Temporal Lobe Epilepsy

Complex MONDO:0005115 Pathograph 14 Show in embeddings browser Epilepsy

Temporal lobe epilepsy is a focal epilepsy in which seizures arise from temporal lobe networks, often involving mesial temporal structures and commonly associated with memory and other cognitive deficits.

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Classifications

Harrison's Part
NEUROLOGIC
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Subtypes

5
Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis
Mesial temporal lobe epilepsy subtype defined by hippocampal sclerosis, memory impairment, and frequent drug resistance.
Show evidence (1 reference)
PMID:40693462 SUPPORT Human clinical
"Hippocampal sclerosis was defined as neuronal loss and gliosis primarily involving the CA1 and CA4/3 subfields with relative resistance of the CA2 region and sparing of the subiculum (if the latter were included in the resected specimen)."
Defines the characteristic hippocampal sclerosis subtype of temporal lobe epilepsy.
Familial temporal lobe epilepsy 1 (LGI1) MONDO:0700090
LGI1 hgnc:6572 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in LGI1 (hgnc:6572). hgnc:6572 is a gene from the HUGO Gene Nomenclature Committee.
The LGI1 form of familial lateral temporal lobe epilepsy, in which focal seizures carry prominent auditory symptoms or ictal receptive aphasia. It is curated as its own entry under the syndrome name the field now uses, epilepsy with auditory features, which is where its mechanism chain and penetrance evidence live.
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."
GeneReviews names LGI1 as an established molecular cause of the auditory-features form of familial temporal lobe epilepsy.
Familial temporal lobe epilepsy 5 (CPA6) MONDO:0013741
CPA6 hgnc:17245 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in CPA6 (hgnc:17245). hgnc:17245 is a gene from the HUGO Gene Nomenclature Committee.
The CPA6 form, and the one form of familial temporal lobe epilepsy reported with recessive inheritance: a homozygous missense variant segregated with febrile seizures and temporal lobe epilepsy in four of seven siblings of consanguineous parents. A separate heterozygous variant was found in three unrelated patients with sporadic temporal lobe epilepsy, so the allelic picture is not purely recessive.
Show evidence (1 reference)
PMID:21922598 SUPPORT DIRECT PRIMARY RESULT Human clinical
"Sequencing of the 38 genes mapped within the linked interval revealed a homozygous missense mutation c.809C>T (p.Ala270Val) in the carboxypeptidase A6 gene (CPA6)."
Identifies the homozygous CPA6 variant within the mapped linkage interval in the consanguineous family, which is what defines this gene-based form.
Familial temporal lobe epilepsy 7 (RELN) MONDO:0014639
RELN hgnc:9957 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in RELN (hgnc:9957). hgnc:9957 is a gene from the HUGO Gene Nomenclature Committee.
The RELN form of familial lateral temporal lobe epilepsy. Like the LGI1 form it presents with auditory seizures, and it is curated in the same epilepsy-with-auditory-features entry, which carries the reelin secretion and degradation mechanism.
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."
GeneReviews names RELN alongside LGI1 as an established molecular cause of the auditory-features form.
Familial temporal lobe epilepsy 8 (GAL) MONDO:0014650
GAL hgnc:4114 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in GAL (hgnc:4114). hgnc:4114 is a gene from the HUGO Gene Nomenclature Committee.
The GAL form, reported in a single family: a de novo galanin variant carried by both of a pair of monozygotic twins with temporal lobe epilepsy and absent from their unaffected siblings and parents. Screening 582 further cases found no other pathogenic GAL variant, so this is a rare cause and the class rests on one pedigree plus receptor-level functional work.
Show evidence (1 reference)
PMID:25691535 SUPPORT DIRECT PRIMARY RESULT Human clinical
"Exome sequencing revealed that both twins carried a novel de novo mutation (p.A39E) in the GAL gene."
The single pedigree on which the GAL-defined form of familial temporal lobe epilepsy rests.
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Pathophysiology

6
Hippocampal Sclerosis and Neuronal Loss
In mesial temporal lobe epilepsy, hippocampal sclerosis is characterized by selective loss of pyramidal neurons and reactive gliosis predominantly in the CA1 and CA4/CA3 subfields with relative sparing of CA2 and the subiculum, remodeling mesial temporal circuitry and promoting seizure generation.
pyramidal neuron CL:0000598 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves pyramidal neuron (CL:0000598). CL:0000598 is a cell type from the Cell Ontology. glial cell CL:0000125 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves glial cell (CL:0000125). CL:0000125 is a cell type from the Cell Ontology.
Ammon's horn UBERON:0001954 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Ammon's horn (UBERON:0001954). UBERON:0001954 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Seizures Hippocampal sclerosis is the primary histopathological lesion in drug-resistant temporal lobe epilepsy and is associated with recurrent mesial temporal lobe seizures.
Show evidence (3 references)
PMID:33197783 SUPPORT Human clinical
"We confirmed histologically that all MTLE-HS cases examined exhibited severe neuronal cell loss and remarkable astrocytic gliosis in the hippocampi."
Histological confirmation in human MTLE-HS hippocampi of severe neuronal cell loss and astrocytic gliosis.
DOI:10.1111/epi.12220 SUPPORT Other
"Hippocampal sclerosis (HS) is the most frequent histopathology encountered in patients with drug‐resistant temporal lobe epilepsy (TLE)."
Establishes hippocampal sclerosis as the most frequent histopathology in drug-resistant temporal lobe epilepsy.
PMID:40693462 SUPPORT Human clinical
"Hippocampal sclerosis was defined as neuronal loss and gliosis primarily involving the CA1 and CA4/3 subfields with relative resistance of the CA2 region and sparing of the subiculum (if the latter were included in the resected specimen)."
Directly supports selective CA1 and CA4/3 neuronal loss and gliosis as the defining pathology of hippocampal sclerosis in TLE.
Epitranscriptomic m6A RNA Methylation Dysregulation
Dysregulation of N6-methyladenosine (m6A) RNA methylation in temporal lobe epilepsy involves upregulation of m6A writers and erasers with predominant transcript hypermethylation in hippocampal tissue, where m6A levels inversely correlate with protein pathway activation across metabolic and autophagic pathways; recreating this post-status epilepticus hypermethylation state via pharmacological FTO inhibition (FB23-2) in naive mice challenged with pentylenetetrazol (PTZ) decreases acute seizure susceptibility and severity.
RNA methylation GO:0001510 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal RNA methylation (GO:0001510). GO:0001510 is a biological process from the Gene Ontology.
Ammon's horn UBERON:0001954 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Ammon's horn (UBERON:0001954). UBERON:0001954 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Excitation-Inhibition Imbalance Epitranscriptomic m6A dysregulation in TLE hippocampal tissue—marked by upregulated writer/eraser machinery and predominant transcript hypermethylation that inversely correlates with protein pathway activation—modulates cellular and temporal network excitability, and pharmacologically elevating m6A via FTO inhibition decreases PTZ-induced seizure susceptibility in mice.
Seizures Epitranscriptomic m6A RNA methylation changes in TLE modulate seizure thresholds, with pharmacological elevation of m6A via FTO inhibition (recreating the post-status epilepticus hypermethylation state) decreasing pentylenetetrazol-induced seizure susceptibility and severity in mice.
Show evidence (2 references)
PMID:40693462 SUPPORT Human clinical
"Specifically, our results suggest that m6A levels inversely correlate with protein pathway activation."
Primary experimental finding showing m6A dysregulation inversely correlates with protein pathway activation in TLE.
PMID:40693462 SUPPORT Model organism
"Finally, we show that elevated levels of m6A decrease seizure susceptibility and severity in mice."
Primary experimental finding showing m6A levels functionally regulate seizure susceptibility and severity.
Excitation-Inhibition Imbalance
Temporal lobe epilepsy is associated with altered excitation/inhibition balance across temporal and connected cortical regions, with molecular correlates implicating both GABAergic and glutamatergic signaling.
pyramidal neuron CL:0000598 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves pyramidal neuron (CL:0000598). CL:0000598 is a cell type from the Cell Ontology. GABAergic interneuron CL:0000617 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves GABAergic interneuron, annotated with GABAergic neuron (CL:0000617). CL:0000617 is a cell type from the Cell Ontology.
chemical synaptic transmission GO:0007268 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves chemical synaptic transmission (GO:0007268). GO:0007268 is a biological process from the Gene Ontology.
temporal lobe UBERON:0001871 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in temporal lobe (UBERON:0001871). UBERON:0001871 is an anatomical location from the Uberon multi-species anatomy ontology. entorhinal cortex UBERON:0002728 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in entorhinal cortex (UBERON:0002728). UBERON:0002728 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Seizures Altered excitation/inhibition balance in temporal and frontal cortical networks is associated with temporal lobe epilepsy and recurrent focal seizures.
Memory Impairment Altered excitation/inhibition balance in the left entorhinal and bilateral dorsolateral prefrontal cortices correlates with lower performance on short-term verbal memory.
Show evidence (2 references)
PMID:39056027 SUPPORT Human clinical
"Patients with temporal lobe epilepsy showed a significantly larger exponent, corresponding to inhibition-directed E/I balance, in bilateral frontal and temporal regions."
Directly supports altered excitation/inhibition balance in temporal lobe epilepsy at the network level.
PMID:39056027 SUPPORT Human clinical
"Limited to patients with temporal lobe epilepsy, we detected a significant correlation between the exponent and the cortical expression of GABRA1, GRIN2A, GABRD, GABRG2, KCNA2 and PDYN genes."
Supports molecular correlates of altered excitation/inhibition balance in temporal lobe epilepsy.
Thalamocortical Network Dysfunction
Vulnerable thalamocortical pathways can contribute to cognitive dysfunction in temporal lobe epilepsy, indicating that the disorder affects distributed neural circuits beyond the temporal focus itself.
transmission of nerve impulse GO:0019226 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves transmission of nerve impulse (GO:0019226). GO:0019226 is a biological process from the Gene Ontology.
temporal lobe UBERON:0001871 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in temporal lobe (UBERON:0001871). UBERON:0001871 is an anatomical location from the Uberon multi-species anatomy ontology. dorsal plus ventral thalamus UBERON:0001897 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in dorsal plus ventral thalamus (UBERON:0001897). UBERON:0001897 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Executive Dysfunction Microstructural damage to thalamocortical pathways is associated with poorer executive function performance in temporal lobe epilepsy.
Show evidence (1 reference)
PMID:29880477 SUPPORT Human clinical
"Our results give insight into vulnerable neural networks in pediatric focal epilepsy and suggest thalamocortical pathway damage as a potential mechanism of executive function impairment in temporal lobe epilepsy but not frontal lobe epilepsy."
Supports a distributed thalamocortical circuit mechanism for cognitive dysfunction in temporal lobe epilepsy, though this evidence is specific to a pediatric cohort.
Impaired Galanin Neuropeptide Signaling
Galanin is an inhibitory neuropeptide released in the hippocampus, and galanin receptor agonists suppress seizures in animal models. In a family with monozygotic twins affected by temporal lobe epilepsy, a de novo GAL variant (p.A39E) produced a peptide that antagonized galanin receptor 1 signaling and bound galanin receptor 2 with reduced affinity and reduced agonist activity, so galanin-mediated restraint of hippocampal glutamatergic transmission is lost. GAL variants are a rare cause: no further pathogenic variant was found in a cohort of 582 cases.
GAL hgnc:4114 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves GAL (hgnc:4114). hgnc:4114 is a gene from the HUGO Gene Nomenclature Committee.
galanin receptor signaling GO:0090663 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased galanin receptor signaling, annotated with galanin-activated signaling pathway (GO:0090663). GO:0090663 is a biological process from the Gene Ontology.
galanin neuropeptide hormone activity GO:0005184 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased galanin neuropeptide hormone activity, annotated with neuropeptide hormone activity (GO:0005184). GO:0005184 is a molecular function from the Gene Ontology.
hippocampal formation UBERON:0002421 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in hippocampal formation (UBERON:0002421). UBERON:0002421 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Excitation-Inhibition Imbalance Loss of galanin signaling at GalR1 and GalR2 is proposed to release hippocampal glutamatergic transmission from inhibitory restraint. The step from the receptor assays to the human network state is an inference drawn by the authors, not a measurement they made in patients.
Show evidence (2 references)
PMID:25691535 SUPPORT DIRECT PRIMARY RESULT In vitro / ex vivo
"Functional analysis revealed that the p.A39E mutant showed antagonistic activity against galanin receptor 1 (GalR1)-mediated response, and decreased binding affinity and reduced agonist properties for GalR2."
Receptor-level measurements establishing that the patient variant impairs signaling at both galanin receptors.
PMID:25691535 SUPPORT INDIRECT BACKGROUND Model organism
"A role for the galanin neuropeptide in the regulation of epileptic seizures has been established in animal models more than two decades ago."
Records that the seizure-regulating role of galanin comes from animal models, which is the basis on which the gene was treated as a candidate.
Reduced Extracellular Carboxypeptidase A6 Activity
Carboxypeptidase A6 is secreted and binds the extracellular matrix, where it processes neuropeptides. Epilepsy-associated CPA6 variants cluster near the active site and act in two ways: some reduce catalytic activity, while others are retained inside the cell so that little or no enzyme reaches the matrix. Which neuropeptide substrates matter for seizure threshold in humans is not established, so the route from this node to seizures is not resolved.
CPA6 hgnc:17245 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CPA6 (hgnc:17245). hgnc:17245 is a gene from the HUGO Gene Nomenclature Committee.
carboxypeptidase A6 activity GO:0004181 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased carboxypeptidase A6 activity, annotated with metallocarboxypeptidase activity (GO:0004181). GO:0004181 is a molecular function from the Gene Ontology.
Downstream
Seizures The link rests on human genetics rather than on a traced mechanism: a homozygous CPA6 variant segregated with febrile seizures and temporal lobe epilepsy in a consanguineous family, and inactivating variants were found more often in epilepsy patients than in controls.
Show evidence (2 references)
PMID:21922598 SUPPORT DIRECT PRIMARY RESULT In vitro / ex vivo
"Ala270Val CPA6 was secreted at about 40% of the level of the wild-type CPA6 and was fully active, while Gly267Arg CPA6 was not detected in the medium or extracellular matrix."
Shows the two variants reduce the amount of enzyme reaching the extracellular matrix, the compartment where CPA6 is active.
PMID:23105115 SUPPORT DIRECT PRIMARY RESULT In vitro / ex vivo
"Several mutations resulted in reduced enzyme activity or CPA6 protein levels in the extracellular matrix."
Confirms the same two-mode effect across a wider allelic series, with folding largely preserved.
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Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Temporal Lobe Epilepsy Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

5
Seizures VERY_FREQUENT Neurological HP:0007359 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Focal-onset seizure (HP:0007359). HP:0007359 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:9046965 SUPPORT Other
"Initial management of patients with temporal lobe epilepsy is with antiepileptic drugs, but these control seizures in only half the patients."
Supports recurrent seizures as the defining clinical feature of temporal lobe epilepsy.
PMID:11484687 SUPPORT Human clinical
"At one year, the cumulative proportion of patients who were free of seizures impairing awareness was 58 percent in the surgical group and 8 percent in the medical group (P<0.001)."
Documents focal seizures impairing awareness as the primary seizure type in temporal lobe epilepsy.
Memory Impairment FREQUENT Cognitive HP:0002354 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Memory impairment (HP:0002354). HP:0002354 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39056027 SUPPORT Human clinical
"Lower E/I in the left entorhinal and bilateral dorsolateral prefrontal cortices corresponded to a lower performance of short-term verbal memory."
Supports memory impairment in temporal lobe epilepsy, but the cited study specifically addresses short-term verbal memory performance.
Executive Dysfunction Cognitive HP:0033051 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Impaired executive functioning (HP:0033051). HP:0033051 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29880477 SUPPORT Human clinical
"In patients with temporal lobe epilepsy, poorer performance on all measures of executive function was associated with DTI indices reflective of damaged/less developed pathways."
Supports executive function impairment associated with thalamocortical tract changes in TLE.
Depression Psychiatric HP:0000716 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Depression (HP:0000716). HP:0000716 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40693462 SUPPORT BACKGROUND Human clinical
"Often caused by direct brain insults such as traumatic brain injury (TBI) (1), stroke (2–4), central nervous system (CNS) infections, and status epilepticus (SE) (5), it is associated with high rates of drug refractoriness and comorbid symptoms such as persistent learning and memory impairment,..."
Documents depression as a comorbid symptom associated with temporal lobe epilepsy.
Anxiety Psychiatric HP:0000739 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anxiety (HP:0000739). HP:0000739 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40693462 SUPPORT BACKGROUND Human clinical
"Often caused by direct brain insults such as traumatic brain injury (TBI) (1), stroke (2–4), central nervous system (CNS) infections, and status epilepticus (SE) (5), it is associated with high rates of drug refractoriness and comorbid symptoms such as persistent learning and memory impairment,..."
Documents anxiety as a comorbid symptom associated with temporal lobe epilepsy.
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Genetic Associations

4
LGI1
Gene: LGI1 hgnc:6572 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is LGI1 (hgnc:6572). hgnc:6572 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (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."
Names LGI1 as an established molecular cause.
RELN
Gene: RELN hgnc:9957 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is RELN (hgnc:9957). hgnc:9957 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID: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 RELN as an established molecular cause.
CPA6
Gene: CPA6 hgnc:17245 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CPA6 (hgnc:17245). hgnc:17245 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:21922598 SUPPORT DIRECT PRIMARY RESULT Human clinical
"This study suggests that CPA6 is genetically linked to an AR familial form of FS and TLE, and is associated with sporadic TLE cases."
The paper's own statement of the gene-disease claim, covering both the recessive family and the sporadic cases.
Variants (2)
p.Ala270Val
Homozygous missense variant (c.809C>T) identified in the consanguineous pedigree. The protein is fully active but is secreted at about 40% of wild-type levels.
Show evidence (1 reference)
PMID:21922598 SUPPORT DIRECT PRIMARY RESULT In vitro / ex vivo
"Ala270Val CPA6 was secreted at about 40% of the level of the wild-type CPA6 and was fully active, while Gly267Arg CPA6 was not detected in the medium or extracellular matrix."
Gives the secretion and activity result for this allele.
p.Gly267Arg
Heterozygous missense variant (c.799G>A) found in three unrelated patients with temporal lobe epilepsy. The protein does not reach the medium or the extracellular matrix.
Show evidence (1 reference)
PMID:21922598 SUPPORT DIRECT PRIMARY RESULT Human clinical
"Screening all exons of CPA6 in unrelated patients with partial epilepsy (n = 195) and FS (n = 145) revealed a new heterozygous missense mutation c.799G>A (p.Gly267Arg) in three TLE patients."
Reports the allele and the cohort it was found in.
GAL
Gene: GAL hgnc:4114 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GAL (hgnc:4114). hgnc:4114 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:25691535 SUPPORT DIRECT PRIMARY RESULT Human clinical
"The identification of a novel de novo mutation in a biologically-relevant candidate gene, coupled with functional evidence that the mutant protein disrupts galanin signaling, strongly supports GAL as the causal gene for the TLE in this family."
The authors' gene-disease claim, scoped explicitly to this one family.
PMID:25691535 SUPPORT DIRECT PRIMARY RESULT Human clinical
"In a cohort of 582 cases, we did not observe any pathogenic mutations indicating that mutations in GAL are a rare cause of TLE."
A negative screening result bounding how much of temporal lobe epilepsy this gene accounts for.
Variants (1)
p.A39E
De novo missense variant carried by both monozygotic twins. The mutant peptide antagonizes GalR1 and has reduced affinity and agonist activity at GalR2.
Show evidence (1 reference)
PMID:25691535 SUPPORT DIRECT PRIMARY RESULT In vitro / ex vivo
"Functional analysis revealed that the p.A39E mutant showed antagonistic activity against galanin receptor 1 (GalR1)-mediated response, and decreased binding affinity and reduced agonist properties for GalR2."
The receptor-level characterization of this allele.
💊

Medical Actions

2
Antiseizure Medication Therapy
Action: antiepileptic drug therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is antiepileptic drug therapy, annotated with Anticonvulsant Therapy (NCIT:C64172). NCIT:C64172 is a clinical intervention from the NCI Thesaurus. Ontology label: Anticonvulsant Therapy NCIT:C64172
Initial management of temporal lobe epilepsy is pharmacotherapy using antiseizure medications used across focal epilepsies, although many patients do not achieve durable seizure freedom and later meet criteria for drug-resistant disease.
Show evidence (2 references)
PMID:9046965 SUPPORT Other
"Initial management of patients with temporal lobe epilepsy is with antiepileptic drugs, but these control seizures in only half the patients."
Supports antiseizure medication therapy as first-line management in TLE, while also showing that medication failure is common.
PMID:38888005 SUPPORT Human clinical
"All approved ASMs were effective as add-on treatment for focal epilepsy."
Supports ongoing pharmacotherapy in TLE because TLE is a focal epilepsy syndrome, although the evidence is not specific to TLE alone.
Epilepsy Surgery for Drug-Resistant Disease
Action: surgical procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surgical procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
In carefully selected patients with drug-resistant temporal lobe epilepsy, surgical treatment offers substantially higher rates of seizure freedom than continued medical therapy and remains a key escalation path once pharmacoresistance is established.
Show evidence (1 reference)
PMID:11484687 SUPPORT Human clinical
"At one year, the cumulative proportion of patients who were free of seizures impairing awareness was 58 percent in the surgical group and 8 percent in the medical group (P<0.001)."
Supports surgical treatment as an effective option for carefully selected patients with drug-resistant temporal lobe epilepsy.
🔬

Diagnosis

2
Electroencephalography (EEG)
Surface and, when needed, intracranial electroencephalography are used to localize the temporal lobe seizure onset focus and guide surgical or medical management.
Electroencephalography NCIT:C38054 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:9046965 SUPPORT Other
"That evaluation requires identification of a focus of onset of seizures, as well as establishing that the focus is in an area of the brain that can be removed with a low risk of new neurologic deficits. Techniques used in that evaluation, including electroencephalography, imaging, recording form..."
Supports scalp and intracranial EEG as primary diagnostic modalities for localizing seizure onset in TLE.
Brain Neuroimaging (MRI and PET)
Structural brain MRI (to identify hippocampal T2 hyperintensity, hippocampal sclerosis, or other epileptogenic lesions) and functional imaging such as positron emission tomography (PET) support localization of the epileptogenic temporal lobe focus.
Magnetic Resonance Imaging NCIT:C16809 NCI Thesaurus (NCIT)
Show evidence (2 references)
DOI:10.1111/epi.17979 SUPPORT Human clinical
"Hippocampal T2 hyperintensity following febrile status epilepticus predicted hippocampal sclerosis and significant likelihood of mesial temporal lobe epilepsy."
Supports brain MRI detection of hippocampal T2 hyperintensity and hippocampal sclerosis in temporal lobe epilepsy.
PMID:9046965 SUPPORT Other
"Techniques used in that evaluation, including electroencephalography, imaging, recording form intracranial electrodes, use of the intracarotid amobarbitol perfusion test, and the role of specialized studies such as positron emission tomography, are reviewed"
Supports neuroimaging and PET as core components of the diagnostic and presurgical evaluation of TLE.
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Progression

2
Post-Insult Latent Epileptogenesis and Chronic Epilepsy
Often triggered by an initial brain insult (such as traumatic brain injury, stroke, central nervous system infection, or status epilepticus), followed by persistent transcriptional and network remodeling that establishes a chronic hyperexcitable seizure network.
Show evidence (1 reference)
PMID:40693462 SUPPORT BACKGROUND Human clinical
"Often caused by direct brain insults such as traumatic brain injury (TBI) (1), stroke (2–4), central nervous system (CNS) infections, and status epilepticus (SE) (5), it is associated with high rates of drug refractoriness and comorbid symptoms such as persistent learning and memory impairment,..."
Documents precipitating brain insults and progression to chronic drug-refractory TLE with cognitive and psychiatric comorbidities.
Drug-Refractory Progression
Roughly half of patients do not achieve seizure control with antiseizure medications and progress to pharmacoresistant temporal lobe epilepsy requiring surgical evaluation.
Show evidence (1 reference)
PMID:9046965 SUPPORT Other
"Initial management of patients with temporal lobe epilepsy is with antiepileptic drugs, but these control seizures in only half the patients. Patients refractory to drugs should be evaluated for resective surgery."
Supports progression to drug-refractory disease in approximately half of patients with TLE.
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Prevalence

1
Adults with Epilepsy
Unknown
Temporal lobe epilepsy is the most common focal epilepsy syndrome in adults and is associated with high rates of pharmacoresistance and neuropsychiatric comorbidities.
Show evidence (1 reference)
PMID:40693462 SUPPORT BACKGROUND Human clinical
"Temporal lobe epilepsy (TLE) is the most common epilepsy syndrome in adults."
Establishes temporal lobe epilepsy as the most common adult epilepsy syndrome.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Temporal Lobe Epilepsy:

Frontal Lobe Epilepsy
Overlapping Features Another common focal epilepsy syndrome that can share aura, automatisms, and executive dysfunction with temporal lobe epilepsy, distinguished by seizure semiology, EEG localization, and distinct thalamocortical network involvement.
Distinguishing Features
  • Frontal lobe seizure onset on EEG
  • Distinct executive function and thalamocortical tract profiles
Show evidence (1 reference)
PMID:29880477 SUPPORT Human clinical
"Our results give insight into vulnerable neural networks in pediatric focal epilepsy and suggest thalamocortical pathway damage as a potential mechanism of executive function impairment in temporal lobe epilepsy but not frontal lobe epilepsy."
Contrasts temporal lobe epilepsy with frontal lobe epilepsy across cognitive and thalamocortical network features.
📊

Related Datasets

4
Hippocampal epitranscriptomic (m6A) in human model of Temporal Lobe Epilepsy geo:GSE297566
Analogous to DNA methylation and protein phosphorylation it is now well understood that RNA is also subject to extensive processing and modification. N6-methyladenosine (m6A) is the most abundant internal RNA modification and regulates RNA fate in several ways including stability and translational efficiency. The role of m6A in both experimental and human epilepsy remains unknown. Here we use transcriptome-wide m6A arrays to obtain a detailed analysis of the hippocampal m6A-ome from human temporal lobe epilepsy samples. We show that epileptic tissue displays disrupted metabolic and autophagic pathways which may be directly linked to m6A-processing.
human METHYLATION n=48
PMID:40693462
Identified by GEO DataSets index search for Temporal Lobe Epilepsy (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
Genome‑wideBrain DNAMethylationandGeneExpression Patterns Unravel Epigenetic Reprogramming in Mesial Temporal Lobe Epilepsy geo:GSE272142
Mesial temporal lobe epilepsy (MTLE) is the most common drug-resistant epilepsy in adults, characterized by hippocampus sclerosis. To date, the etiology of MTLE epileptogenesis and the molecular mechanisms underlying hippocampus sclerosis remain largely unclear. Altered genome-wide DNA methylation patterns and differential gene expression have been reported to be involved in the pathophysiological mechanism of epileptogenesis. To discover epigenetic reprogramming patterns associated with MTLE, we used a higher-throughput microarray, Illumina Infinium 850 K BeadChip, and RNA sequence to analyze epigenome-wide DNA methylation and related gene expressions.
human BULK RNA SEQ n=12
Identified by GEO DataSets index search for Temporal Lobe Epilepsy (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
Meisal temporal lobe epilepsy sequencing study ega:EGAS00001003922
Our understanding of mesial temporal lobe epilepsy (MTLE) is one of the most common forms of drug-resistant epilepsy in humans. Using RNA- and small RNA-sequencing in parallel, we explored differentially expressed genes in the hippocampus and cortex of MTLE patients who had undergone surgical resection and non-epileptic controls. We found significant enrichment for astrocytic and microglial genes amongst up-regulated genes and down-regulation of neuron-specific genes in the hippocampus of MTLE patients. The transcriptome profile of the small RNAs reflected disease state more robustly than mRNAs, even across brain regions which show very little pathology.
human
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Temporal Lobe Epilepsy"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
Proteomic profile of hippocampus regions from the pilocarpine medial temporal lobe epilepsy model massive:MSV000094401
Label-free Proteomic profile of the dentate gyrus (dorsal and ventral) and CA3 (dorsal and ventral) microdissected from the hippocampus of the pilocarpine model of Mesial Temporal Lobe Epilepsy.
Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Temporal Lobe Epilepsy"). Retrieved 2026-08-02.
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name: Temporal Lobe Epilepsy
creation_date: '2026-04-05T18:58:47Z'
description: >-
  Temporal lobe epilepsy is a focal epilepsy in which seizures arise from
  temporal lobe networks, often involving mesial temporal structures and
  commonly associated with memory and other cognitive deficits.
category: Complex
parents:
- Epilepsy
synonyms:
- TLE
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
disease_term:
  preferred_term: temporal lobe epilepsy
  term:
    id: MONDO:0005115
    label: temporal lobe epilepsy
prevalence:
- population: Adults with Epilepsy
  measure_type: UNKNOWN
  notes: >-
    Temporal lobe epilepsy is the most common focal epilepsy syndrome in adults
    and is associated with high rates of pharmacoresistance and neuropsychiatric
    comorbidities.
  evidence:
  - reference: PMID:40693462
    reference_title: "N6-methyladenosine (m6A) dysregulation contributes to network excitability in temporal lobe epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Temporal lobe epilepsy (TLE) is the most common epilepsy syndrome in adults."
    explanation: Establishes temporal lobe epilepsy as the most common adult epilepsy syndrome.
progression:
- phase: Post-Insult Latent Epileptogenesis and Chronic Epilepsy
  notes: >-
    Often triggered by an initial brain insult (such as traumatic brain injury,
    stroke, central nervous system infection, or status epilepticus), followed
    by persistent transcriptional and network remodeling that establishes a
    chronic hyperexcitable seizure network.
  evidence:
  - reference: PMID:40693462
    reference_title: "N6-methyladenosine (m6A) dysregulation contributes to network excitability in temporal lobe epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Often caused by direct brain insults such as traumatic brain injury (TBI) (1), stroke (2–4), central nervous system (CNS) infections, and status epilepticus (SE) (5), it is associated with high rates of drug refractoriness and comorbid symptoms such as persistent learning and memory impairment, depression, and anxiety (6)."
    explanation: Documents precipitating brain insults and progression to chronic drug-refractory TLE with cognitive and psychiatric comorbidities.
- phase: Drug-Refractory Progression
  notes: >-
    Roughly half of patients do not achieve seizure control with antiseizure
    medications and progress to pharmacoresistant temporal lobe epilepsy
    requiring surgical evaluation.
  evidence:
  - reference: PMID:9046965
    reference_title: "Treatment of temporal lobe epilepsy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Initial management of patients with temporal lobe epilepsy is with antiepileptic drugs, but these control seizures in only half the patients. Patients refractory to drugs should be evaluated for resective surgery."
    explanation: Supports progression to drug-refractory disease in approximately half of patients with TLE.
has_subtypes:
- name: Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis
  curated_in: Mesial_Temporal_Lobe_Epilepsy_with_Hippocampal_Sclerosis
  description: >-
    Mesial temporal lobe epilepsy subtype defined by hippocampal sclerosis,
    memory impairment, and frequent drug resistance.
  evidence:
  - reference: PMID:40693462
    reference_title: "N6-methyladenosine (m6A) dysregulation contributes to network excitability in temporal lobe epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hippocampal sclerosis was defined as neuronal loss and gliosis primarily involving the CA1 and CA4/3 subfields with relative resistance of the CA2 region and sparing of the subiculum (if the latter were included in the resected specimen)."
    explanation: Defines the characteristic hippocampal sclerosis subtype of temporal lobe epilepsy.
- name: ETL1
  display_name: "Familial temporal lobe epilepsy 1 (LGI1)"
  curated_in: Autosomal_Dominant_Epilepsy_with_Auditory_Features
  description: >-
    The LGI1 form of familial lateral temporal lobe epilepsy, in which focal
    seizures carry prominent auditory symptoms or ictal receptive aphasia. It
    is curated as its own entry under the syndrome name the field now uses,
    epilepsy with auditory features, which is where its mechanism chain and
    penetrance evidence live.
  subtype_term:
    preferred_term: "epilepsy, familial temporal lobe, 1"
    term:
      id: MONDO:0700090
      label: "epilepsy, familial temporal lobe, 1"
  genes:
  - preferred_term: LGI1
    term:
      id: hgnc:6572
      label: LGI1
  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 names LGI1 as an established molecular cause of the
      auditory-features form of familial temporal lobe epilepsy.
- name: ETL5
  display_name: "Familial temporal lobe epilepsy 5 (CPA6)"
  description: >-
    The CPA6 form, and the one form of familial temporal lobe epilepsy reported
    with recessive inheritance: a homozygous missense variant segregated with
    febrile seizures and temporal lobe epilepsy in four of seven siblings of
    consanguineous parents. A separate heterozygous variant was found in three
    unrelated patients with sporadic temporal lobe epilepsy, so the allelic
    picture is not purely recessive.
  subtype_term:
    preferred_term: familial temporal lobe epilepsy 5
    term:
      id: MONDO:0013741
      label: familial temporal lobe epilepsy 5
  genes:
  - preferred_term: CPA6
    term:
      id: hgnc:17245
      label: CPA6
  evidence:
  - reference: PMID:21922598
    reference_title: Carboxypeptidase A6 gene (CPA6) mutations in a recessive familial form of febrile seizures and temporal lobe epilepsy and in sporadic temporal lobe epilepsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Sequencing of the 38 genes mapped within the linked interval revealed a homozygous missense mutation c.809C>T (p.Ala270Val) in the carboxypeptidase A6 gene (CPA6).
    explanation: >-
      Identifies the homozygous CPA6 variant within the mapped linkage interval
      in the consanguineous family, which is what defines this gene-based form.
- name: ETL7
  display_name: "Familial temporal lobe epilepsy 7 (RELN)"
  curated_in: Autosomal_Dominant_Epilepsy_with_Auditory_Features
  description: >-
    The RELN form of familial lateral temporal lobe epilepsy. Like the LGI1
    form it presents with auditory seizures, and it is curated in the same
    epilepsy-with-auditory-features entry, which carries the reelin secretion
    and degradation mechanism.
  subtype_term:
    preferred_term: familial temporal lobe epilepsy 7
    term:
      id: MONDO:0014639
      label: familial temporal lobe epilepsy 7
  genes:
  - preferred_term: RELN
    term:
      id: hgnc:9957
      label: RELN
  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 names RELN alongside LGI1 as an established molecular cause
      of the auditory-features form.
- name: ETL8
  display_name: "Familial temporal lobe epilepsy 8 (GAL)"
  description: >-
    The GAL form, reported in a single family: a de novo galanin variant
    carried by both of a pair of monozygotic twins with temporal lobe epilepsy
    and absent from their unaffected siblings and parents. Screening 582
    further cases found no other pathogenic GAL variant, so this is a rare
    cause and the class rests on one pedigree plus receptor-level functional
    work.
  subtype_term:
    preferred_term: familial temporal lobe epilepsy 8
    term:
      id: MONDO:0014650
      label: familial temporal lobe epilepsy 8
  genes:
  - preferred_term: GAL
    term:
      id: hgnc:4114
      label: GAL
  evidence:
  - reference: PMID:25691535
    reference_title: Galanin pathogenic mutations in temporal lobe epilepsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Exome sequencing revealed that both twins carried a novel de novo mutation (p.A39E) in the GAL gene.
    explanation: >-
      The single pedigree on which the GAL-defined form of familial temporal
      lobe epilepsy rests.
pathophysiology:
- name: Hippocampal Sclerosis and Neuronal Loss
  description: >-
    In mesial temporal lobe epilepsy, hippocampal sclerosis is characterized by
    selective loss of pyramidal neurons and reactive gliosis predominantly in
    the CA1 and CA4/CA3 subfields with relative sparing of CA2 and the
    subiculum, remodeling mesial temporal circuitry and promoting seizure
    generation.
  cell_types:
  - preferred_term: pyramidal neuron
    term:
      id: CL:0000598
      label: pyramidal neuron
  - preferred_term: glial cell
    term:
      id: CL:0000125
      label: glial cell
  locations:
  - preferred_term: Ammon's horn
    term:
      id: UBERON:0001954
      label: Ammon's horn
  downstream:
  - target: Seizures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Hippocampal sclerosis is the primary histopathological lesion in
      drug-resistant temporal lobe epilepsy and is associated with recurrent
      mesial temporal lobe seizures.
    evidence:
    - reference: DOI:10.1111/epi.12220
      reference_title: "International consensus classification of hippocampal sclerosis in temporal lobe epilepsy: A Task Force report from the <scp>ILAE</scp> Commission on Diagnostic Methods"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Hippocampal sclerosis (HS) is the most frequent histopathology encountered in patients with drug‐resistant temporal lobe epilepsy (TLE)."
      explanation: ILAE consensus report links hippocampal sclerosis to drug-resistant temporal lobe epilepsy seizures.
    - reference: PMID:40693462
      reference_title: "N6-methyladenosine (m6A) dysregulation contributes to network excitability in temporal lobe epilepsy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Hippocampal sclerosis was defined as neuronal loss and gliosis primarily involving the CA1 and CA4/3 subfields with relative resistance of the CA2 region and sparing of the subiculum (if the latter were included in the resected specimen)."
      explanation: Documents hippocampal sclerosis in resected human TLE tissue from patients with refractory seizures.
  evidence:
  - reference: PMID:33197783
    reference_title: "Proteomic profile differentiating between mesial temporal lobe epilepsy with and without hippocampal sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We confirmed histologically that all MTLE-HS cases examined exhibited severe neuronal cell loss and remarkable astrocytic gliosis in the hippocampi."
    explanation: Histological confirmation in human MTLE-HS hippocampi of severe neuronal cell loss and astrocytic gliosis.
  - reference: DOI:10.1111/epi.12220
    reference_title: "International consensus classification of hippocampal sclerosis in temporal lobe epilepsy: A Task Force report from the <scp>ILAE</scp> Commission on Diagnostic Methods"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Hippocampal sclerosis (HS) is the most frequent histopathology encountered in patients with drug‐resistant temporal lobe epilepsy (TLE)."
    explanation: Establishes hippocampal sclerosis as the most frequent histopathology in drug-resistant temporal lobe epilepsy.
  - reference: PMID:40693462
    reference_title: "N6-methyladenosine (m6A) dysregulation contributes to network excitability in temporal lobe epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hippocampal sclerosis was defined as neuronal loss and gliosis primarily involving the CA1 and CA4/3 subfields with relative resistance of the CA2 region and sparing of the subiculum (if the latter were included in the resected specimen)."
    explanation: Directly supports selective CA1 and CA4/3 neuronal loss and gliosis as the defining pathology of hippocampal sclerosis in TLE.
- name: Epitranscriptomic m6A RNA Methylation Dysregulation
  description: >-
    Dysregulation of N6-methyladenosine (m6A) RNA methylation in temporal lobe
    epilepsy involves upregulation of m6A writers and erasers with predominant
    transcript hypermethylation in hippocampal tissue, where m6A levels
    inversely correlate with protein pathway activation across metabolic and
    autophagic pathways; recreating this post-status epilepticus
    hypermethylation state via pharmacological FTO inhibition (FB23-2) in naive
    mice challenged with pentylenetetrazol (PTZ) decreases acute seizure
    susceptibility and severity.
  biological_processes:
  - preferred_term: RNA methylation
    modifier: ABNORMAL
    term:
      id: GO:0001510
      label: RNA methylation
  locations:
  - preferred_term: Ammon's horn
    term:
      id: UBERON:0001954
      label: Ammon's horn
  downstream:
  - target: Excitation-Inhibition Imbalance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Epitranscriptomic m6A dysregulation in TLE hippocampal tissue—marked by
      upregulated writer/eraser machinery and predominant transcript
      hypermethylation that inversely correlates with protein pathway
      activation—modulates cellular and temporal network excitability, and
      pharmacologically elevating m6A via FTO inhibition decreases PTZ-induced
      seizure susceptibility in mice.
    evidence:
    - reference: PMID:40693462
      reference_title: "N6-methyladenosine (m6A) dysregulation contributes to network excitability in temporal lobe epilepsy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Specifically, our results suggest that m6A levels inversely correlate with protein pathway activation."
      explanation: Demonstrates that m6A levels inversely correlate with protein pathway activation in TLE hippocampal tissue.
    - reference: PMID:40693462
      reference_title: "N6-methyladenosine (m6A) dysregulation contributes to network excitability in temporal lobe epilepsy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Finally, we show that elevated levels of m6A decrease seizure susceptibility and severity in mice."
      explanation: Experimental elevation of m6A via FTO inhibition in mice alters network excitability and reduces PTZ-induced seizure susceptibility.
  - target: Seizures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Epitranscriptomic m6A RNA methylation changes in TLE modulate seizure
      thresholds, with pharmacological elevation of m6A via FTO inhibition
      (recreating the post-status epilepticus hypermethylation state) decreasing
      pentylenetetrazol-induced seizure susceptibility and severity in mice.
    evidence:
    - reference: PMID:40693462
      reference_title: "N6-methyladenosine (m6A) dysregulation contributes to network excitability in temporal lobe epilepsy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Finally, we show that elevated levels of m6A decrease seizure susceptibility and severity in mice."
      explanation: Demonstrates that pharmacologically elevating m6A levels decreases PTZ-induced seizure susceptibility and severity in mice.
  evidence:
  - reference: PMID:40693462
    reference_title: "N6-methyladenosine (m6A) dysregulation contributes to network excitability in temporal lobe epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Specifically, our results suggest that m6A levels inversely correlate with protein pathway activation."
    explanation: Primary experimental finding showing m6A dysregulation inversely correlates with protein pathway activation in TLE.
  - reference: PMID:40693462
    reference_title: "N6-methyladenosine (m6A) dysregulation contributes to network excitability in temporal lobe epilepsy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Finally, we show that elevated levels of m6A decrease seizure susceptibility and severity in mice."
    explanation: Primary experimental finding showing m6A levels functionally regulate seizure susceptibility and severity.
- name: Excitation-Inhibition Imbalance
  description: >-
    Temporal lobe epilepsy is associated with altered excitation/inhibition
    balance across temporal and connected cortical regions, with molecular
    correlates implicating both GABAergic and glutamatergic signaling.
  cell_types:
  - preferred_term: pyramidal neuron
    term:
      id: CL:0000598
      label: pyramidal neuron
  - preferred_term: GABAergic interneuron
    term:
      id: CL:0000617
      label: GABAergic neuron
  biological_processes:
  - preferred_term: chemical synaptic transmission
    term:
      id: GO:0007268
      label: chemical synaptic transmission
  locations:
  - preferred_term: temporal lobe
    term:
      id: UBERON:0001871
      label: temporal lobe
  - preferred_term: entorhinal cortex
    term:
      id: UBERON:0002728
      label: entorhinal cortex
  downstream:
  - target: Seizures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Altered excitation/inhibition balance in temporal and frontal cortical
      networks is associated with temporal lobe epilepsy and recurrent focal
      seizures.
    evidence:
    - reference: PMID:39056027
      reference_title: "Excitation/Inhibition balance relates to cognitive function and gene expression in temporal lobe epilepsy: a high density EEG assessment with aperiodic exponent."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients with temporal lobe epilepsy showed a significantly larger exponent, corresponding to inhibition-directed E/I balance, in bilateral frontal and temporal regions."
      explanation: Demonstrates altered network excitation/inhibition balance in temporal and frontal regions of patients with TLE.
  - target: Memory Impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Altered excitation/inhibition balance in the left entorhinal and bilateral
      dorsolateral prefrontal cortices correlates with lower performance on
      short-term verbal memory.
    evidence:
    - reference: PMID:39056027
      reference_title: "Excitation/Inhibition balance relates to cognitive function and gene expression in temporal lobe epilepsy: a high density EEG assessment with aperiodic exponent."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Lower E/I in the left entorhinal and bilateral dorsolateral prefrontal cortices corresponded to a lower performance of short-term verbal memory."
      explanation: Links altered E/I balance in entorhinal and prefrontal cortices to impaired short-term verbal memory in TLE.
  evidence:
  - reference: PMID:39056027
    reference_title: "Excitation/Inhibition balance relates to cognitive function and gene expression in temporal lobe epilepsy: a high density EEG assessment with aperiodic exponent."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with temporal lobe epilepsy showed a significantly larger
      exponent, corresponding to inhibition-directed E/I balance, in bilateral
      frontal and temporal regions.
    explanation: >-
      Directly supports altered excitation/inhibition balance in temporal lobe
      epilepsy at the network level.
  - reference: PMID:39056027
    reference_title: "Excitation/Inhibition balance relates to cognitive function and gene expression in temporal lobe epilepsy: a high density EEG assessment with aperiodic exponent."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Limited to patients with temporal lobe epilepsy, we detected a
      significant correlation between the exponent and the cortical expression
      of GABRA1, GRIN2A, GABRD, GABRG2, KCNA2 and PDYN genes.
    explanation: >-
      Supports molecular correlates of altered excitation/inhibition balance in
      temporal lobe epilepsy.
- name: Thalamocortical Network Dysfunction
  description: >-
    Vulnerable thalamocortical pathways can contribute to cognitive dysfunction
    in temporal lobe epilepsy, indicating that the disorder affects distributed
    neural circuits beyond the temporal focus itself.
  biological_processes:
  - preferred_term: transmission of nerve impulse
    term:
      id: GO:0019226
      label: transmission of nerve impulse
  locations:
  - preferred_term: temporal lobe
    term:
      id: UBERON:0001871
      label: temporal lobe
  - preferred_term: dorsal plus ventral thalamus
    term:
      id: UBERON:0001897
      label: dorsal plus ventral thalamus
  downstream:
  - target: Executive Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Microstructural damage to thalamocortical pathways is associated with
      poorer executive function performance in temporal lobe epilepsy.
    evidence:
    - reference: PMID:29880477
      reference_title: "Thalamocortical Connections and Executive Function in Pediatric Temporal and Frontal Lobe Epilepsy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In patients with temporal lobe epilepsy, poorer performance on all measures of executive function was associated with DTI indices reflective of damaged/less developed pathways."
      explanation: Links thalamocortical pathway microstructural damage on DTI to impaired executive function in TLE.
  evidence:
  - reference: PMID:29880477
    reference_title: "Thalamocortical Connections and Executive Function in Pediatric Temporal and Frontal Lobe Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our results give insight into vulnerable neural networks in pediatric
      focal epilepsy and suggest thalamocortical pathway damage as a potential
      mechanism of executive function impairment in temporal lobe epilepsy but
      not frontal lobe epilepsy.
    explanation: >-
      Supports a distributed thalamocortical circuit mechanism for cognitive
      dysfunction in temporal lobe epilepsy, though this evidence is specific
      to a pediatric cohort.
- name: Impaired Galanin Neuropeptide Signaling
  description: >-
    Galanin is an inhibitory neuropeptide released in the hippocampus, and
    galanin receptor agonists suppress seizures in animal models. In a family
    with monozygotic twins affected by temporal lobe epilepsy, a de novo GAL
    variant (p.A39E) produced a peptide that antagonized galanin receptor 1
    signaling and bound galanin receptor 2 with reduced affinity and reduced
    agonist activity, so galanin-mediated restraint of hippocampal
    glutamatergic transmission is lost. GAL variants are a rare cause: no
    further pathogenic variant was found in a cohort of 582 cases.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: GAL
    term:
      id: hgnc:4114
      label: GAL
  molecular_functions:
  - preferred_term: galanin neuropeptide hormone activity
    modifier: DECREASED
    term:
      id: GO:0005184
      label: neuropeptide hormone activity
  biological_processes:
  - preferred_term: galanin receptor signaling
    modifier: DECREASED
    term:
      id: GO:0090663
      label: galanin-activated signaling pathway
  locations:
  - preferred_term: hippocampal formation
    term:
      id: UBERON:0002421
      label: hippocampal formation
  downstream:
  - target: Excitation-Inhibition Imbalance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Loss of galanin signaling at GalR1 and GalR2 is proposed to release
      hippocampal glutamatergic transmission from inhibitory restraint. The
      step from the receptor assays to the human network state is an inference
      drawn by the authors, not a measurement they made in patients.
    evidence:
    - reference: PMID:25691535
      reference_title: Galanin pathogenic mutations in temporal lobe epilepsy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: These findings suggest that the p.A39E mutant could impair galanin signaling in the hippocampus, leading to increased glutamatergic excitation and ultimately to TLE.
      explanation: >-
        The authors' own reading of their receptor assays as an excitatory
        shift in hippocampal transmission; stated as a suggestion, and not
        measured in patient tissue.
  evidence:
  - reference: PMID:25691535
    reference_title: Galanin pathogenic mutations in temporal lobe epilepsy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Functional analysis revealed that the p.A39E mutant showed antagonistic activity against galanin receptor 1 (GalR1)-mediated response, and decreased binding affinity and reduced agonist properties for GalR2.
    explanation: >-
      Receptor-level measurements establishing that the patient variant
      impairs signaling at both galanin receptors.
  - reference: PMID:25691535
    reference_title: Galanin pathogenic mutations in temporal lobe epilepsy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    quote_role: BACKGROUND
    snippet: A role for the galanin neuropeptide in the regulation of epileptic seizures has been established in animal models more than two decades ago.
    explanation: >-
      Records that the seizure-regulating role of galanin comes from animal
      models, which is the basis on which the gene was treated as a candidate.
- name: Reduced Extracellular Carboxypeptidase A6 Activity
  description: >-
    Carboxypeptidase A6 is secreted and binds the extracellular matrix, where
    it processes neuropeptides. Epilepsy-associated CPA6 variants cluster near
    the active site and act in two ways: some reduce catalytic activity, while
    others are retained inside the cell so that little or no enzyme reaches the
    matrix. Which neuropeptide substrates matter for seizure threshold in
    humans is not established, so the route from this node to seizures is not
    resolved.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: CPA6
    term:
      id: hgnc:17245
      label: CPA6
  molecular_functions:
  - preferred_term: carboxypeptidase A6 activity
    modifier: DECREASED
    term:
      id: GO:0004181
      label: metallocarboxypeptidase activity
  downstream:
  - target: Seizures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The link rests on human genetics rather than on a traced mechanism: a
      homozygous CPA6 variant segregated with febrile seizures and temporal
      lobe epilepsy in a consanguineous family, and inactivating variants were
      found more often in epilepsy patients than in controls.
    evidence:
    - reference: PMID:21922598
      reference_title: Carboxypeptidase A6 gene (CPA6) mutations in a recessive familial form of febrile seizures and temporal lobe epilepsy and in sporadic temporal lobe epilepsy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: This study suggests that CPA6 is genetically linked to an AR familial form of FS and TLE, and is associated with sporadic TLE cases.
      explanation: >-
        Genetic linkage and an association in sporadic cases; the intervening
        steps between enzyme loss and seizures are not identified.
    - reference: PMID:23105115
      reference_title: "Naturally occurring carboxypeptidase A6 mutations: effect on enzyme function and association with epilepsy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: Some inactivated CPA6 and were more frequently found in epilepsy patients than controls.
      explanation: >-
        Ties the inactivating variants specifically, rather than CPA6 variants
        in general, to the epilepsy phenotype.
  evidence:
  - reference: PMID:21922598
    reference_title: Carboxypeptidase A6 gene (CPA6) mutations in a recessive familial form of febrile seizures and temporal lobe epilepsy and in sporadic temporal lobe epilepsy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Ala270Val CPA6 was secreted at about 40% of the level of the wild-type CPA6 and was fully active, while Gly267Arg CPA6 was not detected in the medium or extracellular matrix.
    explanation: >-
      Shows the two variants reduce the amount of enzyme reaching the
      extracellular matrix, the compartment where CPA6 is active.
  - reference: PMID:23105115
    reference_title: "Naturally occurring carboxypeptidase A6 mutations: effect on enzyme function and association with epilepsy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Several mutations resulted in reduced enzyme activity or CPA6 protein levels in the extracellular matrix.
    explanation: >-
      Confirms the same two-mode effect across a wider allelic series, with
      folding largely preserved.
phenotypes:
- name: Seizures
  category: Neurological
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Recurrent focal seizures originating from temporal lobe networks, often
    with impaired awareness and temporal-lobe semiology.
  phenotype_term:
    preferred_term: Focal-onset seizure
    term:
      id: HP:0007359
      label: Focal-onset seizure
  evidence:
  - reference: PMID:9046965
    reference_title: "Treatment of temporal lobe epilepsy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Initial management of patients with temporal lobe epilepsy is with antiepileptic drugs, but these control seizures in only half the patients."
    explanation: Supports recurrent seizures as the defining clinical feature of temporal lobe epilepsy.
  - reference: PMID:11484687
    reference_title: "A randomized, controlled trial of surgery for temporal-lobe epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At one year, the cumulative proportion of patients who were free of seizures impairing awareness was 58 percent in the surgical group and 8 percent in the medical group (P<0.001)."
    explanation: Documents focal seizures impairing awareness as the primary seizure type in temporal lobe epilepsy.
- name: Memory Impairment
  category: Cognitive
  frequency: FREQUENT
  description: >-
    Verbal short-term memory can be impaired and correlates with altered
    excitation/inhibition balance in entorhinal and frontal cortical regions.
  phenotype_term:
    preferred_term: Memory impairment
    term:
      id: HP:0002354
      label: Memory impairment
  evidence:
  - reference: PMID:39056027
    reference_title: "Excitation/Inhibition balance relates to cognitive function and gene expression in temporal lobe epilepsy: a high density EEG assessment with aperiodic exponent."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lower E/I in the left entorhinal and bilateral dorsolateral prefrontal
      cortices corresponded to a lower performance of short-term verbal memory.
    explanation: >-
      Supports memory impairment in temporal lobe epilepsy, but the cited study
      specifically addresses short-term verbal memory performance.
- name: Executive Dysfunction
  category: Cognitive
  description: >-
    Impairment of executive functions (including mental flexibility, inhibition,
    and shifting) associated with microstructural disruption of thalamocortical
    pathways.
  phenotype_term:
    preferred_term: Impaired executive functioning
    term:
      id: HP:0033051
      label: Impaired executive functioning
  evidence:
  - reference: PMID:29880477
    reference_title: "Thalamocortical Connections and Executive Function in Pediatric Temporal and Frontal Lobe Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In patients with temporal lobe epilepsy, poorer performance on all measures of executive function was associated with DTI indices reflective of damaged/less developed pathways."
    explanation: Supports executive function impairment associated with thalamocortical tract changes in TLE.
- name: Depression
  category: Psychiatric
  description: >-
    Depressive disorder is a recognized neuropsychiatric comorbidity in patients
    with chronic temporal lobe epilepsy.
  phenotype_term:
    preferred_term: Depression
    term:
      id: HP:0000716
      label: Depression
  evidence:
  - reference: PMID:40693462
    reference_title: "N6-methyladenosine (m6A) dysregulation contributes to network excitability in temporal lobe epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Often caused by direct brain insults such as traumatic brain injury (TBI) (1), stroke (2–4), central nervous system (CNS) infections, and status epilepticus (SE) (5), it is associated with high rates of drug refractoriness and comorbid symptoms such as persistent learning and memory impairment, depression, and anxiety (6)."
    explanation: Documents depression as a comorbid symptom associated with temporal lobe epilepsy.
- name: Anxiety
  category: Psychiatric
  description: >-
    Anxiety is a recognized psychiatric comorbidity accompanying chronic temporal
    lobe epilepsy.
  phenotype_term:
    preferred_term: Anxiety
    term:
      id: HP:0000739
      label: Anxiety
  evidence:
  - reference: PMID:40693462
    reference_title: "N6-methyladenosine (m6A) dysregulation contributes to network excitability in temporal lobe epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Often caused by direct brain insults such as traumatic brain injury (TBI) (1), stroke (2–4), central nervous system (CNS) infections, and status epilepticus (SE) (5), it is associated with high rates of drug refractoriness and comorbid symptoms such as persistent learning and memory impairment, depression, and anxiety (6)."
    explanation: Documents anxiety as a comorbid symptom associated with temporal lobe epilepsy.
genetic:
- name: LGI1
  gene_term:
    preferred_term: LGI1
    term:
      id: hgnc:6572
      label: LGI1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: ETL1
  notes: >-
    Heterozygous LGI1 variants cause the auditory-features form of familial
    lateral temporal lobe epilepsy. The mechanism chain, the penetrance
    estimate and the allelic series are curated in
    Autosomal_Dominant_Epilepsy_with_Auditory_Features rather than here, so
    this record carries no mechanism node in this entry.
  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 LGI1 as an established molecular cause.
- name: RELN
  gene_term:
    preferred_term: RELN
    term:
      id: hgnc:9957
      label: RELN
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: ETL7
  notes: >-
    Heterozygous RELN variants cause a second auditory-features form. As with
    LGI1, the mechanism is curated in
    Autosomal_Dominant_Epilepsy_with_Auditory_Features, which also records that
    the reduced circulating reelin finding is largely liver-derived protein and
    does not measure brain secretion.
  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 RELN as an established molecular cause.
- name: CPA6
  gene_term:
    preferred_term: CPA6
    term:
      id: hgnc:17245
      label: CPA6
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: ETL5
  frequency: rare
  notes: >-
    Reported in both zygosity states for different phenotypes: homozygous
    p.Ala270Val in the recessive familial febrile-seizure and temporal lobe
    epilepsy pedigree, and heterozygous p.Gly267Arg in three of 195 unrelated
    patients with partial epilepsy. No external body has classified the
    gene-disease pair, so no gene_disease_validity tier is recorded. The
    sporadic-case association is a candidate-gene screen in a selected cohort,
    not a population genetic study. CAUSATIVE records CPA6 as the gene that
    defines the ETL5 subtype; one pedigree and one candidate-gene
    screen fall short of the Definitive or Strong level that the schema
    attaches to CAUSATIVE, so read the relationship type as uncalibrated.
  variants:
  - name: p.Ala270Val
    description: >-
      Homozygous missense variant (c.809C>T) identified in the consanguineous
      pedigree. The protein is fully active but is secreted at about 40% of
      wild-type levels.
    evidence:
    - reference: PMID:21922598
      reference_title: Carboxypeptidase A6 gene (CPA6) mutations in a recessive familial form of febrile seizures and temporal lobe epilepsy and in sporadic temporal lobe epilepsy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: Ala270Val CPA6 was secreted at about 40% of the level of the wild-type CPA6 and was fully active, while Gly267Arg CPA6 was not detected in the medium or extracellular matrix.
      explanation: Gives the secretion and activity result for this allele.
  - name: p.Gly267Arg
    description: >-
      Heterozygous missense variant (c.799G>A) found in three unrelated
      patients with temporal lobe epilepsy. The protein does not reach the
      medium or the extracellular matrix.
    evidence:
    - reference: PMID:21922598
      reference_title: Carboxypeptidase A6 gene (CPA6) mutations in a recessive familial form of febrile seizures and temporal lobe epilepsy and in sporadic temporal lobe epilepsy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: Screening all exons of CPA6 in unrelated patients with partial epilepsy (n = 195) and FS (n = 145) revealed a new heterozygous missense mutation c.799G>A (p.Gly267Arg) in three TLE patients.
      explanation: Reports the allele and the cohort it was found in.
  evidence:
  - reference: PMID:21922598
    reference_title: Carboxypeptidase A6 gene (CPA6) mutations in a recessive familial form of febrile seizures and temporal lobe epilepsy and in sporadic temporal lobe epilepsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: This study suggests that CPA6 is genetically linked to an AR familial form of FS and TLE, and is associated with sporadic TLE cases.
    explanation: >-
      The paper's own statement of the gene-disease claim, covering both the
      recessive family and the sporadic cases.
- name: GAL
  gene_term:
    preferred_term: GAL
    term:
      id: hgnc:4114
      label: GAL
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: ETL8
  frequency: rare
  notes: >-
    One de novo variant in one family, with no second pathogenic variant in 582
    further cases. Treat the gene-disease claim as resting on that pedigree
    together with the receptor assays; no external body has classified the pair.
    The variant arose de novo in the twins, so it is germline but not inherited.
    CAUSATIVE records GAL as the gene that defines the ETL8 subtype; a single
    pedigree falls short of the Definitive or Strong level that the
    schema attaches to CAUSATIVE, so read the relationship type as uncalibrated.
  variants:
  - name: p.A39E
    description: >-
      De novo missense variant carried by both monozygotic twins. The mutant
      peptide antagonizes GalR1 and has reduced affinity and agonist activity
      at GalR2.
    evidence:
    - reference: PMID:25691535
      reference_title: Galanin pathogenic mutations in temporal lobe epilepsy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: Functional analysis revealed that the p.A39E mutant showed antagonistic activity against galanin receptor 1 (GalR1)-mediated response, and decreased binding affinity and reduced agonist properties for GalR2.
      explanation: The receptor-level characterization of this allele.
  evidence:
  - reference: PMID:25691535
    reference_title: Galanin pathogenic mutations in temporal lobe epilepsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: The identification of a novel de novo mutation in a biologically-relevant candidate gene, coupled with functional evidence that the mutant protein disrupts galanin signaling, strongly supports GAL as the causal gene for the TLE in this family.
    explanation: >-
      The authors' gene-disease claim, scoped explicitly to this one family.
  - reference: PMID:25691535
    reference_title: Galanin pathogenic mutations in temporal lobe epilepsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: In a cohort of 582 cases, we did not observe any pathogenic mutations indicating that mutations in GAL are a rare cause of TLE.
    explanation: >-
      A negative screening result bounding how much of temporal lobe epilepsy
      this gene accounts for.
diagnosis:
- name: Electroencephalography (EEG)
  diagnosis_term:
    preferred_term: Electroencephalography
    term:
      id: NCIT:C38054
      label: Electroencephalography
  description: >-
    Surface and, when needed, intracranial electroencephalography are used to
    localize the temporal lobe seizure onset focus and guide surgical or
    medical management.
  evidence:
  - reference: PMID:9046965
    reference_title: "Treatment of temporal lobe epilepsy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "That evaluation requires identification of a focus of onset of seizures, as well as establishing that the focus is in an area of the brain that can be removed with a low risk of new neurologic deficits. Techniques used in that evaluation, including electroencephalography, imaging, recording form intracranial electrodes, use of the intracarotid amobarbitol perfusion test, and the role of specialized studies such as positron emission tomography, are reviewed"
    explanation: Supports scalp and intracranial EEG as primary diagnostic modalities for localizing seizure onset in TLE.
- name: Brain Neuroimaging (MRI and PET)
  diagnosis_term:
    preferred_term: Magnetic Resonance Imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  description: >-
    Structural brain MRI (to identify hippocampal T2 hyperintensity, hippocampal
    sclerosis, or other epileptogenic lesions) and functional imaging such as
    positron emission tomography (PET) support localization of the epileptogenic
    temporal lobe focus.
  evidence:
  - reference: DOI:10.1111/epi.17979
    reference_title: "Hippocampal sclerosis and temporal lobe epilepsy following febrile status epilepticus: The <scp>FEBSTAT</scp> study"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hippocampal T2 hyperintensity following febrile status epilepticus predicted hippocampal sclerosis and significant likelihood of mesial temporal lobe epilepsy."
    explanation: Supports brain MRI detection of hippocampal T2 hyperintensity and hippocampal sclerosis in temporal lobe epilepsy.
  - reference: PMID:9046965
    reference_title: "Treatment of temporal lobe epilepsy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Techniques used in that evaluation, including electroencephalography, imaging, recording form intracranial electrodes, use of the intracarotid amobarbitol perfusion test, and the role of specialized studies such as positron emission tomography, are reviewed"
    explanation: Supports neuroimaging and PET as core components of the diagnostic and presurgical evaluation of TLE.
differential_diagnoses:
- name: Frontal Lobe Epilepsy
  description: >-
    Another common focal epilepsy syndrome that can share aura, automatisms,
    and executive dysfunction with temporal lobe epilepsy, distinguished by
    seizure semiology, EEG localization, and distinct thalamocortical network
    involvement.
  distinguishing_features:
  - Frontal lobe seizure onset on EEG
  - Distinct executive function and thalamocortical tract profiles
  evidence:
  - reference: PMID:29880477
    reference_title: "Thalamocortical Connections and Executive Function in Pediatric Temporal and Frontal Lobe Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our results give insight into vulnerable neural networks in pediatric focal epilepsy and suggest thalamocortical pathway damage as a potential mechanism of executive function impairment in temporal lobe epilepsy but not frontal lobe epilepsy."
    explanation: Contrasts temporal lobe epilepsy with frontal lobe epilepsy across cognitive and thalamocortical network features.
treatments:
- name: Antiseizure Medication Therapy
  description: >-
    Initial management of temporal lobe epilepsy is pharmacotherapy using
    antiseizure medications used across focal epilepsies, although many
    patients do not achieve durable seizure freedom and later meet criteria for
    drug-resistant disease.
  treatment_term:
    preferred_term: antiepileptic drug therapy
    term:
      id: NCIT:C64172
      label: Anticonvulsant Therapy
  evidence:
  - reference: PMID:9046965
    reference_title: "Treatment of temporal lobe epilepsy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Initial management of patients with temporal lobe epilepsy is with
      antiepileptic drugs, but these control seizures in only half the
      patients.
    explanation: >-
      Supports antiseizure medication therapy as first-line management in TLE,
      while also showing that medication failure is common.
  - reference: PMID:38888005
    reference_title: "Efficacy and safety of add-on antiseizure medications for focal epilepsy: A network meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All approved ASMs were effective as add-on treatment for focal epilepsy.
    explanation: >-
      Supports ongoing pharmacotherapy in TLE because TLE is a focal epilepsy
      syndrome, although the evidence is not specific to TLE alone.
- name: Epilepsy Surgery for Drug-Resistant Disease
  description: >-
    In carefully selected patients with drug-resistant temporal lobe epilepsy,
    surgical treatment offers substantially higher rates of seizure freedom
    than continued medical therapy and remains a key escalation path once
    pharmacoresistance is established.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:11484687
    reference_title: "A randomized, controlled trial of surgery for temporal-lobe epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At one year, the cumulative proportion of patients who were free of
      seizures impairing awareness was 58 percent in the surgical group and 8
      percent in the medical group (P<0.001).
    explanation: >-
      Supports surgical treatment as an effective option for carefully selected
      patients with drug-resistant temporal lobe epilepsy.
review_notes: >-
  The Mendelian familial temporal lobe epilepsy classes are recorded as
  has_subtypes rows only where MONDO's class is defined by a gene (ETL1 LGI1,
  ETL5 CPA6, ETL7 RELN, ETL8 GAL). The remaining numbered classes are linkage
  intervals with no gene named - ETL2 (MONDO:0011965, 12q22-q23.3), ETL3
  (MONDO:0012705), ETL4 (MONDO:0012706, 9q21-q22) and ETL6 (MONDO:0014308,
  3q25-q26) - so no gene-level or mechanistic claim can be written for them and
  they are deliberately left out rather than added as empty rows. MONDO also
  carries familial mesial temporal lobe epilepsy (MONDO:0800493), which is not
  bound here: it is an ILAE syndrome with complex inheritance and normal MRI,
  and it is not the same concept as this entry's mesial-temporal-lobe-epilepsy
  with hippocampal sclerosis subtype, which is curated separately.
datasets:
- accession: geo:GSE297566
  title: Hippocampal epitranscriptomic (m6A) in human model of Temporal Lobe Epilepsy
  description: Analogous to DNA methylation and protein phosphorylation it is now well understood that RNA is also subject to extensive processing and modification. N6-methyladenosine (m6A) is the most abundant internal RNA modification and regulates RNA fate in several ways including stability and translational efficiency. The role of m6A in both experimental and human epilepsy remains unknown. Here we use transcriptome-wide m6A arrays to obtain a detailed analysis of the hippocampal m6A-ome from human temporal lobe epilepsy samples. We show that epileptic tissue displays disrupted metabolic and autophagic pathways which may be directly linked to m6A-processing.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: METHYLATION
  sample_count: 48
  publication: PMID:40693462
  notes: Identified by GEO DataSets index search for Temporal Lobe Epilepsy (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE272142
  title: Genome‑wideBrain DNAMethylationandGeneExpression Patterns Unravel Epigenetic Reprogramming in Mesial Temporal Lobe Epilepsy
  description: Mesial temporal lobe epilepsy (MTLE) is the most common drug-resistant epilepsy in adults, characterized by hippocampus sclerosis. To date, the etiology of MTLE epileptogenesis and the molecular mechanisms underlying hippocampus sclerosis remain largely unclear. Altered genome-wide DNA methylation patterns and differential gene expression have been reported to be involved in the pathophysiological mechanism of epileptogenesis. To discover epigenetic reprogramming patterns associated with MTLE, we used a higher-throughput microarray, Illumina Infinium 850 K BeadChip, and RNA sequence to analyze epigenome-wide DNA methylation and related gene expressions.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 12
  notes: Identified by GEO DataSets index search for Temporal Lobe Epilepsy (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: ega:EGAS00001003922
  title: Meisal temporal lobe epilepsy sequencing study
  description: Our understanding of mesial temporal lobe epilepsy (MTLE) is one of the most common forms of drug-resistant epilepsy in humans. Using RNA- and small RNA-sequencing in parallel, we explored differentially expressed genes in the hippocampus and cortex of MTLE patients who had undergone surgical resection and non-epileptic controls. We found significant enrichment for astrocytic and microglial genes amongst up-regulated genes and down-regulation of neuron-specific genes in the hippocampus of MTLE patients. The transcriptome profile of the small RNAs reflected disease state more robustly than mRNAs, even across brain regions which show very little pathology.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Temporal Lobe Epilepsy"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: massive:MSV000094401
  title: Proteomic profile of hippocampus regions from the pilocarpine medial temporal lobe epilepsy model
  description: Label-free Proteomic profile of the dentate gyrus (dorsal and ventral) and CA3 (dorsal and ventral) microdissected from the hippocampus of the pilocarpine model of Mesial Temporal Lobe Epilepsy.
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Temporal Lobe Epilepsy"). Retrieved 2026-08-02.
references:
- reference: PMID:20301709
  title: "Autosomal Dominant Epilepsy with Auditory Features."
  tags:
  - GeneReviews
  findings: []
📚

References & Deep Research

References

1
PMID:20301709
Autosomal Dominant Epilepsy with Auditory Features.
No top-level findings curated for this source.