CPLX1-Related Developmental and Epileptic Encephalopathy

👪

Inheritance

1

Autosomal Recessive HP:0000007

The disorder is caused by biallelic (homozygous) loss-of-function CPLX1 variants, identified in consanguineous/unrelated families.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:28422131 SUPPORT Human Clinical

"identified homozygous CPLX1 variants in three patients with ID from two unrelated families."

Establishes the autosomal-recessive (homozygous) genetic basis.

?

Discussions and Knowledge Gaps

3

Complexin-1 both clamps spontaneous vesicle fusion and facilitates fast calcium-evoked release; which arm of this dual function, when lost in CPLX1 disease, dominates the pathogenic synaptic defect — disinhibited spontaneous release, failed evoked release, or both?

OPEN QUESTION OPEN gap_cplx1_clamp_versus_facilitator_dominant_lesion

Attached to

pathophysiology#Dysregulated SNARE-Mediated Vesicle Fusion

Complexin's dual clamp/facilitator function means CPLX1 loss can degrade synaptic transmission by two mechanistically opposite routes: unclamping spontaneous (calcium-independent) fusion, and abolishing the synchronized calcium-triggered evoked release. These have different predicted circuit consequences (tonic noise versus loss of phasic drive), so which predominates in human CPLX1-null neurons is unresolved and bears directly on how the "dysregulated fusion" node should be interpreted and, ultimately, on rational therapy.

Proposed experiments

CPLX1-null human neuron spontaneous-versus-evoked release dissection

electrophysiological release-mode dissection experiment

exp_cplx1_spontaneous_versus_evoked_release_dissection

In CPLX1-null human iPSC-derived neurons, quantify spontaneous (miniature) release frequency and fast calcium-evoked release amplitude, then rescue with wild-type complexin-1 versus separation-of-function mutants that selectively restore clamping or facilitation, to attribute the pathogenic defect to a specific arm.

Perturbations

CPLX1 knockout and separation-of-function rescue

pathophysiology#Dysregulated SNARE-Mediated Vesicle Fusion

Compare CPLX1-null neurons rescued with wild-type complexin-1 versus clamp-selective or facilitation-selective complexin-1 variants.

CPLX1 hgnc:2309

Readouts

Spontaneous and evoked release readouts

pathophysiology#Dysregulated SNARE-Mediated Vesicle Fusion

synaptic vesicle exocytosis GO:0016079 ↕ DYSREGULATED calcium-dependent activation of synaptic vesicle fusion GO:0099502 ↕ DYSREGULATED

patch-clamp electrophysiology

Direction: POSITIVE

Controls

Wild-type complexin-1 rescue

CPLX1-null neurons rescued with wild-type human complexin-1.

Isogenic wild-type neurons

Isogenic CPLX1-intact neurons from the same iPSC background.

Decision criterion

The clamp arm dominates if the pathogenic defect is a selective rise in spontaneous release rescued only by clamp-competent complexin-1; the facilitator arm dominates if the defect is a selective loss of evoked release rescued only by facilitation-competent complexin-1.

Would support

pathophysiology#Dysregulated SNARE-Mediated Vesicle Fusion

Show evidence (2 references)

PMID:19164751 SUPPORT Model Organism

"complexin simultaneously suppressed spontaneous fusion and activated fast calcium ion-evoked fusion"

Establishes complexin's dual clamp (suppresses spontaneous) and facilitator (activates evoked) function, the two arms whose relative contribution to CPLX1 disease is the open question.

PMID:32559416 SUPPORT Other

"Neuronal SNAREs and their key regulators together drive synaptic vesicle exocytosis and synaptic transmission as a single integrated membrane fusion machine."

Frames complexin-1 as a key SNARE regulator within the fusion machine, whose specific loss-of-function mode is unresolved.

Is biallelic CPLX1 loss best defined as a developmental and epileptic encephalopathy, as a progressive neurodegenerative/movement disorder, or as a single spectrum encompassing both — and what determines which phenotype predominates in a given patient?

KNOWLEDGE GAP OPEN gap_cplx1_phenotype_boundary_dee_versus_neurodegeneration

Attached to

pathophysiology#Complexin-1 Loss of Function pathophysiology#Cortical Hyperexcitability and Seizures

Reported CPLX1-null individuals show a complex and variable phenotype spanning severe infantile epileptic encephalopathy, developmental impairment, structural brain changes, and (in the mouse) prominent ataxia/movement features. Whether the human disorder is fundamentally an epileptic encephalopathy, a neurodegenerative/movement disorder, or a unified spectrum is a genuine phenotype-definition (lump/split) gap that is currently unresolvable from the small published cohort and affects how this entry's boundaries and downstream nodes should be drawn.

Proposed experiments

CPLX1 natural-history and genotype-phenotype cohort

natural-history cohort study

exp_cplx1_natural_history_genotype_phenotype_cohort

Assemble an international cohort of biallelic CPLX1 cases with standardized longitudinal phenotyping (seizure semiology and course, motor/movement features, developmental trajectory, and serial neuroimaging) to test whether epileptic and neurodegenerative/movement features co-segregate or define distinct subgroups, and whether variant class predicts phenotype.

Readouts

Longitudinal phenotype and course readouts

pathophysiology#Cortical Hyperexcitability and Seizures

chemical synaptic transmission GO:0007268 ⚠ ABNORMAL

electroencephalography magnetic resonance imaging

Direction: POSITIVE

Controls

Other synaptic vesicle cycle disorders

Comparison cohorts with STXBP1, SNAP25, STX1B, or SYT1 disorders to contextualize the CPLX1 phenotype spectrum.

Decision criterion

A unified spectrum is supported if epileptic and movement/neurodegenerative features consistently co-occur across cases; a split is supported if distinct, variant-correlated subgroups emerge.

Would support

pathophysiology#Cortical Hyperexcitability and Seizures

Show evidence (2 references)

PMID:28422131 SUPPORT Human Clinical

"loss of complexin 1 function may lead to a complex but variable clinical phenotype"

The reporting authors explicitly flag phenotypic variability, motivating the phenotype-definition gap.

PMID:28422131 SUPPORT Human Clinical

"All displayed marked developmental delay and migrating myoclonic epilepsy, and one showed a cerebellar cleft in addition."

Documents the mixed epileptic, developmental, and structural/cerebellar features underlying the lump/split question.

How faithfully does the Cplx1-knockout mouse — dominated by ataxia and a movement phenotype with variable seizures — model the human CPLX1 epileptic encephalopathy, versus mainly recapitulating the motor arm of the disease?

HUMAN MODEL MISMATCH OPEN gap_cplx1_mouse_model_fidelity_to_human_encephalopathy

Attached to

pathophysiology#Cortical Hyperexcitability and Seizures

The principal in vivo evidence for CPLX1 loss is the Cplx1-knockout mouse, whose most striking, earliest phenotype is ataxia (a cerebellar/motor feature) rather than the severe cortical epileptic encephalopathy that defines the human disorder. This is a translational-fidelity mismatch: the model clearly demonstrates that complexin-1 loss is neurologically catastrophic, but whether it reproduces the human seizure/cortical phenotype — as opposed to a predominantly movement phenotype — is the open question, so its evidence weight for the seizure node should be qualified.

Proposed experiments

CPLX1 cross-species network-excitability comparison

cross-species network-excitability comparison

exp_cplx1_cross_species_network_excitability_comparison

Directly compare cortical network excitability and seizure-like activity between Cplx1-knockout mouse cortical preparations and human CPLX1-null iPSC-derived cortical neurons/organoids, to test whether the human cortical hyperexcitability phenotype is reproduced by the mouse or is human-specific.

Perturbations

CPLX1 loss of function across species

pathophysiology#Cortical Hyperexcitability and Seizures

Cplx1-knockout mouse cortex versus isogenic human CPLX1-null cortical neurons/organoids.

CPLX1 hgnc:2309

Readouts

Network hyperexcitability readouts

pathophysiology#Cortical Hyperexcitability and Seizures

trans-synaptic signaling GO:0099537 ↕ DYSREGULATED chemical synaptic transmission GO:0007268 ⚠ ABNORMAL

multielectrode array recording

Direction: POSITIVE

Controls

Isogenic wild-type human neurons

CPLX1-intact human neurons from the same iPSC background.

Wild-type mouse cortex

Cplx1 wild-type littermate cortical preparations.

Decision criterion

The mouse is a faithful model of the human seizure phenotype if Cplx1-null mouse cortex shows network hyperexcitability matching human CPLX1-null cortical neurons; a human-specific cortical phenotype is supported if hyperexcitability appears in human but not mouse preparations.

Would support

pathophysiology#Cortical Hyperexcitability and Seizures

Show evidence (1 reference)

PMID:28422131 SUPPORT Model Organism

"homozygous Cplx1 knockout mice have the earliest known onset of ataxia seen in a mouse model."

Shows the mouse phenotype is dominated by early ataxia, not the cortical epilepsy that defines the human disorder — the basis of the mismatch.

⚙

Pathophysiology

3

Complexin-1 Loss of Function

Biallelic loss-of-function variants in CPLX1 abolish complexin-1, a cytosolic protein crucially involved in neuronal synaptic regulation. Complexin-1 binds the assembled SNARE complex, acting as a fusion clamp and a facilitator of calcium-triggered release, so its loss removes a key regulator of the fusion machinery.

neuron CL:0000540

synaptic vesicle cycle GO:0099504 ⚠ ABNORMAL

brain UBERON:0000955

Downstream

Dysregulated SNARE-Mediated Vesicle Fusion

Show evidence (2 references)

PMID:28422131 SUPPORT Human Clinical

"The encoded protein, complexin 1, is crucially involved in neuronal synaptic regulation, and homozygous Cplx1 knockout mice have the earliest known onset of ataxia seen in a mouse model."

Identifies complexin-1 as a synaptic regulator whose loss causes neurological disease, the trigger of this node.

PMID:28422131 SUPPORT Human Clinical

"loss of complexin 1 function may lead to a complex but variable clinical phenotype"

Frames the disorder as a loss-of-complexin-1-function condition.

Dysregulated SNARE-Mediated Vesicle Fusion

Complexin-1 is a key regulator of the SNARE fusion machine: it clamps the assembled SNARE complex to prevent premature vesicle fusion and, together with synaptotagmin-1, synchronizes calcium-triggered release. Loss of complexin-1 dysregulates calcium-triggered SNARE-mediated fusion, degrading the temporal control of neurotransmitter release. This is the module's key conformance target — the fusion-machinery arm, here at the level of the SNARE-complex regulator rather than a SNARE subunit.

neuron CL:0000540

calcium-dependent activation of synaptic vesicle fusion GO:0099502 ↕ DYSREGULATED synaptic vesicle exocytosis GO:0016079 ↕ DYSREGULATED

Downstream

Cortical Hyperexcitability and Seizures

Show evidence (2 references)

PMID:32559416 SUPPORT Other

"Neuronal SNAREs and their key regulators together drive synaptic vesicle exocytosis and synaptic transmission as a single integrated membrane fusion machine."

Establishes complexin-1 (a key SNARE regulator) as part of the integrated fusion machine impaired in this disorder.

PMID:28422131 SUPPORT Human Clinical

"The encoded protein, complexin 1, is crucially involved in neuronal synaptic regulation"

Links complexin-1's synaptic-regulatory (fusion-clamp) role to the disorder.

Cortical Hyperexcitability and Seizures

Dysregulated, poorly synchronized neurotransmitter release disturbs cortical excitatory/inhibitory balance, producing neuronal hyperexcitability and a severe infantile epilepsy (migrating myoclonic seizures), together with impaired activity-dependent neurodevelopment.

neuron CL:0000540

chemical synaptic transmission GO:0007268 ⚠ ABNORMAL

brain UBERON:0000955

Downstream

Epilepsy

Global Developmental Delay

Show evidence (1 reference)

PMID:28422131 SUPPORT Human Clinical

"All displayed marked developmental delay and migrating myoclonic epilepsy, and one showed a cerebellar cleft in addition."

Documents the severe epilepsy (migrating myoclonic seizures) and developmental impairment produced by the disorder.

⬡

Pathograph

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

●

Phenotypes

3

Nervous System 2

Global Developmental Delay HP:0001263

Show evidence (1 reference)

PMID:28422131 SUPPORT Human Clinical

"All displayed marked developmental delay and migrating myoclonic epilepsy"

Documents marked developmental delay as a universal feature.

Intellectual Disability HP:0001249

Show evidence (1 reference)

PMID:28422131 SUPPORT Human Clinical

"identified homozygous CPLX1 variants in three patients with ID from two unrelated families."

Documents intellectual disability in the affected individuals.

Other 1

Epilepsy Myoclonic seizure HP:0032794

Show evidence (1 reference)

PMID:28422131 SUPPORT Human Clinical

"All displayed marked developmental delay and migrating myoclonic epilepsy, and one showed a cerebellar cleft in addition."

Documents migrating myoclonic epilepsy as a core feature.

🧬

Genetic Associations

1

CPLX1 (Loss-of-Function Mutations)

Gene: CPLX1 hgnc:2309 variant_origin: GERMLINE

Autosomal Recessive

Show evidence (1 reference)

PMID:28422131 SUPPORT Human Clinical

"Recently, a homozygous truncating variant in CPLX1 was suggested to be causative for migrating epilepsy and structural brain abnormalities."

Corroborates biallelic loss-of-function CPLX1 as causative of migrating epilepsy with brain abnormalities.

💊

Medical Actions

3

Antiseizure Medication

Action: Pharmacotherapy NCIT:C15986

Agent: levetiracetam CHEBI:6437

Seizures are managed with antiseizure medications; the severe migrating myoclonic epilepsy is often refractory.

Supportive and Developmental Care

Action: Supportive Care NCIT:C15747

Multidisciplinary supportive care with developmental therapies is the mainstay.

Genetic Counseling

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

Genetic counseling addresses the autosomal-recessive inheritance and 25% sibling recurrence risk.

🔬

Diagnosis

1

CPLX1 Molecular Diagnosis

Diagnosis is established by identifying biallelic pathogenic CPLX1 loss-of-function variants in a child with severe infantile epilepsy and developmental impairment.

molecular genetic testing NCIT:C19770

Results: Biallelic pathogenic CPLX1 loss-of-function variants establish the diagnosis.

Show evidence (1 reference)

PMID:28422131 SUPPORT Human Clinical

"we performed trio-based WES in 311 patients with unsolved ID and additional clinical features, and identified homozygous CPLX1 variants in three patients"

Whole-exome sequencing established the molecular diagnosis of homozygous CPLX1 variants.

📈

Progression

1

Infancy

Onset is in infancy with severe migrating myoclonic epilepsy and marked developmental delay; a structural brain abnormality (cerebellar cleft) was present in one individual.

Show evidence (1 reference)

PMID:28422131 SUPPORT Human Clinical

"All displayed marked developmental delay and migrating myoclonic epilepsy, and one showed a cerebellar cleft in addition."

Documents the infantile-onset severe epilepsy and developmental course.

📊

Prevalence

1

Worldwide

Unknown Ultra Rare

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

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from CPLX1-Related Developmental and Epileptic Encephalopathy:

Other causes of epilepsy of infancy with migrating focal seizures

Overlapping Features Migrating seizures of infancy are genetically heterogeneous (e.g. KCNT1, SCN2A); CPLX1 disease is distinguished by biallelic loss-of-function variants and the recessive inheritance.

Distinguishing Features

Biallelic CPLX1 loss-of-function variants favor this disorder.
A variant in another migrating-seizure gene (e.g. KCNT1) favors that diagnosis.

Other synaptic vesicle cycle disorders

Overlapping Features Other synaptic vesicle cycle / SNAREopathy disorders (STXBP1, SNAP25, STX1B, VAMP2, SYT1) overlap through early-onset epilepsy and developmental impairment and are distinguished by molecular testing.

Distinguishing Features

Biallelic CPLX1 loss-of-function variants favor this disorder.
A variant in another vesicle-cycle gene favors the corresponding disorder.

🐁

Animal Models

1

Cplx1 knockout Mouse (Mus musculus)

Homozygous Cplx1 knockout mice have the earliest known onset of ataxia seen in a mouse model, demonstrating the essential role of complexin-1 in synaptic function.

Species

Mouse (Mus musculus)

Genotype

Cplx1 knockout

Show evidence (1 reference)

PMID:28422131 SUPPORT Model Organism

"homozygous Cplx1 knockout mice have the earliest known onset of ataxia seen in a mouse model."

The Cplx1 knockout mouse establishes the neurological consequence of complexin-1 loss.

{ }

Source YAML

click to show

name: CPLX1-Related Developmental and Epileptic Encephalopathy
creation_date: "2026-07-06T00:00:00Z"
description: >-
  An autosomal-recessive developmental and epileptic encephalopathy caused by
  biallelic loss-of-function variants in CPLX1, which encodes complexin-1, a
  cytosolic regulator of the neuronal SNARE complex. Complexin-1 both clamps the
  assembled SNARE complex to prevent premature fusion and cooperates with the
  calcium sensor synaptotagmin-1 to synchronize calcium-triggered synaptic vesicle
  fusion; loss of complexin-1 dysregulates neurotransmitter release. Affected
  individuals present with marked developmental delay, intellectual disability, and
  a severe infantile epilepsy (migrating myoclonic seizures). It is one of the
  synaptic vesicle cycle disorders and completes the fusion-machinery arm of the
  module, representing the SNARE-complex regulator/fusion clamp alongside the SNARE
  subunits (SNAP25, STX1B, VAMP2) and the calcium sensor (SYT1).
category: Mendelian
parents:
- Neurodevelopmental Disorder
- Epileptic Encephalopathy
disease_term:
  preferred_term: CPLX1 developmental and epileptic encephalopathy
  term:
    id: MONDO:0033372
    label: developmental and epileptic encephalopathy, 63
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: ULTRA_RARE
  notes: >-
    Ultra-rare autosomal-recessive developmental and epileptic encephalopathy; precise population prevalence not established.
references:
- reference: PMID:28422131
  title: "Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID."
- reference: PMID:32559416
  title: "SNAREopathies: Diversity in Mechanisms and Symptoms."
inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    The disorder is caused by biallelic (homozygous) loss-of-function CPLX1
    variants, identified in consanguineous/unrelated families.
  evidence:
  - reference: PMID:28422131
    reference_title: "Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      identified homozygous CPLX1 variants in three patients with ID from two
      unrelated families.
    explanation: >-
      Establishes the autosomal-recessive (homozygous) genetic basis.
pathophysiology:
- name: Complexin-1 Loss of Function
  conforms_to: "synaptic_vesicle_cycle#Synaptic Vesicle Cycle Protein Deficiency"
  description: >-
    Biallelic loss-of-function variants in CPLX1 abolish complexin-1, a cytosolic
    protein crucially involved in neuronal synaptic regulation. Complexin-1 binds
    the assembled SNARE complex, acting as a fusion clamp and a facilitator of
    calcium-triggered release, so its loss removes a key regulator of the fusion
    machinery.
  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:28422131
    reference_title: "Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The encoded protein, complexin 1, is crucially involved in neuronal synaptic
      regulation, and homozygous Cplx1 knockout mice have the earliest known onset
      of ataxia seen in a mouse model.
    explanation: >-
      Identifies complexin-1 as a synaptic regulator whose loss causes neurological
      disease, the trigger of this node.
  - reference: PMID:28422131
    reference_title: "Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      loss of complexin 1 function may lead to a complex but variable clinical
      phenotype
    explanation: >-
      Frames the disorder as a loss-of-complexin-1-function condition.
  downstream:
  - target: Dysregulated SNARE-Mediated Vesicle Fusion
    causal_link_type: DIRECT
- name: Dysregulated SNARE-Mediated Vesicle Fusion
  conforms_to: "synaptic_vesicle_cycle#Impaired Calcium-Triggered SNARE-Mediated Vesicle Fusion"
  description: >-
    Complexin-1 is a key regulator of the SNARE fusion machine: it clamps the
    assembled SNARE complex to prevent premature vesicle fusion and, together with
    synaptotagmin-1, synchronizes calcium-triggered release. Loss of complexin-1
    dysregulates calcium-triggered SNARE-mediated fusion, degrading the temporal
    control of neurotransmitter release. This is the module's key conformance
    target — the fusion-machinery arm, here at the level of the SNARE-complex
    regulator rather than a SNARE subunit.
  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: DYSREGULATED
  - preferred_term: synaptic vesicle exocytosis
    term:
      id: GO:0016079
      label: synaptic vesicle exocytosis
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:32559416
    reference_title: "SNAREopathies: Diversity in Mechanisms and Symptoms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Neuronal SNAREs and their key regulators together drive synaptic vesicle
      exocytosis and synaptic transmission as a single integrated membrane fusion
      machine.
    explanation: >-
      Establishes complexin-1 (a key SNARE regulator) as part of the integrated
      fusion machine impaired in this disorder.
  - reference: PMID:28422131
    reference_title: "Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The encoded protein, complexin 1, is crucially involved in neuronal synaptic
      regulation
    explanation: >-
      Links complexin-1's synaptic-regulatory (fusion-clamp) role to the disorder.
  downstream:
  - target: Cortical Hyperexcitability and Seizures
    causal_link_type: DIRECT
- name: Cortical Hyperexcitability and Seizures
  conforms_to: "epilepsy_excitation_inhibition_imbalance#Neuronal Hyperexcitability and Hypersynchrony"
  description: >-
    Dysregulated, poorly synchronized neurotransmitter release disturbs cortical
    excitatory/inhibitory balance, producing neuronal hyperexcitability and a severe
    infantile epilepsy (migrating myoclonic seizures), together with 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: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:28422131
    reference_title: "Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All displayed marked developmental delay and migrating myoclonic epilepsy,
      and one showed a cerebellar cleft in addition.
    explanation: >-
      Documents the severe epilepsy (migrating myoclonic seizures) and
      developmental impairment produced by the disorder.
  downstream:
  - target: Epilepsy
    causal_link_type: DIRECT
  - target: Global Developmental Delay
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Impaired activity-dependent synaptic transmission during development.
phenotypes:
- name: Epilepsy
  category: Clinical
  description: >-
    Severe infantile epilepsy with migrating myoclonic seizures.
  diagnostic: true
  phenotype_term:
    preferred_term: Myoclonic seizure
    term:
      id: HP:0032794
      label: Myoclonic seizure
  evidence:
  - reference: PMID:28422131
    reference_title: "Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All displayed marked developmental delay and migrating myoclonic epilepsy,
      and one showed a cerebellar cleft in addition.
    explanation: >-
      Documents migrating myoclonic epilepsy as a core feature.
- name: Global Developmental Delay
  category: Clinical
  description: >-
    Marked developmental delay in all affected individuals.
  diagnostic: true
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:28422131
    reference_title: "Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All displayed marked developmental delay and migrating myoclonic epilepsy
    explanation: >-
      Documents marked developmental delay as a universal feature.
- name: Intellectual Disability
  category: Clinical
  description: >-
    Intellectual disability accompanies the developmental delay.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:28422131
    reference_title: "Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      identified homozygous CPLX1 variants in three patients with ID from two
      unrelated families.
    explanation: >-
      Documents intellectual disability in the affected individuals.
genetic:
- name: CPLX1
  gene_term:
    preferred_term: CPLX1
    term:
      id: hgnc:2309
      label: CPLX1
  association: Loss-of-Function Mutations
  presence: Positive
  variant_origin: GERMLINE
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  notes: >-
    Biallelic (homozygous) loss-of-function CPLX1 variants, including truncating
    variants, cause the disorder; a homozygous truncating variant was also
    independently linked to migrating epilepsy and structural brain abnormalities.
  evidence:
  - reference: PMID:28422131
    reference_title: "Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recently, a homozygous truncating variant in CPLX1 was suggested to be
      causative for migrating epilepsy and structural brain abnormalities.
    explanation: >-
      Corroborates biallelic loss-of-function CPLX1 as causative of migrating
      epilepsy with brain abnormalities.
diagnosis:
- name: CPLX1 Molecular Diagnosis
  description: >-
    Diagnosis is established by identifying biallelic pathogenic CPLX1
    loss-of-function variants in a child with severe infantile epilepsy and
    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: CPLX1
        term:
          id: hgnc:2309
          label: CPLX1
  results: Biallelic pathogenic CPLX1 loss-of-function variants establish the diagnosis.
  evidence:
  - reference: PMID:28422131
    reference_title: "Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we performed trio-based WES in 311 patients with unsolved ID and additional
      clinical features, and identified homozygous CPLX1 variants in three patients
    explanation: >-
      Whole-exome sequencing established the molecular diagnosis of homozygous
      CPLX1 variants.
differential_diagnoses:
- name: Other causes of epilepsy of infancy with migrating focal seizures
  description: >-
    Migrating seizures of infancy are genetically heterogeneous (e.g. KCNT1,
    SCN2A); CPLX1 disease is distinguished by biallelic loss-of-function variants
    and the recessive inheritance.
  distinguishing_features:
  - Biallelic CPLX1 loss-of-function variants favor this disorder.
  - A variant in another migrating-seizure gene (e.g. KCNT1) favors that diagnosis.
- name: Other synaptic vesicle cycle disorders
  description: >-
    Other synaptic vesicle cycle / SNAREopathy disorders (STXBP1, SNAP25, STX1B,
    VAMP2, SYT1) overlap through early-onset epilepsy and developmental impairment
    and are distinguished by molecular testing.
  distinguishing_features:
  - Biallelic CPLX1 loss-of-function variants favor this disorder.
  - A variant in another vesicle-cycle gene favors the corresponding disorder.
animal_models:
- species: Mouse (Mus musculus)
  genotype: Cplx1 knockout
  description: >-
    Homozygous Cplx1 knockout mice have the earliest known onset of ataxia seen in
    a mouse model, demonstrating the essential role of complexin-1 in synaptic
    function.
  evidence:
  - reference: PMID:28422131
    reference_title: "Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      homozygous Cplx1 knockout mice have the earliest known onset of ataxia seen
      in a mouse model.
    explanation: >-
      The Cplx1 knockout mouse establishes the neurological consequence of
      complexin-1 loss.
progression:
- phase: Infancy
  notes: >-
    Onset is in infancy with severe migrating myoclonic epilepsy and marked
    developmental delay; a structural brain abnormality (cerebellar cleft) was
    present in one individual.
  evidence:
  - reference: PMID:28422131
    reference_title: "Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All displayed marked developmental delay and migrating myoclonic epilepsy,
      and one showed a cerebellar cleft in addition.
    explanation: >-
      Documents the infantile-onset severe epilepsy and developmental course.
treatments:
- name: Antiseizure Medication
  description: >-
    Seizures are managed with antiseizure medications; the severe migrating
    myoclonic epilepsy is often refractory.
  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
- name: Supportive and Developmental Care
  description: >-
    Multidisciplinary supportive care with developmental therapies is the mainstay.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Genetic Counseling
  description: >-
    Genetic counseling addresses the autosomal-recessive inheritance and 25%
    sibling recurrence risk.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
discussions:
- discussion_id: gap_cplx1_clamp_versus_facilitator_dominant_lesion
  prompt: >-
    Complexin-1 both clamps spontaneous vesicle fusion and facilitates fast
    calcium-evoked release; which arm of this dual function, when lost in CPLX1
    disease, dominates the pathogenic synaptic defect — disinhibited spontaneous
    release, failed evoked release, or both?
  kind: OPEN_QUESTION
  status: OPEN
  attaches_to:
  - pathophysiology#Dysregulated SNARE-Mediated Vesicle Fusion
  rationale: >-
    Complexin's dual clamp/facilitator function means CPLX1 loss can degrade
    synaptic transmission by two mechanistically opposite routes: unclamping
    spontaneous (calcium-independent) fusion, and abolishing the synchronized
    calcium-triggered evoked release. These have different predicted circuit
    consequences (tonic noise versus loss of phasic drive), so which
    predominates in human CPLX1-null neurons is unresolved and bears directly on
    how the "dysregulated fusion" node should be interpreted and, ultimately, on
    rational therapy.
  evidence:
  - reference: PMID:19164751
    reference_title: Complexin controls the force transfer from SNARE complexes to membranes in fusion.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      complexin simultaneously suppressed spontaneous fusion and activated fast
      calcium ion-evoked fusion
    explanation: >-
      Establishes complexin's dual clamp (suppresses spontaneous) and
      facilitator (activates evoked) function, the two arms whose relative
      contribution to CPLX1 disease is the open question.
  - reference: PMID:32559416
    reference_title: "SNAREopathies: Diversity in Mechanisms and Symptoms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Neuronal SNAREs and their key regulators together drive synaptic vesicle
      exocytosis and synaptic transmission as a single integrated membrane
      fusion machine.
    explanation: >-
      Frames complexin-1 as a key SNARE regulator within the fusion machine,
      whose specific loss-of-function mode is unresolved.
  proposed_experiments:
  - experiment_id: exp_cplx1_spontaneous_versus_evoked_release_dissection
    name: CPLX1-null human neuron spontaneous-versus-evoked release dissection
    description: >-
      In CPLX1-null human iPSC-derived neurons, quantify spontaneous
      (miniature) release frequency and fast calcium-evoked release amplitude,
      then rescue with wild-type complexin-1 versus separation-of-function
      mutants that selectively restore clamping or facilitation, to attribute
      the pathogenic defect to a specific arm.
    experiment_type:
      preferred_term: electrophysiological release-mode dissection experiment
    perturbations:
    - name: CPLX1 knockout and separation-of-function rescue
      target: pathophysiology#Dysregulated SNARE-Mediated Vesicle Fusion
      genes:
      - preferred_term: CPLX1
        term:
          id: hgnc:2309
          label: CPLX1
      description: >-
        Compare CPLX1-null neurons rescued with wild-type complexin-1 versus
        clamp-selective or facilitation-selective complexin-1 variants.
    readouts:
    - name: Spontaneous and evoked release readouts
      target: pathophysiology#Dysregulated SNARE-Mediated Vesicle Fusion
      biological_processes:
      - preferred_term: synaptic vesicle exocytosis
        term:
          id: GO:0016079
          label: synaptic vesicle exocytosis
        modifier: DYSREGULATED
      - preferred_term: calcium-dependent activation of synaptic vesicle fusion
        term:
          id: GO:0099502
          label: calcium-dependent activation of synaptic vesicle fusion
        modifier: DYSREGULATED
      assays:
      - preferred_term: patch-clamp electrophysiology
      direction: POSITIVE
    controls:
    - name: Wild-type complexin-1 rescue
      description: CPLX1-null neurons rescued with wild-type human complexin-1.
    - name: Isogenic wild-type neurons
      description: Isogenic CPLX1-intact neurons from the same iPSC background.
    decision_criterion: >-
      The clamp arm dominates if the pathogenic defect is a selective rise in
      spontaneous release rescued only by clamp-competent complexin-1; the
      facilitator arm dominates if the defect is a selective loss of evoked
      release rescued only by facilitation-competent complexin-1.
    would_support:
    - pathophysiology#Dysregulated SNARE-Mediated Vesicle Fusion
- discussion_id: gap_cplx1_phenotype_boundary_dee_versus_neurodegeneration
  prompt: >-
    Is biallelic CPLX1 loss best defined as a developmental and epileptic
    encephalopathy, as a progressive neurodegenerative/movement disorder, or as
    a single spectrum encompassing both — and what determines which phenotype
    predominates in a given patient?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Complexin-1 Loss of Function
  - pathophysiology#Cortical Hyperexcitability and Seizures
  rationale: >-
    Reported CPLX1-null individuals show a complex and variable phenotype
    spanning severe infantile epileptic encephalopathy, developmental
    impairment, structural brain changes, and (in the mouse) prominent
    ataxia/movement features. Whether the human disorder is fundamentally an
    epileptic encephalopathy, a neurodegenerative/movement disorder, or a
    unified spectrum is a genuine phenotype-definition (lump/split) gap that is
    currently unresolvable from the small published cohort and affects how this
    entry's boundaries and downstream nodes should be drawn.
  evidence:
  - reference: PMID:28422131
    reference_title: "Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      loss of complexin 1 function may lead to a complex but variable clinical
      phenotype
    explanation: >-
      The reporting authors explicitly flag phenotypic variability, motivating
      the phenotype-definition gap.
  - reference: PMID:28422131
    reference_title: "Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All displayed marked developmental delay and migrating myoclonic epilepsy,
      and one showed a cerebellar cleft in addition.
    explanation: >-
      Documents the mixed epileptic, developmental, and structural/cerebellar
      features underlying the lump/split question.
  proposed_experiments:
  - experiment_id: exp_cplx1_natural_history_genotype_phenotype_cohort
    name: CPLX1 natural-history and genotype-phenotype cohort
    description: >-
      Assemble an international cohort of biallelic CPLX1 cases with
      standardized longitudinal phenotyping (seizure semiology and course,
      motor/movement features, developmental trajectory, and serial
      neuroimaging) to test whether epileptic and neurodegenerative/movement
      features co-segregate or define distinct subgroups, and whether variant
      class predicts phenotype.
    experiment_type:
      preferred_term: natural-history cohort study
    readouts:
    - name: Longitudinal phenotype and course readouts
      target: pathophysiology#Cortical Hyperexcitability and Seizures
      biological_processes:
      - preferred_term: chemical synaptic transmission
        term:
          id: GO:0007268
          label: chemical synaptic transmission
        modifier: ABNORMAL
      assays:
      - preferred_term: electroencephalography
      - preferred_term: magnetic resonance imaging
      direction: POSITIVE
    controls:
    - name: Other synaptic vesicle cycle disorders
      description: >-
        Comparison cohorts with STXBP1, SNAP25, STX1B, or SYT1 disorders to
        contextualize the CPLX1 phenotype spectrum.
    decision_criterion: >-
      A unified spectrum is supported if epileptic and movement/neurodegenerative
      features consistently co-occur across cases; a split is supported if
      distinct, variant-correlated subgroups emerge.
    would_support:
    - pathophysiology#Cortical Hyperexcitability and Seizures
- discussion_id: gap_cplx1_mouse_model_fidelity_to_human_encephalopathy
  prompt: >-
    How faithfully does the Cplx1-knockout mouse — dominated by ataxia and a
    movement phenotype with variable seizures — model the human CPLX1 epileptic
    encephalopathy, versus mainly recapitulating the motor arm of the disease?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Cortical Hyperexcitability and Seizures
  rationale: >-
    The principal in vivo evidence for CPLX1 loss is the Cplx1-knockout mouse,
    whose most striking, earliest phenotype is ataxia (a cerebellar/motor
    feature) rather than the severe cortical epileptic encephalopathy that
    defines the human disorder. This is a translational-fidelity mismatch: the
    model clearly demonstrates that complexin-1 loss is neurologically
    catastrophic, but whether it reproduces the human seizure/cortical
    phenotype — as opposed to a predominantly movement phenotype — is the open
    question, so its evidence weight for the seizure node should be qualified.
  evidence:
  - reference: PMID:28422131
    reference_title: "Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      homozygous Cplx1 knockout mice have the earliest known onset of ataxia
      seen in a mouse model.
    explanation: >-
      Shows the mouse phenotype is dominated by early ataxia, not the cortical
      epilepsy that defines the human disorder — the basis of the mismatch.
  proposed_experiments:
  - experiment_id: exp_cplx1_cross_species_network_excitability_comparison
    name: CPLX1 cross-species network-excitability comparison
    description: >-
      Directly compare cortical network excitability and seizure-like activity
      between Cplx1-knockout mouse cortical preparations and human CPLX1-null
      iPSC-derived cortical neurons/organoids, to test whether the human cortical
      hyperexcitability phenotype is reproduced by the mouse or is human-specific.
    experiment_type:
      preferred_term: cross-species network-excitability comparison
    perturbations:
    - name: CPLX1 loss of function across species
      target: pathophysiology#Cortical Hyperexcitability and Seizures
      genes:
      - preferred_term: CPLX1
        term:
          id: hgnc:2309
          label: CPLX1
      description: >-
        Cplx1-knockout mouse cortex versus isogenic human CPLX1-null cortical
        neurons/organoids.
    readouts:
    - name: Network hyperexcitability readouts
      target: pathophysiology#Cortical Hyperexcitability and Seizures
      biological_processes:
      - preferred_term: trans-synaptic signaling
        term:
          id: GO:0099537
          label: trans-synaptic signaling
        modifier: DYSREGULATED
      - preferred_term: chemical synaptic transmission
        term:
          id: GO:0007268
          label: chemical synaptic transmission
        modifier: ABNORMAL
      assays:
      - preferred_term: multielectrode array recording
      direction: POSITIVE
    controls:
    - name: Isogenic wild-type human neurons
      description: CPLX1-intact human neurons from the same iPSC background.
    - name: Wild-type mouse cortex
      description: Cplx1 wild-type littermate cortical preparations.
    decision_criterion: >-
      The mouse is a faithful model of the human seizure phenotype if
      Cplx1-null mouse cortex shows network hyperexcitability matching human
      CPLX1-null cortical neurons; a human-specific cortical phenotype is
      supported if hyperexcitability appears in human but not mouse preparations.
    would_support:
    - pathophysiology#Cortical Hyperexcitability and Seizures

📚

References & Deep Research

References

2

PMID:28422131

Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.

No top-level findings curated for this source.

PMID:32559416

SNAREopathies: Diversity in Mechanisms and Symptoms.

No top-level findings curated for this source.

CPLX1-Related Developmental and Epileptic Encephalopathy

Ask OpenScientist

OpenScientist Report

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Progression

Prevalence

Differential Diagnoses

Animal Models

Source YAML

References & Deep Research

References