Familial Focal Epilepsy With Variable Foci

Mendelian MONDO:0020310 Pathograph 10 Epilepsy

Familial focal epilepsy with variable foci is an autosomal dominant genetic focal epilepsy syndrome in which affected relatives have seizures that arise from different cortical regions, while each person's semiology is usually consistent. The best-established molecular mechanism is loss of GATOR1 complex function through DEPDC5, NPRL2, or NPRL3 variants, causing impaired restraint of mTORC1 signaling. Presentations range from nonlesional focal epilepsy with normal structural MRI to drug-resistant focal epilepsy associated with focal cortical dysplasia.

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1
Inheritance
2
Pathophys.
1
Histopath.
4
Phenotypes
10
Pathograph
3
Genes
3
Treatments
1
Deep Research
👪

Inheritance

1
Autosomal dominant HP:0000006
Familial focal epilepsy with variable foci is inherited in an autosomal dominant pattern, but penetrance is incomplete and expressivity varies across relatives.
Autosomal dominant inheritance Penetrance: INCOMPLETE Expressivity: VARIABLE
Show evidence (2 references)
DOI:10.1038/ng.2599 SUPPORT Human Clinical
"Autosomal dominant familial focal epilepsy with variable foci (FFEVF) is notable because family members have seizures originating from different cortical regions."
The DEPDC5 discovery paper describes the autosomal dominant familial syndrome and its variable cortical foci.
DOI:10.1046/j.1528-1157.2003.62302.x SUPPORT Human Clinical
"Clinical characteristics and results of EEG, computed tomography (CT), and magnetic resonance imaging (MRI) were evaluated in a family with autosomal dominantly inherited partial epilepsy with apparent incomplete penetrance."
The Dutch family study explicitly supports autosomal dominant inheritance with incomplete penetrance.
⚙

Pathophysiology

2
GATOR1 Complex Loss and mTORC1 Disinhibition
Loss-of-function variants in DEPDC5, NPRL2, or NPRL3 impair GATOR1 complex regulation of mTORC1. The resulting excess mTORC1 signal transduction is a plausible upstream mechanism for altered cortical development, neuronal excitability, and focal seizure generation.
pyramidal neuron link GABAergic neuron link
DEPDC5 link NPRL2 link NPRL3 link
TOR signaling link ↑ INCREASED
cerebral cortex link
Downstream
Focal Seizures With Variable Cortical Foci GATOR1 loss disinhibits mTORC1 signaling, increasing risk of focal cortical network hyperexcitability.
Show evidence (4 references)
DOI:10.3390/ijms25042068 SUPPORT In Vitro
"GATOR1 (GAP Activity TOward Rag 1) is an evolutionarily conserved GTPase-activating protein complex that controls the activity of mTORC1 (mammalian Target Of Rapamycin Complex 1) in response to amino acid availability in cells."
This cell-signaling study establishes the GATOR1-mTORC1 regulatory mechanism.
DOI:10.3390/ijms25042068 SUPPORT In Vitro
"NPRL2-L105P is a loss-of-function mutation that disrupts protein interactions with NPRL3 and DEPDC5, impairing GATOR1 complex assembly and resulting in high mTORC1 activity even under conditions of amino acid deprivation."
This directly connects an epilepsy-linked NPRL2 variant to impaired GATOR1 assembly and increased mTORC1 activity.
DOI:10.3389/fgene.2021.766354 SUPPORT In Vitro
"In addition, the expression of downstream molecular Phospho-p70 S6 kinase (P-s6k) are increased consequently."
Peripheral blood assays in NPRL3 variant carriers support downstream mTOR pathway activation.
+ 1 more reference
DEPDC5-Associated Focal Cortical Dysplasia
In some DEPDC5-positive families, germline and brain somatic DEPDC5 variants are associated with focal cortical dysplasia, consistent with a two-hit mTORopathy model for cortical lesions and drug-resistant focal epilepsy.
pyramidal neuron link
DEPDC5 link
TOR signaling link ↑ INCREASED
cerebral cortex link frontal lobe link
Downstream
Focal Cortical Dysplasia DEPDC5/GATOR1 loss is associated with cortical dysplasia lesions in a subset of patients.
Show evidence (3 references)
DOI:10.1002/ana.24368 SUPPORT Human Clinical
"Germline, germline mosaic, and brain somatic DEPDC5 mutations may cause epilepsy associated with FCD, reinforcing the link between mTORC1 pathway and FCDs."
This directly supports a DEPDC5-FCD mTORopathy mechanism.
DOI:10.1002/ana.24368 SUPPORT Human Clinical
"A brain somatic DEPDC5 mutation was identified in 1 patient in addition to the germline mutation."
This supports a two-hit model for cortical lesions in DEPDC5-associated focal epilepsy.
DOI:10.1186/s40478-023-01675-x SUPPORT Human Clinical
"Ten individuals carried loss-of-function variants in the GATOR1 complex encoding genes DEPDC5 (n = 7) and NPRL3 (n = 3), or gain-of-function variants in MTOR (n = 7)."
Surgical brain-tissue analysis supports a GATOR1-associated focal cortical dysplasia subset.
✶

Histopathology

1
GATOR1-Associated FCDIIa Autophagy-Altered Histopathology
Surgical tissue from GATOR1-positive focal cortical dysplasia type IIa can show vacuolizing cells and p62-positive autophagosome aggregates, supporting an autophagy-altered histopathologic pattern in this lesion subset.
Show evidence (1 reference)
DOI:10.1186/s40478-023-01675-x SUPPORT Human Clinical
"Interestingly, 50% of GATOR1-positive cases showed a unique and predominantly vacuolizing phenotype with p62 immunofluorescent aggregates in autophagosomes."
Surgical pathology evidence supports a GATOR1-associated FCDIIa pattern with vacuolizing cells and p62-positive autophagosome aggregates.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Familial Focal Epilepsy With Variable Foci Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

4
Nervous System 2
Focal Seizures With Variable Cortical Foci Focal-onset seizure (HP:0007359)
Show evidence (2 references)
DOI:10.1111/j.0013-9580.2004.30502.x SUPPORT Human Clinical
"Familial partial epilepsy with variable foci (FPEVF) is an autosomal dominant syndrome characterized by partial seizures originating from different brain regions in different family members in the absence of detectable structural abnormalities."
This directly supports the core variable-foci focal seizure phenotype.
DOI:10.1038/ng.2599 SUPPORT Human Clinical
"Autosomal dominant familial focal epilepsy with variable foci (FFEVF) is notable because family members have seizures originating from different cortical regions."
This provides independent human genetic evidence for the defining seizure pattern.
EEG Abnormality EEG abnormality (HP:0002353)
Show evidence (2 references)
DOI:10.1046/j.1528-1157.2003.62302.x SUPPORT Human Clinical
"Most interictal EEGs showed no abnormalities, but some showed frontal, central, and/or temporal spikes and spike-wave complexes."
This supports focal EEG abnormalities in a subset of affected relatives.
DOI:10.1371/journal.pone.0284924 SUPPORT Human Clinical
"normal MRI, and abnormal EEG (epileptiform discharge, slow wave)."
This NPRL3 family study supports abnormal EEG findings in FFEVF.
Other 2
Variable Motor Seizure Semiology Bilateral tonic-clonic seizure with focal onset (HP:0007334)
Show evidence (1 reference)
DOI:10.1046/j.1528-1157.2003.62302.x PARTIAL Human Clinical
"Seizures were mostly tonic, tonic-clonic, or hyperkinetic, with a wide variety in symptoms and severity."
This supports variable motor seizure semiology; the HPO term captures the tonic-clonic component but not all reported semiologies.
Focal Cortical Dysplasia Focal cortical dysplasia (HP:0032046)
Show evidence (2 references)
DOI:10.1002/ana.24368 SUPPORT Human Clinical
"All patients had drug‐resistant focal epilepsy, 5 of them underwent surgery, and 1 had a brain biopsy."
This establishes the DEPDC5-associated FCD clinical subset and its drug-resistant epilepsy context.
DOI:10.1186/s40478-023-01675-x SUPPORT Human Clinical
"Whereas individuals with GATOR1 variants only presented with FCDIIa, i.e., lack of balloon cells, individuals with MTOR variants presented with both histopathology subtypes, FCDIIa and FCDIIb."
Histopathology-genotype analysis supports a GATOR1-associated FCDIIa pattern.
🧬

Genetic Associations

3
DEPDC5 (Causal GATOR1 loss-of-function variant)
Show evidence (2 references)
DOI:10.1038/ng.2599 SUPPORT Human Clinical
"Using exome sequencing, we detected DEPDC5 mutations in two affected families. We subsequently identified mutations in five of six additional published large families with FFEVF."
This directly supports DEPDC5 as a causal gene in FFEVF.
DOI:10.3389/fgene.2024.1414259 SUPPORT Human Clinical
"The results suggest that c.1217 + 2T>A variations in DEPDC5 might be the genetic etiology for FFEVF in this pedigree."
A 2024 family report expands the DEPDC5 FFEVF variant spectrum.
NPRL2 (Causal GATOR1 loss-of-function variant)
Show evidence (2 references)
DOI:10.1038/s10038-021-00969-z SUPPORT Human Clinical
"Here, we describe a variant, 339+2T>C, inNPRL2identified by trio whole-exome sequencing (WES) in a family."
This family report identifies an NPRL2 splice variant in FFEVF.
DOI:10.1038/s10038-021-00969-z SUPPORT In Vitro
"This splicing variant that occurred at the 5′ end of exon 3 was confirmed by minigene assays, which affected alternative splicing and led to exon 3 skipping inNPRL2."
Minigene assay evidence supports a loss-of-function splicing mechanism for the NPRL2 variant.
NPRL3 (Causal GATOR1 loss-of-function variant)
Show evidence (2 references)
DOI:10.3389/fgene.2021.766354 SUPPORT Human Clinical
"Whole exome sequencing confirms a novel pathogenic mutation in the NPRL3 gene (c316C>T; p. Q106*)."
This supports NPRL3 as a causal FFEVF gene.
DOI:10.3389/fgene.2022.1054567 SUPPORT Human Clinical
"In family E1, the trio-WES analysis of the proband and her brother without apparent structural brain abnormalities identified a heterozygous variant in the NPRL3 gene (c.954C>A, p.Y318*, NM_001077350.3)."
Additional family sequencing evidence supports NPRL3-related FFEVF3.
💊

Treatments

3
Antiseizure Medication Therapy
Action: anticonvulsant agent therapy MAXO:0000167
Management generally begins with antiseizure medications used for focal epilepsy. Response is variable; some patients become almost seizure-free, while lesion-associated DEPDC5/GATOR1 cases can be drug resistant.
Target Phenotypes: Focal-onset seizure ↗
Show evidence (2 references)
PMID:38888005 SUPPORT Human Clinical
"All approved ASMs were effective as add-on treatment for focal epilepsy."
This focal epilepsy meta-analysis supports antiseizure medication therapy for focal-onset seizures, including FFEVF by disease class.
DOI:10.1371/journal.pone.0284924 PARTIAL Human Clinical
"different therapeutic effects (refractory epilepsy/almost seizure free)"
This FFEVF family study shows variable medication-era outcomes rather than a specific drug recommendation.
Experimental mTOR Inhibitor Therapy (Rapamycin/Sirolimus)
Action: Pharmacotherapy NCIT:C15986
Agent: sirolimus ↗
Preclinical mouse-model evidence supports mTORC1 inhibition as a rational therapeutic strategy for DEPDC5-related epilepsy. Rapamycin, also known as sirolimus, prolonged survival and partially rescued behavioral hyperactivity in neuronal-specific Depdc5 knockout mice; this is experimental rather than established clinical care for FFEVF.
Mechanism Target:
INHIBITS GATOR1 Complex Loss and mTORC1 Disinhibition — mTORC1 inhibition counteracts downstream hyperactivation caused by GATOR1 loss.
Show evidence (1 reference)
PMID:31174205 SUPPORT Model Organism
"Collectively, our data provide the first evidence of behavioral alterations in mice with Depdc5 loss and support mTOR inhibition as a rational therapeutic strategy for DEPDC5-related epilepsy in humans."
Depdc5 knockout mouse data support rapamycin/sirolimus as a mechanistically rational experimental therapy targeting mTORC1 hyperactivation.
Target Phenotypes: Focal-onset seizure ↗
Epilepsy Surgery for Drug-Resistant DEPDC5/FCD Disease
Action: surgical procedure MAXO:0000004
Focal resection can be considered for drug-resistant focal epilepsy when a seizure focus or focal cortical dysplasia is identified, including DEPDC5-positive cases that have subtle or unremarkable MRI.
Mechanism Target:
MODULATES DEPDC5-Associated Focal Cortical Dysplasia — Focal resection removes the epileptogenic dysplastic cortex when localization is feasible.
Show evidence (1 reference)
DOI:10.1055/a-2213-8584 SUPPORT Human Clinical
"The most common form of epilepsy surgery was focal resection (38/44, 86.4%)."
This supports focal resection as the mechanism-targeting surgical approach in DEPDC5-associated cortical dysplasia.
Target Phenotypes: Focal-onset seizure ↗ Focal cortical dysplasia ↗
Show evidence (2 references)
DOI:10.1002/ana.24368 SUPPORT Human Clinical
"Three patients were seizure‐free postsurgically, and 1 had a worthwhile improvement."
DEPDC5-associated FCD cases showed favorable surgical outcomes in several patients.
DOI:10.1055/a-2213-8584 SUPPORT Human Clinical
"Thirty-seven of the 40 patients (37/40, 92.5%) with reported seizure frequency results had improvement."
Systematic review evidence supports epilepsy surgery benefit in DEPDC5-variant patients with pharmacoresistant epilepsy.
{ }

Source YAML

click to show 
name: Familial Focal Epilepsy With Variable Foci
creation_date: "2026-05-10T18:43:00Z"
updated_date: "2026-05-10T19:45:18Z"
category: Mendelian
description: >-
  Familial focal epilepsy with variable foci is an autosomal dominant genetic
  focal epilepsy syndrome in which affected relatives have seizures that arise
  from different cortical regions, while each person's semiology is usually
  consistent. The best-established molecular mechanism is loss of GATOR1 complex
  function through DEPDC5, NPRL2, or NPRL3 variants, causing impaired restraint
  of mTORC1 signaling. Presentations range from nonlesional focal epilepsy with
  normal structural MRI to drug-resistant focal epilepsy associated with focal
  cortical dysplasia.
disease_term:
  preferred_term: familial focal epilepsy with variable foci
  term:
    id: MONDO:0020310
    label: familial focal epilepsy with variable foci
synonyms:
- FFEVF
- familial partial epilepsy with variable foci
- epilepsy, familial focal, with variable foci
parents:
- Epilepsy
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  expressivity: VARIABLE
  description: >-
    Familial focal epilepsy with variable foci is inherited in an autosomal
    dominant pattern, but penetrance is incomplete and expressivity varies
    across relatives.
  evidence:
  - reference: DOI:10.1038/ng.2599
    reference_title: Mutations in DEPDC5 cause familial focal epilepsy with variable foci.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autosomal dominant familial focal epilepsy with variable foci (FFEVF) is
      notable because family members have seizures originating from different
      cortical regions.
    explanation: The DEPDC5 discovery paper describes the autosomal dominant familial syndrome and its variable cortical foci.
  - reference: DOI:10.1046/j.1528-1157.2003.62302.x
    reference_title: "Familial partial epilepsy with variable foci in a Dutch family: clinical characteristics and confirmation of linkage to chromosome 22q."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical characteristics and results of EEG, computed tomography (CT), and
      magnetic resonance imaging (MRI) were evaluated in a family with autosomal
      dominantly inherited partial epilepsy with apparent incomplete penetrance.
    explanation: The Dutch family study explicitly supports autosomal dominant inheritance with incomplete penetrance.
progression:
- phase: Variable onset focal seizures
  age_range: infancy to adulthood
  notes: >-
    Onset can range from infancy through adulthood. In published families,
    seizure focus and severity vary among relatives, while each individual's
    seizure pattern is generally stable.
  evidence:
  - reference: DOI:10.1046/j.1528-1157.2003.62302.x
    reference_title: "Familial partial epilepsy with variable foci in a Dutch family: clinical characteristics and confirmation of linkage to chromosome 22q."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Age at onset ranged from 3 months to 24 years.
    explanation: This family report demonstrates the wide age-at-onset range.
  - reference: DOI:10.1371/journal.pone.0284924
    reference_title: The clinical features of familial focal epilepsy with variable foci and NPRL3 gene variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with NPRL3: c.1137dupT variant had a wide range of onset age (4
      months to 31 years), diverse seizure types, variable foci (frontal
      lobe/temporal lobe), different seizure times (day/night) and frequencies
      (monthly/seldom/every day), different therapeutic effects (refractory
      epilepsy/almost seizure free), normal MRI, and abnormal EEG (epileptiform
      discharge, slow wave).
    explanation: This NPRL3 family series supports variable onset, foci, seizure timing, and clinical course.
- phase: Drug-resistant lesion-associated focal epilepsy
  notes: >-
    A subset of DEPDC5-associated disease includes focal cortical dysplasia and
    drug-resistant focal epilepsy, for which epilepsy surgery may be considered.
  evidence:
  - reference: DOI:10.1002/ana.24368
    reference_title: Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seven patients from 4 families with DEPDC5 mutations and focal epilepsy
      associated with FCD were recruited and investigated at the clinical,
      neuroimaging, and histopathological levels.
    explanation: This study establishes DEPDC5-associated focal epilepsy with focal cortical dysplasia as a clinically important subset.
genetic:
- name: DEPDC5
  association: Causal GATOR1 loss-of-function variant
  gene_term:
    preferred_term: DEPDC5
    term:
      id: hgnc:18423
      label: DEPDC5
  notes: >-
    DEPDC5 encodes a GATOR1 subcomplex component that negatively regulates the
    amino-acid sensing branch of mTORC1 signaling. Truncating and splice-altering
    variants are a recurrent cause of FFEVF and related familial focal
    epilepsies.
  evidence:
  - reference: DOI:10.1038/ng.2599
    reference_title: Mutations in DEPDC5 cause familial focal epilepsy with variable foci.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using exome sequencing, we detected DEPDC5 mutations in two affected
      families. We subsequently identified mutations in five of six additional
      published large families with FFEVF.
    explanation: This directly supports DEPDC5 as a causal gene in FFEVF.
  - reference: DOI:10.3389/fgene.2024.1414259
    reference_title: A novel variation in DEPDC5 causing familial focal epilepsy with variable foci.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The results suggest that c.1217 + 2T>A variations in DEPDC5 might be the
      genetic etiology for FFEVF in this pedigree.
    explanation: A 2024 family report expands the DEPDC5 FFEVF variant spectrum.
- name: NPRL2
  association: Causal GATOR1 loss-of-function variant
  gene_term:
    preferred_term: NPRL2
    term:
      id: hgnc:24969
      label: NPRL2
  notes: >-
    NPRL2 encodes another GATOR1 subcomplex component. Reported splice-altering
    variants can cause exon skipping and a familial focal epilepsy with variable
    foci phenotype.
  evidence:
  - reference: DOI:10.1038/s10038-021-00969-z
    reference_title: "A splicing variation in NPRL2 causing familial focal epilepsy with variable foci: additional cases and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe a variant, 339+2T>C, inNPRL2identified by trio
      whole-exome sequencing (WES) in a family.
    explanation: This family report identifies an NPRL2 splice variant in FFEVF.
  - reference: DOI:10.1038/s10038-021-00969-z
    reference_title: "A splicing variation in NPRL2 causing familial focal epilepsy with variable foci: additional cases and literature review"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This splicing variant that occurred at the 5′ end of exon 3 was confirmed
      by minigene assays, which affected alternative splicing and led to exon 3
      skipping inNPRL2.
    explanation: Minigene assay evidence supports a loss-of-function splicing mechanism for the NPRL2 variant.
- name: NPRL3
  association: Causal GATOR1 loss-of-function variant
  gene_term:
    preferred_term: NPRL3
    term:
      id: hgnc:14124
      label: NPRL3
  notes: >-
    NPRL3 loss-of-function variants cause FFEVF3 and can show reduced penetrance,
    variable seizure foci, and variable clinical severity among relatives.
  evidence:
  - reference: DOI:10.3389/fgene.2021.766354
    reference_title: A Novel Loss-of-Function Mutation in the NPRL3 Gene Identified in Chinese Familial Focal Epilepsy with Variable Foci.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole exome sequencing confirms a novel pathogenic mutation in the NPRL3
      gene (c316C>T; p. Q106*).
    explanation: This supports NPRL3 as a causal FFEVF gene.
  - reference: DOI:10.3389/fgene.2022.1054567
    reference_title: "Identification of two rare NPRL3 variants in two Chinese families with familial focal epilepsy with variable foci 3: NGS analysis with literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In family E1, the trio-WES analysis of the proband and her brother without
      apparent structural brain abnormalities identified a heterozygous variant
      in the NPRL3 gene (c.954C>A, p.Y318*, NM_001077350.3).
    explanation: Additional family sequencing evidence supports NPRL3-related FFEVF3.
pathophysiology:
- name: GATOR1 Complex Loss and mTORC1 Disinhibition
  description: >-
    Loss-of-function variants in DEPDC5, NPRL2, or NPRL3 impair GATOR1 complex
    regulation of mTORC1. The resulting excess mTORC1 signal transduction is a
    plausible upstream mechanism for altered cortical development, neuronal
    excitability, and focal seizure generation.
  role: central_effector
  genes:
  - preferred_term: DEPDC5
    term:
      id: hgnc:18423
      label: DEPDC5
  - preferred_term: NPRL2
    term:
      id: hgnc:24969
      label: NPRL2
  - preferred_term: NPRL3
    term:
      id: hgnc:14124
      label: NPRL3
  cell_types:
  - preferred_term: pyramidal neuron
    term:
      id: CL:0000598
      label: pyramidal neuron
  - preferred_term: GABAergic neuron
    term:
      id: CL:0000617
      label: GABAergic neuron
  biological_processes:
  - preferred_term: TOR signaling
    modifier: INCREASED
    term:
      id: GO:0031929
      label: TOR signaling
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  evidence:
  - reference: DOI:10.3390/ijms25042068
    reference_title: GATOR1 Mutations Impair PI3 Kinase-Dependent Growth Factor Signaling Regulation of mTORC1
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      GATOR1 (GAP Activity TOward Rag 1) is an evolutionarily conserved
      GTPase-activating protein complex that controls the activity of mTORC1
      (mammalian Target Of Rapamycin Complex 1) in response to amino acid
      availability in cells.
    explanation: This cell-signaling study establishes the GATOR1-mTORC1 regulatory mechanism.
  - reference: DOI:10.3390/ijms25042068
    reference_title: GATOR1 Mutations Impair PI3 Kinase-Dependent Growth Factor Signaling Regulation of mTORC1
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      NPRL2-L105P is a loss-of-function mutation that disrupts protein
      interactions with NPRL3 and DEPDC5, impairing GATOR1 complex assembly and
      resulting in high mTORC1 activity even under conditions of amino acid
      deprivation.
    explanation: This directly connects an epilepsy-linked NPRL2 variant to impaired GATOR1 assembly and increased mTORC1 activity.
  - reference: DOI:10.3389/fgene.2021.766354
    reference_title: A Novel Loss-of-Function Mutation in the NPRL3 Gene Identified in Chinese Familial Focal Epilepsy with Variable Foci.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In addition, the expression of downstream molecular Phospho-p70 S6 kinase
      (P-s6k) are increased consequently.
    explanation: Peripheral blood assays in NPRL3 variant carriers support downstream mTOR pathway activation.
  - reference: PMID:31174205
    reference_title: Chronic mTORC1 inhibition rescues behavioral and biochemical deficits resulting from neuronal Depdc5 loss in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Depdc5flox/flox-Syn1Cre (Depdc5cc+) neuronal-specific Depdc5 knockout
      mice exhibit seizures and neuronal mTORC1 hyperactivation.
    explanation: A neuronal Depdc5 knockout mouse links DEPDC5 loss to seizures and neuronal mTORC1 hyperactivation.
  downstream:
  - target: Focal Seizures With Variable Cortical Foci
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - altered cortical network excitability
    description: GATOR1 loss disinhibits mTORC1 signaling, increasing risk of focal cortical network hyperexcitability.
    evidence:
    - reference: PMID:31174205
      reference_title: Chronic mTORC1 inhibition rescues behavioral and biochemical deficits resulting from neuronal Depdc5 loss in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Depdc5flox/flox-Syn1Cre (Depdc5cc+) neuronal-specific Depdc5 knockout
        mice exhibit seizures and neuronal mTORC1 hyperactivation.
      explanation: The mouse model links neuronal Depdc5 loss and mTORC1 hyperactivation to seizures.
- name: DEPDC5-Associated Focal Cortical Dysplasia
  description: >-
    In some DEPDC5-positive families, germline and brain somatic DEPDC5 variants
    are associated with focal cortical dysplasia, consistent with a two-hit
    mTORopathy model for cortical lesions and drug-resistant focal epilepsy.
  role: lesion_mechanism
  genes:
  - preferred_term: DEPDC5
    term:
      id: hgnc:18423
      label: DEPDC5
  cell_types:
  - preferred_term: pyramidal neuron
    term:
      id: CL:0000598
      label: pyramidal neuron
  biological_processes:
  - preferred_term: TOR signaling
    modifier: INCREASED
    term:
      id: GO:0031929
      label: TOR signaling
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  - preferred_term: frontal lobe
    term:
      id: UBERON:0016525
      label: frontal lobe
  evidence:
  - reference: DOI:10.1002/ana.24368
    reference_title: Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Germline, germline mosaic, and brain somatic DEPDC5 mutations may cause
      epilepsy associated with FCD, reinforcing the link between mTORC1 pathway
      and FCDs.
    explanation: This directly supports a DEPDC5-FCD mTORopathy mechanism.
  - reference: DOI:10.1002/ana.24368
    reference_title: Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A brain somatic DEPDC5 mutation was identified in 1 patient in addition to
      the germline mutation.
    explanation: This supports a two-hit model for cortical lesions in DEPDC5-associated focal epilepsy.
  - reference: DOI:10.1186/s40478-023-01675-x
    reference_title: Deep histopathology genotype-phenotype analysis of focal cortical dysplasia type II differentiates between the GATOR1-altered autophagocytic subtype IIa and MTOR-altered migration deficient subtype IIb
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ten individuals carried loss-of-function variants in the GATOR1 complex
      encoding genes DEPDC5 (n = 7) and NPRL3 (n = 3), or gain-of-function
      variants in MTOR (n = 7).
    explanation: Surgical brain-tissue analysis supports a GATOR1-associated focal cortical dysplasia subset.
  downstream:
  - target: Focal Cortical Dysplasia
    causal_link_type: DIRECT
    description: DEPDC5/GATOR1 loss is associated with cortical dysplasia lesions in a subset of patients.
    evidence:
    - reference: DOI:10.1002/ana.24368
      reference_title: Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Germline, germline mosaic, and brain somatic DEPDC5 mutations may cause
        epilepsy associated with FCD, reinforcing the link between mTORC1 pathway
        and FCDs.
      explanation: Human genetic and surgical evidence links DEPDC5/GATOR1 loss to focal cortical dysplasia.
phenotypes:
- name: Focal Seizures With Variable Cortical Foci
  category: Neurological
  diagnostic: true
  description: >-
    Affected relatives have focal-onset seizures, but the anatomical focus can
    differ between family members, including temporal, frontal, parietal, or
    occipital regions.
  phenotype_term:
    preferred_term: Focal-onset seizure
    term:
      id: HP:0007359
      label: Focal-onset seizure
  evidence:
  - reference: DOI:10.1111/j.0013-9580.2004.30502.x
    reference_title: "Familial partial epilepsy with variable foci: clinical features and linkage to chromosome 22q12."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Familial partial epilepsy with variable foci (FPEVF) is an autosomal
      dominant syndrome characterized by partial seizures originating from
      different brain regions in different family members in the absence of
      detectable structural abnormalities.
    explanation: This directly supports the core variable-foci focal seizure phenotype.
  - reference: DOI:10.1038/ng.2599
    reference_title: Mutations in DEPDC5 cause familial focal epilepsy with variable foci.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autosomal dominant familial focal epilepsy with variable foci (FFEVF) is
      notable because family members have seizures originating from different
      cortical regions.
    explanation: This provides independent human genetic evidence for the defining seizure pattern.
- name: Variable Motor Seizure Semiology
  category: Neurological
  description: >-
    Some families show tonic, tonic-clonic, or hyperkinetic seizures, with
    severity and EEG localization differing between affected relatives.
  phenotype_term:
    preferred_term: Bilateral tonic-clonic seizure with focal onset
    term:
      id: HP:0007334
      label: Bilateral tonic-clonic seizure with focal onset
  evidence:
  - reference: DOI:10.1046/j.1528-1157.2003.62302.x
    reference_title: "Familial partial epilepsy with variable foci in a Dutch family: clinical characteristics and confirmation of linkage to chromosome 22q."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seizures were mostly tonic, tonic-clonic, or hyperkinetic, with a wide
      variety in symptoms and severity.
    explanation: This supports variable motor seizure semiology; the HPO term captures the tonic-clonic component but not all reported semiologies.
- name: EEG Abnormality
  category: Neurological
  description: >-
    EEG may be normal or show focal epileptiform abnormalities involving
    different cortical regions, consistent with variable foci.
  phenotype_term:
    preferred_term: EEG abnormality
    term:
      id: HP:0002353
      label: EEG abnormality
  evidence:
  - reference: DOI:10.1046/j.1528-1157.2003.62302.x
    reference_title: "Familial partial epilepsy with variable foci in a Dutch family: clinical characteristics and confirmation of linkage to chromosome 22q."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most interictal EEGs showed no abnormalities, but some showed frontal,
      central, and/or temporal spikes and spike-wave complexes.
    explanation: This supports focal EEG abnormalities in a subset of affected relatives.
  - reference: DOI:10.1371/journal.pone.0284924
    reference_title: The clinical features of familial focal epilepsy with variable foci and NPRL3 gene variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      normal MRI, and abnormal EEG (epileptiform discharge, slow wave).
    explanation: This NPRL3 family study supports abnormal EEG findings in FFEVF.
- name: Focal Cortical Dysplasia
  category: Neurological
  description: >-
    Focal cortical dysplasia can occur in DEPDC5/GATOR1-positive focal epilepsy,
    sometimes despite normal or atypical MRI, and contributes to drug-resistant
    focal seizures.
  phenotype_term:
    preferred_term: Focal cortical dysplasia
    term:
      id: HP:0032046
      label: Focal cortical dysplasia
  evidence:
  - reference: DOI:10.1002/ana.24368
    reference_title: Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had drug‐resistant focal epilepsy, 5 of them underwent
      surgery, and 1 had a brain biopsy.
    explanation: This establishes the DEPDC5-associated FCD clinical subset and its drug-resistant epilepsy context.
  - reference: DOI:10.1186/s40478-023-01675-x
    reference_title: Deep histopathology genotype-phenotype analysis of focal cortical dysplasia type II differentiates between the GATOR1-altered autophagocytic subtype IIa and MTOR-altered migration deficient subtype IIb
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whereas individuals with GATOR1 variants only presented with FCDIIa, i.e.,
      lack of balloon cells, individuals with MTOR variants presented with both
      histopathology subtypes, FCDIIa and FCDIIb.
    explanation: Histopathology-genotype analysis supports a GATOR1-associated FCDIIa pattern.
histopathology:
- name: GATOR1-Associated FCDIIa Autophagy-Altered Histopathology
  description: >-
    Surgical tissue from GATOR1-positive focal cortical dysplasia type IIa can
    show vacuolizing cells and p62-positive autophagosome aggregates, supporting
    an autophagy-altered histopathologic pattern in this lesion subset.
  diagnostic: false
  evidence:
  - reference: DOI:10.1186/s40478-023-01675-x
    reference_title: Deep histopathology genotype-phenotype analysis of focal cortical dysplasia type II differentiates between the GATOR1-altered autophagocytic subtype IIa and MTOR-altered migration deficient subtype IIb
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Interestingly, 50% of GATOR1-positive cases showed a unique and
      predominantly vacuolizing phenotype with p62 immunofluorescent aggregates
      in autophagosomes.
    explanation: Surgical pathology evidence supports a GATOR1-associated FCDIIa pattern with vacuolizing cells and p62-positive autophagosome aggregates.
diagnosis:
- name: DEPDC5/NPRL2/NPRL3 molecular genetic testing
  description: >-
    Molecular testing with epilepsy gene panels, whole-exome sequencing, or
    targeted family testing can identify heterozygous GATOR1 variants and
    support subtype assignment.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  results: Heterozygous pathogenic or likely pathogenic DEPDC5, NPRL2, or NPRL3 variants support the diagnosis.
  evidence:
  - reference: DOI:10.3389/fgene.2024.1414259
    reference_title: A novel variation in DEPDC5 causing familial focal epilepsy with variable foci.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole exome sequencing (WES) was performed in the proband, and Sanger
      sequencing was used to confirm the variation carrying status of the family
      members.
    explanation: This supports WES with familial confirmation for DEPDC5-associated FFEVF.
  - reference: DOI:10.1371/journal.pone.0284924
    reference_title: The clinical features of familial focal epilepsy with variable foci and NPRL3 gene variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We ran a full workup on a family with FFEVF (four patients, one healthy
      member): an inquiry of medical history, cranial magnetic resonance imaging
      (MRI), electroencephalogram (EEG), and whole exon sequencing.
    explanation: This supports integrated clinical, EEG/MRI, and exome-based diagnostic evaluation.
- name: EEG and brain MRI characterization
  description: >-
    EEG helps localize seizure networks and demonstrate variable foci, while MRI
    may be normal in nonlesional families or reveal focal cortical dysplasia in
    lesion-associated DEPDC5/GATOR1 disease.
  results: Focal EEG abnormalities support seizure localization; normal MRI does not exclude FFEVF.
  evidence:
  - reference: DOI:10.1046/j.1528-1157.2003.62302.x
    reference_title: "Familial partial epilepsy with variable foci in a Dutch family: clinical characteristics and confirmation of linkage to chromosome 22q."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      From two patients, an ictal EEG was available, showing frontotemporal
      abnormalities in one and frontal and central abnormalities in the other.
    explanation: Ictal EEG supported different cortical foci in different relatives.
  - reference: DOI:10.1002/ana.24368
    reference_title: Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Electroclinical phenotypes were compatible with FCD II, although magnetic
      resonance imaging (MRI) was typical in only 4 cases.
    explanation: MRI may be typical in some but not all DEPDC5-associated FCD cases.
treatments:
- name: Antiseizure Medication Therapy
  description: >-
    Management generally begins with antiseizure medications used for focal
    epilepsy. Response is variable; some patients become almost seizure-free,
    while lesion-associated DEPDC5/GATOR1 cases can be drug resistant.
  treatment_term:
    preferred_term: anticonvulsant agent therapy
    term:
      id: MAXO:0000167
      label: anticonvulsant agent therapy
  target_phenotypes:
  - preferred_term: Focal-onset seizure
    term:
      id: HP:0007359
      label: Focal-onset seizure
  evidence:
  - 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: This focal epilepsy meta-analysis supports antiseizure medication therapy for focal-onset seizures, including FFEVF by disease class.
  - reference: DOI:10.1371/journal.pone.0284924
    reference_title: The clinical features of familial focal epilepsy with variable foci and NPRL3 gene variant.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      different therapeutic effects (refractory epilepsy/almost seizure free)
    explanation: This FFEVF family study shows variable medication-era outcomes rather than a specific drug recommendation.
- name: Experimental mTOR Inhibitor Therapy (Rapamycin/Sirolimus)
  description: >-
    Preclinical mouse-model evidence supports mTORC1 inhibition as a rational
    therapeutic strategy for DEPDC5-related epilepsy. Rapamycin, also known as
    sirolimus, prolonged survival and partially rescued behavioral hyperactivity
    in neuronal-specific Depdc5 knockout mice; this is experimental rather than
    established clinical care for FFEVF.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sirolimus
      term:
        id: CHEBI:9168
        label: sirolimus
  target_phenotypes:
  - preferred_term: Focal-onset seizure
    term:
      id: HP:0007359
      label: Focal-onset seizure
  target_mechanisms:
  - target: GATOR1 Complex Loss and mTORC1 Disinhibition
    treatment_effect: INHIBITS
    description: mTORC1 inhibition counteracts downstream hyperactivation caused by GATOR1 loss.
    evidence:
    - reference: PMID:31174205
      reference_title: Chronic mTORC1 inhibition rescues behavioral and biochemical deficits resulting from neuronal Depdc5 loss in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Collectively, our data provide the first evidence of behavioral
        alterations in mice with Depdc5 loss and support mTOR inhibition as a
        rational therapeutic strategy for DEPDC5-related epilepsy in humans.
      explanation: Depdc5 knockout mouse data support rapamycin/sirolimus as a mechanistically rational experimental therapy targeting mTORC1 hyperactivation.
- name: Epilepsy Surgery for Drug-Resistant DEPDC5/FCD Disease
  description: >-
    Focal resection can be considered for drug-resistant focal epilepsy when a
    seizure focus or focal cortical dysplasia is identified, including
    DEPDC5-positive cases that have subtle or unremarkable MRI.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
  target_phenotypes:
  - preferred_term: Focal-onset seizure
    term:
      id: HP:0007359
      label: Focal-onset seizure
  - preferred_term: Focal cortical dysplasia
    term:
      id: HP:0032046
      label: Focal cortical dysplasia
  target_mechanisms:
  - target: DEPDC5-Associated Focal Cortical Dysplasia
    treatment_effect: MODULATES
    description: Focal resection removes the epileptogenic dysplastic cortex when localization is feasible.
    evidence:
    - reference: DOI:10.1055/a-2213-8584
      reference_title: "Seizure Control Outcomes following Resection of Cortical Dysplasia in Patients with DEPDC5 Variants: A Systematic Review and Individual Patient Data Analysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The most common form of epilepsy surgery was focal resection (38/44,
        86.4%).
      explanation: This supports focal resection as the mechanism-targeting surgical approach in DEPDC5-associated cortical dysplasia.
  evidence:
  - reference: DOI:10.1002/ana.24368
    reference_title: Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three patients were seizure‐free postsurgically, and 1 had a worthwhile
      improvement.
    explanation: DEPDC5-associated FCD cases showed favorable surgical outcomes in several patients.
  - reference: DOI:10.1055/a-2213-8584
    reference_title: "Seizure Control Outcomes following Resection of Cortical Dysplasia in Patients with DEPDC5 Variants: A Systematic Review and Individual Patient Data Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thirty-seven of the 40 patients (37/40, 92.5%) with reported seizure
      frequency results had improvement.
    explanation: Systematic review evidence supports epilepsy surgery benefit in DEPDC5-variant patients with pharmacoresistant epilepsy.
📚

References & Deep Research

Deep Research

1
Falcon ▸
Familial Focal Epilepsy With Variable Foci (FFEVF): Disease Characteristics Research Report
42 citations

Familial Focal Epilepsy With Variable Foci (FFEVF): Disease Characteristics Research Report

Executive summary

Familial focal epilepsy with variable foci (FFEVF; MIM 604364) is an autosomal dominant familial focal epilepsy in which affected relatives have focal seizures arising from different cortical regions (e.g., temporal, frontal, parietal, occipital), while each individual typically has a consistent focal onset pattern. It is most commonly caused by germline loss-of-function variants in genes encoding the GATOR1 complex (DEPDC5, NPRL2, NPRL3), a negative regulator of mTORC1 signaling, and it shows incomplete penetrance and highly variable expressivity. Key real-world implementations include broad epilepsy gene panel/WES testing, epilepsy-protocol MRI and long-term video-EEG, consideration of epilepsy surgery in drug-resistant cases (especially with focal cortical dysplasia), and increased attention to cardiorespiratory peri-ictal monitoring in some DEPDC5-related presentations. (kaur2013noveldepdc5mutations pages 1-4, dibbens2013mutationsindepdc5 pages 1-2, muller2024gator1mutationsimpair pages 1-2, baulac2015familialfocalepilepsy pages 1-4, meletti2024ictalandpostictal pages 1-3, mcginley2024seizurecontroloutcomes pages 1-2)

1. Disease information

1.1 Overview / definition

  • Definition (clinical): FFEVF is an autosomal dominant focal epilepsy syndrome notable because family members have seizures originating from different cortical regions. (dibbens2013mutationsindepdc5 pages 1-2)
  • Key defining feature: intrafamilial variability in seizure focus (temporal/frontal/frontotemporal/parietal/occipital) with often unremarkable structural MRI in many cases. (dibbens2013mutationsindepdc5 pages 1-2)

1.2 Key identifiers

  • OMIM/MIM:
  • FFEVF: MIM 604364 (explicitly cited). (kaur2013noveldepdc5mutations pages 1-4)
  • NPRL3-associated subtype: FFEVF3, OMIM 617118 (explicitly cited in NPRL3-focused report). (hu2023identificationoftwo pages 1-2)
  • MONDO / Orphanet / MeSH / ICD-10/ICD-11: Not available from the retrieved documents in this run; these should be filled from OMIM/Orphanet/MONDO/MeSH/ICD lookups outside the present evidence set.

1.3 Synonyms / alternative names

  • “Familial focal epilepsy with variable foci” (FFEVF). (dibbens2013mutationsindepdc5 pages 1-2)
  • Subtype naming by gene is used in the literature and clinical genetics (e.g., FFEVF3 for NPRL3). (hu2023identificationoftwo pages 1-2)

1.4 Evidence source type

The content summarized here is derived from aggregated disease-level resources within peer-reviewed primary literature (family studies, case series, surgical cohorts) and from recent reviews/analyses, rather than EHR-only sources. (dibbens2013mutationsindepdc5 pages 1-2, baulac2015familialfocalepilepsy pages 1-4, honke2023deephistopathologygenotype–phenotype pages 1-2)

Item Details Key citations (pqac ids) URL Publication year
Disease name Familial focal epilepsy with variable foci (FFEVF) is an autosomal dominant familial focal epilepsy characterized by focal seizures arising from different cortical regions in different affected relatives. (dibbens2013mutationsindepdc5 pages 1-2, kaur2013noveldepdc5mutations pages 1-4, wang2023theclinicalfeatures pages 1-2) https://doi.org/10.1038/ng.2599 2013
Synonyms Familial focal epilepsy with variable foci; focal epilepsy with variable foci; FFEVF; FFEVF3 (for NPRL3-related subtype); earlier literature also refers to the same syndrome as FPEVF/partial epilepsy with variable foci. (dibbens2013mutationsindepdc5 pages 1-2, hu2023identificationoftwo pages 1-2, wang2023theclinicalfeatures pages 1-2) https://doi.org/10.3389/fgene.2022.1054567 2023
OMIM / MIM phenotype numbers MIM 604364 is explicitly cited for FFEVF; OMIM 617118 is explicitly cited for FFEVF3 / NPRL3-associated disease. (kaur2013noveldepdc5mutations pages 1-4, hu2023identificationoftwo pages 1-2) https://doi.org/10.1111/cge.12239 2013
Inheritance Autosomal dominant inheritance with incomplete penetrance and variable expressivity are recurrently reported across DEPDC5-, NPRL2-, and NPRL3-related families. (kaur2013noveldepdc5mutations pages 1-4, yang2024phenotypicandgenotypic pages 1-2, wang2023theclinicalfeatures pages 1-2) https://doi.org/10.1371/journal.pone.0284924 2023
Key gene DEPDC5; identified as a common cause of familial focal epilepsies/FFEVF, including large linked families; many variants are truncating and support haploinsufficiency. (dibbens2013mutationsindepdc5 pages 1-2, baulac2014geneticsadvancesin pages 6-9, zhang2021phenotypicandgenotypic pages 1-2) https://doi.org/10.1038/ng.2599 2013
Key gene NPRL2; GATOR1 component implicated in FFEVF, including splice-site variants causing aberrant splicing and exon skipping. (zhang2022asplicingvariation pages 1-2, muller2024gator1mutationsimpair pages 1-2) https://doi.org/10.1038/s10038-021-00969-z 2022
Key gene NPRL3; GATOR1 component implicated in FFEVF3, with nonsense, frameshift, splice, deletion, and other loss-of-function variants reported. (hu2023identificationoftwo pages 1-2, yang2024phenotypicandgenotypic pages 1-2, nouri2024fromalphathalassemiatrait pages 1-2) https://doi.org/10.3389/fgene.2022.1054567 2023
Brief mechanistic note DEPDC5, NPRL2, and NPRL3 form the GATOR1 complex, a negative regulator of the amino-acid sensing branch of mTORC1 signaling; pathogenic variants generally reduce GATOR1 function, leading to mTORC1 hyperactivation. (muller2024gator1mutationsimpair pages 1-2, hu2023identificationoftwo pages 1-2, wang2023theclinicalfeatures pages 1-2) https://doi.org/10.3390/ijms25042068 2024

Table: This table summarizes the core disease identity, identifiers, inheritance, major genes, and shared GATOR1–mTORC1 mechanism for familial focal epilepsy with variable foci. It is useful as a compact reference for knowledge-base curation grounded only in the cited evidence.

2. Etiology

2.1 Primary causal factors

Genetic (major): Heterozygous pathogenic variants in DEPDC5, and also NPRL2/NPRL3, are repeatedly implicated in FFEVF and related focal epilepsy spectra. (dibbens2013mutationsindepdc5 pages 1-2, zhang2022asplicingvariation pages 1-2, hu2023identificationoftwo pages 1-2)

Illustrative primary-literature statement (DEPDC5 discovery): Dibbens et al. report that exome sequencing identified DEPDC5 mutations in linked FFEVF families and that “Study of families with focal epilepsy that were too small for conventional clinical diagnosis with FFEVF identified DEPDC5 mutations in approximately 12% of families (10/82).” (Nature Genetics; published online 31 Mar 2013; https://doi.org/10.1038/ng.2599) (dibbens2013mutationsindepdc5 pages 1-2)

2.2 Risk factors

  • Family history / inherited variants: autosomal dominant inheritance is typical. (dibbens2013mutationsindepdc5 pages 1-2, kaur2013noveldepdc5mutations pages 1-4)
  • Two-hit biology as risk modifier for malformations: in DEPDC5-associated focal cortical dysplasia (FCD), evidence supports a “two-hit” model in which a germline DEPDC5 variant plus a second (somatic) DEPDC5 variant in brain tissue may contribute to lesion formation and severe drug-resistant epilepsy. (baulac2015familialfocalepilepsy pages 1-4)

Environmental risk factors: Not specifically established for this Mendelian syndrome in the retrieved evidence set.

2.3 Protective factors

No validated protective genetic or environmental factors specific to FFEVF were found in the retrieved corpus.

2.4 Gene–environment interactions

No direct gene–environment interaction studies specific to FFEVF were found in the retrieved corpus.

3. Phenotypes (clinical spectrum)

3.1 Core seizure phenotypes

  • Variable cortical foci across relatives: frontal, temporal, frontotemporal, parietal, occipital regions. (dibbens2013mutationsindepdc5 pages 1-2)
  • Age of onset: reported to vary from infancy to adult life. (dibbens2013mutationsindepdc5 pages 1-2)
  • DEPDC5 cohorts: in one Nature Genetics family-based series, mean seizure onset with DEPDC5 mutations was 12.5 years with a wide range (6 weeks to 52 years). (dibbens2013mutationsindepdc5 pages 1-2)
  • NPRL3 family example (China): onset age ranged 4 months to 31 years, with variable foci (frontal/temporal), variable timing (day/night), and outcomes spanning refractory epilepsy to near seizure freedom. (PLOS ONE; Apr 2023; https://doi.org/10.1371/journal.pone.0284924) (wang2023theclinicalfeatures pages 1-2)
  • NPRL2 variant family: multiple seizure types including “febrile seizures, infantile spasms, focal seizures, or focal to generalized tonic-clonic seizures.” (Journal of Human Genetics; 2022; https://doi.org/10.1038/s10038-021-00969-z) (zhang2022asplicingvariation pages 1-2)

3.2 EEG, imaging, and lesion-associated phenotypes

  • MRI often unremarkable in non-lesional familial presentations (structural MRI “usually unremarkable” in the large family description). (dibbens2013mutationsindepdc5 pages 1-2)
  • Focal cortical dysplasia (FCD) association (DEPDC5): Seven patients from four families with truncating DEPDC5 variants had focal epilepsy associated with FCD (types included FCD IIa and FCD I); MRI could be negative/atypical, and favorable surgical outcomes occurred in several patients. (Annals of Neurology; Apr 2015; https://doi.org/10.1002/ana.24368) (baulac2015familialfocalepilepsy pages 1-4)
  • Genotype–histopathology correlation (brain-tissue genetics, 2023): In a 17-individual surgical cohort, GATOR1 loss-of-function variants (DEPDC5 n=7; NPRL3 n=3) were associated with FCDIIa and often subtle/negative MRI (seven individuals), and 50% showed a vacuolizing phenotype with p62 aggregates in autophagosomes. (Acta Neuropathologica Communications; Nov 2023; https://doi.org/10.1186/s40478-023-01675-x) (honke2023deephistopathologygenotype–phenotype pages 1-2)

3.3 Comorbidities / neurodevelopment

  • Most affected individuals in the initial Nature Genetics description “typically have normal intellect,” but some relatives can have “intellectual disability, psychiatric disorders … or autism spectrum disorders.” (dibbens2013mutationsindepdc5 pages 1-2)

3.4 Cardiorespiratory and SUDEP-relevant phenotypes (recent development)

A 2024 Neurology Genetics cohort study evaluated ictal central apnea (ICA) in focal epilepsy patients undergoing long-term video-EEG with cardiorespiratory polygraphy and found DEPDC5 variants enriched among those with ICA: 5/14 (35%) of ICA patients had pathogenic DEPDC5 variants vs 0/15 without ICA. In DEPDC5 patients, ICA occurred in all recorded seizures (n=15) with apnea durations 20 seconds to >1 minute, with temporal EEG involvement in all events and severe oxygen desaturation in 2 cases. (Neurology Genetics; Oct 2024; https://doi.org/10.1212/nxg.0000000000200183) (meletti2024ictalandpostictal pages 1-3)

Visual evidence from this paper (pedigrees/variant schematic/clinical table) is available in extracted figure/table crops. (meletti2024ictalandpostictal media 949a04e5, meletti2024ictalandpostictal media 1e3201ae)

3.5 Suggested HPO terms (examples)

(ontology suggestions; not exhaustive) - Focal seizures: HP:0007359 - Focal to bilateral tonic-clonic seizures: HP:0007334 - Febrile seizures: HP:0002373 - Infantile spasms: HP:0012469 - Abnormal EEG: HP:0002353 - Epileptiform discharges: HP:0002350 - Focal cortical dysplasia: HP:0010636 - Hemimegalencephaly: HP:0007315 (noted as part of NPRL3 phenotypic expansion in broader literature; not directly extracted in this run) - Developmental delay: HP:0001263 - Autism: HP:0000717

4. Genetic / molecular information

4.1 Causal genes

Causal genes in this disorder cluster in the GATOR1 complex: - DEPDC5 (most commonly reported in familial focal epilepsies/FFEVF). (dibbens2013mutationsindepdc5 pages 1-2, baulac2014geneticsadvancesin pages 6-9) - NPRL2 (splicing variants reported; functional splicing assays used). (zhang2022asplicingvariation pages 1-2) - NPRL3 (nonsense, frameshift, splice, deletion). (hu2023identificationoftwo pages 1-2, nouri2024fromalphathalassemiatrait pages 1-2)

4.2 Variant classes and functional consequences

  • DEPDC5: multiple nonsense/truncating variants and deletions have been described; the 2014 review notes that “≈two-thirds” are loss-of-function (premature stop/frameshift/splice) with evidence for nonsense-mediated decay in patient lymphoblasts, consistent with haploinsufficiency. (Progress in Brain Research; 2014; https://doi.org/10.1016/b978-0-444-63326-2.00007-7) (baulac2014geneticsadvancesin pages 6-9)
  • NPRL2: splicing variant c.339+2T>C causes exon skipping (minigene assay) and is linked to FFEVF phenotypes. (zhang2022asplicingvariation pages 1-2)
  • NPRL3: truncating variants (e.g., c.954C>A p.Tyr318*; c.1545-1G>C splice) can be inherited from unaffected mothers (illustrating incomplete penetrance). (Frontiers in Genetics; Jan 2023; https://doi.org/10.3389/fgene.2022.1054567) (hu2023identificationoftwo pages 1-2)

4.3 Penetrance and expressivity

  • Penetrance is explicitly described as incomplete and variable. (kaur2013noveldepdc5mutations pages 1-4, yang2024phenotypicandgenotypic pages 1-2)
  • A family-based estimate cited in a commentary summary of the 2013 discovery work reported penetrance ~66% (69/105) in seven large families (secondary summary of Dibbens/Ishida studies). (kaur2013noveldepdc5mutations pages 1-4)
  • For NPRL3, literature review notes “the penetrance of NPRL3-related epilepsy is incomplete.” (Epilepsia Open; 2024; https://doi.org/10.1002/epi4.12856) (yang2024phenotypicandgenotypic pages 1-2)

4.4 Genotype–phenotype correlations (selected)

  • DEPDC5 variants can present as non-lesional familial focal epilepsy or as focal epilepsy with FCD; in DEPDC5-associated FCD, brain somatic second hits have been detected, consistent with a two-hit lesion model. (baulac2015familialfocalepilepsy pages 1-4)
  • Brain-tissue sequencing in FCDII suggests GATOR1 variants correlate with FCDIIa subtype and an autophagy-altered phenotype (p62 aggregates), contrasting with MTOR-associated lesions. (honke2023deephistopathologygenotype–phenotype pages 1-2)

5. Environmental information

No consistent non-genetic environmental contributors specific to FFEVF were identified in the retrieved evidence.

6. Mechanism / pathophysiology

6.1 Current mechanistic model (GATOR1–mTORC1)

GATOR1 (DEPDC5–NPRL2–NPRL3) is a GTPase-activating protein complex regulating mTORC1 in response to amino acids and other upstream signals; epilepsy-associated mutations in GATOR1 subunits are linked to dysregulated mTORC1 activity. (muller2024gator1mutationsimpair pages 1-2, hu2023identificationoftwo pages 1-2)

Direct abstract quote (cell biology; Feb 2024): “GATOR1 … controls the activity of mTORC1 … in response to amino acid availability… epilepsy-linked mutations in the NPRL2 subunit … increase basal mTORC1 signal transduction…” and “NPRL2-L105P is a loss-of-function mutation that disrupts protein interactions with NPRL3 and DEPDC5, impairing GATOR1 complex assembly and resulting in high mTORC1 activity…” (Int J Mol Sci; published 8 Feb 2024; https://doi.org/10.3390/ijms25042068) (muller2024gator1mutationsimpair pages 1-2)

6.2 From molecular defect to seizures (causal chain; synthesis)

1) Germline loss-of-function variant in DEPDC5/NPRL2/NPRL3 → 2) impaired GATOR1 inhibition → 3) relative mTORC1 hyperactivation → 4) altered neurodevelopmental processes and/or cortical network excitability; in some patients, second-hit/somatic events in brain tissue contribute to focal malformations such as FCD → 5) focal seizure generation with variable anatomic foci within families. Evidence for steps 1–3 is supported by GATOR1 mechanistic studies and genetic association; steps 4–5 are supported by surgical pathology/genetic “two-hit” observations. (muller2024gator1mutationsimpair pages 1-2, baulac2015familialfocalepilepsy pages 1-4, honke2023deephistopathologygenotype–phenotype pages 1-2)

6.3 Cellular/tissue processes implicated

  • mTOR pathway activation markers in dysmorphic neurons: pS6 immunoreactivity is noted as indicating constitutive mTOR pathway activation in FCDII. (honke2023deephistopathologygenotype–phenotype pages 1-2)
  • Autophagy-related phenotype in GATOR1-positive FCDIIa: 50% vacuolizing phenotype with p62 aggregates in autophagosomes. (honke2023deephistopathologygenotype–phenotype pages 1-2)

6.4 Suggested GO / CL terms (examples)

(ontology suggestions) - GO biological process: “mTOR signaling” (e.g., GO:0048015), “autophagy” (e.g., GO:0006914), “regulation of synaptic transmission” (broad) - CL terms: “cortical pyramidal neuron” (broad), “GABAergic interneuron” (broad; mechanistic neurophysiology studies suggest hyperexcitability without direct GABA inhibition changes in some carriers—see below)

6.5 Neurophysiology (recent development)

A 2023 multimodal study in DEPDC5/NPRL3 mutation carriers reported no effect on cortical GABAergic receptor-mediated inhibition or GABA concentration by TMS/MRS, but stronger EEG theta and stronger/more synchronous gamma oscillations, interpreted as increased neural entrainment consistent with cortical hyperexcitability mediated by increased mTORC1 signaling. (Orphanet Journal of Rare Diseases; Jan 2023; https://doi.org/10.1186/s13023-022-02600-6) (meletti2024ictalandpostictal pages 1-3)

7. Anatomical structures affected

7.1 Organ/system

  • Primary system: central nervous system. (dibbens2013mutationsindepdc5 pages 1-2)

7.2 Brain regions (variable by individual/family)

  • Temporal, frontal, frontotemporal, parietal, occipital cortical regions. (dibbens2013mutationsindepdc5 pages 1-2)
  • In surgical FCD cohorts with GATOR1 variants, lesions often involve the frontal lobe and may be confined to cortical ribbon. (honke2023deephistopathologygenotype–phenotype pages 1-2)

7.3 Suggested UBERON terms (examples)

(ontology suggestions) - Cerebral cortex: UBERON:0000956 - Frontal lobe: UBERON:0001870 - Temporal lobe: UBERON:0001874 - Hippocampus: UBERON:0001954 (e.g., hippocampal sclerosis noted in a 2024 NPRL3 deletion case). (nouri2024fromalphathalassemiatrait pages 1-2)

8. Temporal development

  • Onset: infancy through adulthood reported; mean onset ~12.5 years in one DEPDC5 series, but range extends to 6 weeks. (dibbens2013mutationsindepdc5 pages 1-2)
  • Course: highly variable; some patients are near seizure-free on ASMs while others are drug-resistant and may require surgery. (wang2023theclinicalfeatures pages 1-2, baulac2015familialfocalepilepsy pages 1-4)

9. Inheritance and population

9.1 Inheritance

  • Autosomal dominant inheritance with incomplete penetrance and variable expressivity. (dibbens2013mutationsindepdc5 pages 1-2, kaur2013noveldepdc5mutations pages 1-4, yang2024phenotypicandgenotypic pages 1-2)

9.2 Epidemiology

FFEVF-specific incidence/prevalence estimates were not found in the retrieved corpus.

For context (epilepsy overall): - A large 2024 exome-sequencing study introduction states epilepsy prevalence is 4–10 per 1,000 individuals worldwide. (Nat Neurosci; Oct 2024; https://doi.org/10.1038/s41593-024-01747-8) (anders2024exomesequencingof pages 1-2) - SUDEP background incidence is cited as 0.22 to 1.2 per 1,000 individuals per year and may account for up to 17% of deaths among people with epilepsy (general estimate; not specific to FFEVF). (Neurology Genetics; Oct 2024; https://doi.org/10.1212/nxg.0000000000200183) (meletti2024ictalandpostictal pages 1-3)

9.3 Demographics / founder effects

No population-specific founder effects for FFEVF variants were extractable from the retrieved text (some shared ancestry is discussed in the 2013 DEPDC5 paper but not fully extracted here). (dibbens2013mutationsindepdc5 pages 1-2)

10. Diagnostics

10.1 Clinical tests and findings

  • EEG: abnormal EEG findings are common but variable; examples include epileptiform discharges and slow waves (NPRL3 family report). (wang2023theclinicalfeatures pages 1-2)
  • MRI: may be normal in many; in lesion-associated cases, epilepsy-protocol MRI and advanced review/post-processing can identify subtle FCD or hippocampal sclerosis (NPRL3 deletion case review). (nouri2024fromalphathalassemiatrait pages 1-2)
  • Long-term video-EEG with cardiorespiratory polygraphy: recommended/clinically motivated in DEPDC5-related focal epilepsy when ictal apnea is suspected. (meletti2024ictalandpostictal pages 1-3)

10.2 Genetic testing

  • WES / epilepsy gene panels: used to identify germline variants in DEPDC5/NPRL2/NPRL3; trio-WES and targeted pipelines are reported. (hu2023identificationoftwo pages 1-2, zhang2022asplicingvariation pages 1-2)
  • Variant interpretation: ACMG-guided variant assessment is explicitly mentioned in NPRL3 WES report. (hu2023identificationoftwo pages 1-2)
  • Brain tissue sequencing (selected surgical cases): brain-derived DNA sequencing can identify somatic “second hits” in FCD contexts. (baulac2015familialfocalepilepsy pages 1-4, honke2023deephistopathologygenotype–phenotype pages 1-2)

10.3 Differential diagnosis

Differential diagnoses include other genetic focal epilepsies and malformations of cortical development (e.g., MTOR-pathway focal cortical dysplasia not driven by GATOR1). (honke2023deephistopathologygenotype–phenotype pages 1-2)

11. Outcomes / prognosis

11.1 Drug resistance

  • A DEPDC5-focused 2024 cohort (ictal apnea study) reported drug resistance in 4/5 DEPDC5 patients. (meletti2024ictalandpostictal pages 1-3)
  • DEPDC5-related FCD family series emphasized drug-resistant focal epilepsy in all seven reported patients. (baulac2015familialfocalepilepsy pages 1-4)

11.2 Surgical outcomes (real-world implementation)

  • DEPDC5-FCD family series: after surgery, multiple patients achieved seizure freedom or worthwhile improvement; authors conclude surgery is valuable even with normal MRI. (baulac2015familialfocalepilepsy pages 1-4)
  • Systematic review / individual patient data (2024): Among 44 DEPDC5-variant patients undergoing surgery, 37/40 (92.5%) with reported seizure-frequency outcomes improved; 29/38 (78.4%) undergoing focal resection achieved Engel class I postoperatively. (Neuropediatrics; online Dec 2023 / print 2024; https://doi.org/10.1055/a-2213-8584) (mcginley2024seizurecontroloutcomes pages 1-2)

12. Treatment

12.1 Pharmacotherapy (ASMs)

No FFEVF gene-specific randomized controlled trials were found in the retrieved corpus; management follows standard focal epilepsy approaches.

  • Case and cohort evidence supports use of standard ASMs (e.g., levetiracetam, valproate, lamotrigine, carbamazepine, lacosamide), with variable response. (meletti2024ictalandpostictal pages 1-3)
  • NPRL2 splicing variant case series reported “a favorable prognosis … in response to vitamin B6 and topiramate” in an infant. (zhang2022asplicingvariation pages 1-2)

MAXO suggestions (examples): - Anti-seizure medication therapy: MAXO:0000744 (anticonvulsant therapy; approximate) - Vitamin B6 supplementation: (MAXO term for pyridoxine supplementation)

12.2 Surgical and interventional

  • For drug-resistant focal epilepsy with DEPDC5 variants and FCD, focal resection is commonly used and frequently beneficial. (mcginley2024seizurecontroloutcomes pages 1-2)

MAXO suggestions: epilepsy surgery / focal resection.

12.3 Monitoring and SUDEP-risk mitigation

Given evidence that ictal central apnea may be common in some DEPDC5-related seizures and that the cohort authors support respiratory polygraphy during LTVM, implementation includes cardiorespiratory monitoring during presurgical evaluation and consideration of genetic testing in focal epilepsy with unexplained ictal apnea. (meletti2024ictalandpostictal pages 1-3)

13. Prevention

No primary prevention strategies specific to FFEVF are established in the retrieved evidence.

Secondary/tertiary prevention in practice includes: - Cascade genetic testing and counseling in families once a pathogenic GATOR1 variant is identified (implied by autosomal dominant inheritance and use of family testing in reports). (hu2023identificationoftwo pages 1-2, dibbens2013mutationsindepdc5 pages 1-2) - Early identification of drug resistance and timely referral for surgical evaluation in appropriate candidates. (baulac2015familialfocalepilepsy pages 1-4, mcginley2024seizurecontroloutcomes pages 1-2)

14. Other species / natural disease

No naturally occurring non-human disease analogs were identified in the retrieved evidence set.

15. Model organisms

No organismal model studies were directly extracted in this run; however, mechanistic cellular studies of GATOR1 complex function and mTORC1 regulation provide functional context for epilepsy-associated variants. (muller2024gator1mutationsimpair pages 1-2)

Recent developments (prioritizing 2023–2024)

1) Brain-tissue genotype–histopathology: GATOR1 variants correlate with FCDIIa and autophagy-altered pathology (p62 aggregates) and subtle MRI findings in many cases, supporting integrated molecular neuropathology workflows. (Honke et al., Nov 2023; https://doi.org/10.1186/s40478-023-01675-x) (honke2023deephistopathologygenotype–phenotype pages 1-2) 2) Cardiorespiratory phenotyping: ICA enrichment among DEPDC5 pathogenic variant carriers during LTVM suggests new clinical attention to respiratory monitoring and genetic testing in ICA presentations. (Meletti et al., Oct 2024; https://doi.org/10.1212/nxg.0000000000200183) (meletti2024ictalandpostictal pages 1-3, meletti2024ictalandpostictal media 949a04e5) 3) Surgery outcomes synthesis: Systematic review indicates high postoperative improvement and substantial Engel class I rates among DEPDC5-variant patients with cortical dysplasia undergoing resection. (McGinley et al., 2024; https://doi.org/10.1055/a-2213-8584) (mcginley2024seizurecontroloutcomes pages 1-2) 4) Mechanistic refinement: Cell-signaling work shows epilepsy-linked NPRL2 mutations can disrupt GATOR1 assembly and impair mTORC1 regulation by amino acids and PI3K-dependent growth factor signaling. (Muller et al., Feb 2024; https://doi.org/10.3390/ijms25042068) (muller2024gator1mutationsimpair pages 1-2) 5) Genomic diagnostic odysseys / syndromic overlap: A 2024 report highlights that deletions encompassing NPRL3 can co-present with α-thalassemia trait due to regulatory-region overlap, and that delayed diagnosis can occur without early comprehensive genetic assessment. (Nouri et al., Jun 2024; https://doi.org/10.3390/genes15070836) (nouri2024fromalphathalassemiatrait pages 1-2)

Current applications and real-world implementations

  • Diagnostic pipelines: epilepsy-protocol MRI + EEG + WES/panels; in surgical cases, brain-tissue sequencing for somatic variants/second hits. (hu2023identificationoftwo pages 1-2, baulac2015familialfocalepilepsy pages 1-4, honke2023deephistopathologygenotype–phenotype pages 1-2)
  • Precision monitoring: LTVM with cardiorespiratory polygraphy when ictal apnea is suspected, particularly in DEPDC5-related epilepsy. (meletti2024ictalandpostictal pages 1-3)
  • Surgical programs: focal resection for drug-resistant FCD in DEPDC5 variant carriers, often with good outcomes. (mcginley2024seizurecontroloutcomes pages 1-2)

Clinical trials (latest; real-world precision-medicine implementation)

NCT05450822 — “Precision Medicine in the Treatment of Epilepsy” (BrainDrugs-Epilepsy Study; Denmark) - Study type/status: observational, recruiting; first posted 2022-07-11, last update posted 2024-04-11. (NCT05450822 chunk 1) - Design: prospective cohort with multimodal biomarkers (EEG/MRI; subset PET) and ASM initiation with lamotrigine or levetiracetam; genetic biomarkers list includes DEPDC5, NPRL2, NPRL3 (among many). (NCT05450822 chunk 1) - URL: https://clinicaltrials.gov/study/NCT05450822 (derived from NCT ID; trial record text in context) (NCT05450822 chunk 1)

Limitations of this report (evidence availability)

  • Many papers in this corpus do not display PMIDs in the extracted text, so PMID-based referencing could not be reliably completed for several key sources despite strong DOI/venue metadata. Claims are therefore cited to the retrieved full-text context IDs and DOIs. (wang2023theclinicalfeatures pages 1-2, meletti2024ictalandpostictal pages 1-3, mcginley2024seizurecontroloutcomes pages 1-2)
  • MONDO/Orphanet/MeSH/ICD identifiers were not retrievable with the available tools in this run and should be filled using the specified databases.

Cited figure/table evidence available

  • Meletti et al. 2024 extracted: flowchart/pedigrees/variant schematic and clinical features table. (meletti2024ictalandpostictal media 949a04e5, meletti2024ictalandpostictal media 1e3201ae)

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  18. (NCT05450822 chunk 1): Gitte Moos Knudsen. Precision Medicine in the Treatment of Epilepsy. Gitte Moos Knudsen. 2022. ClinicalTrials.gov Identifier: NCT05450822

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