STXBP1 Encephalopathy

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Inheritance

1

Autosomal Dominant (De Novo) HP:0000006

Nearly all cases arise from de novo heterozygous STXBP1 variants; the disorder acts through haploinsufficiency, so a single loss-of-function allele is sufficient to cause disease.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:26865513 SUPPORT Human Clinical

"De novo STXBP1 mutations are among the most frequent causes of epilepsy and encephalopathy."

Establishes the de novo dominant genetic basis of STXBP1 encephalopathy in a large patient cohort.

PMID:27905812 SUPPORT Human Clinical

"STXBP1 encephalopathy with epilepsy is an autosomal dominant disorder typically caused by a de novo pathogenic variant."

The GeneReviews genetic-counseling section confirms autosomal dominant inheritance arising typically from a de novo pathogenic variant.

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Discussions and Knowledge Gaps

3

Is STXBP1 encephalopathy a pure loss-of-dose (haploinsufficiency) disorder, or do destabilized missense variants act dominant-negatively by aggregating and co-depleting wild-type Munc18-1, and does the answer differ by variant class with direct consequences for therapy (gene/dosage restoration versus chemical-chaperone/proteostasis approaches)?

CONTROVERSY OPEN gap_stxbp1_haploinsufficiency_vs_dominant_negative

Attached to

pathophysiology#STXBP1 Haploinsufficiency and Munc18-1 Deficiency pathophysiology#Impaired Syntaxin-1 Chaperoning and SNARE-Mediated Vesicle Fusion

The entry models both truncating and missense variants as converging on Munc18-1 haploinsufficiency, and an allelic-series mouse study concludes that impaired protein stability plus haploinsufficiency explain the disease. A competing biochemical model finds that missense mutants aggregate and sequester wild-type Munc18-1 below hemizygous levels, i.e. an additional dominant-negative effect. The two models are not merely academic: pure haploinsufficiency motivates gene-dosage or expression-restoration strategies, whereas a dominant-negative aggregation mechanism motivates chemical-chaperone/proteostasis rescue and possibly allele-specific knockdown. Which mechanism dominates, and whether it is variant-dependent, remains unresolved.

Proposed experiments

STXBP1 loss-of-function versus dominant-negative allelic-series test

allelic-series gain/loss-of-function experiment

exp_stxbp1_lof_vs_dn_allelic_series

In a shared neuronal background, express an allelic series of STXBP1 variants (truncating, deletion, and multiple missense) on both null and heterozygous (wild-type-present) backgrounds and measure whether the variant lowers functional Munc18-1 below the hemizygous level and whether chemical chaperones (4-phenylbutyrate, trehalose) restore protein level and release. A variant that depletes wild-type Munc18-1 and impairs release below hemizygous levels indicates a dominant-negative component.

Perturbations

STXBP1 variant expression on null versus heterozygous background

pathophysiology#STXBP1 Haploinsufficiency and Munc18-1 Deficiency

Introduce each STXBP1 variant on a Munc18-1 null background (isolated variant function) and on a wild-type-present background (test for wild-type co-depletion), with and without chemical-chaperone treatment.

STXBP1 hgnc:11444

Readouts

Munc18-1 protein level and synaptic vesicle release

pathophysiology#Impaired Syntaxin-1 Chaperoning and SNARE-Mediated Vesicle Fusion

synaptic vesicle exocytosis GO:0016079 ↓ DECREASED neurotransmitter secretion GO:0007269 ↓ DECREASED

immunoblot assay patch-clamp recording

Direction: NEGATIVE

Controls

Wild-type STXBP1

Wild-type Munc18-1 expressed on the same backgrounds.

Vehicle versus chemical chaperone

Matched untreated versus chemical-chaperone-treated conditions.

Decision criterion

A dominant-negative component is supported if a variant reduces functional Munc18-1 and release below hemizygous levels on a wild-type-present background and is rescued by chemical chaperones; pure haploinsufficiency is supported if variants have no effect beyond loss of dose.

Would support

pathophysiology#STXBP1 Haploinsufficiency and Munc18-1 Deficiency pathophysiology#Impaired Syntaxin-1 Chaperoning and SNARE-Mediated Vesicle Fusion

Show evidence (2 references)

PMID:30266908 SUPPORT In Vitro

"Aggregates of mutant Munc18-1 incorporate wild-type Munc18-1, depleting functional Munc18-1 levels beyond hemizygous levels."

Provides the biochemical basis for a dominant-negative (aggregation and wild-type co-depletion) mechanism, the alternative to pure haploinsufficiency.

PMID:29538625 SUPPORT Model Organism

"impaired protein stability and STXBP1 haploinsufficiency explain STXBP1-encephalopathy and that, therefore, Stxbp1+/- mice provide a valid mouse model."

Supports the competing haploinsufficiency-only interpretation, in which Stxbp1+/- (loss-of-dose) alone reproduces the disease.

Why do STXBP1 variants produce a phenotypic spectrum ranging from classic early-onset epileptic encephalopathy to intellectual disability without epilepsy to a movement-disorder-predominant picture, and what genetic, variant-level, or network modifiers determine which arm dominates in a given patient?

OPEN QUESTION OPEN gap_stxbp1_genotype_phenotype_modifiers

Attached to

pathophysiology#Cortical Excitation-Inhibition Imbalance and Seizures pathophysiology#Impaired Synaptic Network Development

The entry already notes that cognitive impairment and seizures are partly independent, and cohort data find no correlation between seizure severity and the degree of intellectual disability. This dissociation implies that the epilepsy arm and the developmental/cognitive (and movement-disorder) arms are separably modifiable, yet no variant-class, residual-protein-level, cell-type (excitatory versus inhibitory), or modifier-gene predictor reliably explains why one arm dominates. Resolving this is prerequisite to prognostic counseling and to arm-specific therapy.

Proposed experiments

STXBP1 genotype-phenotype and modifier stratification study

genotype-phenotype correlation study

exp_stxbp1_genotype_phenotype_stratification

In a deeply phenotyped STXBP1 cohort, stratify patients by variant class (truncating, deletion, missense) and estimated residual Munc18-1 level and test whether these, together with polygenic background and candidate modifier loci, predict the dominant phenotypic arm (epilepsy-predominant, intellectual-disability-without-epilepsy, or movement-disorder-predominant).

Perturbations

Variant-class and residual-dose stratification

pathophysiology#Impaired Synaptic Network Development

Group patients by STXBP1 variant class and modeled residual protein dose rather than introducing a perturbation, as an observational human study.

STXBP1 hgnc:11444

Readouts

Dominant phenotypic arm and network phenotype

pathophysiology#Cortical Excitation-Inhibition Imbalance and Seizures

chemical synaptic transmission GO:0007268 ⚠ ABNORMAL

electroencephalography

Direction: POSITIVE

Controls

Variant-class comparison groups

Truncating, deletion, and missense groups compared against one another.

Decision criterion

A modifier is supported if variant class, residual protein level, or a modifier locus significantly predicts the dominant phenotypic arm across the cohort after correction for multiple testing.

Would support

pathophysiology#Cortical Excitation-Inhibition Imbalance and Seizures pathophysiology#Impaired Synaptic Network Development

Show evidence (1 reference)

PMID:26865513 SUPPORT Human Clinical

"We found no correlation between severity of seizures and severity of ID"

Documents the clinical dissociation between the seizure arm and the cognitive arm that the modifier question seeks to explain.

Does the Stxbp1+/- mouse, which reproduces spike-wave/spasm EEG activity and mild cognitive changes, capture the severity and developmental trajectory of human STXBP1 encephalopathy — in particular the severe-to-profound intellectual disability and Ohtahara/West-syndrome-level epileptic encephalopathy — or does it under-represent the human disease?

HUMAN MODEL MISMATCH OPEN gap_stxbp1_mouse_model_fidelity

Attached to

pathophysiology#Reduced Neurotransmitter Release and Synaptic Transmission Deficit pathophysiology#Impaired Synaptic Network Development

Model evidence clearly exists: Stxbp1+/- mice recapitulate the seizure/spasm EEG phenotype and show impaired cognition, hyperactivity, and anxiety-like behaviour, and the seizures respond to levetiracetam. The open question is translational fidelity — human patients almost universally have severe-to-profound intellectual disability and early catastrophic epileptic encephalopathy (Ohtahara/West syndrome), a severity that the comparatively mild murine cognitive and behavioural phenotype may not fully reproduce. Whether the mouse captures the human developmental trajectory, or whether human-specific cortical biology is required, gates its use for preclinical therapeutic testing.

Proposed experiments

STXBP1 mouse-to-human developmental-trajectory comparison

cross-species developmental phenotyping experiment

exp_stxbp1_mouse_human_trajectory_comparison

Longitudinally phenotype Stxbp1+/- mice across postnatal development for EEG severity, learning/memory, and motor phenotypes, and compare the developmental trajectory and severity against matched human natural-history data and STXBP1 patient iPSC-derived cortical neuron/organoid synaptic readouts, to quantify where the mouse under-represents human severity.

Perturbations

Stxbp1 heterozygous loss of function

pathophysiology#Reduced Neurotransmitter Release and Synaptic Transmission Deficit

Stxbp1+/- mice and STXBP1 patient-variant human iPSC-derived neurons compared against wild-type and isogenic-corrected controls.

STXBP1 hgnc:11444

Readouts

Synaptic transmission and network activity across development

pathophysiology#Reduced Neurotransmitter Release and Synaptic Transmission Deficit

chemical synaptic transmission GO:0007268 ⚠ ABNORMAL neurotransmitter secretion GO:0007269 ↓ DECREASED

multielectrode array recording electroencephalography

Direction: NEGATIVE

Controls

Wild-type littermate mice

Age-matched wild-type littermates across the same developmental windows.

Isogenic-corrected human neurons

Patient iPSC lines in which the STXBP1 variant is corrected.

Decision criterion

The mouse is a faithful model if its developmental severity trajectory matches human natural history and iPSC readouts; a mismatch is supported if murine phenotypes are substantially milder or follow a divergent trajectory despite equivalent loss of dose.

Would support

pathophysiology#Reduced Neurotransmitter Release and Synaptic Transmission Deficit pathophysiology#Impaired Synaptic Network Development

Show evidence (2 references)

PMID:29538625 SUPPORT Model Organism

"Stxbp1+/- mice with different genomic backgrounds recapitulate the seizure/spasm phenotype observed in humans, characterized by myoclonic jerks and spike-wave discharges that were suppressed by the antiepileptic drug levetiracetam."

Establishes that the mouse model reproduces the seizure component, confirming model evidence exists for the mismatch question.

PMID:26865513 SUPPORT Human Clinical

"All patients have intellectual disability (ID), which is mostly severe to profound (88%)."

Documents the severe-to-profound human cognitive phenotype whose murine fidelity is the open translational question.

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Pathophysiology

5

STXBP1 Haploinsufficiency and Munc18-1 Deficiency

De novo heterozygous loss-of-function variants (nonsense, frameshift, splice-site, whole-gene/partial deletions) and destabilizing missense variants in STXBP1 reduce the functional dose of Munc18-1, an evolutionarily conserved Sec1/Munc18 protein essential for synaptic vesicle release. Missense variants render the protein thermolabile and prone to aggregation/degradation, so both truncating and missense mechanisms converge on haploinsufficiency of Munc18-1 at presynaptic terminals.

neuron CL:0000540

synaptic vesicle cycle GO:0099504 ⚠ ABNORMAL

brain UBERON:0000955

Downstream

Impaired Syntaxin-1 Chaperoning and SNARE-Mediated Vesicle Fusion

Reduced Neurotransmitter Release and Synaptic Transmission Deficit

Show evidence (3 references)

PMID:18469812 SUPPORT Human Clinical

"STXBP1 (also known as MUNC18-1) is an evolutionally conserved neuronal Sec1/Munc-18 (SM) protein that is essential in synaptic vesicle release in several species."

Establishes STXBP1/Munc18-1 as a synaptic-vesicle-release protein, the vesicle-cycle component whose deficiency defines this disorder.

PMID:18469812 SUPPORT Human Clinical

"These findings suggest that haploinsufficiency of STXBP1 causes EIEE."

Identifies haploinsufficiency as the disease mechanism, the trigger modeled by this node.

PMID:18469812 SUPPORT In Vitro

"Circular dichroism melting experiments revealed that a mutant form of the protein was significantly thermolabile compared to wild type."

Demonstrates that a disease missense variant destabilizes Munc18-1, supporting protein instability as a route to haploinsufficiency.

Impaired Syntaxin-1 Chaperoning and SNARE-Mediated Vesicle Fusion

Munc18-1 binds syntaxin-1 and templates assembly of the neuronal SNARE complex (syntaxin-1, SNAP-25, synaptobrevin-2/VAMP2) that mediates Ca2+-triggered synaptic vesicle fusion. Reduced Munc18-1 dose, and disease variants with impaired syntaxin binding, compromise SNARE-complex assembly and the vesicle fusion step. In the Munc18-1 null model, loss of this protein abolishes neurotransmitter secretion, demonstrating that Munc18-1 is indispensable for the fusion reaction.

neuron CL:0000540

calcium-dependent activation of synaptic vesicle fusion GO:0099502 ↓ DECREASED synaptic vesicle exocytosis GO:0016079 ↓ DECREASED

Downstream

Reduced Neurotransmitter Release and Synaptic Transmission Deficit

Show evidence (2 references)

PMID:18469812 SUPPORT In Vitro

"Furthermore, binding of the mutant protein to syntaxin was impaired."

Shows a disease variant impairs Munc18-1 binding to syntaxin-1, the interaction that licenses SNARE-mediated fusion.

PMID:10657302 SUPPORT Model Organism

"Deletion of a single protein, Munc18-1, in mice leads to a complete loss of neurotransmitter secretion from synaptic vesicles throughout development."

The Munc18-1 null mouse demonstrates that Munc18-1 is required for the vesicle-fusion/neurotransmitter-release step this node models.

Reduced Neurotransmitter Release and Synaptic Transmission Deficit

Impaired SNARE-mediated fusion reduces Ca2+-evoked neurotransmitter release and disturbs chemical synaptic transmission across cortical circuits. Because Munc18-1 is required at both excitatory and inhibitory synapses, the net effect is a disturbance of cortical excitatory/inhibitory balance that both drives seizures and impairs the activity-dependent synaptic signaling needed for normal neurodevelopment.

glutamatergic neuron CL:0000679 GABAergic neuron CL:0000617

neurotransmitter secretion GO:0007269 ↓ DECREASED chemical synaptic transmission GO:0007268 ⚠ ABNORMAL

neocortex UBERON:0001950

Downstream

Cortical Excitation-Inhibition Imbalance and Seizures

Impaired Synaptic Network Development

Show evidence (1 reference)

PMID:26865513 SUPPORT Human Clinical

"STXBP1-E may be conceptualized as a complex neurodevelopmental disorder rather than a primary epileptic encephalopathy."

Supports the view that the synaptic-transmission deficit produces a broad neurodevelopmental phenotype, not seizures alone.

Cortical Excitation-Inhibition Imbalance and Seizures

Reduced and imbalanced neurotransmitter release destabilizes cortical excitatory/inhibitory balance, producing neuronal hyperexcitability and hypersynchronous discharges. Clinically this manifests as early-onset epilepsy, frequently as Ohtahara syndrome with a burst-suppression EEG or as West syndrome with epileptic spasms, and as a nonsyndromic early-onset epileptic encephalopathy with epileptic spasms or tonic seizures.

neuron CL:0000540

chemical synaptic transmission GO:0007268 ⚠ ABNORMAL

neocortex UBERON:0001950

Downstream

Epilepsy

EEG Abnormality

Show evidence (2 references)

PMID:26865513 SUPPORT Human Clinical

"While one-third of patients presented with Ohtahara syndrome (21%) or West syndrome (9.5%), the majority has a nonsyndromic early-onset epilepsy and encephalopathy (53%) with epileptic spasms or tonic seizures as main seizure type."

Documents the epilepsy syndromes and seizure types produced by the cortical excitability disturbance.

PMID:18469812 SUPPORT Human Clinical

"Early infantile epileptic encephalopathy with suppression-burst (EIEE), also known as Ohtahara syndrome, is one of the most severe and earliest forms of epilepsy."

Anchors the Ohtahara-syndrome / burst-suppression presentation to STXBP1 disease.

Impaired Synaptic Network Development

Reduced activity-dependent synaptic transmission during a critical developmental window impairs maturation of cortical networks, producing severe global developmental delay, intellectual disability, absent or limited speech, autistic features, and movement disorders. In STXBP1 disease the cognitive impairment is largely independent of seizure burden. In the Munc18-1 null model, synapses initially assemble but neurons subsequently degenerate, indicating a maintenance/neurodegenerative component in the extreme loss-of-function state.

neuron CL:0000540

chemical synaptic transmission GO:0007268 ↓ DECREASED

brain UBERON:0000955

Downstream

Severe Global Developmental Delay

Intellectual Disability

Autistic Behavior

Movement Disorder

Show evidence (3 references)

PMID:26865513 SUPPORT Human Clinical

"All patients have intellectual disability (ID), which is mostly severe to profound (88%)."

Establishes severe-to-profound intellectual disability as a universal outcome of the impaired synaptic-network development.

PMID:26865513 SUPPORT Human Clinical

"We found no correlation between severity of seizures and severity of ID"

Supports the partial independence of the developmental/cognitive impairment from the seizure burden.

PMID:10657302 SUPPORT Model Organism

"After assembly is completed, neurons undergo apoptosis, leading to widespread neurodegeneration."

The Munc18-1 null model shows a neurodegenerative/maintenance component when neurotransmitter secretion is lost, relevant to the severe developmental outcome.

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Pathograph

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

Referential integrity issues (2):

Target 'EEG Abnormality' (from 'Cortical Excitation-Inhibition Imbalance and Seizures') not found in named elements
Target 'Intellectual Disability' (from 'Impaired Synaptic Network Development') not found in named elements

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Phenotypes

10

Musculoskeletal 1

Hypotonia HP:0001252

Show evidence (2 references)

PMID:27905812 SUPPORT Human Clinical

"Other neurologic findings include abnormal tone, movement disorders (especially ataxia and dystonia), and behavioral issues and autism spectrum disorder."

The GeneReviews chapter lists abnormal muscle tone among the core neurologic findings of STXBP1 encephalopathy.

PMID:32815282 SUPPORT Human Clinical

"Through exome sequencing of a child with developmental delay, hypotonia, and spasticity, we found a novel de novo insertion mutation of three nucleotides in the STXBP1 coding region"

A molecularly confirmed STXBP1 case presenting with hypotonia, documenting hypotonia within the phenotypic spectrum.

Nervous System 7

Epileptic Spasms HP:0011097

Show evidence (1 reference)

PMID:26865513 SUPPORT Human Clinical

"the majority has a nonsyndromic early-onset epilepsy and encephalopathy (53%) with epileptic spasms or tonic seizures as main seizure type."

Documents epileptic spasms as a main seizure type in the disorder.

Tonic Seizures HP:0032792

Show evidence (1 reference)

PMID:26865513 SUPPORT Human Clinical

"with epileptic spasms or tonic seizures as main seizure type."

Documents tonic seizures as a main seizure type.

EEG with Burst Suppression HP:0010851

Show evidence (1 reference)

PMID:18469812 SUPPORT Human Clinical

"Early infantile epileptic encephalopathy with suppression-burst (EIEE), also known as Ohtahara syndrome, is one of the most severe and earliest forms of epilepsy."

The Ohtahara-syndrome (suppression-burst) presentation is the discovery phenotype for STXBP1.

Severe Global Developmental Delay HP:0011344

Show evidence (1 reference)

PMID:26865513 SUPPORT Human Clinical

"Most patients have severe to profound ID with little correlation among seizure onset, seizure severity, and the degree of ID."

Supports severe global developmental impairment independent of seizure severity.

Autistic Behavior HP:0000729

Show evidence (1 reference)

PMID:26865513 SUPPORT Human Clinical

"Neurologic comorbidities including autistic features and movement disorders are frequent."

Documents autistic features as a frequent comorbidity.

Movement Disorder Abnormality of movement HP:0100022

Show evidence (2 references)

PMID:26865513 SUPPORT Human Clinical

"Neurologic comorbidities including autistic features and movement disorders are frequent."

Documents movement disorders as a frequent comorbidity.

PMID:26865513 SUPPORT Human Clinical

"We also report 2 previously unreported adult patients with prominent extrapyramidal features."

Documents prominent extrapyramidal movement features in adult patients.

Tremor HP:0001337

Show evidence (1 reference)

PMID:26865513 SUPPORT Human Clinical

"Neurologic comorbidities including autistic features and movement disorders are frequent."

Tremor is part of the frequent movement-disorder comorbidity; the cohort documents the broader movement-disorder category.

Other 2

Epilepsy Epileptic encephalopathy HP:0200134

Show evidence (1 reference)

PMID:26865513 SUPPORT Human Clinical

"Ninety-five percent of patients have epilepsy."

Quantifies epilepsy as a near-universal feature of STXBP1 encephalopathy.

Severe to Profound Intellectual Disability HP:0002187

Show evidence (1 reference)

PMID:26865513 SUPPORT Human Clinical

"All patients have intellectual disability (ID), which is mostly severe to profound (88%)."

Quantifies severe-to-profound intellectual disability as universal.

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Genetic Associations

1

STXBP1 (Loss-of-Function Mutations)

Gene: STXBP1 hgnc:11444 variant_origin: GERMLINE

Autosomal Dominant (De Novo)

Show evidence (2 references)

PMID:18469812 SUPPORT Human Clinical

"four unrelated individuals with EIEE had heterozygous missense mutations in the gene encoding syntaxin binding protein 1 (STXBP1)."

Original identification of heterozygous STXBP1 variants as the cause of early infantile epileptic encephalopathy.

PMID:26865513 SUPPORT Human Clinical

"De novo STXBP1 mutations are among the most frequent causes of epilepsy and encephalopathy."

Confirms de novo STXBP1 variants as a leading genetic cause in a large cohort.

💊

Medical Actions

3

Antiseizure Medication

Action: Pharmacotherapy NCIT:C15986

Agent: levetiracetam CHEBI:6437 vigabatrin CHEBI:63638

Seizures are managed with antiseizure medications; response is variable and often incomplete. Agents used for the associated epilepsy syndromes include levetiracetam and, for epileptic/infantile spasms, vigabatrin. No agent corrects the underlying Munc18-1 deficiency.

Show evidence (1 reference)

PMID:27905812 SUPPORT Human Clinical

"The most commonly used anti-seizure medications (ASMs) are phenobarbital, valproic acid, and vigabatrin. About 20% of individuals require more than one ASM and approximately 25% are refractory to ASM therapy."

The GeneReviews management section documents first-line ASM choices and the substantial rate of pharmacoresistance in STXBP1 encephalopathy.

Supportive and Developmental Care

Action: Supportive Care NCIT:C15747

Multidisciplinary supportive care — developmental therapies, feeding and respiratory support, and management of movement disorders — is the mainstay given the severe neurodevelopmental impairment.

Genetic Counseling

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

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

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Diagnosis

3

STXBP1 Molecular Diagnosis

Diagnosis is established by identifying a heterozygous pathogenic or likely pathogenic STXBP1 variant (sequence variant or copy-number deletion), typically de novo, in an infant or child with early-onset epileptic encephalopathy and severe developmental impairment. Parental testing confirms de novo status.

molecular genetic testing NCIT:C19770

Results: A heterozygous pathogenic STXBP1 loss-of-function variant establishes the diagnosis.

Show evidence (2 references)

PMID:18469812 SUPPORT Human Clinical

"four unrelated individuals with EIEE had heterozygous missense mutations in the gene encoding syntaxin binding protein 1 (STXBP1)."

Molecular identification of STXBP1 variants established the genetic diagnosis.

PMID:27905812 SUPPORT Human Clinical

"The diagnosis is established in a proband with a heterozygous STXBP1 pathogenic variant identified by molecular genetic testing."

The GeneReviews chapter defines the molecular-genetic-testing basis for establishing the diagnosis.

EEG and Seizure Phenotyping

EEG documents the encephalopathic background and epilepsy syndrome — burst-suppression in Ohtahara syndrome, hypsarrhythmia in West syndrome, or multifocal epileptiform activity — and guides antiseizure treatment.

electroencephalography NCIT:C38054

Results: A burst-suppression or hypsarrhythmic pattern supports the epileptic encephalopathy.

Show evidence (1 reference)

PMID:18469812 SUPPORT Human Clinical

"Early infantile epileptic encephalopathy with suppression-burst (EIEE), also known as Ohtahara syndrome, is one of the most severe and earliest forms of epilepsy."

The suppression-burst EEG pattern is the defining electrophysiologic feature of the Ohtahara presentation.

Brain MRI

Brain MRI is used to exclude structural and metabolic causes of neonatal or infantile epileptic encephalopathy; findings in STXBP1 encephalopathy are frequently normal or nonspecific.

magnetic resonance imaging procedure NCIT:C16809

Results: Usually normal or nonspecific; used mainly to exclude structural causes.

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Progression

2

Infancy

Onset is typically in the first months of life with epileptic encephalopathy (often Ohtahara or West syndrome) and evolving severe developmental impairment.

Show evidence (1 reference)

PMID:18469812 SUPPORT Human Clinical

"Early infantile epileptic encephalopathy with suppression-burst (EIEE), also known as Ohtahara syndrome, is one of the most severe and earliest forms of epilepsy."

Documents the early-infantile onset of the epileptic encephalopathy.

Childhood to Adulthood

Seizures may evolve in type and, in some patients, become less prominent, while severe-to-profound intellectual disability persists and movement disorders, including prominent extrapyramidal features in some adults, become apparent.

Show evidence (1 reference)

PMID:26865513 SUPPORT Human Clinical

"We also report 2 previously unreported adult patients with prominent extrapyramidal features."

Documents persistence into adulthood with prominent extrapyramidal movement features.

📊

Prevalence

1

Worldwide

Unknown Rare

STXBP1 encephalopathy is one of the more frequently identified single-gene causes of developmental and epileptic encephalopathy, but it remains individually rare and a precise population prevalence has not been firmly established.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from STXBP1 Encephalopathy:

Other SNAREopathies and synaptic vesicle cycle disorders

Overlapping Features Developmental and epileptic encephalopathies caused by other synaptic vesicle cycle / SNARE-machinery genes (e.g. UNC13A, SNAP25, STX1B, VAMP2, SYT1, DNM1) overlap through early-onset epilepsy, hypotonia, and developmental impairment and are distinguished by molecular testing.

Distinguishing Features

A de novo heterozygous STXBP1 loss-of-function variant favors this disorder.
A variant in a different vesicle-cycle gene favors the corresponding SNAREopathy.

Show evidence (1 reference)

PMID:32559416 SUPPORT Other

"Human pathogenic mutations have now been reported for all eight core components, but patients are diagnosed with very different neurodevelopmental syndromes."

Establishes the family of SNAREopathies that constitutes the molecular differential diagnosis.

Other early-onset developmental and epileptic encephalopathies

Overlapping Features DEEs from ion-channel and other genes (e.g. KCNQ2, SCN2A, CDKL5, ARX) can present with Ohtahara or West syndrome and are distinguished by genetic testing.

Distinguishing Features

A pathogenic STXBP1 variant favors this disorder.
A causal variant in another DEE gene favors that diagnosis.

🐁

Animal Models

1

Munc18-1 (Stxbp1) knockout Mouse (Mus musculus)

Munc18-1 null mice show a complete loss of neurotransmitter secretion from synaptic vesicles throughout development; the brain assembles morphologically but neurons subsequently undergo apoptosis with widespread neurodegeneration, demonstrating that Munc18-1 is essential for synaptic transmission and for maintenance of established synapses.

Species

Mouse (Mus musculus)

Genotype

Munc18-1 (Stxbp1) knockout

Show evidence (1 reference)

PMID:10657302 SUPPORT Model Organism

"Deletion of a single protein, Munc18-1, in mice leads to a complete loss of neurotransmitter secretion from synaptic vesicles throughout development."

The Munc18-1 knockout establishes the presynaptic release requirement whose partial loss (haploinsufficiency) underlies human STXBP1 encephalopathy.

{ }

Source YAML

click to show

name: STXBP1 Encephalopathy
creation_date: "2026-07-06T00:00:00Z"
description: >-
  A developmental and epileptic encephalopathy caused by de novo heterozygous
  loss-of-function variants in STXBP1, which encodes Munc18-1 (syntaxin-binding
  protein 1), a Sec1/Munc18 protein essential for synaptic vesicle release.
  Munc18-1 chaperones syntaxin-1 and templates assembly of the neuronal SNARE
  complex that drives Ca2+-triggered synaptic vesicle fusion, so its
  haploinsufficiency reduces neurotransmitter release across cortical synapses.
  Affected individuals present in infancy with epilepsy — frequently Ohtahara
  syndrome (early infantile epileptic encephalopathy with burst-suppression) or
  West syndrome, or a nonsyndromic early-onset epileptic encephalopathy — together
  with severe-to-profound intellectual disability. Movement disorders (tremor,
  dystonia, ataxia) and autistic features are common, and STXBP1 encephalopathy is
  now understood as a complex neurodevelopmental disorder in which cognitive
  impairment and seizures are partly independent, rather than a primary epileptic
  encephalopathy. It is one of the SNAREopathies and one of the synaptic vesicle
  cycle disorders.
category: Mendelian
parents:
- Neurodevelopmental Disorder
- Epileptic Encephalopathy
disease_term:
  preferred_term: STXBP1 encephalopathy
  term:
    id: MONDO:0012812
    label: developmental and epileptic encephalopathy, 4
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 arise from de novo heterozygous STXBP1 variants; the disorder
    acts through haploinsufficiency, so a single loss-of-function allele is
    sufficient to cause disease.
  evidence:
  - reference: PMID:26865513
    reference_title: "STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      De novo STXBP1 mutations are among the most frequent causes of epilepsy and
      encephalopathy.
    explanation: >-
      Establishes the de novo dominant genetic basis of STXBP1 encephalopathy in a
      large patient cohort.
  - reference: PMID:27905812
    reference_title: "STXBP1 Encephalopathy with Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      STXBP1 encephalopathy with epilepsy is an autosomal dominant disorder
      typically caused by a de novo pathogenic variant.
    explanation: >-
      The GeneReviews genetic-counseling section confirms autosomal dominant
      inheritance arising typically from a de novo pathogenic variant.
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: RARE
  notes: >-
    STXBP1 encephalopathy is one of the more frequently identified single-gene
    causes of developmental and epileptic encephalopathy, but it remains
    individually rare and a precise population prevalence has not been firmly
    established.
references:
- reference: PMID:18469812
  title: "De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy."
- reference: PMID:26865513
  title: "STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy."
- reference: PMID:32559416
  title: "SNAREopathies: Diversity in Mechanisms and Symptoms."
- reference: PMID:27905812
  title: "STXBP1 Encephalopathy with Epilepsy."
  tags:
  - GeneReviews
pathophysiology:
- name: STXBP1 Haploinsufficiency and Munc18-1 Deficiency
  conforms_to: "synaptic_vesicle_cycle#Synaptic Vesicle Cycle Protein Deficiency"
  description: >-
    De novo heterozygous loss-of-function variants (nonsense, frameshift,
    splice-site, whole-gene/partial deletions) and destabilizing missense variants
    in STXBP1 reduce the functional dose of Munc18-1, an evolutionarily conserved
    Sec1/Munc18 protein essential for synaptic vesicle release. Missense variants
    render the protein thermolabile and prone to aggregation/degradation, so both
    truncating and missense mechanisms converge on haploinsufficiency of Munc18-1
    at presynaptic terminals.
  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:18469812
    reference_title: "De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      STXBP1 (also known as MUNC18-1) is an evolutionally conserved neuronal
      Sec1/Munc-18 (SM) protein that is essential in synaptic vesicle release in
      several species.
    explanation: >-
      Establishes STXBP1/Munc18-1 as a synaptic-vesicle-release protein, the
      vesicle-cycle component whose deficiency defines this disorder.
  - reference: PMID:18469812
    reference_title: "De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings suggest that haploinsufficiency of STXBP1 causes EIEE.
    explanation: >-
      Identifies haploinsufficiency as the disease mechanism, the trigger modeled
      by this node.
  - reference: PMID:18469812
    reference_title: "De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Circular dichroism melting experiments revealed that a mutant form of the
      protein was significantly thermolabile compared to wild type.
    explanation: >-
      Demonstrates that a disease missense variant destabilizes Munc18-1,
      supporting protein instability as a route to haploinsufficiency.
  downstream:
  - target: Impaired Syntaxin-1 Chaperoning and SNARE-Mediated Vesicle Fusion
    causal_link_type: DIRECT
  - target: Reduced Neurotransmitter Release and Synaptic Transmission Deficit
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Impaired SNARE-mediated synaptic vesicle fusion.
- name: Impaired Syntaxin-1 Chaperoning and SNARE-Mediated Vesicle Fusion
  conforms_to: "synaptic_vesicle_cycle#Impaired Calcium-Triggered SNARE-Mediated Vesicle Fusion"
  description: >-
    Munc18-1 binds syntaxin-1 and templates assembly of the neuronal SNARE complex
    (syntaxin-1, SNAP-25, synaptobrevin-2/VAMP2) that mediates Ca2+-triggered
    synaptic vesicle fusion. Reduced Munc18-1 dose, and disease variants with
    impaired syntaxin binding, compromise SNARE-complex assembly and the vesicle
    fusion step. In the Munc18-1 null model, loss of this protein abolishes
    neurotransmitter secretion, demonstrating that Munc18-1 is indispensable for
    the fusion reaction.
  role: central_effector
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: calcium-dependent activation of synaptic vesicle fusion
    term:
      id: GO:0099502
      label: calcium-dependent activation of synaptic vesicle fusion
    modifier: DECREASED
  - preferred_term: synaptic vesicle exocytosis
    term:
      id: GO:0016079
      label: synaptic vesicle exocytosis
    modifier: DECREASED
  evidence:
  - reference: PMID:18469812
    reference_title: "De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Furthermore, binding of the mutant protein to syntaxin was impaired.
    explanation: >-
      Shows a disease variant impairs Munc18-1 binding to syntaxin-1, the
      interaction that licenses SNARE-mediated fusion.
  - reference: PMID:10657302
    reference_title: "Synaptic assembly of the brain in the absence of neurotransmitter secretion."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Deletion of a single protein, Munc18-1, in mice leads to a complete loss of
      neurotransmitter secretion from synaptic vesicles throughout development.
    explanation: >-
      The Munc18-1 null mouse demonstrates that Munc18-1 is required for the
      vesicle-fusion/neurotransmitter-release step this node models.
  downstream:
  - target: Reduced Neurotransmitter Release and Synaptic Transmission Deficit
    causal_link_type: DIRECT
- name: Reduced Neurotransmitter Release and Synaptic Transmission Deficit
  conforms_to: "synaptic_vesicle_cycle#Neurotransmitter Release Failure and Synaptic Transmission Deficit"
  description: >-
    Impaired SNARE-mediated fusion reduces Ca2+-evoked neurotransmitter release and
    disturbs chemical synaptic transmission across cortical circuits. Because
    Munc18-1 is required at both excitatory and inhibitory synapses, the net effect
    is a disturbance of cortical excitatory/inhibitory balance that both drives
    seizures and impairs the activity-dependent synaptic signaling needed for
    normal neurodevelopment.
  role: effector
  cell_types:
  - preferred_term: glutamatergic neuron
    term:
      id: CL:0000679
      label: glutamatergic neuron
  - preferred_term: GABAergic neuron
    term:
      id: CL:0000617
      label: GABAergic neuron
  biological_processes:
  - preferred_term: neurotransmitter secretion
    term:
      id: GO:0007269
      label: neurotransmitter secretion
    modifier: DECREASED
  - 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:26865513
    reference_title: "STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      STXBP1-E may be conceptualized as a complex neurodevelopmental disorder
      rather than a primary epileptic encephalopathy.
    explanation: >-
      Supports the view that the synaptic-transmission deficit produces a broad
      neurodevelopmental phenotype, not seizures alone.
  downstream:
  - target: Cortical Excitation-Inhibition Imbalance and Seizures
    causal_link_type: DIRECT
  - target: Impaired Synaptic Network Development
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Reduced activity-dependent synaptic signaling during brain development.
- name: Cortical Excitation-Inhibition Imbalance and Seizures
  conforms_to: "epilepsy_excitation_inhibition_imbalance#Neuronal Hyperexcitability and Hypersynchrony"
  description: >-
    Reduced and imbalanced neurotransmitter release destabilizes cortical
    excitatory/inhibitory balance, producing neuronal hyperexcitability and
    hypersynchronous discharges. Clinically this manifests as early-onset epilepsy,
    frequently as Ohtahara syndrome with a burst-suppression EEG or as West
    syndrome with epileptic spasms, and as a nonsyndromic early-onset epileptic
    encephalopathy with epileptic spasms or tonic seizures.
  role: amplifier
  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:26865513
    reference_title: "STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While one-third of patients presented with Ohtahara syndrome (21%) or West
      syndrome (9.5%), the majority has a nonsyndromic early-onset epilepsy and
      encephalopathy (53%) with epileptic spasms or tonic seizures as main seizure
      type.
    explanation: >-
      Documents the epilepsy syndromes and seizure types produced by the cortical
      excitability disturbance.
  - reference: PMID:18469812
    reference_title: "De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early infantile epileptic encephalopathy with suppression-burst (EIEE), also
      known as Ohtahara syndrome, is one of the most severe and earliest forms of
      epilepsy.
    explanation: >-
      Anchors the Ohtahara-syndrome / burst-suppression presentation to STXBP1
      disease.
  downstream:
  - target: Epilepsy
    causal_link_type: DIRECT
  - target: EEG Abnormality
    causal_link_type: DIRECT
- name: Impaired Synaptic Network Development
  description: >-
    Reduced activity-dependent synaptic transmission during a critical
    developmental window impairs maturation of cortical networks, producing severe
    global developmental delay, intellectual disability, absent or limited speech,
    autistic features, and movement disorders. In STXBP1 disease the cognitive
    impairment is largely independent of seizure burden. In the Munc18-1 null
    model, synapses initially assemble but neurons subsequently degenerate,
    indicating a maintenance/neurodegenerative component in the extreme
    loss-of-function state.
  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: DECREASED
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:26865513
    reference_title: "STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients have intellectual disability (ID), which is mostly severe to
      profound (88%).
    explanation: >-
      Establishes severe-to-profound intellectual disability as a universal outcome
      of the impaired synaptic-network development.
  - reference: PMID:26865513
    reference_title: "STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found no correlation between severity of seizures and severity of ID
    explanation: >-
      Supports the partial independence of the developmental/cognitive impairment
      from the seizure burden.
  - reference: PMID:10657302
    reference_title: "Synaptic assembly of the brain in the absence of neurotransmitter secretion."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      After assembly is completed, neurons undergo apoptosis, leading to widespread
      neurodegeneration.
    explanation: >-
      The Munc18-1 null model shows a neurodegenerative/maintenance component when
      neurotransmitter secretion is lost, relevant to the severe developmental
      outcome.
  downstream:
  - target: Severe Global Developmental Delay
    causal_link_type: DIRECT
  - target: Intellectual Disability
    causal_link_type: DIRECT
  - target: Autistic Behavior
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Movement Disorder
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- name: Epilepsy
  category: Clinical
  description: >-
    Early-onset epilepsy affecting the great majority of patients, ranging from
    Ohtahara syndrome and West syndrome to nonsyndromic early-onset epileptic
    encephalopathy.
  diagnostic: true
  phenotype_term:
    preferred_term: Epileptic encephalopathy
    term:
      id: HP:0200134
      label: Epileptic encephalopathy
  evidence:
  - reference: PMID:26865513
    reference_title: "STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ninety-five percent of patients have epilepsy.
    explanation: >-
      Quantifies epilepsy as a near-universal feature of STXBP1 encephalopathy.
- name: Epileptic Spasms
  category: Clinical
  description: >-
    Epileptic spasms (including infantile spasms in West syndrome) are a common
    seizure type in STXBP1 encephalopathy.
  phenotype_term:
    preferred_term: Epileptic spasm
    term:
      id: HP:0011097
      label: Epileptic spasm
  evidence:
  - reference: PMID:26865513
    reference_title: "STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the majority has a nonsyndromic early-onset epilepsy and encephalopathy (53%)
      with epileptic spasms or tonic seizures as main seizure type.
    explanation: >-
      Documents epileptic spasms as a main seizure type in the disorder.
- name: Tonic Seizures
  category: Clinical
  description: >-
    Tonic seizures are one of the main seizure types in the nonsyndromic
    early-onset epileptic encephalopathy presentation.
  phenotype_term:
    preferred_term: Tonic seizure
    term:
      id: HP:0032792
      label: Tonic seizure
  evidence:
  - reference: PMID:26865513
    reference_title: "STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      with epileptic spasms or tonic seizures as main seizure type.
    explanation: >-
      Documents tonic seizures as a main seizure type.
- name: EEG with Burst Suppression
  category: Clinical
  description: >-
    A burst-suppression EEG pattern characterizes the Ohtahara-syndrome
    (early infantile epileptic encephalopathy with suppression-burst) presentation.
  phenotype_term:
    preferred_term: EEG with burst suppression
    term:
      id: HP:0010851
      label: EEG with burst suppression
  evidence:
  - reference: PMID:18469812
    reference_title: "De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early infantile epileptic encephalopathy with suppression-burst (EIEE), also
      known as Ohtahara syndrome, is one of the most severe and earliest forms of
      epilepsy.
    explanation: >-
      The Ohtahara-syndrome (suppression-burst) presentation is the discovery
      phenotype for STXBP1.
- name: Severe to Profound Intellectual Disability
  category: Clinical
  description: >-
    Intellectual disability is present in all patients and is mostly severe to
    profound, with little correlation to seizure severity.
  diagnostic: true
  phenotype_term:
    preferred_term: Profound intellectual disability
    term:
      id: HP:0002187
      label: Profound intellectual disability
  evidence:
  - reference: PMID:26865513
    reference_title: "STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients have intellectual disability (ID), which is mostly severe to
      profound (88%).
    explanation: >-
      Quantifies severe-to-profound intellectual disability as universal.
- name: Severe Global Developmental Delay
  category: Clinical
  description: >-
    Severe global developmental delay is characteristic, with markedly delayed or
    absent developmental milestones.
  phenotype_term:
    preferred_term: Severe global developmental delay
    term:
      id: HP:0011344
      label: Severe global developmental delay
  evidence:
  - reference: PMID:26865513
    reference_title: "STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most patients have severe to profound ID with little correlation among
      seizure onset, seizure severity, and the degree of ID.
    explanation: >-
      Supports severe global developmental impairment independent of seizure
      severity.
- name: Autistic Behavior
  category: Clinical
  description: >-
    Autistic features are a frequent neurologic comorbidity in STXBP1
    encephalopathy.
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:26865513
    reference_title: "STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurologic comorbidities including autistic features and movement disorders
      are frequent.
    explanation: >-
      Documents autistic features as a frequent comorbidity.
- name: Movement Disorder
  category: Clinical
  description: >-
    Movement disorders — including tremor, dystonia, ataxia, and prominent
    extrapyramidal features in some adults — are frequent.
  phenotype_term:
    preferred_term: Abnormality of movement
    term:
      id: HP:0100022
      label: Abnormality of movement
  evidence:
  - reference: PMID:26865513
    reference_title: "STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurologic comorbidities including autistic features and movement disorders
      are frequent.
    explanation: >-
      Documents movement disorders as a frequent comorbidity.
  - reference: PMID:26865513
    reference_title: "STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We also report 2 previously unreported adult patients with prominent
      extrapyramidal features.
    explanation: >-
      Documents prominent extrapyramidal movement features in adult patients.
- name: Tremor
  category: Clinical
  description: >-
    Tremor is a recurrent component of the movement-disorder spectrum in STXBP1
    encephalopathy.
  phenotype_term:
    preferred_term: Tremor
    term:
      id: HP:0001337
      label: Tremor
  evidence:
  - reference: PMID:26865513
    reference_title: "STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurologic comorbidities including autistic features and movement disorders
      are frequent.
    explanation: >-
      Tremor is part of the frequent movement-disorder comorbidity; the cohort
      documents the broader movement-disorder category.
- name: Hypotonia
  category: Clinical
  description: >-
    Abnormal muscle tone, including axial hypotonia, is a recognized neurologic
    feature of STXBP1 encephalopathy, occurring alongside the movement-disorder
    spectrum (dystonia, ataxia) and, in some individuals, coexisting spasticity.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:27905812
    reference_title: "STXBP1 Encephalopathy with Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other neurologic findings include abnormal tone, movement disorders
      (especially ataxia and dystonia), and behavioral issues and autism spectrum
      disorder.
    explanation: >-
      The GeneReviews chapter lists abnormal muscle tone among the core neurologic
      findings of STXBP1 encephalopathy.
  - reference: PMID:32815282
    reference_title: "De novo STXBP1 mutation in a child with developmental delay and spasticity reveals a major structural alteration in the interface with syntaxin 1A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Through exome sequencing of a child with developmental delay, hypotonia, and
      spasticity, we found a novel de novo insertion mutation of three nucleotides
      in the STXBP1 coding region
    explanation: >-
      A molecularly confirmed STXBP1 case presenting with hypotonia, documenting
      hypotonia within the phenotypic spectrum.
genetic:
- name: STXBP1
  gene_term:
    preferred_term: STXBP1
    term:
      id: hgnc:11444
      label: STXBP1
  association: Loss-of-Function 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 heterozygous STXBP1 variants act through haploinsufficiency. The
    spectrum includes nonsense, frameshift, and splice-site variants,
    intragenic and whole-gene deletions, and destabilizing missense variants that
    reduce Munc18-1 protein stability and/or syntaxin-1 binding.
  evidence:
  - reference: PMID:18469812
    reference_title: "De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      four unrelated individuals with EIEE had heterozygous missense mutations in
      the gene encoding syntaxin binding protein 1 (STXBP1).
    explanation: >-
      Original identification of heterozygous STXBP1 variants as the cause of early
      infantile epileptic encephalopathy.
  - reference: PMID:26865513
    reference_title: "STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      De novo STXBP1 mutations are among the most frequent causes of epilepsy and
      encephalopathy.
    explanation: >-
      Confirms de novo STXBP1 variants as a leading genetic cause in a large
      cohort.
diagnosis:
- name: STXBP1 Molecular Diagnosis
  description: >-
    Diagnosis is established by identifying a heterozygous pathogenic or likely
    pathogenic STXBP1 variant (sequence variant or copy-number deletion), typically
    de novo, in an infant or child with early-onset epileptic encephalopathy and
    severe developmental impairment. Parental testing confirms de novo status.
  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: STXBP1
        term:
          id: hgnc:11444
          label: STXBP1
  results: A heterozygous pathogenic STXBP1 loss-of-function variant establishes the diagnosis.
  evidence:
  - reference: PMID:18469812
    reference_title: "De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      four unrelated individuals with EIEE had heterozygous missense mutations in
      the gene encoding syntaxin binding protein 1 (STXBP1).
    explanation: >-
      Molecular identification of STXBP1 variants established the genetic diagnosis.
  - reference: PMID:27905812
    reference_title: "STXBP1 Encephalopathy with Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis is established in a proband with a heterozygous STXBP1
      pathogenic variant identified by molecular genetic testing.
    explanation: >-
      The GeneReviews chapter defines the molecular-genetic-testing basis for
      establishing the diagnosis.
- name: EEG and Seizure Phenotyping
  description: >-
    EEG documents the encephalopathic background and epilepsy syndrome —
    burst-suppression in Ohtahara syndrome, hypsarrhythmia in West syndrome, or
    multifocal epileptiform activity — and guides antiseizure treatment.
  diagnosis_term:
    preferred_term: electroencephalography
    term:
      id: NCIT:C38054
      label: Electroencephalography
  results: A burst-suppression or hypsarrhythmic pattern supports the epileptic encephalopathy.
  evidence:
  - reference: PMID:18469812
    reference_title: "De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early infantile epileptic encephalopathy with suppression-burst (EIEE), also
      known as Ohtahara syndrome, is one of the most severe and earliest forms of
      epilepsy.
    explanation: >-
      The suppression-burst EEG pattern is the defining electrophysiologic feature
      of the Ohtahara presentation.
- name: Brain MRI
  description: >-
    Brain MRI is used to exclude structural and metabolic causes of neonatal or
    infantile epileptic encephalopathy; findings in STXBP1 encephalopathy are
    frequently normal or nonspecific.
  diagnosis_term:
    preferred_term: magnetic resonance imaging procedure
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  results: Usually normal or nonspecific; used mainly to exclude structural causes.
differential_diagnoses:
- name: Other SNAREopathies and synaptic vesicle cycle disorders
  description: >-
    Developmental and epileptic encephalopathies caused by other synaptic vesicle
    cycle / SNARE-machinery genes (e.g. UNC13A, SNAP25, STX1B, VAMP2, SYT1, DNM1)
    overlap through early-onset epilepsy, hypotonia, and developmental impairment
    and are distinguished by molecular testing.
  distinguishing_features:
  - A de novo heterozygous STXBP1 loss-of-function variant favors this disorder.
  - A variant in a different vesicle-cycle gene favors the corresponding SNAREopathy.
  evidence:
  - reference: PMID:32559416
    reference_title: "SNAREopathies: Diversity in Mechanisms and Symptoms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Human pathogenic mutations have now been reported for all eight core
      components, but patients are diagnosed with very different neurodevelopmental
      syndromes.
    explanation: >-
      Establishes the family of SNAREopathies that constitutes the molecular
      differential diagnosis.
- name: Other early-onset developmental and epileptic encephalopathies
  description: >-
    DEEs from ion-channel and other genes (e.g. KCNQ2, SCN2A, CDKL5, ARX) can
    present with Ohtahara or West syndrome and are distinguished by genetic testing.
  distinguishing_features:
  - A pathogenic STXBP1 variant favors this disorder.
  - A causal variant in another DEE gene favors that diagnosis.
animal_models:
- species: Mouse (Mus musculus)
  genotype: Munc18-1 (Stxbp1) knockout
  description: >-
    Munc18-1 null mice show a complete loss of neurotransmitter secretion from
    synaptic vesicles throughout development; the brain assembles morphologically
    but neurons subsequently undergo apoptosis with widespread neurodegeneration,
    demonstrating that Munc18-1 is essential for synaptic transmission and for
    maintenance of established synapses.
  evidence:
  - reference: PMID:10657302
    reference_title: "Synaptic assembly of the brain in the absence of neurotransmitter secretion."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Deletion of a single protein, Munc18-1, in mice leads to a complete loss of
      neurotransmitter secretion from synaptic vesicles throughout development.
    explanation: >-
      The Munc18-1 knockout establishes the presynaptic release requirement whose
      partial loss (haploinsufficiency) underlies human STXBP1 encephalopathy.
progression:
- phase: Infancy
  notes: >-
    Onset is typically in the first months of life with epileptic encephalopathy
    (often Ohtahara or West syndrome) and evolving severe developmental impairment.
  evidence:
  - reference: PMID:18469812
    reference_title: "De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early infantile epileptic encephalopathy with suppression-burst (EIEE), also
      known as Ohtahara syndrome, is one of the most severe and earliest forms of
      epilepsy.
    explanation: >-
      Documents the early-infantile onset of the epileptic encephalopathy.
- phase: Childhood to Adulthood
  notes: >-
    Seizures may evolve in type and, in some patients, become less prominent, while
    severe-to-profound intellectual disability persists and movement disorders,
    including prominent extrapyramidal features in some adults, become apparent.
  evidence:
  - reference: PMID:26865513
    reference_title: "STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We also report 2 previously unreported adult patients with prominent
      extrapyramidal features.
    explanation: >-
      Documents persistence into adulthood with prominent extrapyramidal movement
      features.
treatments:
- name: Antiseizure Medication
  description: >-
    Seizures are managed with antiseizure medications; response is variable and
    often incomplete. Agents used for the associated epilepsy syndromes include
    levetiracetam and, for epileptic/infantile spasms, vigabatrin. No agent
    corrects the underlying Munc18-1 deficiency.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: levetiracetam
      term:
        id: CHEBI:6437
        label: levetiracetam
    - preferred_term: vigabatrin
      term:
        id: CHEBI:63638
        label: vigabatrin
  evidence:
  - reference: PMID:27905812
    reference_title: "STXBP1 Encephalopathy with Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most commonly used anti-seizure medications (ASMs) are phenobarbital,
      valproic acid, and vigabatrin. About 20% of individuals require more than
      one ASM and approximately 25% are refractory to ASM therapy.
    explanation: >-
      The GeneReviews management section documents first-line ASM choices and the
      substantial rate of pharmacoresistance in STXBP1 encephalopathy.
- name: Supportive and Developmental Care
  description: >-
    Multidisciplinary supportive care — developmental therapies, feeding and
    respiratory support, and management of movement disorders — is the mainstay
    given the severe neurodevelopmental impairment.
  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 and the generally
    low recurrence risk, with attention to the rare possibility of parental
    mosaicism.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
discussions:
- discussion_id: gap_stxbp1_haploinsufficiency_vs_dominant_negative
  prompt: >-
    Is STXBP1 encephalopathy a pure loss-of-dose (haploinsufficiency) disorder,
    or do destabilized missense variants act dominant-negatively by aggregating
    and co-depleting wild-type Munc18-1, and does the answer differ by variant
    class with direct consequences for therapy (gene/dosage restoration versus
    chemical-chaperone/proteostasis approaches)?
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - pathophysiology#STXBP1 Haploinsufficiency and Munc18-1 Deficiency
  - pathophysiology#Impaired Syntaxin-1 Chaperoning and SNARE-Mediated Vesicle Fusion
  rationale: >-
    The entry models both truncating and missense variants as converging on
    Munc18-1 haploinsufficiency, and an allelic-series mouse study concludes that
    impaired protein stability plus haploinsufficiency explain the disease. A
    competing biochemical model finds that missense mutants aggregate and
    sequester wild-type Munc18-1 below hemizygous levels, i.e. an additional
    dominant-negative effect. The two models are not merely academic: pure
    haploinsufficiency motivates gene-dosage or expression-restoration
    strategies, whereas a dominant-negative aggregation mechanism motivates
    chemical-chaperone/proteostasis rescue and possibly allele-specific
    knockdown. Which mechanism dominates, and whether it is variant-dependent,
    remains unresolved.
  evidence:
  - reference: PMID:30266908
    reference_title: "Mechanism-based rescue of Munc18-1 dysfunction in varied encephalopathies by chemical chaperones."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Aggregates of mutant Munc18-1 incorporate wild-type Munc18-1, depleting
      functional Munc18-1 levels beyond hemizygous levels.
    explanation: >-
      Provides the biochemical basis for a dominant-negative (aggregation and
      wild-type co-depletion) mechanism, the alternative to pure
      haploinsufficiency.
  - reference: PMID:29538625
    reference_title: "Protein instability, haploinsufficiency, and cortical hyper-excitability underlie STXBP1 encephalopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      impaired protein stability and STXBP1 haploinsufficiency explain
      STXBP1-encephalopathy and that, therefore, Stxbp1+/- mice provide a valid
      mouse model.
    explanation: >-
      Supports the competing haploinsufficiency-only interpretation, in which
      Stxbp1+/- (loss-of-dose) alone reproduces the disease.
  proposed_experiments:
  - experiment_id: exp_stxbp1_lof_vs_dn_allelic_series
    name: STXBP1 loss-of-function versus dominant-negative allelic-series test
    description: >-
      In a shared neuronal background, express an allelic series of STXBP1
      variants (truncating, deletion, and multiple missense) on both null and
      heterozygous (wild-type-present) backgrounds and measure whether the
      variant lowers functional Munc18-1 below the hemizygous level and whether
      chemical chaperones (4-phenylbutyrate, trehalose) restore protein level
      and release. A variant that depletes wild-type Munc18-1 and impairs release
      below hemizygous levels indicates a dominant-negative component.
    experiment_type:
      preferred_term: allelic-series gain/loss-of-function experiment
    perturbations:
    - name: STXBP1 variant expression on null versus heterozygous background
      target: pathophysiology#STXBP1 Haploinsufficiency and Munc18-1 Deficiency
      genes:
      - preferred_term: STXBP1
        term:
          id: hgnc:11444
          label: STXBP1
      description: >-
        Introduce each STXBP1 variant on a Munc18-1 null background (isolated
        variant function) and on a wild-type-present background (test for
        wild-type co-depletion), with and without chemical-chaperone treatment.
    readouts:
    - name: Munc18-1 protein level and synaptic vesicle release
      target: pathophysiology#Impaired Syntaxin-1 Chaperoning and SNARE-Mediated Vesicle Fusion
      biological_processes:
      - preferred_term: synaptic vesicle exocytosis
        term:
          id: GO:0016079
          label: synaptic vesicle exocytosis
        modifier: DECREASED
      - preferred_term: neurotransmitter secretion
        term:
          id: GO:0007269
          label: neurotransmitter secretion
        modifier: DECREASED
      assays:
      - preferred_term: immunoblot assay
      - preferred_term: patch-clamp recording
      direction: NEGATIVE
    controls:
    - name: Wild-type STXBP1
      description: Wild-type Munc18-1 expressed on the same backgrounds.
    - name: Vehicle versus chemical chaperone
      description: Matched untreated versus chemical-chaperone-treated conditions.
    decision_criterion: >-
      A dominant-negative component is supported if a variant reduces functional
      Munc18-1 and release below hemizygous levels on a wild-type-present
      background and is rescued by chemical chaperones; pure haploinsufficiency
      is supported if variants have no effect beyond loss of dose.
    would_support:
    - pathophysiology#STXBP1 Haploinsufficiency and Munc18-1 Deficiency
    - pathophysiology#Impaired Syntaxin-1 Chaperoning and SNARE-Mediated Vesicle Fusion

- discussion_id: gap_stxbp1_genotype_phenotype_modifiers
  prompt: >-
    Why do STXBP1 variants produce a phenotypic spectrum ranging from classic
    early-onset epileptic encephalopathy to intellectual disability without
    epilepsy to a movement-disorder-predominant picture, and what genetic,
    variant-level, or network modifiers determine which arm dominates in a given
    patient?
  kind: OPEN_QUESTION
  status: OPEN
  attaches_to:
  - pathophysiology#Cortical Excitation-Inhibition Imbalance and Seizures
  - pathophysiology#Impaired Synaptic Network Development
  rationale: >-
    The entry already notes that cognitive impairment and seizures are partly
    independent, and cohort data find no correlation between seizure severity and
    the degree of intellectual disability. This dissociation implies that the
    epilepsy arm and the developmental/cognitive (and movement-disorder) arms are
    separably modifiable, yet no variant-class, residual-protein-level, cell-type
    (excitatory versus inhibitory), or modifier-gene predictor reliably explains
    why one arm dominates. Resolving this is prerequisite to prognostic
    counseling and to arm-specific therapy.
  evidence:
  - reference: PMID:26865513
    reference_title: "STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found no correlation between severity of seizures and severity of ID
    explanation: >-
      Documents the clinical dissociation between the seizure arm and the
      cognitive arm that the modifier question seeks to explain.
  proposed_experiments:
  - experiment_id: exp_stxbp1_genotype_phenotype_stratification
    name: STXBP1 genotype-phenotype and modifier stratification study
    description: >-
      In a deeply phenotyped STXBP1 cohort, stratify patients by variant class
      (truncating, deletion, missense) and estimated residual Munc18-1 level and
      test whether these, together with polygenic background and candidate
      modifier loci, predict the dominant phenotypic arm (epilepsy-predominant,
      intellectual-disability-without-epilepsy, or movement-disorder-predominant).
    experiment_type:
      preferred_term: genotype-phenotype correlation study
    perturbations:
    - name: Variant-class and residual-dose stratification
      target: pathophysiology#Impaired Synaptic Network Development
      genes:
      - preferred_term: STXBP1
        term:
          id: hgnc:11444
          label: STXBP1
      description: >-
        Group patients by STXBP1 variant class and modeled residual protein dose
        rather than introducing a perturbation, as an observational human study.
    readouts:
    - name: Dominant phenotypic arm and network phenotype
      target: pathophysiology#Cortical Excitation-Inhibition Imbalance and Seizures
      biological_processes:
      - preferred_term: chemical synaptic transmission
        term:
          id: GO:0007268
          label: chemical synaptic transmission
        modifier: ABNORMAL
      assays:
      - preferred_term: electroencephalography
      direction: POSITIVE
    controls:
    - name: Variant-class comparison groups
      description: Truncating, deletion, and missense groups compared against one another.
    decision_criterion: >-
      A modifier is supported if variant class, residual protein level, or a
      modifier locus significantly predicts the dominant phenotypic arm across
      the cohort after correction for multiple testing.
    would_support:
    - pathophysiology#Cortical Excitation-Inhibition Imbalance and Seizures
    - pathophysiology#Impaired Synaptic Network Development

- discussion_id: gap_stxbp1_mouse_model_fidelity
  prompt: >-
    Does the Stxbp1+/- mouse, which reproduces spike-wave/spasm EEG activity and
    mild cognitive changes, capture the severity and developmental trajectory of
    human STXBP1 encephalopathy — in particular the severe-to-profound
    intellectual disability and Ohtahara/West-syndrome-level epileptic
    encephalopathy — or does it under-represent the human disease?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Reduced Neurotransmitter Release and Synaptic Transmission Deficit
  - pathophysiology#Impaired Synaptic Network Development
  rationale: >-
    Model evidence clearly exists: Stxbp1+/- mice recapitulate the seizure/spasm
    EEG phenotype and show impaired cognition, hyperactivity, and anxiety-like
    behaviour, and the seizures respond to levetiracetam. The open question is
    translational fidelity — human patients almost universally have
    severe-to-profound intellectual disability and early catastrophic epileptic
    encephalopathy (Ohtahara/West syndrome), a severity that the comparatively
    mild murine cognitive and behavioural phenotype may not fully reproduce.
    Whether the mouse captures the human developmental trajectory, or whether
    human-specific cortical biology is required, gates its use for preclinical
    therapeutic testing.
  evidence:
  - reference: PMID:29538625
    reference_title: "Protein instability, haploinsufficiency, and cortical hyper-excitability underlie STXBP1 encephalopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Stxbp1+/- mice with different genomic backgrounds recapitulate the
      seizure/spasm phenotype observed in humans, characterized by myoclonic
      jerks and spike-wave discharges that were suppressed by the antiepileptic
      drug levetiracetam.
    explanation: >-
      Establishes that the mouse model reproduces the seizure component,
      confirming model evidence exists for the mismatch question.
  - reference: PMID:26865513
    reference_title: "STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients have intellectual disability (ID), which is mostly severe to
      profound (88%).
    explanation: >-
      Documents the severe-to-profound human cognitive phenotype whose murine
      fidelity is the open translational question.
  proposed_experiments:
  - experiment_id: exp_stxbp1_mouse_human_trajectory_comparison
    name: STXBP1 mouse-to-human developmental-trajectory comparison
    description: >-
      Longitudinally phenotype Stxbp1+/- mice across postnatal development for
      EEG severity, learning/memory, and motor phenotypes, and compare the
      developmental trajectory and severity against matched human natural-history
      data and STXBP1 patient iPSC-derived cortical neuron/organoid synaptic
      readouts, to quantify where the mouse under-represents human severity.
    experiment_type:
      preferred_term: cross-species developmental phenotyping experiment
    perturbations:
    - name: Stxbp1 heterozygous loss of function
      target: pathophysiology#Reduced Neurotransmitter Release and Synaptic Transmission Deficit
      genes:
      - preferred_term: STXBP1
        term:
          id: hgnc:11444
          label: STXBP1
      description: >-
        Stxbp1+/- mice and STXBP1 patient-variant human iPSC-derived neurons
        compared against wild-type and isogenic-corrected controls.
    readouts:
    - name: Synaptic transmission and network activity across development
      target: pathophysiology#Reduced Neurotransmitter Release and Synaptic Transmission Deficit
      biological_processes:
      - preferred_term: chemical synaptic transmission
        term:
          id: GO:0007268
          label: chemical synaptic transmission
        modifier: ABNORMAL
      - preferred_term: neurotransmitter secretion
        term:
          id: GO:0007269
          label: neurotransmitter secretion
        modifier: DECREASED
      assays:
      - preferred_term: multielectrode array recording
      - preferred_term: electroencephalography
      direction: NEGATIVE
    controls:
    - name: Wild-type littermate mice
      description: Age-matched wild-type littermates across the same developmental windows.
    - name: Isogenic-corrected human neurons
      description: Patient iPSC lines in which the STXBP1 variant is corrected.
    decision_criterion: >-
      The mouse is a faithful model if its developmental severity trajectory
      matches human natural history and iPSC readouts; a mismatch is supported if
      murine phenotypes are substantially milder or follow a divergent trajectory
      despite equivalent loss of dose.
    would_support:
    - pathophysiology#Reduced Neurotransmitter Release and Synaptic Transmission Deficit
    - pathophysiology#Impaired Synaptic Network Development

📚

References & Deep Research

References

4

PMID:18469812

De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy.

No top-level findings curated for this source.

PMID:26865513

STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy.

No top-level findings curated for this source.

PMID:32559416

SNAREopathies: Diversity in Mechanisms and Symptoms.

No top-level findings curated for this source.

PMID:27905812

STXBP1 Encephalopathy with Epilepsy.

No top-level findings curated for this source.

STXBP1 Encephalopathy

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