DNM1 Encephalopathy

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Inheritance

1

Autosomal Dominant (De Novo) HP:0000006

Nearly all cases are de novo; a dominant-negative mechanism means a single heterozygous variant impairs the dynamin-1 oligomer. A rare inherited sibling pair from a mosaic parent has been reported.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:28667181 SUPPORT Human Clinical

"We identified 19 patients with de novo mutations in DNM1 and a sibling pair who had an inherited mutation from a mosaic parent."

Establishes the predominantly de novo dominant genetic basis, with a rare mosaic-inherited exception.

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Discussions and Knowledge Gaps

3

How firmly established is the dominant-negative "oligomer-poisoning" mechanism relative to simple haploinsufficiency for DNM1-DEE variants, and if it is dominant-negative, would allele-selective knockdown of the mutant transcript (e.g., an antisense oligonucleotide) rescue endocytic function better than gene supplementation?

KNOWLEDGE GAP OPEN gap_dnm1_dominant_negative_vs_haploinsufficiency

Attached to

pathophysiology#Dominant-Negative Dynamin-1 Dysfunction

Most DNM1-DEE variants cluster in the GTPase and middle/stalk domains and are inferred to poison the wild-type dynamin oligomer rather than merely halve dosage, and mutant DNM1a fails to self-assemble and interferes with endocytic recycling in cell culture. The mechanistic distinction is therapeutically decisive: a true dominant-negative allele predicts benefit from allele-selective mutant knockdown (leaving the wild-type allele intact), whereas haploinsufficiency would call for gene supplementation. The strength of the dominant-negative inference — currently structural modeling plus limited functional data — and its variant-by-variant generality remain open.

Proposed experiments

Allele-selective mutant DNM1 knockdown rescue in patient-derived neurons

allele-selective knockdown and rescue experiment

exp_dnm1_allele_selective_knockdown_rescue

In patient-derived (or isogenic knock-in, e.g. p.Arg237Trp) human neurons, selectively knock down the mutant DNM1 transcript with an allele-selective antisense oligonucleotide and test whether activity-dependent synaptic vesicle endocytosis is restored, versus wild-type DNM1 supplementation.

Perturbations

Allele-selective mutant DNM1 knockdown

pathophysiology#Dominant-Negative Dynamin-1 Dysfunction

Allele-selective antisense-oligonucleotide knockdown of the mutant DNM1 allele, compared in parallel with wild-type DNM1 supplementation.

DNM1 hgnc:2972

Readouts

Restoration of synaptic vesicle endocytosis

pathophysiology#Impaired Synaptic Vesicle Endocytosis and Recycling

synaptic vesicle endocytosis GO:0048488 ↑ INCREASED

synaptic vesicle recycling assay

Direction: POSITIVE

Controls

Non-targeting oligonucleotide

Scrambled/non-targeting antisense oligonucleotide control.

Wild-type neurons

Isogenic wild-type (variant-corrected) neurons as baseline.

Decision criterion

A dominant-negative mechanism is supported if allele-selective mutant knockdown restores endocytosis toward wild-type levels more effectively than wild-type supplementation.

Would support

pathophysiology#Dominant-Negative Dynamin-1 Dysfunction

Show evidence (2 references)

PMID:28667181 SUPPORT Human Clinical

"All mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function."

Frames the dominant-negative inference as based on structural modeling and limited functional data, motivating deeper mechanistic confirmation.

PMID:20700442 SUPPORT In Vitro

"Mutant DNM1a does not efficiently self-assemble into higher order complexes known to be necessary for proper dynamin function, and it also interferes with endocytic recycling in cell culture."

Provides cell-culture functional support for a dominant-negative (oligomer-assembly-poisoning) mechanism, though for a mouse Dnm1a variant rather than a human DEE allele.

Is the epileptic, excitability phenotype of DNM1-DEE driven by activity-dependent vesicle-recycling failure that preferentially depletes fast-spiking inhibitory interneurons during high-frequency firing, and does that selective vulnerability explain how a vesicle-recycling (endocytosis) defect produces cortical hyperexcitability rather than global synaptic silencing?

OPEN QUESTION OPEN gap_dnm1_endocytosis_release_causality_selective_vulnerability

Attached to

pathophysiology#Impaired Synaptic Vesicle Endocytosis and Recycling pathophysiology#Reduced Neurotransmission and Cortical Hyperexcitability

Dynamin-1 acts in the recycling (endocytic) arm of the synaptic vesicle cycle, yet the disease manifests as a release/excitability disorder. A parsimonious reconciliation is that impaired fission slows vesicle retrieval only under sustained high-frequency activity, so neurons that fire fastest — parvalbumin-positive inhibitory interneurons — deplete their release-ready pool first, disinhibiting cortex and generating seizures. The fitful mouse shows exactly this activity-dependent signature (slower recovery from depression after stimulus trains), but whether interneuron-selective vulnerability is the causal driver of human hyperexcitability is unresolved.

Proposed experiments

Cell-type-resolved activity-dependent vesicle-depletion assay

cell-type-resolved electrophysiology and imaging experiment

exp_dnm1_interneuron_activity_dependent_depletion

Compare fast-spiking (parvalbumin-positive) interneurons and pyramidal neurons carrying a DNM1-DEE variant during high-frequency stimulation, measuring vesicle-pool depletion and transmission failure to test whether interneurons are preferentially affected.

Perturbations

High-frequency stimulation of DNM1-variant neurons

pathophysiology#Impaired Synaptic Vesicle Endocytosis and Recycling

Sustained high-frequency stimulus trains applied separately to fast-spiking interneurons and pyramidal neurons expressing a DNM1-DEE variant.

DNM1 hgnc:2972

Readouts

Activity-dependent synaptic transmission failure

pathophysiology#Reduced Neurotransmission and Cortical Hyperexcitability

synaptic vesicle endocytosis GO:0048488 ↓ DECREASED chemical synaptic transmission GO:0007268 ↓ DECREASED

patch-clamp electrophysiology synaptic vesicle recycling assay

Direction: NEGATIVE

Controls

Wild-type neurons

Isogenic wild-type neurons of each cell type under identical stimulation.

Low-frequency stimulation

Same neurons stimulated at low frequency, where recycling demand is minimal.

Decision criterion

Selective interneuron vulnerability is supported if fast-spiking interneurons show greater activity-dependent depletion and transmission failure than pyramidal neurons at high, but not low, stimulation frequency.

Would support

pathophysiology#Reduced Neurotransmission and Cortical Hyperexcitability

Show evidence (1 reference)

PMID:20700442 SUPPORT Model Organism

"In mice, the mutation results in defective synaptic transmission characterized by a slower recovery from depression after trains of stimulation."

Documents the activity-dependent nature of the synaptic defect (impaired recovery after high-frequency trains), the basis for the selective vulnerability hypothesis.

Does the Dnm1 fitful mouse faithfully model the human DNM1-DEE trajectory (infantile spasms evolving to Lennox-Gastaut syndrome with profound intellectual disability), given that fitful is a DNM1a-isoform-specific missense allele and the DNM1a/DNM1b isoform pair follows a developmental expression switch that may itself shape the human phenotypic window?

HUMAN MODEL MISMATCH OPEN gap_dnm1_fitful_mouse_human_fidelity_isoform_switch

Attached to

pathophysiology#Reduced Neurotransmission and Cortical Hyperexcitability

The fitful mouse reproduces recurrent seizures and an activity-dependent synaptic defect, making it the primary in vivo DNM1 epilepsy model. But its fidelity to human DNM1-DEE is uncertain on two counts: fitful mutates only the DNM1a-defining exon while sparing DNM1b, whereas most human DEE variants sit in shared GTPase/middle domains affecting both isoforms; and DNM1b is highest in early development with DNM1a rising postnatally, so an isoform-restricted allele may engage a different developmental window than the human disease. Whether the mouse recapitulates the specific human trajectory (infantile spasms to Lennox-Gastaut, profound intellectual disability) rather than seizures in general is the open translational question.

Proposed experiments

Shared-domain DNM1 knock-in developmental-trajectory benchmark

knock-in model developmental phenotyping experiment

exp_dnm1_shared_domain_knockin_trajectory_benchmark

Generate a mouse carrying a recurrent human shared-domain DEE variant (e.g., p.Arg237Trp) that affects both DNM1a and DNM1b, and benchmark its seizure semiology, EEG evolution, and cognitive/developmental trajectory against the DNM1a-restricted fitful allele and against the human disease course.

Perturbations

Shared-domain DNM1 knock-in allele

pathophysiology#Dominant-Negative Dynamin-1 Dysfunction

Knock-in of a recurrent human GTPase/middle-domain DEE variant affecting both DNM1a and DNM1b, compared with the DNM1a-restricted fitful allele.

DNM1 hgnc:2972

Readouts

Seizure and developmental trajectory concordance

pathophysiology#Reduced Neurotransmission and Cortical Hyperexcitability

chemical synaptic transmission GO:0007268 ⚠ ABNORMAL

video-EEG monitoring behavioral neurodevelopmental battery

Direction: POSITIVE

Controls

Fitful allele mice

DNM1a-restricted fitful mice as the isoform-specific comparator.

Wild-type littermates

Wild-type littermate controls.

Decision criterion

Model-to-human fidelity is supported if a shared-domain knock-in reproduces the human trajectory (early spasms evolving to Lennox-Gastaut-like EEG with profound developmental impairment) more closely than the isoform-restricted fitful allele.

Would support

pathophysiology#Reduced Neurotransmission and Cortical Hyperexcitability

Show evidence (2 references)

PMID:20700442 SUPPORT Model Organism

"Fitful is a missense mutation in an exon that defines the DNM1a isoform, leaving intact the alternatively spliced exon that encodes DNM1b."

Establishes that the mouse model is isoform-restricted (DNM1a only), unlike shared-domain human DEE variants, a key fidelity caveat.

PMID:20700442 SUPPORT Model Organism

"The expression of the corresponding alternate transcripts is developmentally regulated, with DNM1b expression highest during early neuronal development and DNM1a expression increasing postnatally with synaptic maturation."

Documents the developmental DNM1a/DNM1b switch that may cause the isoform-restricted model to engage a different developmental window than human DNM1-DEE.

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Pathophysiology

3

Dominant-Negative Dynamin-1 Dysfunction

De novo missense variants in DNM1 cluster in the GTPase and middle domains of dynamin-1 and act by a dominant-negative mechanism: mutant subunits incorporate into the dynamin oligomer that assembles around the neck of an endocytosing vesicle and poison its GTP-dependent fission activity. The recurrent p.Arg237Trp variant accounts for about one-third of cases.

neuron CL:0000540

synaptic vesicle cycle GO:0099504 ⚠ ABNORMAL

brain UBERON:0000955

Downstream

Impaired Synaptic Vesicle Endocytosis and Recycling

Show evidence (2 references)

PMID:28667181 SUPPORT Human Clinical

"All mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function."

Establishes the GTPase/middle-domain clustering and dominant-negative mechanism of DNM1 variants.

PMID:28667181 SUPPORT Human Clinical

"Seven patients (33.3%) carried the recurrent p.Arg237Trp mutation."

Documents the recurrent p.Arg237Trp variant as the most common DNM1 allele.

Impaired Synaptic Vesicle Endocytosis and Recycling

Dynamin-1 is the fission GTPase that pinches off endocytosing synaptic vesicles from the presynaptic plasma membrane to regenerate the recycling vesicle pool. Dominant-negative impairment of dynamin-1 slows vesicle fission and retrieval, depleting release-ready vesicles during sustained neuronal firing and causing activity-dependent synaptic transmission failure — the "vesicle fission" disease.

neuron CL:0000540

synaptic vesicle endocytosis GO:0048488 ↓ DECREASED

Downstream

Reduced Neurotransmission and Cortical Hyperexcitability

Show evidence (2 references)

PMID:15217342 SUPPORT Other

"The focal point of the vesicle cycle is Ca2+-triggered exocytosis that is followed by different routes of endocytosis and recycling."

Establishes endocytosis/recycling as the vesicle-cycle arm mediated by dynamin-1 and disrupted in this disorder.

PMID:25262651 SUPPORT Human Clinical

"We bring statistical evidence that mutations in DNM1 cause epileptic encephalopathy"

Establishes DNM1 (dynamin-1) loss as a cause of epileptic encephalopathy via disrupted synaptic transmission.

Reduced Neurotransmission and Cortical Hyperexcitability

Activity-dependent failure of vesicle recycling disturbs the balance of cortical synaptic transmission, producing neuronal hyperexcitability and a severe early-onset epilepsy that characteristically begins with infantile spasms and often evolves into Lennox-Gastaut syndrome, alongside impaired activity-dependent neurodevelopment.

neuron CL:0000540

chemical synaptic transmission GO:0007268 ⚠ ABNORMAL

neocortex UBERON:0001950

Downstream

Epilepsy

Severe to Profound Intellectual Disability

Show evidence (1 reference)

PMID:28667181 SUPPORT Human Clinical

"A common phenotype emerged that included severe to profound intellectual disability and muscular hypotonia in all patients and an epilepsy characterized by infantile spasms in 16 of 21 patients, frequently evolving into Lennox-Gastaut syndrome."

Documents the epilepsy (infantile spasms evolving to Lennox-Gastaut) and the severe neurodevelopmental impairment produced by the disorder.

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Pathograph

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Phenotypes

4

Musculoskeletal 1

Muscular Hypotonia HP:0001252

Show evidence (1 reference)

PMID:28667181 SUPPORT Human Clinical

"severe to profound intellectual disability and muscular hypotonia in all patients"

Documents universal muscular hypotonia.

Nervous System 1

Global Developmental Delay HP:0001263

Show evidence (1 reference)

PMID:28667181 SUPPORT Human Clinical

"Two patients had profound global developmental delay without seizures."

Documents profound global developmental delay, including a seizure-free minority.

Other 2

Epilepsy Infantile spasms HP:0012469

Show evidence (1 reference)

PMID:28667181 SUPPORT Human Clinical

"an epilepsy characterized by infantile spasms in 16 of 21 patients, frequently evolving into Lennox-Gastaut syndrome."

Quantifies infantile spasms as the characteristic seizure onset in DNM1 encephalopathy.

Severe to Profound Intellectual Disability HP:0002187

Show evidence (1 reference)

PMID:28667181 SUPPORT Human Clinical

"A common phenotype emerged that included severe to profound intellectual disability and muscular hypotonia in all patients"

Documents universal severe-to-profound intellectual disability.

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Genetic Associations

1

DNM1 (Dominant-Negative Mutations)

Gene: DNM1 hgnc:2972 variant_origin: GERMLINE

Autosomal Dominant (De Novo)

Show evidence (2 references)

PMID:28667181 SUPPORT Human Clinical

"All mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function."

Establishes the domain clustering and dominant-negative mechanism of DNM1 variants.

PMID:25262651 SUPPORT Human Clinical

"We bring statistical evidence that mutations in DNM1 cause epileptic encephalopathy"

Independent statistical evidence that DNM1 variants cause epileptic encephalopathy.

💊

Medical Actions

3

Antiseizure Medication

Action: Pharmacotherapy NCIT:C15986

Agent: vigabatrin CHEBI:63638

Seizures, including infantile spasms and Lennox-Gastaut syndrome, are managed with antiseizure medications and spasm-directed therapies; response is often incomplete. No agent corrects the underlying dynamin-1 fission defect.

Supportive and Developmental Care

Action: Supportive Care NCIT:C15747

Multidisciplinary supportive care, including developmental therapies and management of hypotonia and feeding, is the mainstay.

Genetic Counseling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Genetic counseling addresses the de novo dominant mechanism, generally low recurrence risk, and the rare possibility of parental mosaicism.

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Diagnosis

2

DNM1 Molecular Diagnosis

Diagnosis is established by identifying a heterozygous pathogenic DNM1 variant, typically de novo and clustering in the GTPase or middle domain, in a child with early-onset epileptic encephalopathy, hypotonia, and profound developmental impairment.

molecular genetic testing NCIT:C19770

Results: A heterozygous pathogenic DNM1 variant establishes the diagnosis.

Show evidence (1 reference)

PMID:28667181 SUPPORT Human Clinical

"Seven patients (33.3%) carried the recurrent p.Arg237Trp mutation."

Molecular identification of DNM1 variants, including the recurrent p.Arg237Trp, establishes the diagnosis.

EEG and Seizure Phenotyping

EEG documents the epileptic encephalopathy, including hypsarrhythmia with infantile spasms and later the slow spike-wave of Lennox-Gastaut syndrome.

electroencephalography NCIT:C38054

Results: An epileptic encephalopathy pattern (hypsarrhythmia, slow spike-wave) supports the diagnosis.

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Progression

1

Infancy to Childhood

Onset is in infancy with infantile spasms, frequently evolving into Lennox-Gastaut syndrome, on a background of severe-to-profound developmental impairment; the phenotype is relatively homogeneous across patients.

Show evidence (1 reference)

PMID:28667181 SUPPORT Human Clinical

"The phenotypic spectrum of DNM1-related encephalopathy is relatively homogeneous, in contrast to many other genetic epilepsies."

Documents the relatively homogeneous clinical course of DNM1 encephalopathy.

📊

Prevalence

1

Worldwide

Unknown Ultra Rare

Ultra-rare monogenic developmental and epileptic encephalopathy; precise population prevalence not established.

🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from DNM1 Encephalopathy:

Other synaptic vesicle cycle disorders and DEEs

Overlapping Features Other synaptic vesicle cycle disorders (STXBP1, UNC13A, SYT1, SNAP25) and other infantile-onset developmental and epileptic encephalopathies overlap through infantile spasms, hypotonia, and profound developmental impairment, and are distinguished by molecular testing.

Distinguishing Features

A de novo GTPase/middle-domain DNM1 variant favors this disorder.
A variant in a different vesicle-cycle or DEE gene favors that diagnosis.

Show evidence (1 reference)

PMID:25262651 SUPPORT Human Clinical

"Strikingly, 75% of mutations in these probands are predicted to disrupt a protein involved in regulating synaptic transmission"

Places DNM1 within the broader set of synaptic-transmission genes that cause epileptic encephalopathy, the molecular differential.

{ }

Source YAML

click to show

name: DNM1 Encephalopathy
creation_date: "2026-07-06T00:00:00Z"
description: >-
  A developmental and epileptic encephalopathy caused by de novo variants in DNM1,
  which encodes the presynaptic large GTPase dynamin-1 that mediates the fission
  step of synaptic vesicle endocytosis — the retrieval and recycling arm of the
  synaptic vesicle cycle. Pathogenic variants cluster in the GTPase and middle
  domains and act by a dominant-negative mechanism (impairing the function of
  wild-type dynamin-1 in the oligomer), producing a relatively homogeneous
  phenotype of severe-to-profound intellectual disability, muscular hypotonia, and
  an epilepsy that typically begins with infantile spasms and frequently evolves
  into Lennox-Gastaut syndrome. It is one of the synaptic vesicle cycle disorders
  and represents the endocytic/recycling arm of that mechanism, complementary to
  the docking/priming (STXBP1, UNC13A) and fusion (SYT1, SNAREs) disorders.
category: Mendelian
parents:
- Neurodevelopmental Disorder
- Epileptic Encephalopathy
disease_term:
  preferred_term: DNM1 developmental and epileptic encephalopathy
  term:
    id: MONDO:0014598
    label: developmental and epileptic encephalopathy, 31A
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: ULTRA_RARE
  notes: >-
    Ultra-rare monogenic developmental and epileptic encephalopathy; precise population prevalence not established.
references:
- reference: PMID:25262651
  title: "De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies."
- reference: PMID:28667181
  title: "DNM1 encephalopathy: A new disease of vesicle fission."
- reference: PMID:15217342
  title: "The synaptic vesicle cycle."
inheritance:
- name: Autosomal Dominant (De Novo)
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Nearly all cases are de novo; a dominant-negative mechanism means a single
    heterozygous variant impairs the dynamin-1 oligomer. A rare inherited sibling
    pair from a mosaic parent has been reported.
  evidence:
  - reference: PMID:28667181
    reference_title: "DNM1 encephalopathy: A new disease of vesicle fission."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified 19 patients with de novo mutations in DNM1 and a sibling pair
      who had an inherited mutation from a mosaic parent.
    explanation: >-
      Establishes the predominantly de novo dominant genetic basis, with a rare
      mosaic-inherited exception.
pathophysiology:
- name: Dominant-Negative Dynamin-1 Dysfunction
  conforms_to: "synaptic_vesicle_cycle#Synaptic Vesicle Cycle Protein Deficiency"
  description: >-
    De novo missense variants in DNM1 cluster in the GTPase and middle domains of
    dynamin-1 and act by a dominant-negative mechanism: mutant subunits incorporate
    into the dynamin oligomer that assembles around the neck of an endocytosing
    vesicle and poison its GTP-dependent fission activity. The recurrent
    p.Arg237Trp variant accounts for about one-third of cases.
  role: trigger
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: synaptic vesicle cycle
    term:
      id: GO:0099504
      label: synaptic vesicle cycle
    modifier: ABNORMAL
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:28667181
    reference_title: "DNM1 encephalopathy: A new disease of vesicle fission."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All mutations cluster within the GTPase or middle domains, and structural
      modeling and existing functional data suggest a dominant-negative effect on
      DMN1 function.
    explanation: >-
      Establishes the GTPase/middle-domain clustering and dominant-negative
      mechanism of DNM1 variants.
  - reference: PMID:28667181
    reference_title: "DNM1 encephalopathy: A new disease of vesicle fission."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seven patients (33.3%) carried the recurrent p.Arg237Trp mutation.
    explanation: >-
      Documents the recurrent p.Arg237Trp variant as the most common DNM1 allele.
  downstream:
  - target: Impaired Synaptic Vesicle Endocytosis and Recycling
    causal_link_type: DIRECT
- name: Impaired Synaptic Vesicle Endocytosis and Recycling
  conforms_to: "synaptic_vesicle_cycle#Impaired Synaptic Vesicle Endocytosis and Recycling"
  description: >-
    Dynamin-1 is the fission GTPase that pinches off endocytosing synaptic vesicles
    from the presynaptic plasma membrane to regenerate the recycling vesicle pool.
    Dominant-negative impairment of dynamin-1 slows vesicle fission and retrieval,
    depleting release-ready vesicles during sustained neuronal firing and causing
    activity-dependent synaptic transmission failure — the "vesicle fission"
    disease.
  role: central_effector
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: synaptic vesicle endocytosis
    term:
      id: GO:0048488
      label: synaptic vesicle endocytosis
    modifier: DECREASED
  evidence:
  - reference: PMID:15217342
    reference_title: "The synaptic vesicle cycle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The focal point of the vesicle cycle is Ca2+-triggered exocytosis that is
      followed by different routes of endocytosis and recycling.
    explanation: >-
      Establishes endocytosis/recycling as the vesicle-cycle arm mediated by
      dynamin-1 and disrupted in this disorder.
  - reference: PMID:25262651
    reference_title: "De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We bring statistical evidence that mutations in DNM1 cause epileptic
      encephalopathy
    explanation: >-
      Establishes DNM1 (dynamin-1) loss as a cause of epileptic encephalopathy via
      disrupted synaptic transmission.
  downstream:
  - target: Reduced Neurotransmission and Cortical Hyperexcitability
    causal_link_type: DIRECT
- name: Reduced Neurotransmission and Cortical Hyperexcitability
  conforms_to: "epilepsy_excitation_inhibition_imbalance#Neuronal Hyperexcitability and Hypersynchrony"
  description: >-
    Activity-dependent failure of vesicle recycling disturbs the balance of
    cortical synaptic transmission, producing neuronal hyperexcitability and a
    severe early-onset epilepsy that characteristically begins with infantile
    spasms and often evolves into Lennox-Gastaut syndrome, alongside impaired
    activity-dependent neurodevelopment.
  role: effector
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: chemical synaptic transmission
    term:
      id: GO:0007268
      label: chemical synaptic transmission
    modifier: ABNORMAL
  locations:
  - preferred_term: neocortex
    term:
      id: UBERON:0001950
      label: neocortex
  evidence:
  - reference: PMID:28667181
    reference_title: "DNM1 encephalopathy: A new disease of vesicle fission."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A common phenotype emerged that included severe to profound intellectual
      disability and muscular hypotonia in all patients and an epilepsy
      characterized by infantile spasms in 16 of 21 patients, frequently evolving
      into Lennox-Gastaut syndrome.
    explanation: >-
      Documents the epilepsy (infantile spasms evolving to Lennox-Gastaut) and the
      severe neurodevelopmental impairment produced by the disorder.
  downstream:
  - target: Epilepsy
    causal_link_type: DIRECT
  - target: Severe to Profound Intellectual Disability
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Impaired activity-dependent synaptic transmission during development.
phenotypes:
- name: Epilepsy
  category: Clinical
  description: >-
    Early-onset epilepsy that typically begins with infantile spasms and frequently
    evolves into Lennox-Gastaut syndrome.
  diagnostic: true
  phenotype_term:
    preferred_term: Infantile spasms
    term:
      id: HP:0012469
      label: Infantile spasms
  evidence:
  - reference: PMID:28667181
    reference_title: "DNM1 encephalopathy: A new disease of vesicle fission."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      an epilepsy characterized by infantile spasms in 16 of 21
      patients, frequently evolving into Lennox-Gastaut syndrome.
    explanation: >-
      Quantifies infantile spasms as the characteristic seizure onset in DNM1
      encephalopathy.
- name: Severe to Profound Intellectual Disability
  category: Clinical
  description: >-
    Severe to profound intellectual disability is present in all patients.
  diagnostic: true
  phenotype_term:
    preferred_term: Profound intellectual disability
    term:
      id: HP:0002187
      label: Profound intellectual disability
  evidence:
  - reference: PMID:28667181
    reference_title: "DNM1 encephalopathy: A new disease of vesicle fission."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A common phenotype emerged that included severe to profound intellectual
      disability and muscular hypotonia in all patients
    explanation: >-
      Documents universal severe-to-profound intellectual disability.
- name: Muscular Hypotonia
  category: Clinical
  description: >-
    Muscular hypotonia is a universal feature.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:28667181
    reference_title: "DNM1 encephalopathy: A new disease of vesicle fission."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      severe to profound intellectual disability and muscular hypotonia in all
      patients
    explanation: >-
      Documents universal muscular hypotonia.
- name: Global Developmental Delay
  category: Clinical
  description: >-
    Profound global developmental delay, which in a minority of patients occurs
    without seizures.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:28667181
    reference_title: "DNM1 encephalopathy: A new disease of vesicle fission."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two patients had profound global developmental delay without seizures.
    explanation: >-
      Documents profound global developmental delay, including a seizure-free
      minority.
genetic:
- name: DNM1
  gene_term:
    preferred_term: DNM1
    term:
      id: hgnc:2972
      label: DNM1
  association: Dominant-Negative Mutations
  presence: Positive
  variant_origin: GERMLINE
  inheritance:
  - name: Autosomal Dominant (De Novo)
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  notes: >-
    De novo missense variants clustering in the GTPase and middle domains act by a
    dominant-negative mechanism. The recurrent p.Arg237Trp variant is among the
    most common recurrent variants in the epileptic encephalopathies.
  evidence:
  - reference: PMID:28667181
    reference_title: "DNM1 encephalopathy: A new disease of vesicle fission."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All mutations cluster within the GTPase or middle domains, and structural
      modeling and existing functional data suggest a dominant-negative effect on
      DMN1 function.
    explanation: >-
      Establishes the domain clustering and dominant-negative mechanism of DNM1
      variants.
  - reference: PMID:25262651
    reference_title: "De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We bring statistical evidence that mutations in DNM1 cause epileptic
      encephalopathy
    explanation: >-
      Independent statistical evidence that DNM1 variants cause epileptic
      encephalopathy.
diagnosis:
- name: DNM1 Molecular Diagnosis
  description: >-
    Diagnosis is established by identifying a heterozygous pathogenic DNM1 variant,
    typically de novo and clustering in the GTPase or middle domain, in a child
    with early-onset epileptic encephalopathy, hypotonia, and profound
    developmental impairment.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
    qualifiers:
    - predicate:
        preferred_term: has participant
        term:
          id: RO:0000057
          label: has participant
      value:
        preferred_term: DNM1
        term:
          id: hgnc:2972
          label: DNM1
  results: A heterozygous pathogenic DNM1 variant establishes the diagnosis.
  evidence:
  - reference: PMID:28667181
    reference_title: "DNM1 encephalopathy: A new disease of vesicle fission."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seven patients (33.3%) carried the recurrent p.Arg237Trp mutation.
    explanation: >-
      Molecular identification of DNM1 variants, including the recurrent
      p.Arg237Trp, establishes the diagnosis.
- name: EEG and Seizure Phenotyping
  description: >-
    EEG documents the epileptic encephalopathy, including hypsarrhythmia with
    infantile spasms and later the slow spike-wave of Lennox-Gastaut syndrome.
  diagnosis_term:
    preferred_term: electroencephalography
    term:
      id: NCIT:C38054
      label: Electroencephalography
  results: An epileptic encephalopathy pattern (hypsarrhythmia, slow spike-wave) supports the diagnosis.
differential_diagnoses:
- name: Other synaptic vesicle cycle disorders and DEEs
  description: >-
    Other synaptic vesicle cycle disorders (STXBP1, UNC13A, SYT1, SNAP25) and other
    infantile-onset developmental and epileptic encephalopathies overlap through
    infantile spasms, hypotonia, and profound developmental impairment, and are
    distinguished by molecular testing.
  distinguishing_features:
  - A de novo GTPase/middle-domain DNM1 variant favors this disorder.
  - A variant in a different vesicle-cycle or DEE gene favors that diagnosis.
  evidence:
  - reference: PMID:25262651
    reference_title: "De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Strikingly, 75% of mutations in these probands are predicted to disrupt a
      protein involved in regulating synaptic transmission
    explanation: >-
      Places DNM1 within the broader set of synaptic-transmission genes that cause
      epileptic encephalopathy, the molecular differential.
progression:
- phase: Infancy to Childhood
  notes: >-
    Onset is in infancy with infantile spasms, frequently evolving into
    Lennox-Gastaut syndrome, on a background of severe-to-profound developmental
    impairment; the phenotype is relatively homogeneous across patients.
  evidence:
  - reference: PMID:28667181
    reference_title: "DNM1 encephalopathy: A new disease of vesicle fission."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The phenotypic spectrum of DNM1-related encephalopathy is relatively
      homogeneous, in contrast to many other genetic epilepsies.
    explanation: >-
      Documents the relatively homogeneous clinical course of DNM1 encephalopathy.
treatments:
- name: Antiseizure Medication
  description: >-
    Seizures, including infantile spasms and Lennox-Gastaut syndrome, are managed
    with antiseizure medications and spasm-directed therapies; response is often
    incomplete. No agent corrects the underlying dynamin-1 fission defect.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: vigabatrin
      term:
        id: CHEBI:63638
        label: vigabatrin
- name: Supportive and Developmental Care
  description: >-
    Multidisciplinary supportive care, including developmental therapies and
    management of hypotonia and feeding, is the mainstay.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Genetic Counseling
  description: >-
    Genetic counseling addresses the de novo dominant mechanism, generally low
    recurrence risk, and the rare possibility of parental mosaicism.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
discussions:
- discussion_id: gap_dnm1_dominant_negative_vs_haploinsufficiency
  prompt: >-
    How firmly established is the dominant-negative "oligomer-poisoning"
    mechanism relative to simple haploinsufficiency for DNM1-DEE variants, and
    if it is dominant-negative, would allele-selective knockdown of the mutant
    transcript (e.g., an antisense oligonucleotide) rescue endocytic function
    better than gene supplementation?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Dominant-Negative Dynamin-1 Dysfunction
  rationale: >-
    Most DNM1-DEE variants cluster in the GTPase and middle/stalk domains and are
    inferred to poison the wild-type dynamin oligomer rather than merely halve
    dosage, and mutant DNM1a fails to self-assemble and interferes with endocytic
    recycling in cell culture. The mechanistic distinction is therapeutically
    decisive: a true dominant-negative allele predicts benefit from
    allele-selective mutant knockdown (leaving the wild-type allele intact),
    whereas haploinsufficiency would call for gene supplementation. The strength
    of the dominant-negative inference — currently structural modeling plus
    limited functional data — and its variant-by-variant generality remain open.
  evidence:
  - reference: PMID:28667181
    reference_title: "DNM1 encephalopathy: A new disease of vesicle fission."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All mutations cluster within the GTPase or middle domains, and structural
      modeling and existing functional data suggest a dominant-negative effect on
      DMN1 function.
    explanation: >-
      Frames the dominant-negative inference as based on structural modeling and
      limited functional data, motivating deeper mechanistic confirmation.
  - reference: PMID:20700442
    reference_title: "A missense mutation in a highly conserved alternate exon of dynamin-1 causes epilepsy in fitful mice."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Mutant DNM1a does not efficiently self-assemble into higher order complexes
      known to be necessary for proper dynamin function, and it also interferes
      with endocytic recycling in cell culture.
    explanation: >-
      Provides cell-culture functional support for a dominant-negative
      (oligomer-assembly-poisoning) mechanism, though for a mouse Dnm1a variant
      rather than a human DEE allele.
  proposed_experiments:
  - experiment_id: exp_dnm1_allele_selective_knockdown_rescue
    name: Allele-selective mutant DNM1 knockdown rescue in patient-derived neurons
    description: >-
      In patient-derived (or isogenic knock-in, e.g. p.Arg237Trp) human neurons,
      selectively knock down the mutant DNM1 transcript with an allele-selective
      antisense oligonucleotide and test whether activity-dependent synaptic
      vesicle endocytosis is restored, versus wild-type DNM1 supplementation.
    experiment_type:
      preferred_term: allele-selective knockdown and rescue experiment
    perturbations:
    - name: Allele-selective mutant DNM1 knockdown
      target: pathophysiology#Dominant-Negative Dynamin-1 Dysfunction
      genes:
      - preferred_term: DNM1
        term:
          id: hgnc:2972
          label: DNM1
      description: >-
        Allele-selective antisense-oligonucleotide knockdown of the mutant DNM1
        allele, compared in parallel with wild-type DNM1 supplementation.
    readouts:
    - name: Restoration of synaptic vesicle endocytosis
      target: pathophysiology#Impaired Synaptic Vesicle Endocytosis and Recycling
      biological_processes:
      - preferred_term: synaptic vesicle endocytosis
        term:
          id: GO:0048488
          label: synaptic vesicle endocytosis
        modifier: INCREASED
      assays:
      - preferred_term: synaptic vesicle recycling assay
      direction: POSITIVE
    controls:
    - name: Non-targeting oligonucleotide
      description: Scrambled/non-targeting antisense oligonucleotide control.
    - name: Wild-type neurons
      description: Isogenic wild-type (variant-corrected) neurons as baseline.
    decision_criterion: >-
      A dominant-negative mechanism is supported if allele-selective mutant
      knockdown restores endocytosis toward wild-type levels more effectively
      than wild-type supplementation.
    would_support:
    - pathophysiology#Dominant-Negative Dynamin-1 Dysfunction

- discussion_id: gap_dnm1_endocytosis_release_causality_selective_vulnerability
  prompt: >-
    Is the epileptic, excitability phenotype of DNM1-DEE driven by
    activity-dependent vesicle-recycling failure that preferentially depletes
    fast-spiking inhibitory interneurons during high-frequency firing, and does
    that selective vulnerability explain how a vesicle-recycling (endocytosis)
    defect produces cortical hyperexcitability rather than global synaptic
    silencing?
  kind: OPEN_QUESTION
  status: OPEN
  attaches_to:
  - pathophysiology#Impaired Synaptic Vesicle Endocytosis and Recycling
  - pathophysiology#Reduced Neurotransmission and Cortical Hyperexcitability
  rationale: >-
    Dynamin-1 acts in the recycling (endocytic) arm of the synaptic vesicle
    cycle, yet the disease manifests as a release/excitability disorder. A
    parsimonious reconciliation is that impaired fission slows vesicle retrieval
    only under sustained high-frequency activity, so neurons that fire fastest —
    parvalbumin-positive inhibitory interneurons — deplete their release-ready
    pool first, disinhibiting cortex and generating seizures. The fitful mouse
    shows exactly this activity-dependent signature (slower recovery from
    depression after stimulus trains), but whether interneuron-selective
    vulnerability is the causal driver of human hyperexcitability is unresolved.
  evidence:
  - reference: PMID:20700442
    reference_title: "A missense mutation in a highly conserved alternate exon of dynamin-1 causes epilepsy in fitful mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In mice, the mutation results in defective synaptic transmission
      characterized by a slower recovery from depression after trains of
      stimulation.
    explanation: >-
      Documents the activity-dependent nature of the synaptic defect (impaired
      recovery after high-frequency trains), the basis for the selective
      vulnerability hypothesis.
  proposed_experiments:
  - experiment_id: exp_dnm1_interneuron_activity_dependent_depletion
    name: Cell-type-resolved activity-dependent vesicle-depletion assay
    description: >-
      Compare fast-spiking (parvalbumin-positive) interneurons and pyramidal
      neurons carrying a DNM1-DEE variant during high-frequency stimulation,
      measuring vesicle-pool depletion and transmission failure to test whether
      interneurons are preferentially affected.
    experiment_type:
      preferred_term: cell-type-resolved electrophysiology and imaging experiment
    perturbations:
    - name: High-frequency stimulation of DNM1-variant neurons
      target: pathophysiology#Impaired Synaptic Vesicle Endocytosis and Recycling
      genes:
      - preferred_term: DNM1
        term:
          id: hgnc:2972
          label: DNM1
      description: >-
        Sustained high-frequency stimulus trains applied separately to
        fast-spiking interneurons and pyramidal neurons expressing a DNM1-DEE
        variant.
    readouts:
    - name: Activity-dependent synaptic transmission failure
      target: pathophysiology#Reduced Neurotransmission and Cortical Hyperexcitability
      biological_processes:
      - preferred_term: synaptic vesicle endocytosis
        term:
          id: GO:0048488
          label: synaptic vesicle endocytosis
        modifier: DECREASED
      - preferred_term: chemical synaptic transmission
        term:
          id: GO:0007268
          label: chemical synaptic transmission
        modifier: DECREASED
      assays:
      - preferred_term: patch-clamp electrophysiology
      - preferred_term: synaptic vesicle recycling assay
      direction: NEGATIVE
    controls:
    - name: Wild-type neurons
      description: Isogenic wild-type neurons of each cell type under identical stimulation.
    - name: Low-frequency stimulation
      description: Same neurons stimulated at low frequency, where recycling demand is minimal.
    decision_criterion: >-
      Selective interneuron vulnerability is supported if fast-spiking
      interneurons show greater activity-dependent depletion and transmission
      failure than pyramidal neurons at high, but not low, stimulation frequency.
    would_support:
    - pathophysiology#Reduced Neurotransmission and Cortical Hyperexcitability

- discussion_id: gap_dnm1_fitful_mouse_human_fidelity_isoform_switch
  prompt: >-
    Does the Dnm1 fitful mouse faithfully model the human DNM1-DEE trajectory
    (infantile spasms evolving to Lennox-Gastaut syndrome with profound
    intellectual disability), given that fitful is a DNM1a-isoform-specific
    missense allele and the DNM1a/DNM1b isoform pair follows a developmental
    expression switch that may itself shape the human phenotypic window?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Reduced Neurotransmission and Cortical Hyperexcitability
  rationale: >-
    The fitful mouse reproduces recurrent seizures and an activity-dependent
    synaptic defect, making it the primary in vivo DNM1 epilepsy model. But its
    fidelity to human DNM1-DEE is uncertain on two counts: fitful mutates only
    the DNM1a-defining exon while sparing DNM1b, whereas most human DEE variants
    sit in shared GTPase/middle domains affecting both isoforms; and DNM1b is
    highest in early development with DNM1a rising postnatally, so an
    isoform-restricted allele may engage a different developmental window than
    the human disease. Whether the mouse recapitulates the specific human
    trajectory (infantile spasms to Lennox-Gastaut, profound intellectual
    disability) rather than seizures in general is the open translational
    question.
  evidence:
  - reference: PMID:20700442
    reference_title: "A missense mutation in a highly conserved alternate exon of dynamin-1 causes epilepsy in fitful mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Fitful is a missense mutation in an exon that defines the DNM1a isoform,
      leaving intact the alternatively spliced exon that encodes DNM1b.
    explanation: >-
      Establishes that the mouse model is isoform-restricted (DNM1a only),
      unlike shared-domain human DEE variants, a key fidelity caveat.
  - reference: PMID:20700442
    reference_title: "A missense mutation in a highly conserved alternate exon of dynamin-1 causes epilepsy in fitful mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The expression of the corresponding alternate transcripts is
      developmentally regulated, with DNM1b expression highest during early
      neuronal development and DNM1a expression increasing postnatally with
      synaptic maturation.
    explanation: >-
      Documents the developmental DNM1a/DNM1b switch that may cause the
      isoform-restricted model to engage a different developmental window than
      human DNM1-DEE.
  proposed_experiments:
  - experiment_id: exp_dnm1_shared_domain_knockin_trajectory_benchmark
    name: Shared-domain DNM1 knock-in developmental-trajectory benchmark
    description: >-
      Generate a mouse carrying a recurrent human shared-domain DEE variant
      (e.g., p.Arg237Trp) that affects both DNM1a and DNM1b, and benchmark its
      seizure semiology, EEG evolution, and cognitive/developmental trajectory
      against the DNM1a-restricted fitful allele and against the human disease
      course.
    experiment_type:
      preferred_term: knock-in model developmental phenotyping experiment
    perturbations:
    - name: Shared-domain DNM1 knock-in allele
      target: pathophysiology#Dominant-Negative Dynamin-1 Dysfunction
      genes:
      - preferred_term: DNM1
        term:
          id: hgnc:2972
          label: DNM1
      description: >-
        Knock-in of a recurrent human GTPase/middle-domain DEE variant affecting
        both DNM1a and DNM1b, compared with the DNM1a-restricted fitful allele.
    readouts:
    - name: Seizure and developmental trajectory concordance
      target: pathophysiology#Reduced Neurotransmission and Cortical Hyperexcitability
      biological_processes:
      - preferred_term: chemical synaptic transmission
        term:
          id: GO:0007268
          label: chemical synaptic transmission
        modifier: ABNORMAL
      assays:
      - preferred_term: video-EEG monitoring
      - preferred_term: behavioral neurodevelopmental battery
      direction: POSITIVE
    controls:
    - name: Fitful allele mice
      description: DNM1a-restricted fitful mice as the isoform-specific comparator.
    - name: Wild-type littermates
      description: Wild-type littermate controls.
    decision_criterion: >-
      Model-to-human fidelity is supported if a shared-domain knock-in
      reproduces the human trajectory (early spasms evolving to
      Lennox-Gastaut-like EEG with profound developmental impairment) more
      closely than the isoform-restricted fitful allele.
    would_support:
    - pathophysiology#Reduced Neurotransmission and Cortical Hyperexcitability

📚

References & Deep Research

References

3

PMID:25262651

De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies.

No top-level findings curated for this source.

PMID:28667181

DNM1 encephalopathy: A new disease of vesicle fission.

No top-level findings curated for this source.

PMID:15217342

The synaptic vesicle cycle.

No top-level findings curated for this source.

DNM1 Encephalopathy

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