaptic transmission.
explanation: 835delC BAC transgene model supports a developmental synaptic branch; it is not a heterozygous knock-in or a universal patient finding.
- target: Epileptic Network Activity
relationship: PARTIALLY_RECAPITULATES
description: Mutant transgene enhances susceptibility under the reported chemical-kindling protocol.
fidelity: UNKNOWN
evidence:
- reference: PMID:19701204
reference_title: Arrested maturation of excitatory synapses in autosomal dominant lateral temporal lobe epilepsy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: Furthermore, mutant LGI1 promoted epileptiform discharge in vitro and kindling epileptogenesis in vivo with partial gamma-aminobutyric acid(A) (GABA(A)) receptor blockade.
explanation: The paper separates slice epileptiform activity from chemically challenged in-vivo kindling.
limitations: Chemical challenge and altered transgene dosage limit transfer to spontaneous heterozygous human seizures.
readouts:
- name: Kindling epileptogenesis
target: Epileptic Network Activity
direction: INCREASED
interpretation: Mutant transgene enhances susceptibility under the reported chemical-kindling protocol.
evidence:
- reference: PMID:19701204
reference_title: Arrested maturation of excitatory synapses in autosomal dominant lateral temporal lobe epilepsy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: Furthermore, mutant LGI1 promoted epileptiform discharge in vitro and kindling epileptogenesis in vivo with partial gamma-aminobutyric acid(A) (GABA(A)) receptor blockade.
explanation: The paper separates slice epileptiform activity from chemically challenged in-vivo kindling.
- name: Glutamatergic-neuron conditional Lgi1 knockout mice
species: Mouse
genotype: Emx1-Lgi1cKO or CaMKIIα-Lgi1cKO
description: Embryonic Emx1-targeted deletion produced early lethal seizures, whereas later CaMKIIα-targeted deletion produced occasional later seizures with variable lifespan. These models support both developmental and later requirements; they do not show that a single early pruning lesion explains all disease.
evidence:
- *id012
modeled_mechanisms:
- target: Epileptic Network Activity
relationship: PARTIALLY_RECAPITULATES
description: Loss restricted to the studied excitatory-neuron populations is sufficient for seizures with timing-dependent severity.
fidelity: UNKNOWN
evidence:
- reference: PMID:25234641
reference_title: Glutamatergic neuron-targeted loss of LGI1 epilepsy gene results in seizures.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: Emx1-Lgi1cKO mice displayed early-onset and lethal seizures, whereas CaMKIIα-Lgi1cKO mice presented late-onset occasional seizures associated with variable reduced lifespan.
explanation: Conditional deletion separates embryonic from later postnatal glutamatergic-neuron perturbations; details beyond the abstract are not inferred.
limitations: Abstract-only recovery; precise recombination completeness, strain and human-allele correspondence were not established here.
readouts:
- name: Spontaneous seizure occurrence
target: Epileptic Network Activity
direction: INCREASED
interpretation: Loss restricted to the studied excitatory-neuron populations is sufficient for seizures with timing-dependent severity.
evidence:
- reference: PMID:25234641
reference_title: Glutamatergic neuron-targeted loss of LGI1 epilepsy gene results in seizures.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: Emx1-Lgi1cKO mice displayed early-onset and lethal seizures, whereas CaMKIIα-Lgi1cKO mice presented late-onset occasional seizures associated with variable reduced lifespan.
explanation: Conditional deletion separates embryonic from later postnatal glutamatergic-neuron perturbations; details beyond the abstract are not inferred.
- name: Parvalbumin-neuron conditional Lgi1 knockout mice
species: Mouse
genotype: PV-Lgi1cKO
description: The tested PV-targeted deletion did not produce observed spontaneous seizures or increased convulsant susceptibility. This cell-population and protocol-specific negative result cannot exclude roles for other inhibitory neurons or assay conditions.
evidence:
- reference: PMID:25234641
reference_title: Glutamatergic neuron-targeted loss of LGI1 epilepsy gene results in seizures.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: In contrast, neither spontaneous seizures nor increased seizure susceptibility to convulsant were observed when Lgi1 was deleted in parvalbumin interneurons.
explanation: Negative result in the specific PV-targeted conditional model, not every inhibitory cell population.
modeled_mechanisms:
- target: Epileptic Network Activity
relationship: FAILS_TO_RECAPITULATE
description: The reported seizure endpoints were not increased in the PV-targeted conditional model.
fidelity: UNKNOWN
evidence:
- reference: PMID:25234641
reference_title: Glutamatergic neuron-targeted loss of LGI1 epilepsy gene results in seizures.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: In contrast, neither spontaneous seizures nor increased seizure susceptibility to convulsant were observed when Lgi1 was deleted in parvalbumin interneurons.
explanation: Negative result in the specific PV-targeted conditional model, not every inhibitory cell population.
limitations: Negative result is restricted to the targeted PV population and the reported tests; source available only as an abstract.
readouts:
- name: Seizure susceptibility
target: Epileptic Network Activity
direction: UNCHANGED
interpretation: The reported seizure endpoints were not increased in the PV-targeted conditional model.
evidence:
- reference: PMID:25234641
reference_title: Glutamatergic neuron-targeted loss of LGI1 epilepsy gene results in seizures.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: In contrast, neither spontaneous seizures nor increased seizure susceptibility to convulsant were observed when Lgi1 was deleted in parvalbumin interneurons.
explanation: Negative result in the specific PV-targeted conditional model, not every inhibitory cell population.
experimental_models:
- name: Lgi1-null acute hippocampal slices
experimental_model_type: OTHER
description: P14–18 null and wild-type mouse hippocampal slices were studied with CA1 recordings. Miniature-event frequency and evoked AMPA/NMDA responses increased, while measured inhibitory currents and baseline intrinsic properties were similar. Enhanced spontaneous bursts were recorded in magnesium-free, low-calcium, high-potassium ACSF, which is a proconvulsant condition.
evidence:
- *id004
- reference: PMID:20130004
reference_title: Lgi1 null mutant mice exhibit myoclonic seizures and CA1 neuronal hyperexcitability.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: the spontaneous burst discharge frequency was significantly increased in the Lgi1-mutant mice
explanation: In this sentence the observation is in excised slices exposed to modified proconvulsant ACSF, not unprovoked whole-animal EEG.
- *id013
modeled_mechanisms:
- target: Increased Excitatory Synaptic Transmission
relationship: MEASURES
description: mEPSC frequency increases without a significant amplitude change; this is not a direct glutamate-concentration assay.
fidelity: UNKNOWN
evidence:
- reference: PMID:20130004
reference_title: Lgi1 null mutant mice exhibit myoclonic seizures and CA1 neuronal hyperexcitability.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: Remarkably, however, the frequency of mEPSCs was dramatically increased in the mutant mice
explanation: Mouse hippocampal slice readout; mEPSC frequency is not a direct extracellular glutamate-concentration measurement.
readouts:
- name: mEPSC frequency
target: Increased Excitatory Synaptic Transmission
direction: INCREASED
interpretation: mEPSC frequency increases without a significant amplitude change; this is not a direct glutamate-concentration assay.
evidence:
- reference: PMID:20130004
reference_title: Lgi1 null mutant mice exhibit myoclonic seizures and CA1 neuronal hyperexcitability.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: Remarkably, however, the frequency of mEPSCs was dramatically increased in the mutant mice
explanation: Mouse hippocampal slice readout; mEPSC frequency is not a direct extracellular glutamate-concentration measurement.
- target: Epileptic Network Activity
relationship: MEASURES
description: Burst frequency increases under modified proconvulsant ACSF.
fidelity: UNKNOWN
evidence:
- reference: PMID:20130004
reference_title: Lgi1 null mutant mice exhibit myoclonic seizures and CA1 neuronal hyperexcitability.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: the spontaneous burst discharge frequency was significantly increased in the Lgi1-mutant mice
explanation: In this sentence the observation is in excised slices exposed to modified proconvulsant ACSF, not unprovoked whole-animal EEG.
readouts:
- name: Epileptiform burst frequency
target: Epileptic Network Activity
direction: INCREASED
interpretation: Burst frequency increases under modified proconvulsant ACSF.
evidence:
- reference: PMID:20130004
reference_title: Lgi1 null mutant mice exhibit myoclonic seizures and CA1 neuronal hyperexcitability.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: the spontaneous burst discharge frequency was significantly increased in the Lgi1-mutant mice
explanation: In this sentence the observation is in excised slices exposed to modified proconvulsant ACSF, not unprovoked whole-animal EEG.
- target: Increased Intrinsic Neuronal Excitability
relationship: FAILS_TO_RECAPITULATE
description: Measured CA1 intrinsic properties are unchanged in this preparation.
fidelity: UNKNOWN
evidence:
- reference: PMID:20130004
reference_title: Lgi1 null mutant mice exhibit myoclonic seizures and CA1 neuronal hyperexcitability.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: These results indicate that Lgi1 mutation did not change the intrinsic properties of pyramidal neurons in the hippocampal CA1 region.
explanation: Baseline intrinsic firing, membrane potential and input resistance were unchanged in this acute-slice preparation.
limitations: Cell region, developmental stage and preparation differ from cultured CA3 restoration experiments.
readouts:
- name: Baseline intrinsic firing properties
target: Increased Intrinsic Neuronal Excitability
direction: UNCHANGED
interpretation: Measured CA1 intrinsic properties are unchanged in this preparation.
evidence:
- reference: PMID:20130004
reference_title: Lgi1 null mutant mice exhibit myoclonic seizures and CA1 neuronal hyperexcitability.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: These results indicate that Lgi1 mutation did not change the intrinsic properties of pyramidal neurons in the hippocampal CA1 region.
explanation: Baseline intrinsic firing, membrane potential and input resistance were unchanged in this acute-slice preparation.
- name: Local LGI1 restoration in organotypic hippocampal culture
experimental_model_type: OTHER
description: Organotypic slices from P7–10 homozygous-null mice of both sexes underwent single-cell electroporation of 8–10 selected neurons per slice. Inducible LGI1 expression was assessed with CA3 recordings after three days; extracellular tagged-protein visualization used a separate six-day interval. Intrinsic recordings blocked ionotropic glutamate and GABA receptors. Current, firing and AIS Kv1.1 rescue were measured in expressing cells; nearby rheobase improved, but nearby Kv1.1 staining was not significantly increased.
evidence:
- *id003
- *id014
- *id010
modeled_mechanisms:
- target: Reduced Kv1-Mediated D-Type Current
relationship: RESCUES
description: Local LGI1 expression restores the DTx-K-sensitive conductance; toxin reapplication supports a channel contribution to intrinsic rescue.
fidelity: UNKNOWN
evidence:
- reference: PMID:37863654
reference_title: Rescue of Normal Excitability in LGI1-Deficient Epileptic Neurons.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: Here, we show that 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.
explanation: Restoration in organotypic mouse hippocampal neurons supports a Kv1-related excitability mechanism; this is not a human treatment.
- reference: PMID:37863654
reference_title: Rescue of Normal Excitability in LGI1-Deficient Epileptic Neurons.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: The value of DTx-k-sensitive conductance reported in KO/lgi1 neurons was similar to that found in WT neurons
explanation: Restoration of toxin-sensitive conductance in the electroporated neurons.
readouts:
- name: DTx-K-sensitive conductance
target: Reduced Kv1-Mediated D-Type Current
direction: RESTORED
interpretation: Local LGI1 expression restores the DTx-K-sensitive conductance; toxin reapplication supports a channel contribution to intrinsic rescue.
evidence:
- reference: PMID:37863654
reference_title: Rescue of Normal Excitability in LGI1-Deficient Epileptic Neurons.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: Here, we show that 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.
explanation: Restoration in organotypic mouse hippocampal neurons supports a Kv1-related excitability mechanism; this is not a human treatment.
- reference: PMID:37863654
reference_title: Rescue of Normal Excitability in LGI1-Deficient Epileptic Neurons.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: The value of DTx-k-sensitive conductance reported in KO/lgi1 neurons was similar to that found in WT neurons
explanation: Restoration of toxin-sensitive conductance in the electroporated neurons.
- target: Reduced Axon Initial Segment Kv1.1 Density
relationship: RESCUES
description: AIS Kv1.1 immunostaining recovers in expressing neurons; significant density rescue was not demonstrated in neighboring neurons.
fidelity: UNKNOWN
evidence:
- reference: PMID:37863654
reference_title: Rescue of Normal Excitability in LGI1-Deficient Epileptic Neurons.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: Here, we show that 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.
explanation: Restoration in organotypic mouse hippocampal neurons supports a Kv1-related excitability mechanism; this is not a human treatment.
readouts:
- name: AIS Kv1.1 staining
target: Reduced Axon Initial Segment Kv1.1 Density
direction: RESTORED
interpretation: AIS Kv1.1 immunostaining recovers in expressing neurons; significant density rescue was not demonstrated in neighboring neurons.
evidence:
- reference: PMID:37863654
reference_title: Rescue of Normal Excitability in LGI1-Deficient Epileptic Neurons.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: Here, we show that 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.
explanation: Restoration in organotypic mouse hippocampal neurons supports a Kv1-related excitability mechanism; this is not a human treatment.
- target: Increased Intrinsic Neuronal Excitability
relationship: RESCUES
description: Current-evoked excitability decreases after local expression in deficient CA3 cells.
fidelity: UNKNOWN
evidence:
- reference: PMID:37863654
reference_title: Rescue of Normal Excitability in LGI1-Deficient Epileptic Neurons.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: Here, we show that 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.
explanation: Restoration in organotypic mouse hippocampal neurons supports a Kv1-related excitability mechanism; this is not a human treatment.
readouts:
- name: Intrinsic neuronal firing
target: Increased Intrinsic Neuronal Excitability
direction: DECREASED
interpretation: Current-evoked excitability decreases after local expression in deficient CA3 cells.
evidence:
- reference: PMID:37863654
reference_title: Rescue of Normal Excitability in LGI1-Deficient Epileptic Neurons.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: Here, we show that 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.
explanation: Restoration in organotypic mouse hippocampal neurons supports a Kv1-related excitability mechanism; this is not a human treatment.
- target: Shortened Axon Initial Segment
relationship: RESCUES
description: AIS length recovers partially, without evidence that shortening causes the firing phenotype.
fidelity: UNKNOWN
evidence:
- reference: PMID:37863654
reference_title: Rescue of Normal Excitability in LGI1-Deficient Epileptic Neurons.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: We show that rescuing the Lgi1 expression in LGI1-deficient neurons was sufficient to partially suppress the AIS length shortening
explanation: AIS structural rescue is partial and distinct from the current and firing endpoints.
readouts:
- name: AIS length
target: Shortened Axon Initial Segment
direction: INCREASED
interpretation: AIS length recovers partially, without evidence that shortening causes the firing phenotype.
evidence:
- reference: PMID:37863654
reference_title: Rescue of Normal Excitability in LGI1-Deficient Epileptic Neurons.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: We show that rescuing the Lgi1 expression in LGI1-deficient neurons was sufficient to partially suppress the AIS length shortening
explanation: AIS structural rescue is partial and distinct from the current and firing endpoints.
notes: Counts generally represent neurons or AIS objects; animal/slice hierarchy is not explicit for each comparison. No human allele, patient-derived cell, selective secretion blockade, ADAM22 mediation experiment, living-animal seizure reduction or clinical efficacy was tested. Paracrine spread is supported but autocrine versus intracellular contributions remain unresolved.
- name: LGI1 variant secretion and receptor-binding cell assays
experimental_model_type: CELL_LINE
description: 'Transfected-cell assays distinguish secretion-defective E383A from secretion-competent S473L with altered ADAM22 interaction. Later HEK293T secretion and COS7 binding assays studied biallelic-encephalopathy variants: C48F, S524P and a terminal extension. All had reduced net binding, while inferred relative binding differed; these assays did not determine an equilibrium affinity constant. Four-phenylbutyrate responses were allele dependent and were not human treatment outcomes.'
evidence:
- *id001
- reference: PMID:40455867
reference_title: Biallelic LGI1 and ADAM23 variants cause hippocampal epileptic encephalopathy via the LGI1-ADAM22/23 pathway.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: We found differently reduced secretion levels of Cys48Phe, Ser524Pro and Ter558GlyextTer23 variants ∼6.7%, 0.5% and 40% (median, compared to LGI1 WT), respectively (Fig. 1E).
explanation: HEK293T conditioned-medium assay measures variant-specific secretion, not neuronal firing.
- *id015
modeled_mechanisms:
- target: Reduced LGI1 Secretion
relationship: MEASURES
description: Cell-medium protein assays quantify reduced secretion for selected constructs.
fidelity: UNKNOWN
evidence:
- 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
directness: DIRECT
quote_role: PRIMARY_RESULT
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: The abstract reports distinct cellular defects for two variants; neither mechanism is assumed universal.
- reference: PMID:40455867
reference_title: Biallelic LGI1 and ADAM23 variants cause hippocampal epileptic encephalopathy via the LGI1-ADAM22/23 pathway.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: We found differently reduced secretion levels of Cys48Phe, Ser524Pro and Ter558GlyextTer23 variants ∼6.7%, 0.5% and 40% (median, compared to LGI1 WT), respectively (Fig. 1E).
explanation: HEK293T conditioned-medium assay measures variant-specific secretion, not neuronal firing.
readouts:
- name: Secreted LGI1
target: Reduced LGI1 Secretion
direction: DECREASED
interpretation: Cell-medium protein assays quantify reduced secretion for selected constructs.
evidence:
- 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
directness: DIRECT
quote_role: PRIMARY_RESULT
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: The abstract reports distinct cellular defects for two variants; neither mechanism is assumed universal.
- reference: PMID:40455867
reference_title: Biallelic LGI1 and ADAM23 variants cause hippocampal epileptic encephalopathy via the LGI1-ADAM22/23 pathway.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: We found differently reduced secretion levels of Cys48Phe, Ser524Pro and Ter558GlyextTer23 variants ∼6.7%, 0.5% and 40% (median, compared to LGI1 WT), respectively (Fig. 1E).
explanation: HEK293T conditioned-medium assay measures variant-specific secretion, not neuronal firing.
- target: Reduced LGI1-ADAM22 Binding
relationship: MEASURES
description: The S473L construct shows an interaction defect distinct from secretion failure.
fidelity: UNKNOWN
evidence:
- 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
directness: DIRECT
quote_role: PRIMARY_RESULT
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: The abstract reports distinct cellular defects for two variants; neither mechanism is assumed universal.
readouts:
- name: LGI1-ADAM22 interaction
target: Reduced LGI1-ADAM22 Binding
direction: DECREASED
interpretation: The S473L construct shows an interaction defect distinct from secretion failure.
evidence:
- 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
directness: DIRECT
quote_role: PRIMARY_RESULT
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: The abstract reports distinct cellular defects for two variants; neither mechanism is assumed universal.
notes: Heterologous overexpression and distinct dominant versus biallelic alleles limit direct translation. Five mM 4PBA for 72 hours increased C48F and wild-type secretion but reduced S524P and terminal-extension secretion in the later study.
- name: Excised intact Lgi1-null hippocampus
experimental_model_type: OTHER
description: Whole hippocampi from P16–18 homozygous-null mice were studied with CA3 patch and local-field recordings. Abnormal network barrages and oscillations occurred in an isolated preparation without afferents from other brain regions. Baseline spontaneous EPSC/IPSC distributions and sampled intrinsic membrane properties were unchanged. The separate Adam22 mutant behavioral arm of this paper is not an Lgi1 behavioral-rescue experiment.
evidence:
- reference: PMID:40455867
reference_title: Biallelic LGI1 and ADAM23 variants cause hippocampal epileptic encephalopathy via the LGI1-ADAM22/23 pathway.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: Because this recording was obtained from a whole hippocampus without afferents from other brain regions, this suggests that epileptic discharges originate in the hippocampus in Lgi1−/− mice.
explanation: Excised whole-hippocampus recordings localize abnormal network activity within that preparation.
- reference: PMID:40455867
reference_title: Biallelic LGI1 and ADAM23 variants cause hippocampal epileptic encephalopathy via the LGI1-ADAM22/23 pathway.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: The cumulative frequency distribution of amplitude and inter-event interval (IEI) in sEPSCs and sIPSCs showed no significant difference between WT and Lgi1−/− mice (Fig. 2B).
explanation: Baseline spontaneous excitatory and inhibitory events were not significantly different between genotypes.
- *id016
modeled_mechanisms:
- target: Epileptic Network Activity
relationship: MEASURES
description: The isolated preparation supports an intrahippocampal source of the observed abnormal discharges.
fidelity: UNKNOWN
evidence:
- reference: PMID:40455867
reference_title: Biallelic LGI1 and ADAM23 variants cause hippocampal epileptic encephalopathy via the LGI1-ADAM22/23 pathway.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: Because this recording was obtained from a whole hippocampus without afferents from other brain regions, this suggests that epileptic discharges originate in the hippocampus in Lgi1−/− mice.
explanation: Excised whole-hippocampus recordings localize abnormal network activity within that preparation.
readouts:
- name: Epileptic network discharges
target: Epileptic Network Activity
direction: INCREASED
interpretation: The isolated preparation supports an intrahippocampal source of the observed abnormal discharges.
evidence:
- reference: PMID:40455867
reference_title: Biallelic LGI1 and ADAM23 variants cause hippocampal epileptic encephalopathy via the LGI1-ADAM22/23 pathway.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: Because this recording was obtained from a whole hippocampus without afferents from other brain regions, this suggests that epileptic discharges originate in the hippocampus in Lgi1−/− mice.
explanation: Excised whole-hippocampus recordings localize abnormal network activity within that preparation.
- target: Increased Intrinsic Neuronal Excitability
relationship: FAILS_TO_RECAPITULATE
description: The baseline intrinsic properties sampled in this intact preparation were not different.
fidelity: UNKNOWN
evidence:
- reference: PMID:40455867
reference_title: Biallelic LGI1 and ADAM23 variants cause hippocampal epileptic encephalopathy via the LGI1-ADAM22/23 pathway.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: The intrinsic electrical properties of CA3 neurons, such as membrane capacitance, input resistance, resting membrane potential and membrane time constant (Tau) were not different between genotypes (Supplementary Table 3).
explanation: Baseline intrinsic membrane properties did not differ in the sampled CA3 neurons.
limitations: This is not equivalent to every evoked-current test and differs from organotypic culture; absence of a baseline difference does not negate network abnormalities.
readouts:
- name: Baseline intrinsic membrane properties
target: Increased Intrinsic Neuronal Excitability
direction: UNCHANGED
interpretation: The baseline intrinsic properties sampled in this intact preparation were not different.
evidence:
- reference: PMID:40455867
reference_title: Biallelic LGI1 and ADAM23 variants cause hippocampal epileptic encephalopathy via the LGI1-ADAM22/23 pathway.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: The intrinsic electrical properties of CA3 neurons, such as membrane capacitance, input resistance, resting membrane potential and membrane time constant (Tau) were not different between genotypes (Supplementary Table 3).
explanation: Baseline intrinsic membrane properties did not differ in the sampled CA3 neurons.
- name: Mutant reelin trafficking and autophagy cell assays
experimental_model_type: CELL_LINE
description: A cell-based overexpression study reported impaired mutant trafficking and secretion with increased LC3 autophagy flux. Partial pharmacologic rescue of secretion was reported, but the available abstract does not establish the precise culture, constructs, compounds or a neuronal-seizure rescue. No mandatory autophagy-to-secretion causal sequence is imposed.
evidence:
- *id007
- *id017
modeled_mechanisms:
- target: Reduced Reelin Secretion
relationship: MEASURES
description: Mutant-protein secretion is reduced in the reported assay.
fidelity: UNKNOWN
evidence:
- reference: PMID:34508592
reference_title: Epilepsy-causing Reelin mutations result in impaired secretion and intracellular degradation of mutant proteins.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: Using a cell-based secretion assay, we show that pathogenic RELN mutations abolish or significantly reduce secretion of mutant proteins and that this secretion defect results from impaired trafficking of mutant Reelin along the secretory pathway.
explanation: Direct cell-assay result reported in an abstract-only source; precise constructs and culture conditions were not recoverable.
readouts:
- name: Secreted mutant reelin
target: Reduced Reelin Secretion
direction: DECREASED
interpretation: Mutant-protein secretion is reduced in the reported assay.
evidence:
- reference: PMID:34508592
reference_title: Epilepsy-causing Reelin mutations result in impaired secretion and intracellular degradation of mutant proteins.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: Using a cell-based secretion assay, we show that pathogenic RELN mutations abolish or significantly reduce secretion of mutant proteins and that this secretion defect results from impaired trafficking of mutant Reelin along the secretory pathway.
explanation: Direct cell-assay result reported in an abstract-only source; precise constructs and culture conditions were not recoverable.
- target: Increased Mutant Reelin Autophagic Processing
relationship: MEASURES
description: LC3 immunoblotting reports increased flux under mutant overexpression.
fidelity: UNKNOWN
evidence:
- reference: PMID:34508592
reference_title: Epilepsy-causing Reelin mutations result in impaired secretion and intracellular degradation of mutant proteins.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: In addition, LC3 immunoblotting shows a significant increase of autophagy flux due to mutant overexpression.
explanation: Reported LC3 flux response in transfected cells, not a patient neuronal measurement.
readouts:
- name: LC3 autophagy flux
target: Increased Mutant Reelin Autophagic Processing
direction: INCREASED
interpretation: LC3 immunoblotting reports increased flux under mutant overexpression.
evidence:
- reference: PMID:34508592
reference_title: Epilepsy-causing Reelin mutations result in impaired secretion and intracellular degradation of mutant proteins.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: In addition, LC3 immunoblotting shows a significant increase of autophagy flux due to mutant overexpression.
explanation: Reported LC3 flux response in transfected cells, not a patient neuronal measurement.
- name: MICAL1 transfected-cell activity and morphology assays
experimental_model_type: CELL_LINE
description: HEK293T cell-lysate Amplex assays measured NADPH-dependent H2O2 generation for selected MICAL1 variants, with separate COS7 contraction assays in the original study. G150S and the C-terminal extension increased activity, whereas R646Q was a VUS without increased activity. A later R915C assay increased the human and homologous mouse activity proxies. No neuronal actin oxidation, synapse measurement, human rescue or clinical treatment was tested.
evidence:
- *id018
- *id008
modeled_mechanisms:
- target: Increased MICAL1 Oxidoreductase Activity
relationship: MEASURES
description: Selected variant constructs increase an indirect oxidoreductase-activity readout.
fidelity: UNKNOWN
evidence:
- reference: PMID:38654463
reference_title: A de novo pathogenic variant in MICAL-1 causes epilepsy with auditory features.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: To determine the effects of the p.Arg915Cys variant on MICAL‐1 redox activity, we used an indirect enzyme‐linked assay that measures H2O2 production.
explanation: HEK293T lysate H2O2 production is an enzyme-activity proxy, not a direct neuronal F-actin assay.
- reference: PMID:38654463
reference_title: A de novo pathogenic variant in MICAL-1 causes epilepsy with auditory features.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: We found that the oxidoreductase activities of human (hMICAL‐1Arg915Cys) and mouse (mMICAL‐1Arg902Cys) mutants were significantly increased
explanation: Variant-dependent activity increase in transfected-cell lysates.
readouts:
- name: Cell-lysate H2O2 production
target: Increased MICAL1 Oxidoreductase Activity
direction: INCREASED
interpretation: Selected variant constructs increase an indirect oxidoreductase-activity readout.
evidence:
- reference: PMID:38654463
reference_title: A de novo pathogenic variant in MICAL-1 causes epilepsy with auditory features.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: To determine the effects of the p.Arg915Cys variant on MICAL‐1 redox activity, we used an indirect enzyme‐linked assay that measures H2O2 production.
explanation: HEK293T lysate H2O2 production is an enzyme-activity proxy, not a direct neuronal F-actin assay.
- reference: PMID:38654463
reference_title: A de novo pathogenic variant in MICAL-1 causes epilepsy with auditory features.
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: PRIMARY_RESULT
snippet: We found that the oxidoreductase activities of human (hMICAL‐1Arg915Cys) and mouse (mMICAL‐1Arg902Cys) mutants were significantly increased
explanation: Variant-dependent activity increase in transfected-cell lysates.
notes: The original C-terminal extension changes the final three residues and adds a novel tail; it is not deletion of the entire coiled-coil domain. One familial variant co-segregated with an unexcluded GRIN2A variant. Cell contraction is a morphology proxy, not a direct neuronal actin measurement.
biochemical:
- name: Circulating reelin
presence: DECREASED
context: Reduced serum 310-kDa reelin was measured in four variant carriers compared with controls, with repeated assay experiments. Circulating reelin largely reflects liver production. This small research assay is not a validated diagnostic, prognostic or brain-function biomarker.
evidence:
- *id019
readouts:
- target: Reduced Circulating Reelin
relationship: READOUT_OF
interpretation: A lower band measurement reflects the circulating-protein observation, not a direct brain secretion measurement.
evidence:
- *id019
datasets:
- accession: geo:GSE49145
title: Expression data from homozygous deletion of the Lgi1 gene in murine neural precursor-like cells
description: Gene-expression microarray resource comparing Large-T-antigen-immortalized neural precursor-like cultures from E13.5 Lgi1-null and wild-type mice. It is a complete-loss developmental cell model, not a patient cohort or a direct auditory-seizure assay.
organism:
preferred_term: Mus musculus
term:
id: NCBITaxon:10090
label: Mus musculus
data_type: MICROARRAY
sample_count: 6
platform: Affymetrix GeneChip Mouse Gene 1.0 ST Array
notes: Accession, organism and six-sample metadata verified against GEO on 2026-09-21 through the sanctioned reference fetcher. The dataset summary proposes migration and synapse effects; those are not promoted into an established human causal branch without primary experimental adjudication.
evidence:
- reference: GEO:GSE49145
reference_title: Expression data from homozygous deletion of the Lgi1 gene in murine neural precursor-like cells
supports: SUPPORT
evidence_source: IN_VITRO
directness: DIRECT
quote_role: BACKGROUND
snippet: we first generated and immortalized neural precursor-like cells (NPC), isolated from Lgi1 null and wild type mice at E13.5 stage using Large-T antigen.
explanation: Repository description identifies the biological material and perturbation; no patient phenotype or causal migration result is inferred.

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References & Deep Research