CACNA1E-Related Developmental and Epileptic Encephalopathy

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Inheritance

1

Autosomal Dominant (De Novo) HP:0000006

Heterozygous missense variants typically arise de novo. The discovery series confirmed de novo status in 29/30 probands; both parental samples were unavailable for the remaining proband. Variant interpretation and parental testing are required rather than assuming every rare CACNA1E variant is causal.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Molecular genetic testing identified 14 missense variants in CACNA1E (GenBank: NM_000721.3) in 30 unrelated individuals (Table 1). For the 29/30 individuals for whom DNA samples were available for both parents, de novo status of the variants and parentage were confirmed."

Thirty missense-variant probands were reported, with de novo status confirmed in all 29 with both parental samples.

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Subtypes

3

Domain I S6 (p.Gly352Arg hotspot)

CACNA1E hgnc:1392

Cohort-derived domain I S6 group, particularly Gly352Arg and Gly348Arg. All ten such cases in the original series had prominent dystonia, compared with 2/19 other probands. This association is useful for recognition but is not a validated deterministic prognostic classification.

Show evidence (1 reference)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Dystonia was a prominent feature in all nine individuals with the recurrent c.1054G>A (p.Gly352Arg) variant. This variant is in close proximity to the c.1042G>C (p.Gly348Arg) variant in individual 2 who also demonstrated profound dystonia. Dystonia was less common in individuals with other..."

The original cohort associated Gly352Arg/Gly348Arg with dystonia, without establishing a deterministic domain-wide prognosis.

Domain II S6 (p.Ala702Thr hotspot)

CACNA1E hgnc:1392

Cohort-derived domain II S6 group. Six Ala702Thr cases in the original series had profound impairment and refractory epilepsy. Other substitutions, including Ala702Ser and Ala702Val, occur in the broader, milder CACNA1E spectrum, so domain or residue alone cannot predict severity.

Show evidence (2 references)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The six individuals harboring the recurrent c.2104G>A (p.Ala702Thr) variant had a relatively homogeneous phenotype that was representative of the overall CACNA1E-encephalopathy phenotype. All individuals had refractory infantile-onset epilepsy, epileptic spasms, severe hypotonia, and profound..."

The six Ala702Thr cases shared a severe course; this does not establish the prognosis of other substitutions at residue 702.

PMID:34702355 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Age of onset of clinical manifestation, presence or absence of regression and degree of severity were variable, and no clear-cut genotype-phenotype association could be recognized."

The broader cohort cautions against treating the original domain groups as a universal prognostic taxonomy.

Domain III S6 (milder phenotype)

CACNA1E hgnc:1392

Comparatively mild domain III S6 cases in the original series carried Thr1425Asn or Gly1430Arg. Two had no seizures by age four; one was seizure-free for five years and off medication at age six. Single words and independent or assisted walking were achieved. These observations describe a spectrum boundary and do not imply lifetime seizure absence for all DIII-S6 variants.

Show evidence (1 reference)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Two individuals harboring the c.4274C>A (p.Thr1425Asn) variant and one individual with the c.4288G>A (p.Gly1430Arg) variant presented with a comparatively milder clinical picture. All three probands were the only individuals in the cohort to speak single words and walk independently or with..."

Three DIII-S6 cases were comparatively milder; two had not seized by age four and one had sustained remission. Walking could be assisted.

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Discussions and Knowledge Gaps

3

Can variant-specific Cav2.3 modulation improve seizures and developmental outcomes safely?

KNOWLEDGE GAP OPEN gap_cacna1e_rtype_blocker_precision_therapy

Attached to

pathophysiology#Increased R-Type Calcium Entry pathophysiology#Facilitated Cav2.3 Activation

Topiramate responses are heterogeneous and uncontrolled, with relapses and sedation; its multiple actions prevent attribution of benefit solely to Cav2.3 blockade. The CDKL5 study proposes inhibitor testing rather than demonstrating pharmacological rescue. Loss-of-function alleles in the broader spectrum further argue for functional assessment before assuming one therapeutic direction.

Show evidence (3 references)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Two individuals (16 and 27) remain seizure free for 2 and 5 years, respectively. However, in individuals 15 and 21, seizures eventually recurred after seizure-free periods of 4 years and 18 months, respectively; individual 21 died following an episode of status epilepticus. Individual 1 reported..."

The detailed results report ongoing benefit, later relapse, sedation-related discontinuation, ten nonresponders and three reductions without seizure freedom.

PMID:42123681 SUPPORT DIRECT PRIMARY RESULT In Vitro

"M163T and R1182C exhibit depolarizing shifts in the voltage-dependence of activation, whereas R1182C also shows a reduced peak current density. H151L selectively slows recovery from inactivation."

Three experimentally characterized variants show distinct loss-of-function effects in recombinant channels; their clinical presentations span a broader spectrum than DEE69.

PMID:38081835 SUPPORT INDIRECT BACKGROUND Other

"Specific Cav2.3 inhibitors would be required to test if inhibition of Cav2.3 could ameliorate CDKL5 deficiency phenotypes in mouse and human models."

The authors identify selective inhibitor testing as future work, not demonstrated rescue.

How should DEE69 be distinguished from broader CACNA1E neurological presentations?

KNOWLEDGE GAP OPEN cacna1e_dee_scope_and_allele_specificity

Attached to

genetic#CACNA1E

The 2021 seven-person cohort had no ongoing epilepsy, but one adult had successfully treated infantile spasms. Six had no seizure history. Its putative splice effect was not RNA-validated, and variant-specific functional evidence has since emerged for M163T. The 2026 loss-of-function study spans ataxia without epilepsy, neurodevelopmental disorder without epilepsy, and a seizure-associated ClinVar case with limited clinical characterization. These observations expand the gene spectrum without proving that every variant causes DEE69 or that domain location reliably predicts course.

Show evidence (3 references)

PMID:34702355 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"One adult patient (Patient 4) had a history of epileptic spasms, successfully treated with adrenocorticotropic hormone, without subsequent seizures in childhood or adulthood."

The 2021 cohort lacked ongoing epilepsy, but one adult had successfully treated infantile spasms; it was not uniformly lifetime seizure-free.

PMID:34702355 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Four patients (4/7, 57%) also presented with developmental regression, unrelated to any seizures or specific electro-encephalographic (EEG) epileptic activity."

Regression without concurrent seizures supports a developmental component in the wider CACNA1E spectrum, not a shared proven cellular mechanism for every allele.

PMID:42123681 SUPPORT DIRECT PRIMARY RESULT In Vitro

"M163T and R1182C exhibit depolarizing shifts in the voltage-dependence of activation, whereas R1182C also shows a reduced peak current density. H151L selectively slows recovery from inactivation."

Three experimentally characterized variants show distinct loss-of-function effects in recombinant channels; their clinical presentations span a broader spectrum than DEE69.

Which cell types and developmental processes connect variant-specific channel effects to developmental disability?

KNOWLEDGE GAP OPEN cacna1e_developmental_mechanism_gap

Attached to

pathophysiology#Impaired Neurodevelopment pathophysiology#Altered Synaptic Transmission

Seizure-independent regression and early motor manifestations indicate that epileptic activity alone does not explain all disability. Recombinant cells establish channel effects, while the CDKL5-linked phosphomutant is an indirect animal model. Patient-variant effects on native excitatory and inhibitory circuits, neurotransmitter release and development remain insufficiently characterized.

Show evidence (3 references)

PMID:34702355 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Four patients (4/7, 57%) also presented with developmental regression, unrelated to any seizures or specific electro-encephalographic (EEG) epileptic activity."

Regression without concurrent seizures supports a developmental component in the wider CACNA1E spectrum, not a shared proven cellular mechanism for every allele.

PMID:30343943 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"Functional analysis revealed dramatic gain-of-function effects, indicating increased calcium inward currents that may affect neuronal excitability and synaptic transmission."

Recombinant-channel results motivate increased calcium entry in neurons; sustained intracellular calcium overload was not measured in patients.

PMID:38081835 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"The percentage of cells exhibiting at least one DPP or all-or-none afterdepolarization (ADP) > 8 mV upon carbachol treatment was significantly higher in S15A mice, showing an enhanced depolarization response (Fig. 3j, k)."

S15A mouse slices show enhanced cholinergic plateau potentials/afterdepolarizations. This is a convergent engineered model, not direct evidence from a patient variant.

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Pathophysiology

10

CACNA1E Missense Variant

Heterozygous disease-associated missense substitutions affect the Cav2.3 pore-forming alpha1E subunit. Many cluster near S6 activation-gate regions, but pathogenic substitutions also occur elsewhere. The following gain-of-function branches describe tested DEE-associated variants and do not apply automatically to every CACNA1E allele.

CACNA1E hgnc:1392

Downstream

Facilitated Cav2.3 Activation

Slowed Cav2.3 Inactivation

Increased Cav2.3 Current Density

Expanded Cav2.3 Window Current

Impaired Neurodevelopment Genetic association is established; the allele-specific developmental intermediates remain unresolved.

Hyperkinetic Movement Disorder

Spastic Quadriplegia

Hypotonia

Congenital Contractures

Macrocephaly

Dystonia Clinical association with disease-associated CACNA1E variants; the intermediate tissue and cellular mechanisms are not established.

Talipes Equinovarus Clinical association with disease-associated CACNA1E variants; the intermediate tissue and cellular mechanisms are not established.

Areflexia Clinical association with disease-associated CACNA1E variants; the intermediate tissue and cellular mechanisms are not established.

Feeding Difficulties Clinical association with disease-associated CACNA1E variants; the intermediate tissue and cellular mechanisms are not established.

Show evidence (2 references)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Molecular genetic testing identified 14 missense variants in CACNA1E (GenBank: NM_000721.3) in 30 unrelated individuals (Table 1). For the 29/30 individuals for whom DNA samples were available for both parents, de novo status of the variants and parentage were confirmed."

Thirty missense-variant probands were reported, with de novo status confirmed in all 29 with both parental samples.

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Prominent clustering of CACNA1E variants (11/14; 79%) was noted in the cytoplasmic parts of all four S6 segments (Figure 1), which are presumed to form a crucial part of the activation gate in voltage-activated cation channels."

Eleven of fourteen distinct discovery variants clustered in cytoplasmic S6 segments.

Facilitated Cav2.3 Activation

Several DEE-associated variants activate at more negative membrane potentials. The three 2018 DII-S6 variants shifted activation by approximately -10 mV; Ile603Leu and Leu228Pro also facilitate activation under their respective assay conditions. This is a voltage-dependence change, not necessarily faster activation kinetics.

CACNA1E hgnc:1392

Cav2.3 R-type calcium channel activity GO:0008331 ↑ INCREASED

Experimental models

tsA201 DII-S6 DEE Variant Channels CELL LINE Recombinant variant channels shift activation.

tsA201 Ile603Leu Channels CELL LINE Activation shifts to more negative potentials.

tsA201 Broader-Spectrum Loss-of-Function Variants CELL LINE M163T and R1182C shift activation in the opposite direction, demonstrating an allele-specific boundary to the DEE gain-of-function model.

Downstream

Increased R-Type Calcium Entry

Show evidence (3 references)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The activation curve was shifted by approximately −10 mV for all three variants (Figure 2), while the time course of activation was not altered."

The three DII-S6 variants shifted activation about -10 mV in tsA201 cells.

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT In Vitro

"This variant resulted in a massive increase in whole-cell current density (Figures 3 and S2) to a level that in many cases precluded functional biophysical characterization. In a subset of cells where the current could be properly clamped, our analysis revealed a >10 mV hyperpolarizing shift in..."

Ile603Leu increased whole-cell current density and facilitated activation without significantly changing inactivation.

PMID:42392563 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Compared to wild-type, the L228P mutant did not present altered peak current density, inactivation kinetics, or recovery from inactivation, but showed a significant shift towards hyperpolarized voltages in both voltage-dependent activation and steady-state inactivation. This resulted in a..."

Leu228Pro changes activation and steady-state inactivation and broadens the predicted window current without changing peak density or inactivation kinetics.

Slowed Cav2.3 Inactivation

Phe698Ser, Ile701Val and Ala702Thr slow fast inactivation in the 2018 recombinant-channel assays, prolonging current during depolarization. Ile603Leu and Leu228Pro did not share this kinetic change. Loss of CDKL5-dependent phosphorylation produces a convergent gating effect in engineered models; it is not the genetic lesion of DEE69.

CACNA1E hgnc:1392

Cav2.3 R-type calcium channel activity GO:0008331 ↑ INCREASED

Experimental models

tsA201 DII-S6 DEE Variant Channels CELL LINE The three tested DII-S6 variants slow fast inactivation.

Cav2.3 S15A Mouse Hippocampal Slices OTHER The engineered phosphorylation-site lesion prolongs native R-type currents.

Downstream

Increased R-Type Calcium Entry

Show evidence (1 reference)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Additionally, the time course of fast inactivation was significantly slowed, as indicated by an increased residual current after a 400-ms depolarizing pulse normalized to the peak current (r400) (Figures 2 and S1; Table 2)."

Slower fast inactivation was measured for the three tested DII-S6 variants.

Increased Cav2.3 Current Density

The Ile603Leu domain II S4-S5 linker variant substantially increases whole-cell calcium/barium current density in tsA201 cells. Increased peak current density is not a universal property of DEE-associated variants and was absent for Leu228Pro.

CACNA1E hgnc:1392

Cav2.3 R-type calcium channel activity GO:0008331 ↑ INCREASED

Experimental models

tsA201 Ile603Leu Channels CELL LINE Recombinant Ile603Leu strongly increases current density.

Downstream

Increased R-Type Calcium Entry

Show evidence (2 references)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT In Vitro

"This variant resulted in a massive increase in whole-cell current density (Figures 3 and S2) to a level that in many cases precluded functional biophysical characterization. In a subset of cells where the current could be properly clamped, our analysis revealed a >10 mV hyperpolarizing shift in..."

Ile603Leu increased whole-cell current density and facilitated activation without significantly changing inactivation.

PMID:42392563 REFUTE DIRECT PRIMARY RESULT In Vitro

"the L228P mutant did not present altered peak current density, inactivation kinetics, or recovery from inactivation"

Leu228Pro refutes a universal increase in peak current density across DEE variants; this does not contradict the Ile603Leu result.

Expanded Cav2.3 Window Current

Leu228Pro shifts both activation and steady-state inactivation toward more negative voltages, creating a broader window current at hyperpolarized potentials. This predicts increased channel availability at subthreshold voltages despite unchanged peak density and inactivation kinetics.

CACNA1E hgnc:1392

Cav2.3 R-type calcium channel activity GO:0008331 ↑ INCREASED

Experimental models

tsA201 Leu228Pro Channels CELL LINE Variant-specific gating expands the subthreshold window current.

Downstream

Increased R-Type Calcium Entry

Show evidence (1 reference)

PMID:42392563 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Compared to wild-type, the L228P mutant did not present altered peak current density, inactivation kinetics, or recovery from inactivation, but showed a significant shift towards hyperpolarized voltages in both voltage-dependent activation and steady-state inactivation. This resulted in a..."

Leu228Pro changes activation and steady-state inactivation and broadens the predicted window current without changing peak density or inactivation kinetics.

Increased R-Type Calcium Entry

Mechanism confidence: Provisional

Facilitated activation, prolonged opening or altered window current can increase depolarization-dependent Cav2.3-mediated calcium entry. These routes depend on the variant, voltage and accessory-subunit context. Recombinant channel measurements support the conductance effect; chronic calcium overload in patient neurons has not been demonstrated.

neuron CL:0000540

calcium ion transmembrane transport GO:0070588 ↑ INCREASED

brain UBERON:0000955

Downstream

Altered Neuronal Excitability

Altered Synaptic Transmission

Show evidence (1 reference)

PMID:30343943 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"Functional analysis revealed dramatic gain-of-function effects, indicating increased calcium inward currents that may affect neuronal excitability and synaptic transmission."

Recombinant-channel results motivate increased calcium entry in neurons; sustained intracellular calcium overload was not measured in patients.

Altered Neuronal Excitability

Mechanism confidence: Provisional

Cav2.3 gain of function is proposed to alter neuronal excitability. In the engineered S15A phosphomutant mouse, baseline CA1 firing was unchanged, whereas carbachol enhanced depolarizing plateaus and afterdepolarizations; strong stimulation could induce depolarization block. Translation to individual human DEE variants remains provisional.

neuron CL:0000540

brain UBERON:0000955

Experimental models

Cav2.3 S15A Mouse Hippocampal Slices OTHER The effect depends on cholinergic stimulation.

Downstream

Epileptogenic Network Dysfunction

Impaired Neurodevelopment

Show evidence (2 references)

PMID:38081835 REFUTE DIRECT PRIMARY RESULT In Vitro

"firing properties were identical between WT and S15A mice under baseline conditions (Fig. 3g–i)."

This null result refutes an increase in baseline CA1 firing in the S15A model. It does not refute the separately measured enhancement of cholinergic depolarizations.

PMID:38081835 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"The percentage of cells exhibiting at least one DPP or all-or-none afterdepolarization (ADP) > 8 mV upon carbachol treatment was significantly higher in S15A mice, showing an enhanced depolarization response (Fig. 3j, k)."

S15A mouse slices show enhanced cholinergic plateau potentials/afterdepolarizations. This is a convergent engineered model, not direct evidence from a patient variant.

Altered Synaptic Transmission

Mechanism confidence: Hypothetical

Cav2.3 participates in presynaptic neurotransmitter release and postsynaptic integration/plasticity. Variant-dependent disruption of these functions is a plausible contributor to DEE. The direction and magnitude of release changes, and their balance in excitatory versus inhibitory neurons, remain unresolved.

neuron CL:0000540

brain UBERON:0000955

Downstream

Epileptogenic Network Dysfunction

Impaired Neurodevelopment

Show evidence (1 reference)

PMID:31064215 SUPPORT INDIRECT REVIEW SYNTHESIS Other

"CACNA1E encodes Cav2.3, an R-type VGCC implicated in both presynaptic neurotransmitter release and postsynaptic somatodendritic integration and long-term potentiation."

Normal Cav2.3 physiology motivates a synaptic mechanism, but altered transmitter release or plasticity has not been directly measured for the human variants in these studies.

Epileptogenic Network Dysfunction

Mechanism confidence: Provisional

Abnormal neuronal network activity produces seizures and epileptiform EEG abnormalities. An excitation-inhibition imbalance is a mechanistic hypothesis rather than a measured patient-specific ratio. Channel effects and experimental seizure susceptibility support this connection without defining all cellular intermediates.

neuron CL:0000540

brain UBERON:0000955

Animal models

Cav2.3 S15A Phosphomutant Mouse Mus musculus partially recapitulates Provoked seizure susceptibility supports only part of the proposed human mechanism; spontaneous epilepsy was not reproduced.

Cacna1e Knockout Mouse Mus musculus perturbs Loss of the channel tests its contribution to provoked seizures in the opposite direction from most characterized DEE variants.

Downstream

Developmental and Epileptic Encephalopathy

Seizures

Epileptic Spasms A clinical or electrographic manifestation of the epileptic network phenotype; subtype-specific cellular mechanisms remain unresolved.

Focal Motor Seizures A clinical or electrographic manifestation of the epileptic network phenotype; subtype-specific cellular mechanisms remain unresolved.

Hypsarrhythmia A clinical or electrographic manifestation of the epileptic network phenotype; subtype-specific cellular mechanisms remain unresolved.

Status Epilepticus A clinical or electrographic manifestation of the epileptic network phenotype; subtype-specific cellular mechanisms remain unresolved.

Drug-Resistant Seizures Drug resistance is a documented outcome of the epilepsy; the factors determining medication response are not established.

Seizures with Sustained Remission (DIII-S6) A documented seizure course in one DIII-S6 case; the mechanism of remission and its relationship to genotype or treatment are unresolved.

Show evidence (1 reference)

PMID:30343943 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders."

Human seizures establish network dysfunction but do not directly measure an excitation-inhibition ratio or the intervening cellular mechanism.

Impaired Neurodevelopment

Severe developmental impairment often precedes or accompanies epilepsy. The broader CACNA1E spectrum includes regression without seizures, supporting a developmental contribution beyond epileptic activity. This does not establish identical molecular mechanisms for the DEE and non-DEE presentations. Clinical movement, tone and congenital abnormalities are associated outcomes with incompletely resolved causal intermediates.

neuron CL:0000540

brain UBERON:0000955

Downstream

Profound Developmental Impairment

Developmental Regression

Absent Speech An associated functional developmental outcome; contributions from cognition, tone, movement and epilepsy have not been separated.

Inability to Walk An associated functional developmental outcome; contributions from cognition, tone, movement and epilepsy have not been separated.

Show evidence (4 references)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Of the probands older than 2 years, 21/24 (88%) were non-verbal and non-ambulatory."

The 88% figure is 21/24 probands older than two, not all 30 participants.

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Developmental regression occurred in 9/30 (30%) individuals, often in association with seizure onset."

Regression was reported in 9/30; developmental impairment is not uniformly progressive.

PMID:34702355 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Four patients (4/7, 57%) also presented with developmental regression, unrelated to any seizures or specific electro-encephalographic (EEG) epileptic activity."

Regression without concurrent seizures supports a developmental component in the wider CACNA1E spectrum, not a shared proven cellular mechanism for every allele.

+ 1 more reference

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Pathograph

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Phenotypes

21

Digestive 1

Feeding Difficulties HP:0011968

Show evidence (2 references)

PMID:33776624 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"he required a gastrostomy due to a feeding disorder."

Gastrostomy was required in the first case.

PMID:33776624 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The patient also required a gastrostomy due to a feeding disorder (Fig. 1b)."

The second case also needed gastrostomy.

Head and Neck 1

Macrocephaly FREQUENT HP:0000256

Frequency reflects the named retrospective discovery-cohort denominator in the description, including its age or epilepsy ascertainment restriction; it is not population penetrance.

Show evidence (1 reference)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Macrocephaly without other structural abnormalities on brain magnetic resonance imaging was present in 12/28 (43%) individuals for whom data were available."

Macrocephaly was reported in 12/28 with available imaging/head-size data.

Limbs 1

Talipes Equinovarus HP:0001762

Show evidence (1 reference)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"13/30 (43%) affected individuals had congenital joint contractures ranging from isolated talipes equinovarus to arthrogryposis multiplex congenita, frequently prompting initial consideration of a congenital neuromuscular disorder."

Contractures ranged from isolated clubfoot to multiple congenital joint contractures in 13/30.

Musculoskeletal 3

Congenital Contractures FREQUENT HP:0002803

Frequency reflects the named retrospective discovery-cohort denominator in the description, including its age or epilepsy ascertainment restriction; it is not population penetrance.

Show evidence (1 reference)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"13/30 (43%) affected individuals had congenital joint contractures ranging from isolated talipes equinovarus to arthrogryposis multiplex congenita, frequently prompting initial consideration of a congenital neuromuscular disorder."

Contractures ranged from isolated clubfoot to multiple congenital joint contractures in 13/30.

Spastic Quadriplegia FREQUENT Spastic tetraplegia HP:0002510

Frequency reflects the named retrospective discovery-cohort denominator in the description, including its age or epilepsy ascertainment restriction; it is not population penetrance.

Show evidence (1 reference)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"All affected individuals had prominent axial hypotonia, often with appendicular hypertonia; spastic quadriplegia was reported in 16/30 (53%) individuals."

Axial hypotonia was universal in the discovery cohort and spastic quadriplegia occurred in 16/30.

Hypotonia OBLIGATE HP:0001252

Frequency reflects the named retrospective discovery-cohort denominator in the description, including its age or epilepsy ascertainment restriction; it is not population penetrance.

Show evidence (1 reference)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"All affected individuals had prominent axial hypotonia, often with appendicular hypertonia; spastic quadriplegia was reported in 16/30 (53%) individuals."

Axial hypotonia was universal in the discovery cohort and spastic quadriplegia occurred in 16/30.

Nervous System 15

Developmental and Epileptic Encephalopathy HP:0200134

Show evidence (1 reference)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We identified 30 unrelated individuals with missense variants in CACNA1E (GenBank: NM_000721.3). A picture of a profound DEE emerged, with affected individuals typically having pharmaco-resistant seizures beginning in the first year of life, profound developmental impairment, hyperkinetic..."

The discovery cohort establishes the clinical and genetic association; phenotype severity varies.

Seizures VERY_FREQUENT HP:0001250

Frequency reflects the named retrospective discovery-cohort denominator in the description, including its age or epilepsy ascertainment restriction; it is not population penetrance.

Show evidence (1 reference)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Epilepsy was present in 26/30 (87%) individuals, with median age of seizure onset of 4.5 months (range 1 day to 47 months)."

Epilepsy occurred in 26/30, with median onset 4.5 months and a wider onset range.

Drug-Resistant Seizures VERY_FREQUENT HP:0001250

Frequency reflects the named retrospective discovery-cohort denominator in the description, including its age or epilepsy ascertainment restriction; it is not population penetrance.

Show evidence (1 reference)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Although seizures were resistant to multiple anti-epileptic drugs (AEDs) in most individuals for whom data were available (20/25; 80%), five individuals (1, 15, 16, 21, 27) reported significant improvement in seizure control with topiramate, the only AED noted to have a substantial effect on..."

Drug resistance was 20/25 with available data; five reported substantial topiramate benefit.

Profound Developmental Impairment Profound global developmental delay HP:0012736

Show evidence (1 reference)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Of the probands older than 2 years, 21/24 (88%) were non-verbal and non-ambulatory."

The 88% figure is 21/24 probands older than two, not all 30 participants.

Absent Speech VERY_FREQUENT HP:0001344

Frequency reflects the named retrospective discovery-cohort denominator in the description, including its age or epilepsy ascertainment restriction; it is not population penetrance.

Show evidence (1 reference)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Of the probands older than 2 years, 21/24 (88%) were non-verbal and non-ambulatory."

The 88% figure is 21/24 probands older than two, not all 30 participants.

Inability to Walk VERY_FREQUENT HP:0002540

Frequency reflects the named retrospective discovery-cohort denominator in the description, including its age or epilepsy ascertainment restriction; it is not population penetrance.

Show evidence (2 references)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Of the probands older than 2 years, 21/24 (88%) were non-verbal and non-ambulatory."

The 88% figure is 21/24 probands older than two, not all 30 participants.

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Two individuals harboring the c.4274C>A (p.Thr1425Asn) variant and one individual with the c.4288G>A (p.Gly1430Arg) variant presented with a comparatively milder clinical picture. All three probands were the only individuals in the cohort to speak single words and walk independently or with..."

Three DIII-S6 cases were comparatively milder; two had not seized by age four and one had sustained remission. Walking could be assisted.

Developmental Regression FREQUENT HP:0002376

Frequency reflects the named retrospective discovery-cohort denominator in the description, including its age or epilepsy ascertainment restriction; it is not population penetrance.

Show evidence (1 reference)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Developmental regression occurred in 9/30 (30%) individuals, often in association with seizure onset."

Regression was reported in 9/30; developmental impairment is not uniformly progressive.

Hyperkinetic Movement Disorder FREQUENT Hyperkinetic movements HP:0002487

Frequency reflects the named retrospective discovery-cohort denominator in the description, including its age or epilepsy ascertainment restriction; it is not population penetrance.

Show evidence (2 references)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Hyperkinetic movement disorders were prominent, including severe dystonia in 12/30 (40%) and other dyskinesias in 6/30 (20%) individuals; movement disorders were constant and profoundly disabling in some individuals."

Dystonia occurred in 12/30 and other dyskinesias in 6/30; these are distinct reported categories.

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Dystonia was a prominent feature in all nine individuals with the recurrent c.1054G>A (p.Gly352Arg) variant. This variant is in close proximity to the c.1042G>C (p.Gly348Arg) variant in individual 2 who also demonstrated profound dystonia. Dystonia was less common in individuals with other..."

The original cohort associated Gly352Arg/Gly348Arg with dystonia, without establishing a deterministic domain-wide prognosis.

Dystonia FREQUENT HP:0001332

Frequency reflects the named retrospective discovery-cohort denominator in the description, including its age or epilepsy ascertainment restriction; it is not population penetrance.

Show evidence (2 references)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Hyperkinetic movement disorders were prominent, including severe dystonia in 12/30 (40%) and other dyskinesias in 6/30 (20%) individuals; movement disorders were constant and profoundly disabling in some individuals."

Dystonia occurred in 12/30 and other dyskinesias in 6/30; these are distinct reported categories.

PMID:33776624 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Notable findings include congenital contractures and movement disorders predating onset of epilepsy, particularly dystonia."

The two-case study documents movement disorders before epilepsy.

Epileptic Spasms FREQUENT HP:0011097

Frequency reflects the named retrospective discovery-cohort denominator in the description, including its age or epilepsy ascertainment restriction; it is not population penetrance.

Show evidence (1 reference)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Epileptic spasms were the most common initial seizure type (14/26; 54%) followed by focal motor seizures (5/26; 19%)."

Initial spasms occurred in 14/26 participants with epilepsy; initial focal motor seizures in 5/26.

Focal Motor Seizures HP:0011153

Show evidence (1 reference)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Epileptic spasms were the most common initial seizure type (14/26; 54%) followed by focal motor seizures (5/26; 19%)."

Initial spasms occurred in 14/26 participants with epilepsy; initial focal motor seizures in 5/26.

Hypsarrhythmia HP:0002521

Show evidence (1 reference)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The six individuals harboring the recurrent c.2104G>A (p.Ala702Thr) variant had a relatively homogeneous phenotype that was representative of the overall CACNA1E-encephalopathy phenotype. All individuals had refractory infantile-onset epilepsy, epileptic spasms, severe hypotonia, and profound..."

The six Ala702Thr cases shared a severe course; this does not establish the prognosis of other substitutions at residue 702.

Status Epilepticus HP:0002133

Show evidence (1 reference)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Most individuals (20/26; 77%) developed additional seizure types (Table S1); status epilepticus occurred in two individuals."

Multiple seizure types developed in 20/26; status epilepticus was reported in two.

Areflexia HP:0001284

Show evidence (1 reference)

PMID:33776624 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Deep tendon areflexia, as presented by both patients described here, with normal peripheral electroneurogram."

Both new cases had areflexia with normal peripheral nerve studies.

Seizures with Sustained Remission (DIII-S6) HP:0001250

Show evidence (1 reference)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Two individuals harboring the c.4274C>A (p.Thr1425Asn) variant and one individual with the c.4288G>A (p.Gly1430Arg) variant presented with a comparatively milder clinical picture. All three probands were the only individuals in the cohort to speak single words and walk independently or with..."

Three DIII-S6 cases were comparatively milder; two had not seized by age four and one had sustained remission. Walking could be assisted.

🧬

Genetic Associations

1

CACNA1E (Predominantly gain-of-function missense variants in DEE; broader allele-specific functional spectrum)

Gene: CACNA1E hgnc:1392 variant_origin: DE_NOVO

Autosomal Dominant (De Novo)

Show evidence (3 references)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Molecular genetic testing identified 14 missense variants in CACNA1E (GenBank: NM_000721.3) in 30 unrelated individuals (Table 1). For the 29/30 individuals for whom DNA samples were available for both parents, de novo status of the variants and parentage were confirmed."

Thirty missense-variant probands were reported, with de novo status confirmed in all 29 with both parental samples.

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Individual 31 has a mosaic nonsense variant with a mutant allele fraction of 27% (6/22 reads) in peripheral blood leukocytes. In individual 32, a CACNA1E frameshift variant was inherited from an apparently unaffected father. Parental DNA samples were unavailable for individual 33, who has a..."

The 27% value is a variant allele fraction in blood reads, not a percentage of cells; inherited and unphased truncations had uncertain causal significance.

PMID:42123681 SUPPORT DIRECT PRIMARY RESULT In Vitro

"M163T and R1182C exhibit depolarizing shifts in the voltage-dependence of activation, whereas R1182C also shows a reduced peak current density. H151L selectively slows recovery from inactivation."

Three experimentally characterized variants show distinct loss-of-function effects in recombinant channels; their clinical presentations span a broader spectrum than DEE69.

💊

Medical Actions

6

Topiramate

Action: Pharmacotherapy NCIT:C15986

Agent: topiramate CHEBI:63631

Platform: Small molecule

Among 18 treated discovery-cohort participants, five were described as having substantial improvement: two remained seizure-free for two and five years, two relapsed after four years and 18 months, and one had a marked reduction but stopped because of sedation. Ten had no effect and three had reductions without seizure freedom. These uncontrolled observations support possible benefit for some patients, not a predictable response or demonstrated developmental rescue. The detailed results are more qualified than the abstract's statement that five achieved seizure freedom.

Mechanism Target:

INHIBITS Increased R-Type Calcium Entry — R-type channel inhibition is one proposed pharmacological contribution. Topiramate has multiple actions, and selective target-mediated clinical rescue has not been demonstrated.

Show evidence (3 references)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Although seizures were resistant to multiple anti-epileptic drugs (AEDs) in most individuals for whom data were available (20/25; 80%), five individuals (1, 15, 16, 21, 27) reported significant improvement in seizure control with topiramate, the only AED noted to have a substantial effect on..."

Drug resistance was 20/25 with available data; five reported substantial topiramate benefit.

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Two individuals (16 and 27) remain seizure free for 2 and 5 years, respectively. However, in individuals 15 and 21, seizures eventually recurred after seizure-free periods of 4 years and 18 months, respectively; individual 21 died following an episode of status epilepticus. Individual 1 reported..."

The detailed results report ongoing benefit, later relapse, sedation-related discontinuation, ten nonresponders and three reductions without seizure freedom.

PMID:30343943 SUPPORT INDIRECT BACKGROUND Other

"The AEDs topiramate and lamotrigine target CaV2.3 channels and reduce R-type calcium currents.41, 42"

Published channel pharmacology motivates the target; the clinical study did not isolate Cav2.3 inhibition as the cause of benefit.

Genetic Counseling

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

Platform: Behavioral / lifestyle

Discuss the predominantly de novo dominant mechanism, parental testing, individualized recurrence assessment and reproductive options. Possible parental germline mosaicism is a counseling consideration; the mosaic truncating proband in the discovery paper does not demonstrate parental mosaicism. Domain-based associations do not give a certain individual prognosis.

Show evidence (2 references)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Molecular genetic testing identified 14 missense variants in CACNA1E (GenBank: NM_000721.3) in 30 unrelated individuals (Table 1). For the 29/30 individuals for whom DNA samples were available for both parents, de novo status of the variants and parentage were confirmed."

Thirty missense-variant probands were reported, with de novo status confirmed in all 29 with both parental samples.

PMID:41492575 SUPPORT DIRECT BACKGROUND Other

"However, germline mosaicism cannot be entirely ruled out, making prenatal diagnosis a recommended option for future pregnancies [8]."

The case report discusses reproductive counseling; this is general clinical guidance rather than observed parental mosaicism.

Supportive and Developmental Care

Action: Supportive Care NCIT:C15747

Platform: Other

Individualized multidisciplinary care addresses developmental support, mobility, tone, movement disorders, congenital contractures and feeding. Rehabilitation is supportive; controlled CACNA1E-specific evidence for developmental improvement is lacking.

Show evidence (1 reference)

PMID:41492575 SUPPORT DIRECT BACKGROUND Other

"Early genetic diagnosis allows for the cessation of the diagnostic odyssey, informed prognostic counseling for the family, and personalized management plans focusing on anticipatory guidance and targeted rehabilitation [7]."

The clinical report recommends anticipatory guidance and rehabilitation rather than claiming a tested disease-modifying intervention.

ACTH for Epileptic Spasms

Action: Pharmacotherapy NCIT:C15986

Agent: corticotropin CHEBI:3892

Platform: Peptide

ACTH was followed by resolution of infantile spasms without later seizures in one adult in the broader 2021 CACNA1E cohort. A 2026 mixed-gene retrospective DEE series also included CACNA1E among cases seizure-free at day 14, but its abstract does not provide the CACNA1E variant classification or durable gene-specific outcome. These reports do not establish response rates for DEE69 or variant-specific efficacy.

Target Phenotypes: Epileptic spasm HP:0011097

Show evidence (2 references)

PMID:34702355 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"One adult patient (Patient 4) had a history of epileptic spasms, successfully treated with adrenocorticotropic hormone, without subsequent seizures in childhood or adulthood."

The 2021 cohort lacked ongoing epilepsy, but one adult had successfully treated infantile spasms; it was not uniformly lifetime seizure-free.

PMID:42615235 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"At 2-week follow-up, 5 of 10 patients (SCN2A, ELOVL4, CACNA1E, TRRAP) achieved seizure freedom,"

The reported genes include CACNA1E among day-14 responders; the cohort admitted pathogenic, likely pathogenic and uncertain variants.

Perampanel-Containing Combination Therapy

Action: Pharmacotherapy NCIT:C15986

Agent: perampanel CHEBI:71013

Platform: Small molecule

One infant with de novo Ala702Thr achieved reported seizure control after escalation to a regimen including vigabatrin, perampanel and clonazepam. Follow-up duration and the independent effect of perampanel were not established; this is an uncontrolled case observation.

Show evidence (1 reference)

PMID:41492575 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Initial treatment with levetiracetam and clonazepam improved irritability but did not control the spasms. The regimen was escalated to include vigabatrin, and later, a third anti-epileptic drug, Vyncompa (perampanel), which successfully achieved seizure control."

The case reports improvement after regimen escalation, not perampanel monotherapy or comparative efficacy.

Gastrostomy for Severe Feeding Difficulty

Action: Gastrostomy NCIT:C52006

Platform: Surgery

Gastrostomy provided feeding support in both severely affected Gly352Arg cases in the 2021 report. Enteral support is tailored to the individual feeding and nutritional assessment.

Target Phenotypes: Feeding difficulties HP:0011968

Show evidence (2 references)

PMID:33776624 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"he required a gastrostomy due to a feeding disorder."

Gastrostomy was required in the first case.

PMID:33776624 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The patient also required a gastrostomy due to a feeding disorder (Fig. 1b)."

The second case also needed gastrostomy.

🔬

Diagnosis

3

CACNA1E Molecular Diagnosis

Identify a heterozygous pathogenic or likely pathogenic CACNA1E variant in a compatible clinical presentation using a suitable sequencing assay, with parental testing and variant-specific interpretation. Exome analysis and reanalysis identified cases in the discovery cohort. A variant of uncertain significance alone does not establish DEE69, and seizures need not precede the movement disorder.

molecular genetic testing NCIT:C19770

Show evidence (2 references)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Molecular genetic testing identified 14 missense variants in CACNA1E (GenBank: NM_000721.3) in 30 unrelated individuals (Table 1). For the 29/30 individuals for whom DNA samples were available for both parents, de novo status of the variants and parentage were confirmed."

Thirty missense-variant probands were reported, with de novo status confirmed in all 29 with both parental samples.

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Individuals 23 and 26 were ascertained by reanalysis of the data from the Deciphering Developmental Disorders Study28 as part of a local “Solving the Unsolved” project in Manchester (UK) and a Complementary Analysis Project #237.21"

Reanalysis of existing sequencing data diagnosed previously unresolved cases.

EEG

EEG characterizes seizures and epileptiform activity, including hypsarrhythmia in some infants. Prolonged video-EEG can distinguish nonepileptic dystonia/dyskinesia from clinically similar hyperkinetic seizures. Hypsarrhythmia was already documented in the original clinical series.

electroencephalography NCIT:C38054

Results: Abundant epileptiform activity consistent with a developmental and epileptic encephalopathy.

Show evidence (2 references)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The six individuals harboring the recurrent c.2104G>A (p.Ala702Thr) variant had a relatively homogeneous phenotype that was representative of the overall CACNA1E-encephalopathy phenotype. All individuals had refractory infantile-onset epilepsy, epileptic spasms, severe hypotonia, and profound..."

The six Ala702Thr cases shared a severe course; this does not establish the prognosis of other substitutions at residue 702.

PMID:38780451 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Long-term video-EEG-monitoring documented subsequent tonic asymmetric seizures during wakefulness and mild paroxysmal dyskinesias of the trunk out of sleep which were thought to be a movement disorder and instead turned out to be focal hyperkinetic seizures."

Video-EEG identified an ictal correlate for movements initially considered dyskinesia in one child.

Brain MRI

Brain MRI assesses structural causes and associated abnormalities, but a normal scan does not exclude CACNA1E-related DEE. The discovery cohort and later cases included severe disease without explanatory structural abnormalities.

Magnetic Resonance Imaging NCIT:C16809

Show evidence (2 references)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Macrocephaly without other structural abnormalities on brain magnetic resonance imaging was present in 12/28 (43%) individuals for whom data were available."

Macrocephaly was reported in 12/28 with available imaging/head-size data.

PMID:33776624 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Cerebral and spinal magnetic resonance imaging (MRI) scans in both patients were normal at 2 months and when repeated at 6 months in case 1 and at 4 months in case 2."

Serial early MRI was normal in both severely affected Gly352Arg cases.

📈

Progression

2

Early development and seizure onset

Axial hypotonia, congenital contractures and neonatal dystonia can precede seizures. In the discovery cohort onset ranged from one day to 47 months, with 21/25 occurring in the first year; 9/30 had regression. Severe static impairment, regression, drug resistance and sustained remission are distinct possible courses.

Show evidence (3 references)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Epilepsy was present in 26/30 (87%) individuals, with median age of seizure onset of 4.5 months (range 1 day to 47 months)."

Epilepsy occurred in 26/30, with median onset 4.5 months and a wider onset range.

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Developmental regression occurred in 9/30 (30%) individuals, often in association with seizure onset."

Regression was reported in 9/30; developmental impairment is not uniformly progressive.

PMID:33776624 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Notable findings include congenital contractures and movement disorders predating onset of epilepsy, particularly dystonia."

Movement manifestations can precede epilepsy.

Mortality in the discovery cohort

Seven of 30 participants (23%) had died by ascertainment, with median age at death 2.7 years and a range of 11 months to 25 years. Reported causes included cardiorespiratory failure and status epilepticus. This retrospective proportion is not a prospective survival estimate or a uniform infantile prognosis.

Show evidence (1 reference)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Out of 30 individuals, 7 (23%) had died with a median age of death of 2.7 years (range 11 months to 25 years). Reported causes of death were cardiorespiratory failure and status epilepticus."

Reports the observed mortality proportion, ages and causes in the original series.

📊

Prevalence

1

Worldwide

Cases In Literature Ultra Rare

The 2018 discovery series included 30 unrelated missense-variant probands and three additional individuals with truncating variants of less certain causal significance. These are historical case counts, not an estimate of worldwide prevalence or the current number of affected people.

Show evidence (1 reference)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Molecular genetic testing identified 14 missense variants in CACNA1E (GenBank: NM_000721.3) in 30 unrelated individuals (Table 1). For the 29/30 individuals for whom DNA samples were available for both parents, de novo status of the variants and parentage were confirmed."

Thirty missense-variant probands were reported, with de novo status confirmed in all 29 with both parental samples.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from CACNA1E-Related Developmental and Epileptic Encephalopathy:

STXBP1 Encephalopathy MONDO:0012812

Overlapping Features Another de novo dominant developmental and epileptic encephalopathy with early-onset refractory seizures and profound developmental impairment; distinguished by the causative gene (STXBP1 vs CACNA1E) and its synaptic-vesicle-release mechanism.

Other Voltage-Gated Calcium Channel Epileptic Encephalopathies

Overlapping Features Other calcium-channel disorders, including CACNA1A-, CACNA1D- and CACNA1G-related neurological syndromes, can overlap in epilepsy and developmental impairment. Their functional direction and extra-neurological features vary; gene- and variant-specific interpretation distinguishes them.

Show evidence (1 reference)

PMID:30343943 SUPPORT DIRECT BACKGROUND Other

"Developmental and epileptic encephalopathies are genetically heterogeneous and can be caused by pathogenic variants in genes encoding other voltage-gated neuronal ion channels, including SCN2A, SCN8A, KCNQ2, and CACNA1A.3, 37, 38, 39"

The discovery paper places CACNA1E among clinically overlapping genetic channelopathies.

🧫

Experimental Models

5

tsA201 DII-S6 DEE Variant Channels CELL_LINE

Phe698Ser, Ile701Val and Ala702Thr in human alpha1E-1 with beta2d were tested with barium as the charge carrier. These assays establish gating effects but do not reproduce native neuronal subunit composition, developmental circuitry or the complete heterozygous state.

Organism

Homo sapiens NCBITaxon:9606

Cell source

Recombinant human embryonic kidney-derived cells

Publication

PMID:30343943

Pathograph links

Facilitated Cav2.3 Activation partially recapitulates fidelity: moderate Recombinant variant channels shift activation.

Show evidence (1 reference)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The activation curve was shifted by approximately −10 mV for all three variants (Figure 2), while the time course of activation was not altered."

The three DII-S6 variants shifted activation about -10 mV in tsA201 cells.

Slowed Cav2.3 Inactivation partially recapitulates fidelity: moderate The three tested DII-S6 variants slow fast inactivation.

Show evidence (1 reference)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Additionally, the time course of fast inactivation was significantly slowed, as indicated by an increased residual current after a 400-ms depolarizing pulse normalized to the peak current (r400) (Figures 2 and S1; Table 2)."

Slower fast inactivation was measured for the three tested DII-S6 variants.

Show evidence (2 references)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The activation curve was shifted by approximately −10 mV for all three variants (Figure 2), while the time course of activation was not altered."

The three DII-S6 variants shifted activation about -10 mV in tsA201 cells.

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Additionally, the time course of fast inactivation was significantly slowed, as indicated by an increased residual current after a 400-ms depolarizing pulse normalized to the peak current (r400) (Figures 2 and S1; Table 2)."

Slower fast inactivation was measured for the three tested DII-S6 variants.

tsA201 Ile603Leu Channels CELL_LINE

Human alpha1E-3 Ile603Leu was expressed with beta1b and alpha2delta1; calcium and barium recordings showed increased density and facilitated activation without altered inactivation. Assay conditions differ from the DII-S6 experiments, precluding simple quantitative comparisons across the two systems.

Organism

Homo sapiens NCBITaxon:9606

Cell source

Recombinant human embryonic kidney-derived cells

Publication

PMID:30343943

Pathograph links

Increased Cav2.3 Current Density partially recapitulates fidelity: moderate Recombinant Ile603Leu strongly increases current density.

Show evidence (1 reference)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT In Vitro

"This variant resulted in a massive increase in whole-cell current density (Figures 3 and S2) to a level that in many cases precluded functional biophysical characterization. In a subset of cells where the current could be properly clamped, our analysis revealed a >10 mV hyperpolarizing shift in..."

Ile603Leu increased whole-cell current density and facilitated activation without significantly changing inactivation.

Facilitated Cav2.3 Activation partially recapitulates fidelity: moderate Activation shifts to more negative potentials.

Show evidence (1 reference)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT In Vitro

"This variant resulted in a massive increase in whole-cell current density (Figures 3 and S2) to a level that in many cases precluded functional biophysical characterization. In a subset of cells where the current could be properly clamped, our analysis revealed a >10 mV hyperpolarizing shift in..."

Ile603Leu increased whole-cell current density and facilitated activation without significantly changing inactivation.

Show evidence (1 reference)

PMID:30343943 SUPPORT DIRECT PRIMARY RESULT In Vitro

"This variant resulted in a massive increase in whole-cell current density (Figures 3 and S2) to a level that in many cases precluded functional biophysical characterization. In a subset of cells where the current could be properly clamped, our analysis revealed a >10 mV hyperpolarizing shift in..."

Ile603Leu increased whole-cell current density and facilitated activation without significantly changing inactivation.

tsA201 Leu228Pro Channels CELL_LINE

Whole-cell patch clamp of Leu228Pro versus wild type shows hyperpolarized activation and steady-state inactivation, with an expanded window current. Peak density, inactivation kinetics and recovery were unchanged. The published abstract supports these channel findings; neuronal or treatment rescue is not demonstrated.

Organism

Homo sapiens NCBITaxon:9606

Cell source

Recombinant human embryonic kidney-derived cells

Publication

PMID:42392563

Pathograph links

Expanded Cav2.3 Window Current partially recapitulates fidelity: moderate Variant-specific gating expands the subthreshold window current.

Show evidence (1 reference)

PMID:42392563 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Compared to wild-type, the L228P mutant did not present altered peak current density, inactivation kinetics, or recovery from inactivation, but showed a significant shift towards hyperpolarized voltages in both voltage-dependent activation and steady-state inactivation. This resulted in a..."

Leu228Pro changes activation and steady-state inactivation and broadens the predicted window current without changing peak density or inactivation kinetics.

Show evidence (1 reference)

PMID:42392563 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Compared to wild-type, the L228P mutant did not present altered peak current density, inactivation kinetics, or recovery from inactivation, but showed a significant shift towards hyperpolarized voltages in both voltage-dependent activation and steady-state inactivation. This resulted in a..."

Leu228Pro changes activation and steady-state inactivation and broadens the predicted window current without changing peak density or inactivation kinetics.

tsA201 Broader-Spectrum Loss-of-Function Variants CELL_LINE

H151L, M163T and R1182C were expressed in human alpha1E-3 with rat beta1b and alpha2delta1. Electrophysiology demonstrates heterogeneous loss of function; these models address broader CACNA1E neurological presentations and do not reproduce the canonical DEE69 gain-of-function mechanism. Structural predictions are not empirical surface-expression measurements.

Organism

Homo sapiens NCBITaxon:9606

Cell source

Recombinant human embryonic kidney-derived cells

Publication

PMID:42123681

Pathograph links

Facilitated Cav2.3 Activation perturbs fidelity: low M163T and R1182C shift activation in the opposite direction, demonstrating an allele-specific boundary to the DEE gain-of-function model.

Show evidence (1 reference)

PMID:42123681 SUPPORT DIRECT PRIMARY RESULT In Vitro

"M163T and R1182C exhibit depolarizing shifts in the voltage-dependence of activation, whereas R1182C also shows a reduced peak current density. H151L selectively slows recovery from inactivation."

Three experimentally characterized variants show distinct loss-of-function effects in recombinant channels; their clinical presentations span a broader spectrum than DEE69.

Show evidence (1 reference)

PMID:42123681 SUPPORT DIRECT PRIMARY RESULT In Vitro

"M163T and R1182C exhibit depolarizing shifts in the voltage-dependence of activation, whereas R1182C also shows a reduced peak current density. H151L selectively slows recovery from inactivation."

Three experimentally characterized variants show distinct loss-of-function effects in recombinant channels; their clinical presentations span a broader spectrum than DEE69.

Cav2.3 S15A Mouse Hippocampal Slices OTHER

Somatic recordings in CA1 neurons test a phosphorylation-site mutant, not a human DEE allele. Slower R-type current inactivation and enhanced cholinergic depolarizations support mechanistic convergence. Baseline firing was unchanged; strong stimulation could cause depolarization block.

Organism

Mus musculus NCBITaxon:10090

Cell source

Acute hippocampal slices from engineered homozygous S15A mice and wild-type littermates

Publication

PMID:38081835

Pathograph links

Slowed Cav2.3 Inactivation partially recapitulates fidelity: moderate The engineered phosphorylation-site lesion prolongs native R-type currents.

Show evidence (1 reference)

PMID:38081835 SUPPORT DIRECT PRIMARY RESULT In Vitro

"When compared to wild type littermates (WT), HOM S15A mice showed significantly slower inactivation τ at maximal conductance voltages, recapitulating HEK293 cell results (Fig. 3d, e). Current amplitudes at the soma did not differ (Fig. 3f)."

Native CA1 currents in engineered S15A slices inactivate more slowly without increased somatic amplitude.

Altered Neuronal Excitability partially recapitulates fidelity: moderate The effect depends on cholinergic stimulation.

Show evidence (2 references)

PMID:38081835 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"The percentage of cells exhibiting at least one DPP or all-or-none afterdepolarization (ADP) > 8 mV upon carbachol treatment was significantly higher in S15A mice, showing an enhanced depolarization response (Fig. 3j, k)."

S15A mouse slices show enhanced cholinergic plateau potentials/afterdepolarizations. This is a convergent engineered model, not direct evidence from a patient variant.

+ 1 more reference

Show evidence (3 references)

PMID:38081835 SUPPORT DIRECT PRIMARY RESULT In Vitro

"When compared to wild type littermates (WT), HOM S15A mice showed significantly slower inactivation τ at maximal conductance voltages, recapitulating HEK293 cell results (Fig. 3d, e). Current amplitudes at the soma did not differ (Fig. 3f)."

Native CA1 currents in engineered S15A slices inactivate more slowly without increased somatic amplitude.

PMID:38081835 SUPPORT DIRECT PRIMARY RESULT In Vitro

"firing properties were identical between WT and S15A mice under baseline conditions (Fig. 3g–i)."

Baseline firing was unchanged in S15A mouse CA1 cells; the excess depolarization emerged during cholinergic stimulation.

PMID:38081835 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"The percentage of cells exhibiting at least one DPP or all-or-none afterdepolarization (ADP) > 8 mV upon carbachol treatment was significantly higher in S15A mice, showing an enhanced depolarization response (Fig. 3j, k)."

S15A mouse slices show enhanced cholinergic plateau potentials/afterdepolarizations. This is a convergent engineered model, not direct evidence from a patient variant.

🐁

Animal Models

2

Cav2.3 S15A Phosphomutant Mouse

An engineered CDKL5 phosphorylation-site model, not a patient-variant knock-in. Memory, sociability and locomotor effects were observed, with some sex dependence. Female mice had enhanced kainate susceptibility; maximal seizure severity and baseline electrocorticography were unchanged, and spontaneous behavioral seizures were not observed through 40 weeks.

Species

Mus musculus

Genotype

Homozygous Cacna1e S15A phosphorylation-site substitution

Publication

PMID:38081835

Pathograph links

Epileptogenic Network Dysfunction partially recapitulates fidelity: low Provoked seizure susceptibility supports only part of the proposed human mechanism; spontaneous epilepsy was not reproduced.

Show evidence (2 references)

PMID:38081835 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Interestingly, however, female S15A mice had a reduced threshold to stage 5 behavioural seizures along with an increase in ECoG activity during KA (Fig. 5c)."

Female phosphomutants had increased kainate susceptibility; this is a small, sex-dependent provoked-seizure result.

+ 1 more reference

Show evidence (2 references)

PMID:38081835 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Interestingly, however, female S15A mice had a reduced threshold to stage 5 behavioural seizures along with an increase in ECoG activity during KA (Fig. 5c)."

Female phosphomutants had increased kainate susceptibility; this is a small, sex-dependent provoked-seizure result.

PMID:38081835 SUPPORT DIRECT PRIMARY RESULT Model Organism

"We did not observe any spontaneous behavioural seizures in Cav2.3 S15A mice up to 40 weeks of age,"

The model did not reproduce spontaneous behavioral seizures over the observed period.

Cacna1e Knockout Mouse

An inverse perturbation of the predominant DEE gain-of-function mechanism. PTZ seizure susceptibility was reduced while 4-AP sensitivity was unchanged. Kainate produced behavioral limbic seizure resistance and reduced excitotoxic injury, but hippocampal EEG seizure activity was unchanged at the tested suprathreshold dose. These results do not demonstrate neurodegeneration or drug efficacy in human DEE69.

Species

Mus musculus

Genotype

Constitutive or brain-specific Cacna1e knockout

Publication

PMID:16686648

Pathograph links

Epileptogenic Network Dysfunction perturbs fidelity: low Loss of the channel tests its contribution to provoked seizures in the opposite direction from most characterized DEE variants.

Show evidence (2 references)

PMID:16686648 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Surprisingly, PTZ-induced seizure susceptibility was dramatically reduced in Ca(v)2.3-deficient mice, whereas 4-AP sensitivity remained unchanged."

Knockout reduces PTZ susceptibility without a corresponding 4-AP effect.

+ 1 more reference

Show evidence (2 references)

PMID:16686648 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Surprisingly, PTZ-induced seizure susceptibility was dramatically reduced in Ca(v)2.3-deficient mice, whereas 4-AP sensitivity remained unchanged."

Knockout reduces PTZ susceptibility without a corresponding 4-AP effect.

PMID:17376845 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Administration of kainic acid (30 mg/kg ip) revealed clear alteration in behavioral seizure architecture and dramatic resistance to limbic seizures in Ca(v)2.3(-/-) mice compared with controls, whereas no difference in hippocampal EEG seizure activity between both genotypes could be detected at..."

Behavioral limbic seizure resistance did not translate into reduced hippocampal EEG seizure activity at the tested high dose.

{ }

Source YAML

click to show

name: CACNA1E-Related Developmental and Epileptic Encephalopathy
creation_date: '2026-07-25T00:00:00Z'
description: >-
  CACNA1E-related developmental and epileptic encephalopathy (DEE69) is a predominantly de novo dominant
  calcium-channel
  disorder, usually presenting with early-onset seizures, severe developmental impairment and axial hypotonia.
  Movement disorders, congenital contractures, spasticity and macrocephaly are recurrent features. Gain-of-function
  effects are established for several missense variants in recombinant Cav2.3 channels, but the affected
  gating
  parameters differ by variant. The neuronal and developmental consequences are incompletely resolved.
  This
  entry focuses on the DEE presentation; the wider CACNA1E spectrum also includes developmental disorders
  without
  ongoing epilepsy and experimentally characterized loss-of-function variants with variable neurological
  phenotypes.
  Seizure absence at a young assessment age, sustained remission and lifetime absence of seizures are
  distinct
  clinical histories.
category: Mendelian
parents:
- Neurodevelopmental Disorder
- Epileptic Encephalopathy
disease_term:
  preferred_term: CACNA1E-related developmental and epileptic encephalopathy
  term:
    id: MONDO:0032657
    label: developmental and epileptic encephalopathy, 69
inheritance:
- name: Autosomal Dominant (De Novo)
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Heterozygous missense variants typically arise de novo. The discovery series confirmed de novo status
    in
    29/30 probands; both parental samples were unavailable for the remaining proband. Variant interpretation
    and parental testing are required rather than assuming every rare CACNA1E variant is causal.
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: 'Molecular genetic testing identified 14 missense variants in CACNA1E (GenBank: NM_000721.3) in 30 unrelated individuals (Table 1). For the 29/30 individuals for whom DNA samples were available for both parents, de novo status of the variants and parentage were confirmed.'
    explanation: Thirty missense-variant probands were reported, with de novo status confirmed in all 29 with both parental samples.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    The 2018 discovery series included 30 unrelated missense-variant probands and three additional individuals
    with truncating variants of less certain causal significance. These are historical case counts, not
    an
    estimate of worldwide prevalence or the current number of affected people.
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: 'Molecular genetic testing identified 14 missense variants in CACNA1E (GenBank: NM_000721.3) in 30 unrelated individuals (Table 1). For the 29/30 individuals for whom DNA samples were available for both parents, de novo status of the variants and parentage were confirmed.'
    explanation: Thirty missense-variant probands were reported, with de novo status confirmed in all 29 with both parental samples.
has_subtypes:
- name: DI-S6
  display_name: Domain I S6 (p.Gly352Arg hotspot)
  description: >-
    Cohort-derived domain I S6 group, particularly Gly352Arg and Gly348Arg. All ten such cases in the
    original
    series had prominent dystonia, compared with 2/19 other probands. This association is useful for recognition
    but is not a validated deterministic prognostic classification.
  genes:
  - preferred_term: CACNA1E
    term:
      id: hgnc:1392
      label: CACNA1E
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Dystonia was a prominent feature in all nine individuals with the recurrent c.1054G>A (p.Gly352Arg) variant. This variant is in close proximity to the c.1042G>C (p.Gly348Arg) variant in individual 2 who also demonstrated profound dystonia. Dystonia was less common in individuals with other variants, only observed in 2/19 (11%) remaining probands, suggesting that variants in the domain I GX3G motif may predispose to prominent hyperkinetic movement disorders.
    explanation: The original cohort associated Gly352Arg/Gly348Arg with dystonia, without establishing a deterministic domain-wide prognosis.
- name: DII-S6
  display_name: Domain II S6 (p.Ala702Thr hotspot)
  description: >-
    Cohort-derived domain II S6 group. Six Ala702Thr cases in the original series had profound impairment
    and
    refractory epilepsy. Other substitutions, including Ala702Ser and Ala702Val, occur in the broader,
    milder
    CACNA1E spectrum, so domain or residue alone cannot predict severity.
  genes:
  - preferred_term: CACNA1E
    term:
      id: hgnc:1392
      label: CACNA1E
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The six individuals harboring the recurrent c.2104G>A (p.Ala702Thr) variant had a relatively homogeneous phenotype that was representative of the overall CACNA1E-encephalopathy phenotype. All individuals had refractory infantile-onset epilepsy, epileptic spasms, severe hypotonia, and profound developmental impairment. Five out of six individuals (83%) harboring the c.2104G>A (p.Ala702Thr) variant had congenital joint contractures and macrocephaly; hypsarrhythmia on EEG consistent with a diagnosis of West syndrome was observed in four of these individuals (67%). Two of these six individuals died in early childhood at ages 1 and 3 years.
    explanation: The six Ala702Thr cases shared a severe course; this does not establish the prognosis of other substitutions at residue 702.
  - reference: PMID:34702355
    reference_title: De novo variants in CACNA1E found in patients with intellectual disability, developmental regression and social cognition deficit but no seizures.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Age of onset of clinical manifestation, presence or absence of regression and degree of severity were variable, and no clear-cut genotype-phenotype association could be recognized.
    explanation: The broader cohort cautions against treating the original domain groups as a universal prognostic taxonomy.
- name: DIII-S6
  display_name: Domain III S6 (milder phenotype)
  description: >-
    Comparatively mild domain III S6 cases in the original series carried Thr1425Asn or Gly1430Arg. Two
    had
    no seizures by age four; one was seizure-free for five years and off medication at age six. Single
    words
    and independent or assisted walking were achieved. These observations describe a spectrum boundary
    and
    do not imply lifetime seizure absence for all DIII-S6 variants.
  genes:
  - preferred_term: CACNA1E
    term:
      id: hgnc:1392
      label: CACNA1E
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Two individuals harboring the c.4274C>A (p.Thr1425Asn) variant and one individual with the c.4288G>A (p.Gly1430Arg) variant presented with a comparatively milder clinical picture. All three probands were the only individuals in the cohort to speak single words and walk independently or with assistance, in contrast to the profound impairment in the remainder of the cohort. Two of these probands had not developed seizures by age 4 years, and the other had been seizure free for 5 years and off AEDs at age 6 years.
    explanation: Three DIII-S6 cases were comparatively milder; two had not seized by age four and one had sustained remission. Walking could be assisted.
references:
- reference: PMID:30343943
  title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
- reference: PMID:31064215
  title: 'Calcium Channel Dysfunction in Epilepsy: Gain of CACNA1E.'
- reference: PMID:33776624
  title: Dystonia and Contractures are Potential Early Signs of CACNA1E-Related Epileptic Encephalopathy.
- reference: PMID:34702355
  title: De novo variants in CACNA1E found in patients with intellectual disability, developmental regression and social cognition deficit but no seizures.
- reference: PMID:38081835
  title: Epilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2.3, altering inactivation kinetics and neuronal excitability.
- reference: PMID:38780451
  title: 'Seizure and movement disorder in CACNA1E developmental and epileptic encephalopathy: Two sides of the same coin or same side of two different coins?'
- reference: PMID:41492575
  title: A Rare Case of Dual De Novo Mutations Presenting With Infantile Spasms, Congenital Contractures, and Axial Hypotonia.
- reference: PMID:42123681
  title: Characterization of Three Distinct Loss-of-Function Cav2.3 Variants.
- reference: PMID:42392563
  title: Gating effects of a Cav2.3 calcium channel variant linked to developmental and epileptic encephalopathy.
- reference: PMID:42615235
  title: Efficacy of synthetic ACTH in confirmed and presumed monogenic developmental and epileptic encephalopathies.
- reference: PMID:16686648
  title: Altered seizure susceptibility in mice lacking the Ca(v)2.3 E-type Ca2+ channel.
- reference: PMID:17376845
  title: Hippocampal seizure resistance and reduced neuronal excitotoxicity in mice lacking the Cav2.3 E/R-type voltage-gated calcium channel.
pathophysiology:
- name: CACNA1E Missense Variant
  description: Heterozygous disease-associated missense substitutions affect the Cav2.3 pore-forming alpha1E subunit. Many cluster near S6 activation-gate regions, but pathogenic substitutions also occur elsewhere. The following gain-of-function branches describe tested DEE-associated variants and do not apply automatically to every CACNA1E allele.
  biological_scale: MOLECULAR
  role: trigger
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: 'Molecular genetic testing identified 14 missense variants in CACNA1E (GenBank: NM_000721.3) in 30 unrelated individuals (Table 1). For the 29/30 individuals for whom DNA samples were available for both parents, de novo status of the variants and parentage were confirmed.'
    explanation: Thirty missense-variant probands were reported, with de novo status confirmed in all 29 with both parental samples.
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Prominent clustering of CACNA1E variants (11/14; 79%) was noted in the cytoplasmic parts of all four S6 segments (Figure 1), which are presumed to form a crucial part of the activation gate in voltage-activated cation channels.
    explanation: Eleven of fourteen distinct discovery variants clustered in cytoplasmic S6 segments.
  downstream:
  - target: Facilitated Cav2.3 Activation
    causal_link_type: DIRECT
  - target: Slowed Cav2.3 Inactivation
    causal_link_type: DIRECT
  - target: Increased Cav2.3 Current Density
    causal_link_type: DIRECT
  - target: Expanded Cav2.3 Window Current
    causal_link_type: DIRECT
  - target: Impaired Neurodevelopment
    causal_link_type: UNKNOWN
    description: Genetic association is established; the allele-specific developmental intermediates remain unresolved.
  - target: Hyperkinetic Movement Disorder
    causal_link_type: UNKNOWN
  - target: Spastic Quadriplegia
    causal_link_type: UNKNOWN
  - target: Hypotonia
    causal_link_type: UNKNOWN
  - target: Congenital Contractures
    causal_link_type: UNKNOWN
  - target: Macrocephaly
    causal_link_type: UNKNOWN
  - target: Dystonia
    causal_link_type: UNKNOWN
    description: Clinical association with disease-associated CACNA1E variants; the intermediate tissue and cellular mechanisms are not established.
  - target: Talipes Equinovarus
    causal_link_type: UNKNOWN
    description: Clinical association with disease-associated CACNA1E variants; the intermediate tissue and cellular mechanisms are not established.
  - target: Areflexia
    causal_link_type: UNKNOWN
    description: Clinical association with disease-associated CACNA1E variants; the intermediate tissue and cellular mechanisms are not established.
  - target: Feeding Difficulties
    causal_link_type: UNKNOWN
    description: Clinical association with disease-associated CACNA1E variants; the intermediate tissue and cellular mechanisms are not established.
  genes:
  - preferred_term: CACNA1E
    term:
      id: hgnc:1392
      label: CACNA1E
- name: Facilitated Cav2.3 Activation
  description: Several DEE-associated variants activate at more negative membrane potentials. The three 2018 DII-S6 variants shifted activation by approximately -10 mV; Ile603Leu and Leu228Pro also facilitate activation under their respective assay conditions. This is a voltage-dependence change, not necessarily faster activation kinetics.
  biological_scale: MOLECULAR
  role: central_effector
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The activation curve was shifted by approximately −10 mV for all three variants (Figure 2), while the time course of activation was not altered.
    explanation: The three DII-S6 variants shifted activation about -10 mV in tsA201 cells.
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: This variant resulted in a massive increase in whole-cell current density (Figures 3 and S2) to a level that in many cases precluded functional biophysical characterization. In a subset of cells where the current could be properly clamped, our analysis revealed a >10 mV hyperpolarizing shift in half activation voltage (Figures 3 and S2; Table 2). There was no significant effect on channel inactivation.
    explanation: Ile603Leu increased whole-cell current density and facilitated activation without significantly changing inactivation.
  - reference: PMID:42392563
    reference_title: Gating effects of a Cav2.3 calcium channel variant linked to developmental and epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Compared to wild-type, the L228P mutant did not present altered peak current density, inactivation kinetics, or recovery from inactivation, but showed a significant shift towards hyperpolarized voltages in both voltage-dependent activation and steady-state inactivation. This resulted in a broader window current shifted towards more hyperpolarized potentials, which predicts increased channel availability and activity at subthreshold voltages relative to wild-type channels.
    explanation: Leu228Pro changes activation and steady-state inactivation and broadens the predicted window current without changing peak density or inactivation kinetics.
  downstream:
  - target: Increased R-Type Calcium Entry
    causal_link_type: DIRECT
  genes:
  - preferred_term: CACNA1E
    term:
      id: hgnc:1392
      label: CACNA1E
  molecular_functions:
  - preferred_term: Cav2.3 R-type calcium channel activity
    term:
      id: GO:0008331
      label: high voltage-gated calcium channel activity
    modifier: INCREASED
- name: Slowed Cav2.3 Inactivation
  description: Phe698Ser, Ile701Val and Ala702Thr slow fast inactivation in the 2018 recombinant-channel assays, prolonging current during depolarization. Ile603Leu and Leu228Pro did not share this kinetic change. Loss of CDKL5-dependent phosphorylation produces a convergent gating effect in engineered models; it is not the genetic lesion of DEE69.
  biological_scale: MOLECULAR
  role: central_effector
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Additionally, the time course of fast inactivation was significantly slowed, as indicated by an increased residual current after a 400-ms depolarizing pulse normalized to the peak current (r400) (Figures 2 and S1; Table 2).
    explanation: Slower fast inactivation was measured for the three tested DII-S6 variants.
  downstream:
  - target: Increased R-Type Calcium Entry
    causal_link_type: DIRECT
  genes:
  - preferred_term: CACNA1E
    term:
      id: hgnc:1392
      label: CACNA1E
  molecular_functions:
  - preferred_term: Cav2.3 R-type calcium channel activity
    term:
      id: GO:0008331
      label: high voltage-gated calcium channel activity
    modifier: INCREASED
- name: Increased Cav2.3 Current Density
  description: The Ile603Leu domain II S4-S5 linker variant substantially increases whole-cell calcium/barium current density in tsA201 cells. Increased peak current density is not a universal property of DEE-associated variants and was absent for Leu228Pro.
  biological_scale: CELLULAR
  role: central_effector
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: This variant resulted in a massive increase in whole-cell current density (Figures 3 and S2) to a level that in many cases precluded functional biophysical characterization. In a subset of cells where the current could be properly clamped, our analysis revealed a >10 mV hyperpolarizing shift in half activation voltage (Figures 3 and S2; Table 2). There was no significant effect on channel inactivation.
    explanation: Ile603Leu increased whole-cell current density and facilitated activation without significantly changing inactivation.
  - reference: PMID:42392563
    reference_title: Gating effects of a Cav2.3 calcium channel variant linked to developmental and epileptic encephalopathy.
    supports: REFUTE
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: the L228P mutant did not present altered peak current density, inactivation kinetics, or recovery from inactivation
    explanation: Leu228Pro refutes a universal increase in peak current density across DEE variants; this does not contradict the Ile603Leu result.
  downstream:
  - target: Increased R-Type Calcium Entry
    causal_link_type: DIRECT
  genes:
  - preferred_term: CACNA1E
    term:
      id: hgnc:1392
      label: CACNA1E
  molecular_functions:
  - preferred_term: Cav2.3 R-type calcium channel activity
    term:
      id: GO:0008331
      label: high voltage-gated calcium channel activity
    modifier: INCREASED
- name: Expanded Cav2.3 Window Current
  description: Leu228Pro shifts both activation and steady-state inactivation toward more negative voltages, creating a broader window current at hyperpolarized potentials. This predicts increased channel availability at subthreshold voltages despite unchanged peak density and inactivation kinetics.
  biological_scale: MOLECULAR
  role: central_effector
  evidence:
  - reference: PMID:42392563
    reference_title: Gating effects of a Cav2.3 calcium channel variant linked to developmental and epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Compared to wild-type, the L228P mutant did not present altered peak current density, inactivation kinetics, or recovery from inactivation, but showed a significant shift towards hyperpolarized voltages in both voltage-dependent activation and steady-state inactivation. This resulted in a broader window current shifted towards more hyperpolarized potentials, which predicts increased channel availability and activity at subthreshold voltages relative to wild-type channels.
    explanation: Leu228Pro changes activation and steady-state inactivation and broadens the predicted window current without changing peak density or inactivation kinetics.
  downstream:
  - target: Increased R-Type Calcium Entry
    causal_link_type: DIRECT
  genes:
  - preferred_term: CACNA1E
    term:
      id: hgnc:1392
      label: CACNA1E
  molecular_functions:
  - preferred_term: Cav2.3 R-type calcium channel activity
    term:
      id: GO:0008331
      label: high voltage-gated calcium channel activity
    modifier: INCREASED
- name: Increased R-Type Calcium Entry
  description: Facilitated activation, prolonged opening or altered window current can increase depolarization-dependent Cav2.3-mediated calcium entry. These routes depend on the variant, voltage and accessory-subunit context. Recombinant channel measurements support the conductance effect; chronic calcium overload in patient neurons has not been demonstrated.
  biological_scale: CELLULAR
  role: central_effector
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: Functional analysis revealed dramatic gain-of-function effects, indicating increased calcium inward currents that may affect neuronal excitability and synaptic transmission.
    explanation: Recombinant-channel results motivate increased calcium entry in neurons; sustained intracellular calcium overload was not measured in patients.
  downstream:
  - target: Altered Neuronal Excitability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Altered Synaptic Transmission
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: calcium ion transmembrane transport
    term:
      id: GO:0070588
      label: calcium ion transmembrane transport
    modifier: INCREASED
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
- name: Altered Neuronal Excitability
  description: Cav2.3 gain of function is proposed to alter neuronal excitability. In the engineered S15A phosphomutant mouse, baseline CA1 firing was unchanged, whereas carbachol enhanced depolarizing plateaus and afterdepolarizations; strong stimulation could induce depolarization block. Translation to individual human DEE variants remains provisional.
  biological_scale: CELLULAR
  role: central_effector
  evidence:
  - reference: PMID:38081835
    reference_title: Epilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2.3, altering inactivation kinetics and neuronal excitability.
    supports: REFUTE
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: firing properties were identical between WT and S15A mice under baseline conditions (Fig. 3g–i).
    explanation: This null result refutes an increase in baseline CA1 firing in the S15A model. It does not refute the separately measured enhancement of cholinergic depolarizations.
  - reference: PMID:38081835
    reference_title: Epilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2.3, altering inactivation kinetics and neuronal excitability.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: The percentage of cells exhibiting at least one DPP or all-or-none afterdepolarization (ADP) > 8 mV upon carbachol treatment was significantly higher in S15A mice, showing an enhanced depolarization response (Fig. 3j, k).
    explanation: S15A mouse slices show enhanced cholinergic plateau potentials/afterdepolarizations. This is a convergent engineered model, not direct evidence from a patient variant.
  downstream:
  - target: Epileptogenic Network Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Impaired Neurodevelopment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  mechanism_confidence: PROVISIONAL
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
- name: Altered Synaptic Transmission
  description: Cav2.3 participates in presynaptic neurotransmitter release and postsynaptic integration/plasticity. Variant-dependent disruption of these functions is a plausible contributor to DEE. The direction and magnitude of release changes, and their balance in excitatory versus inhibitory neurons, remain unresolved.
  biological_scale: CELLULAR
  role: central_effector
  evidence:
  - reference: PMID:31064215
    reference_title: 'Calcium Channel Dysfunction in Epilepsy: Gain of CACNA1E.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
    snippet: CACNA1E encodes Cav2.3, an R-type VGCC implicated in both presynaptic neurotransmitter release and postsynaptic somatodendritic integration and long-term potentiation.
    explanation: Normal Cav2.3 physiology motivates a synaptic mechanism, but altered transmitter release or plasticity has not been directly measured for the human variants in these studies.
  downstream:
  - target: Epileptogenic Network Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Impaired Neurodevelopment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  mechanism_confidence: HYPOTHETICAL
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
- name: Epileptogenic Network Dysfunction
  description: Abnormal neuronal network activity produces seizures and epileptiform EEG abnormalities. An excitation-inhibition imbalance is a mechanistic hypothesis rather than a measured patient-specific ratio. Channel effects and experimental seizure susceptibility support this connection without defining all cellular intermediates.
  biological_scale: TISSUE
  role: central_effector
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.
    explanation: Human seizures establish network dysfunction but do not directly measure an excitation-inhibition ratio or the intervening cellular mechanism.
  downstream:
  - target: Developmental and Epileptic Encephalopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Seizures
    causal_link_type: DIRECT
  - target: Epileptic Spasms
    causal_link_type: DIRECT
    description: A clinical or electrographic manifestation of the epileptic network phenotype; subtype-specific cellular mechanisms remain unresolved.
  - target: Focal Motor Seizures
    causal_link_type: DIRECT
    description: A clinical or electrographic manifestation of the epileptic network phenotype; subtype-specific cellular mechanisms remain unresolved.
  - target: Hypsarrhythmia
    causal_link_type: DIRECT
    description: A clinical or electrographic manifestation of the epileptic network phenotype; subtype-specific cellular mechanisms remain unresolved.
  - target: Status Epilepticus
    causal_link_type: DIRECT
    description: A clinical or electrographic manifestation of the epileptic network phenotype; subtype-specific cellular mechanisms remain unresolved.
  - target: Drug-Resistant Seizures
    causal_link_type: UNKNOWN
    description: Drug resistance is a documented outcome of the epilepsy; the factors determining medication response are not established.
  - target: Seizures with Sustained Remission (DIII-S6)
    causal_link_type: UNKNOWN
    description: A documented seizure course in one DIII-S6 case; the mechanism of remission and its relationship to genotype or treatment are unresolved.
  mechanism_confidence: PROVISIONAL
  conforms_to: epilepsy_excitation_inhibition_imbalance#Neuronal Hyperexcitability and Hypersynchrony
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
- name: Impaired Neurodevelopment
  description: Severe developmental impairment often precedes or accompanies epilepsy. The broader CACNA1E spectrum includes regression without seizures, supporting a developmental contribution beyond epileptic activity. This does not establish identical molecular mechanisms for the DEE and non-DEE presentations. Clinical movement, tone and congenital abnormalities are associated outcomes with incompletely resolved causal intermediates.
  biological_scale: ORGANISM
  role: outcome
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Of the probands older than 2 years, 21/24 (88%) were non-verbal and non-ambulatory.
    explanation: The 88% figure is 21/24 probands older than two, not all 30 participants.
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Developmental regression occurred in 9/30 (30%) individuals, often in association with seizure onset.
    explanation: Regression was reported in 9/30; developmental impairment is not uniformly progressive.
  - reference: PMID:34702355
    reference_title: De novo variants in CACNA1E found in patients with intellectual disability, developmental regression and social cognition deficit but no seizures.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Four patients (4/7, 57%) also presented with developmental regression, unrelated to any seizures or specific electro-encephalographic (EEG) epileptic activity.
    explanation: Regression without concurrent seizures supports a developmental component in the wider CACNA1E spectrum, not a shared proven cellular mechanism for every allele.
  - reference: PMID:34702355
    reference_title: De novo variants in CACNA1E found in patients with intellectual disability, developmental regression and social cognition deficit but no seizures.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: One adult patient (Patient 4) had a history of epileptic spasms, successfully treated with adrenocorticotropic hormone, without subsequent seizures in childhood or adulthood.
    explanation: The 2021 cohort lacked ongoing epilepsy, but one adult had successfully treated infantile spasms; it was not uniformly lifetime seizure-free.
  downstream:
  - target: Profound Developmental Impairment
    causal_link_type: DIRECT
  - target: Developmental Regression
    causal_link_type: UNKNOWN
  - target: Absent Speech
    causal_link_type: UNKNOWN
    description: An associated functional developmental outcome; contributions from cognition, tone, movement and epilepsy have not been separated.
  - target: Inability to Walk
    causal_link_type: UNKNOWN
    description: An associated functional developmental outcome; contributions from cognition, tone, movement and epilepsy have not been separated.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
phenotypes:
- name: Developmental and Epileptic Encephalopathy
  category: Clinical
  description: The DEE presentation combines developmental impairment with epilepsy; severity and seizure course vary.
  phenotype_term:
    preferred_term: Epileptic encephalopathy
    term:
      id: HP:0200134
      label: Epileptic encephalopathy
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: 'We identified 30 unrelated individuals with missense variants in CACNA1E (GenBank: NM_000721.3). A picture of a profound DEE emerged, with affected individuals typically having pharmaco-resistant seizures beginning in the first year of life, profound developmental impairment, hyperkinetic movement disorders, and severe axial hypotonia (Tables 1 and S1).'
    explanation: The discovery cohort establishes the clinical and genetic association; phenotype severity varies.
  diagnostic: true
- name: Seizures
  category: Clinical
  description: Epilepsy occurred in 26/30 (87%) discovery-cohort missense-variant probands, with median onset 4.5 months (range one day to 47 months). Onset was in the first year in 21/25 with available data. These cohort figures include mild spectrum cases and are not penetrance estimates for a selected DEE-only population.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Epilepsy was present in 26/30 (87%) individuals, with median age of seizure onset of 4.5 months (range 1 day to 47 months).
    explanation: Epilepsy occurred in 26/30, with median onset 4.5 months and a wider onset range.
  frequency: VERY_FREQUENT
  notes: Frequency reflects the named retrospective discovery-cohort denominator in the description, including its age or epilepsy ascertainment restriction; it is not population penetrance.
- name: Drug-Resistant Seizures
  category: Clinical
  description: Seizures were resistant to multiple medications in 20/25 (80%) participants with treatment data, distinct from the 26/30 epilepsy proportion.
  phenotype_term:
    preferred_term: Drug-resistant seizures
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Although seizures were resistant to multiple anti-epileptic drugs (AEDs) in most individuals for whom data were available (20/25; 80%), five individuals (1, 15, 16, 21, 27) reported significant improvement in seizure control with topiramate, the only AED noted to have a substantial effect on seizure control in any participants (Table S1).
    explanation: Drug resistance was 20/25 with available data; five reported substantial topiramate benefit.
  frequency: VERY_FREQUENT
  notes: Frequency reflects the named retrospective discovery-cohort denominator in the description, including its age or epilepsy ascertainment restriction; it is not population penetrance.
- name: Profound Developmental Impairment
  category: Clinical
  description: Severe to profound impairment is typical of DEE69. In the discovery cohort, 21/24 probands older than two years were both nonverbal and nonambulatory; this age-restricted combined endpoint is not a count of every developmental domain in all 30 participants.
  phenotype_term:
    preferred_term: Profound global developmental delay
    term:
      id: HP:0012736
      label: Profound global developmental delay
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Of the probands older than 2 years, 21/24 (88%) were non-verbal and non-ambulatory.
    explanation: The 88% figure is 21/24 probands older than two, not all 30 participants.
  diagnostic: true
- name: Absent Speech
  category: Clinical
  description: Nonverbal status was reported in the 21/24 older-than-two subgroup with combined absent speech and ambulation.
  phenotype_term:
    preferred_term: Absent speech
    term:
      id: HP:0001344
      label: Absent speech
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Of the probands older than 2 years, 21/24 (88%) were non-verbal and non-ambulatory.
    explanation: The 88% figure is 21/24 probands older than two, not all 30 participants.
  frequency: VERY_FREQUENT
  notes: Frequency reflects the named retrospective discovery-cohort denominator in the description, including its age or epilepsy ascertainment restriction; it is not population penetrance.
- name: Inability to Walk
  category: Clinical
  description: Nonambulatory status was reported in the 21/24 older-than-two subgroup; milder DIII-S6 cases could walk independently or with assistance.
  phenotype_term:
    preferred_term: Inability to walk
    term:
      id: HP:0002540
      label: Inability to walk
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Of the probands older than 2 years, 21/24 (88%) were non-verbal and non-ambulatory.
    explanation: The 88% figure is 21/24 probands older than two, not all 30 participants.
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Two individuals harboring the c.4274C>A (p.Thr1425Asn) variant and one individual with the c.4288G>A (p.Gly1430Arg) variant presented with a comparatively milder clinical picture. All three probands were the only individuals in the cohort to speak single words and walk independently or with assistance, in contrast to the profound impairment in the remainder of the cohort. Two of these probands had not developed seizures by age 4 years, and the other had been seizure free for 5 years and off AEDs at age 6 years.
    explanation: Three DIII-S6 cases were comparatively milder; two had not seized by age four and one had sustained remission. Walking could be assisted.
  frequency: VERY_FREQUENT
  notes: Frequency reflects the named retrospective discovery-cohort denominator in the description, including its age or epilepsy ascertainment restriction; it is not population penetrance.
- name: Developmental Regression
  category: Clinical
  description: Regression occurred in 9/30 (30%) discovery cases, often around seizure onset. It is not universal or proof of a relentlessly progressive course.
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Developmental regression occurred in 9/30 (30%) individuals, often in association with seizure onset.
    explanation: Regression was reported in 9/30; developmental impairment is not uniformly progressive.
  frequency: FREQUENT
  notes: Frequency reflects the named retrospective discovery-cohort denominator in the description, including its age or epilepsy ascertainment restriction; it is not population penetrance.
- name: Hyperkinetic Movement Disorder
  category: Clinical
  description: Dystonia and other dyskinesias are prominent; 12/30 had severe dystonia and 6/30 other dyskinesias in the original series.
  phenotype_term:
    preferred_term: Hyperkinetic movements
    term:
      id: HP:0002487
      label: Hyperkinetic movements
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Hyperkinetic movement disorders were prominent, including severe dystonia in 12/30 (40%) and other dyskinesias in 6/30 (20%) individuals; movement disorders were constant and profoundly disabling in some individuals.
    explanation: Dystonia occurred in 12/30 and other dyskinesias in 6/30; these are distinct reported categories.
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Dystonia was a prominent feature in all nine individuals with the recurrent c.1054G>A (p.Gly352Arg) variant. This variant is in close proximity to the c.1042G>C (p.Gly348Arg) variant in individual 2 who also demonstrated profound dystonia. Dystonia was less common in individuals with other variants, only observed in 2/19 (11%) remaining probands, suggesting that variants in the domain I GX3G motif may predispose to prominent hyperkinetic movement disorders.
    explanation: The original cohort associated Gly352Arg/Gly348Arg with dystonia, without establishing a deterministic domain-wide prognosis.
  frequency: FREQUENT
  notes: Frequency reflects the named retrospective discovery-cohort denominator in the description, including its age or epilepsy ascertainment restriction; it is not population penetrance.
- name: Dystonia
  category: Clinical
  description: Severe dystonia affected 12/30 (40%) original cases, especially Gly352Arg/Gly348Arg. It may begin neonatally before epilepsy and can coexist with nonepileptic and epileptic paroxysmal movements.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Hyperkinetic movement disorders were prominent, including severe dystonia in 12/30 (40%) and other dyskinesias in 6/30 (20%) individuals; movement disorders were constant and profoundly disabling in some individuals.
    explanation: Dystonia occurred in 12/30 and other dyskinesias in 6/30; these are distinct reported categories.
  - reference: PMID:33776624
    reference_title: Dystonia and Contractures are Potential Early Signs of CACNA1E-Related Epileptic Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Notable findings include congenital contractures and movement disorders predating onset of epilepsy, particularly dystonia.
    explanation: The two-case study documents movement disorders before epilepsy.
  frequency: FREQUENT
  notes: Frequency reflects the named retrospective discovery-cohort denominator in the description, including its age or epilepsy ascertainment restriction; it is not population penetrance.
- name: Congenital Contractures
  category: Clinical
  description: Congenital joint contractures were reported in 13/30 (43%), ranging from clubfoot to arthrogryposis.
  phenotype_term:
    preferred_term: Congenital contracture
    term:
      id: HP:0002803
      label: Congenital contracture
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: 13/30 (43%) affected individuals had congenital joint contractures ranging from isolated talipes equinovarus to arthrogryposis multiplex congenita, frequently prompting initial consideration of a congenital neuromuscular disorder.
    explanation: Contractures ranged from isolated clubfoot to multiple congenital joint contractures in 13/30.
  frequency: FREQUENT
  notes: Frequency reflects the named retrospective discovery-cohort denominator in the description, including its age or epilepsy ascertainment restriction; it is not population penetrance.
- name: Talipes Equinovarus
  category: Clinical
  description: Clubfoot is one presentation within the congenital contracture spectrum; a separate cohort-wide frequency is not established.
  phenotype_term:
    preferred_term: Talipes equinovarus
    term:
      id: HP:0001762
      label: Talipes equinovarus
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: 13/30 (43%) affected individuals had congenital joint contractures ranging from isolated talipes equinovarus to arthrogryposis multiplex congenita, frequently prompting initial consideration of a congenital neuromuscular disorder.
    explanation: Contractures ranged from isolated clubfoot to multiple congenital joint contractures in 13/30.
- name: Macrocephaly
  category: Clinical
  description: Macrocephaly was reported in 12/28 (43%) with available data and could occur without other structural MRI abnormalities.
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Macrocephaly without other structural abnormalities on brain magnetic resonance imaging was present in 12/28 (43%) individuals for whom data were available.
    explanation: Macrocephaly was reported in 12/28 with available imaging/head-size data.
  frequency: FREQUENT
  notes: Frequency reflects the named retrospective discovery-cohort denominator in the description, including its age or epilepsy ascertainment restriction; it is not population penetrance.
- name: Spastic Quadriplegia
  category: Clinical
  description: Spastic quadriplegia was reported in 16/30 (53%), often alongside axial hypotonia.
  phenotype_term:
    preferred_term: Spastic tetraplegia
    term:
      id: HP:0002510
      label: Spastic tetraplegia
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: All affected individuals had prominent axial hypotonia, often with appendicular hypertonia; spastic quadriplegia was reported in 16/30 (53%) individuals.
    explanation: Axial hypotonia was universal in the discovery cohort and spastic quadriplegia occurred in 16/30.
  frequency: FREQUENT
  notes: Frequency reflects the named retrospective discovery-cohort denominator in the description, including its age or epilepsy ascertainment restriction; it is not population penetrance.
- name: Hypotonia
  category: Clinical
  description: Prominent axial hypotonia was reported in all discovery-cohort participants; appendicular hypertonia can coexist.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: All affected individuals had prominent axial hypotonia, often with appendicular hypertonia; spastic quadriplegia was reported in 16/30 (53%) individuals.
    explanation: Axial hypotonia was universal in the discovery cohort and spastic quadriplegia occurred in 16/30.
  frequency: OBLIGATE
  notes: Frequency reflects the named retrospective discovery-cohort denominator in the description, including its age or epilepsy ascertainment restriction; it is not population penetrance.
- name: Epileptic Spasms
  category: Clinical
  description: The most frequent initial seizure type, reported in 14/26 (54%) participants with epilepsy in the discovery cohort.
  phenotype_term:
    preferred_term: Epileptic spasm
    term:
      id: HP:0011097
      label: Epileptic spasm
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Epileptic spasms were the most common initial seizure type (14/26; 54%) followed by focal motor seizures (5/26; 19%).
    explanation: Initial spasms occurred in 14/26 participants with epilepsy; initial focal motor seizures in 5/26.
  frequency: FREQUENT
  notes: Frequency reflects the named retrospective discovery-cohort denominator in the description, including its age or epilepsy ascertainment restriction; it is not population penetrance.
- name: Focal Motor Seizures
  category: Clinical
  description: Initial focal motor seizures occurred in 5/26 (19%) participants with epilepsy.
  phenotype_term:
    preferred_term: Focal motor seizure
    term:
      id: HP:0011153
      label: Focal motor seizure
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Epileptic spasms were the most common initial seizure type (14/26; 54%) followed by focal motor seizures (5/26; 19%).
    explanation: Initial spasms occurred in 14/26 participants with epilepsy; initial focal motor seizures in 5/26.
- name: Hypsarrhythmia
  category: Clinical
  description: Hypsarrhythmia occurred in 4/6 original Ala702Thr cases and in later Gly352Arg cases. This genotype-enriched proportion is not a whole-disease frequency.
  phenotype_term:
    preferred_term: Hypsarrhythmia
    term:
      id: HP:0002521
      label: Hypsarrhythmia
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The six individuals harboring the recurrent c.2104G>A (p.Ala702Thr) variant had a relatively homogeneous phenotype that was representative of the overall CACNA1E-encephalopathy phenotype. All individuals had refractory infantile-onset epilepsy, epileptic spasms, severe hypotonia, and profound developmental impairment. Five out of six individuals (83%) harboring the c.2104G>A (p.Ala702Thr) variant had congenital joint contractures and macrocephaly; hypsarrhythmia on EEG consistent with a diagnosis of West syndrome was observed in four of these individuals (67%). Two of these six individuals died in early childhood at ages 1 and 3 years.
    explanation: The six Ala702Thr cases shared a severe course; this does not establish the prognosis of other substitutions at residue 702.
- name: Status Epilepticus
  category: Clinical
  description: Reported in two original participants and among reported causes of death.
  phenotype_term:
    preferred_term: Status epilepticus
    term:
      id: HP:0002133
      label: Status epilepticus
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Most individuals (20/26; 77%) developed additional seizure types (Table S1); status epilepticus occurred in two individuals.
    explanation: Multiple seizure types developed in 20/26; status epilepticus was reported in two.
- name: Areflexia
  category: Clinical
  description: Deep-tendon areflexia accompanied severe dystonic developmental impairment in two Gly352Arg cases despite normal peripheral electrophysiology.
  phenotype_term:
    preferred_term: Areflexia
    term:
      id: HP:0001284
      label: Areflexia
  evidence:
  - reference: PMID:33776624
    reference_title: Dystonia and Contractures are Potential Early Signs of CACNA1E-Related Epileptic Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Deep tendon areflexia, as presented by both patients described here, with normal peripheral electroneurogram.
    explanation: Both new cases had areflexia with normal peripheral nerve studies.
- name: Feeding Difficulties
  category: Clinical
  description: Severe feeding difficulty requiring gastrostomy was reported in both Gly352Arg cases in the 2021 study; no population frequency is available.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:33776624
    reference_title: Dystonia and Contractures are Potential Early Signs of CACNA1E-Related Epileptic Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: he required a gastrostomy due to a feeding disorder.
    explanation: Gastrostomy was required in the first case.
  - reference: PMID:33776624
    reference_title: Dystonia and Contractures are Potential Early Signs of CACNA1E-Related Epileptic Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The patient also required a gastrostomy due to a feeding disorder (Fig. 1b).
    explanation: The second case also needed gastrostomy.
- name: Seizures with Sustained Remission (DIII-S6)
  category: Clinical
  description: One DIII-S6 participant had been seizure-free for five years and off medication at age six. Two other DIII-S6 cases had no seizures by age four; those negative histories do not constitute positive seizure findings.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Two individuals harboring the c.4274C>A (p.Thr1425Asn) variant and one individual with the c.4288G>A (p.Gly1430Arg) variant presented with a comparatively milder clinical picture. All three probands were the only individuals in the cohort to speak single words and walk independently or with assistance, in contrast to the profound impairment in the remainder of the cohort. Two of these probands had not developed seizures by age 4 years, and the other had been seizure free for 5 years and off AEDs at age 6 years.
    explanation: Three DIII-S6 cases were comparatively milder; two had not seized by age four and one had sustained remission. Walking could be assisted.
  subtype: DIII-S6
genetic:
- name: CACNA1E
  gene_term:
    preferred_term: CACNA1E
    term:
      id: hgnc:1392
      label: CACNA1E
  association: Predominantly gain-of-function missense variants in DEE; broader allele-specific functional spectrum
  presence: Positive
  variant_origin: DE_NOVO
  inheritance:
  - name: Autosomal Dominant (De Novo)
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  notes: >-
    Most established DEE69 cases carry de novo missense variants, including Gly352Arg, Ile701Val and Ala702Thr;
    the functional effects must be assessed per allele. The three 2018 truncation cases had milder phenotypes
    and uncertain causal significance: one had a 27% mutant allele fraction (6/22 blood reads), one inherited
    the allele from an apparently unaffected father, and parental samples were unavailable for the third.
    This
    is not evidence of parental mosaicism. Later recombinant studies identified loss-of-function effects
    for
    H151L, M163T and R1182C in a broader neurological spectrum; these results do not establish a uniform
    loss-of-function
    mechanism for DEE69.
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: 'Molecular genetic testing identified 14 missense variants in CACNA1E (GenBank: NM_000721.3) in 30 unrelated individuals (Table 1). For the 29/30 individuals for whom DNA samples were available for both parents, de novo status of the variants and parentage were confirmed.'
    explanation: Thirty missense-variant probands were reported, with de novo status confirmed in all 29 with both parental samples.
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Individual 31 has a mosaic nonsense variant with a mutant allele fraction of 27% (6/22 reads) in peripheral blood leukocytes. In individual 32, a CACNA1E frameshift variant was inherited from an apparently unaffected father. Parental DNA samples were unavailable for individual 33, who has a heterozygous germline nonsense variant. All three individuals had comparably milder phenotypes, achieving independent ambulation at 15–18 months and acquiring single words; 2/3 individuals had epilepsy.
    explanation: The 27% value is a variant allele fraction in blood reads, not a percentage of cells; inherited and unphased truncations had uncertain causal significance.
  - reference: PMID:42123681
    reference_title: Characterization of Three Distinct Loss-of-Function Cav2.3 Variants.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: M163T and R1182C exhibit depolarizing shifts in the voltage-dependence of activation, whereas R1182C also shows a reduced peak current density. H151L selectively slows recovery from inactivation.
    explanation: Three experimentally characterized variants show distinct loss-of-function effects in recombinant channels; their clinical presentations span a broader spectrum than DEE69.
diagnosis:
- name: CACNA1E Molecular Diagnosis
  description: >-
    Identify a heterozygous pathogenic or likely pathogenic CACNA1E variant in a compatible clinical presentation
    using a suitable sequencing assay, with parental testing and variant-specific interpretation. Exome
    analysis
    and reanalysis identified cases in the discovery cohort. A variant of uncertain significance alone
    does
    not establish DEE69, and seizures need not precede the movement disorder.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: 'Molecular genetic testing identified 14 missense variants in CACNA1E (GenBank: NM_000721.3) in 30 unrelated individuals (Table 1). For the 29/30 individuals for whom DNA samples were available for both parents, de novo status of the variants and parentage were confirmed.'
    explanation: Thirty missense-variant probands were reported, with de novo status confirmed in all 29 with both parental samples.
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: 'Individuals 23 and 26 were ascertained by reanalysis of the data from the Deciphering Developmental Disorders Study28 as part of a local “Solving the Unsolved” project in Manchester (UK) and a Complementary Analysis Project #237.21'
    explanation: Reanalysis of existing sequencing data diagnosed previously unresolved cases.
- name: EEG
  description: >-
    EEG characterizes seizures and epileptiform activity, including hypsarrhythmia in some infants. Prolonged
    video-EEG can distinguish nonepileptic dystonia/dyskinesia from clinically similar hyperkinetic seizures.
    Hypsarrhythmia was already documented in the original clinical series.
  diagnosis_term:
    preferred_term: electroencephalography
    term:
      id: NCIT:C38054
      label: Electroencephalography
  results: Abundant epileptiform activity consistent with a developmental and epileptic encephalopathy.
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The six individuals harboring the recurrent c.2104G>A (p.Ala702Thr) variant had a relatively homogeneous phenotype that was representative of the overall CACNA1E-encephalopathy phenotype. All individuals had refractory infantile-onset epilepsy, epileptic spasms, severe hypotonia, and profound developmental impairment. Five out of six individuals (83%) harboring the c.2104G>A (p.Ala702Thr) variant had congenital joint contractures and macrocephaly; hypsarrhythmia on EEG consistent with a diagnosis of West syndrome was observed in four of these individuals (67%). Two of these six individuals died in early childhood at ages 1 and 3 years.
    explanation: The six Ala702Thr cases shared a severe course; this does not establish the prognosis of other substitutions at residue 702.
  - reference: PMID:38780451
    reference_title: 'Seizure and movement disorder in CACNA1E developmental and epileptic encephalopathy: Two sides of the same coin or same side of two different coins?'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Long-term video-EEG-monitoring documented subsequent tonic asymmetric seizures during wakefulness and mild paroxysmal dyskinesias of the trunk out of sleep which were thought to be a movement disorder and instead turned out to be focal hyperkinetic seizures.
    explanation: Video-EEG identified an ictal correlate for movements initially considered dyskinesia in one child.
- name: Brain MRI
  description: Brain MRI assesses structural causes and associated abnormalities, but a normal scan does not exclude CACNA1E-related DEE. The discovery cohort and later cases included severe disease without explanatory structural abnormalities.
  diagnosis_term:
    preferred_term: Magnetic Resonance Imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Macrocephaly without other structural abnormalities on brain magnetic resonance imaging was present in 12/28 (43%) individuals for whom data were available.
    explanation: Macrocephaly was reported in 12/28 with available imaging/head-size data.
  - reference: PMID:33776624
    reference_title: Dystonia and Contractures are Potential Early Signs of CACNA1E-Related Epileptic Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Cerebral and spinal magnetic resonance imaging (MRI) scans in both patients were normal at 2 months and when repeated at 6 months in case 1 and at 4 months in case 2.
    explanation: Serial early MRI was normal in both severely affected Gly352Arg cases.
differential_diagnoses:
- name: STXBP1 Encephalopathy
  description: >-
    Another de novo dominant developmental and epileptic encephalopathy with
    early-onset refractory seizures and profound developmental impairment;
    distinguished by the causative gene (STXBP1 vs CACNA1E) and its
    synaptic-vesicle-release mechanism.
  disease_term:
    preferred_term: STXBP1 encephalopathy
    term:
      id: MONDO:0012812
      label: developmental and epileptic encephalopathy, 4
- name: Other Voltage-Gated Calcium Channel Epileptic Encephalopathies
  description: >-
    Other calcium-channel disorders, including CACNA1A-, CACNA1D- and CACNA1G-related neurological syndromes,
    can overlap in epilepsy and developmental impairment. Their functional direction and extra-neurological
    features vary; gene- and variant-specific interpretation distinguishes them.
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: Developmental and epileptic encephalopathies are genetically heterogeneous and can be caused by pathogenic variants in genes encoding other voltage-gated neuronal ion channels, including SCN2A, SCN8A, KCNQ2, and CACNA1A.3, 37, 38, 39
    explanation: The discovery paper places CACNA1E among clinically overlapping genetic channelopathies.
progression:
- phase: Early development and seizure onset
  notes: Axial hypotonia, congenital contractures and neonatal dystonia can precede seizures. In the discovery cohort onset ranged from one day to 47 months, with 21/25 occurring in the first year; 9/30 had regression. Severe static impairment, regression, drug resistance and sustained remission are distinct possible courses.
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Epilepsy was present in 26/30 (87%) individuals, with median age of seizure onset of 4.5 months (range 1 day to 47 months).
    explanation: Epilepsy occurred in 26/30, with median onset 4.5 months and a wider onset range.
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Developmental regression occurred in 9/30 (30%) individuals, often in association with seizure onset.
    explanation: Regression was reported in 9/30; developmental impairment is not uniformly progressive.
  - reference: PMID:33776624
    reference_title: Dystonia and Contractures are Potential Early Signs of CACNA1E-Related Epileptic Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Notable findings include congenital contractures and movement disorders predating onset of epilepsy, particularly dystonia.
    explanation: Movement manifestations can precede epilepsy.
- phase: Mortality in the discovery cohort
  notes: Seven of 30 participants (23%) had died by ascertainment, with median age at death 2.7 years and a range of 11 months to 25 years. Reported causes included cardiorespiratory failure and status epilepticus. This retrospective proportion is not a prospective survival estimate or a uniform infantile prognosis.
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Out of 30 individuals, 7 (23%) had died with a median age of death of 2.7 years (range 11 months to 25 years). Reported causes of death were cardiorespiratory failure and status epilepticus.
    explanation: Reports the observed mortality proportion, ages and causes in the original series.
treatments:
- name: Topiramate
  description: >-
    Among 18 treated discovery-cohort participants, five were described as having substantial improvement:
    two remained seizure-free for two and five years, two relapsed after four years and 18 months, and
    one
    had a marked reduction but stopped because of sedation. Ten had no effect and three had reductions
    without
    seizure freedom. These uncontrolled observations support possible benefit for some patients, not a
    predictable
    response or demonstrated developmental rescue. The detailed results are more qualified than the abstract's
    statement that five achieved seizure freedom.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: topiramate
      term:
        id: CHEBI:63631
        label: topiramate
  target_mechanisms:
  - target: Increased R-Type Calcium Entry
    treatment_effect: INHIBITS
    description: R-type channel inhibition is one proposed pharmacological contribution. Topiramate has multiple actions, and selective target-mediated clinical rescue has not been demonstrated.
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Although seizures were resistant to multiple anti-epileptic drugs (AEDs) in most individuals for whom data were available (20/25; 80%), five individuals (1, 15, 16, 21, 27) reported significant improvement in seizure control with topiramate, the only AED noted to have a substantial effect on seizure control in any participants (Table S1).
    explanation: Drug resistance was 20/25 with available data; five reported substantial topiramate benefit.
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Two individuals (16 and 27) remain seizure free for 2 and 5 years, respectively. However, in individuals 15 and 21, seizures eventually recurred after seizure-free periods of 4 years and 18 months, respectively; individual 21 died following an episode of status epilepticus. Individual 1 reported a substantial reduction in seizure frequency with topiramate, but it was discontinued due to increased sedation. Topiramate had no effect on seizure control in 10/18 (56%) individuals who were prescribed it; 3/18 (17%) individuals who were prescribed topiramate reported a reduction in seizures but were never seizure free.
    explanation: The detailed results report ongoing benefit, later relapse, sedation-related discontinuation, ten nonresponders and three reductions without seizure freedom.
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    directness: INDIRECT
    snippet: The AEDs topiramate and lamotrigine target CaV2.3 channels and reduce R-type calcium currents.41, 42
    explanation: Published channel pharmacology motivates the target; the clinical study did not isolate Cav2.3 inhibition as the cause of benefit.
- name: Genetic Counseling
  description: >-
    Discuss the predominantly de novo dominant mechanism, parental testing, individualized recurrence
    assessment
    and reproductive options. Possible parental germline mosaicism is a counseling consideration; the
    mosaic
    truncating proband in the discovery paper does not demonstrate parental mosaicism. Domain-based associations
    do not give a certain individual prognosis.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  therapeutic_modality: BEHAVIORAL
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: 'Molecular genetic testing identified 14 missense variants in CACNA1E (GenBank: NM_000721.3) in 30 unrelated individuals (Table 1). For the 29/30 individuals for whom DNA samples were available for both parents, de novo status of the variants and parentage were confirmed.'
    explanation: Thirty missense-variant probands were reported, with de novo status confirmed in all 29 with both parental samples.
  - reference: PMID:41492575
    reference_title: A Rare Case of Dual De Novo Mutations Presenting With Infantile Spasms, Congenital Contractures, and Axial Hypotonia.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: However, germline mosaicism cannot be entirely ruled out, making prenatal diagnosis a recommended option for future pregnancies [8].
    explanation: The case report discusses reproductive counseling; this is general clinical guidance rather than observed parental mosaicism.
- name: Supportive and Developmental Care
  description: >-
    Individualized multidisciplinary care addresses developmental support, mobility, tone, movement disorders,
    congenital contractures and feeding. Rehabilitation is supportive; controlled CACNA1E-specific evidence
    for developmental improvement is lacking.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  therapeutic_modality: OTHER
  evidence:
  - reference: PMID:41492575
    reference_title: A Rare Case of Dual De Novo Mutations Presenting With Infantile Spasms, Congenital Contractures, and Axial Hypotonia.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: Early genetic diagnosis allows for the cessation of the diagnostic odyssey, informed prognostic counseling for the family, and personalized management plans focusing on anticipatory guidance and targeted rehabilitation [7].
    explanation: The clinical report recommends anticipatory guidance and rehabilitation rather than claiming a tested disease-modifying intervention.
- name: ACTH for Epileptic Spasms
  description: ACTH was followed by resolution of infantile spasms without later seizures in one adult in the broader 2021 CACNA1E cohort. A 2026 mixed-gene retrospective DEE series also included CACNA1E among cases seizure-free at day 14, but its abstract does not provide the CACNA1E variant classification or durable gene-specific outcome. These reports do not establish response rates for DEE69 or variant-specific efficacy.
  therapeutic_modality: PEPTIDE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: corticotropin
      term:
        id: CHEBI:3892
        label: corticotropin
  evidence:
  - reference: PMID:34702355
    reference_title: De novo variants in CACNA1E found in patients with intellectual disability, developmental regression and social cognition deficit but no seizures.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: One adult patient (Patient 4) had a history of epileptic spasms, successfully treated with adrenocorticotropic hormone, without subsequent seizures in childhood or adulthood.
    explanation: The 2021 cohort lacked ongoing epilepsy, but one adult had successfully treated infantile spasms; it was not uniformly lifetime seizure-free.
  - reference: PMID:42615235
    reference_title: Efficacy of synthetic ACTH in confirmed and presumed monogenic developmental and epileptic encephalopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: At 2-week follow-up, 5 of 10 patients (SCN2A, ELOVL4, CACNA1E, TRRAP) achieved seizure freedom,
    explanation: The reported genes include CACNA1E among day-14 responders; the cohort admitted pathogenic, likely pathogenic and uncertain variants.
  target_phenotypes:
  - preferred_term: Epileptic spasm
    term:
      id: HP:0011097
      label: Epileptic spasm
- name: Perampanel-Containing Combination Therapy
  description: One infant with de novo Ala702Thr achieved reported seizure control after escalation to a regimen including vigabatrin, perampanel and clonazepam. Follow-up duration and the independent effect of perampanel were not established; this is an uncontrolled case observation.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: perampanel
      term:
        id: CHEBI:71013
        label: perampanel
  evidence:
  - reference: PMID:41492575
    reference_title: A Rare Case of Dual De Novo Mutations Presenting With Infantile Spasms, Congenital Contractures, and Axial Hypotonia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Initial treatment with levetiracetam and clonazepam improved irritability but did not control the spasms. The regimen was escalated to include vigabatrin, and later, a third anti-epileptic drug, Vyncompa (perampanel), which successfully achieved seizure control.
    explanation: The case reports improvement after regimen escalation, not perampanel monotherapy or comparative efficacy.
- name: Gastrostomy for Severe Feeding Difficulty
  description: Gastrostomy provided feeding support in both severely affected Gly352Arg cases in the 2021 report. Enteral support is tailored to the individual feeding and nutritional assessment.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Gastrostomy
    term:
      id: NCIT:C52006
      label: Gastrostomy
  evidence:
  - reference: PMID:33776624
    reference_title: Dystonia and Contractures are Potential Early Signs of CACNA1E-Related Epileptic Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: he required a gastrostomy due to a feeding disorder.
    explanation: Gastrostomy was required in the first case.
  - reference: PMID:33776624
    reference_title: Dystonia and Contractures are Potential Early Signs of CACNA1E-Related Epileptic Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The patient also required a gastrostomy due to a feeding disorder (Fig. 1b).
    explanation: The second case also needed gastrostomy.
  target_phenotypes:
  - preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
discussions:
- discussion_id: gap_cacna1e_rtype_blocker_precision_therapy
  prompt: Can variant-specific Cav2.3 modulation improve seizures and developmental outcomes safely?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Increased R-Type Calcium Entry
  - pathophysiology#Facilitated Cav2.3 Activation
  rationale: Topiramate responses are heterogeneous and uncontrolled, with relapses and sedation; its multiple actions prevent attribution of benefit solely to Cav2.3 blockade. The CDKL5 study proposes inhibitor testing rather than demonstrating pharmacological rescue. Loss-of-function alleles in the broader spectrum further argue for functional assessment before assuming one therapeutic direction.
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Two individuals (16 and 27) remain seizure free for 2 and 5 years, respectively. However, in individuals 15 and 21, seizures eventually recurred after seizure-free periods of 4 years and 18 months, respectively; individual 21 died following an episode of status epilepticus. Individual 1 reported a substantial reduction in seizure frequency with topiramate, but it was discontinued due to increased sedation. Topiramate had no effect on seizure control in 10/18 (56%) individuals who were prescribed it; 3/18 (17%) individuals who were prescribed topiramate reported a reduction in seizures but were never seizure free.
    explanation: The detailed results report ongoing benefit, later relapse, sedation-related discontinuation, ten nonresponders and three reductions without seizure freedom.
  - reference: PMID:42123681
    reference_title: Characterization of Three Distinct Loss-of-Function Cav2.3 Variants.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: M163T and R1182C exhibit depolarizing shifts in the voltage-dependence of activation, whereas R1182C also shows a reduced peak current density. H151L selectively slows recovery from inactivation.
    explanation: Three experimentally characterized variants show distinct loss-of-function effects in recombinant channels; their clinical presentations span a broader spectrum than DEE69.
  - reference: PMID:38081835
    reference_title: Epilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2.3, altering inactivation kinetics and neuronal excitability.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    directness: INDIRECT
    snippet: Specific Cav2.3 inhibitors would be required to test if inhibition of Cav2.3 could ameliorate CDKL5 deficiency phenotypes in mouse and human models.
    explanation: The authors identify selective inhibitor testing as future work, not demonstrated rescue.
- discussion_id: cacna1e_dee_scope_and_allele_specificity
  prompt: How should DEE69 be distinguished from broader CACNA1E neurological presentations?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - genetic#CACNA1E
  rationale: The 2021 seven-person cohort had no ongoing epilepsy, but one adult had successfully treated infantile spasms. Six had no seizure history. Its putative splice effect was not RNA-validated, and variant-specific functional evidence has since emerged for M163T. The 2026 loss-of-function study spans ataxia without epilepsy, neurodevelopmental disorder without epilepsy, and a seizure-associated ClinVar case with limited clinical characterization. These observations expand the gene spectrum without proving that every variant causes DEE69 or that domain location reliably predicts course.
  evidence:
  - reference: PMID:34702355
    reference_title: De novo variants in CACNA1E found in patients with intellectual disability, developmental regression and social cognition deficit but no seizures.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: One adult patient (Patient 4) had a history of epileptic spasms, successfully treated with adrenocorticotropic hormone, without subsequent seizures in childhood or adulthood.
    explanation: The 2021 cohort lacked ongoing epilepsy, but one adult had successfully treated infantile spasms; it was not uniformly lifetime seizure-free.
  - reference: PMID:34702355
    reference_title: De novo variants in CACNA1E found in patients with intellectual disability, developmental regression and social cognition deficit but no seizures.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Four patients (4/7, 57%) also presented with developmental regression, unrelated to any seizures or specific electro-encephalographic (EEG) epileptic activity.
    explanation: Regression without concurrent seizures supports a developmental component in the wider CACNA1E spectrum, not a shared proven cellular mechanism for every allele.
  - reference: PMID:42123681
    reference_title: Characterization of Three Distinct Loss-of-Function Cav2.3 Variants.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: M163T and R1182C exhibit depolarizing shifts in the voltage-dependence of activation, whereas R1182C also shows a reduced peak current density. H151L selectively slows recovery from inactivation.
    explanation: Three experimentally characterized variants show distinct loss-of-function effects in recombinant channels; their clinical presentations span a broader spectrum than DEE69.
- discussion_id: cacna1e_developmental_mechanism_gap
  prompt: Which cell types and developmental processes connect variant-specific channel effects to developmental disability?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Impaired Neurodevelopment
  - pathophysiology#Altered Synaptic Transmission
  rationale: Seizure-independent regression and early motor manifestations indicate that epileptic activity alone does not explain all disability. Recombinant cells establish channel effects, while the CDKL5-linked phosphomutant is an indirect animal model. Patient-variant effects on native excitatory and inhibitory circuits, neurotransmitter release and development remain insufficiently characterized.
  evidence:
  - reference: PMID:34702355
    reference_title: De novo variants in CACNA1E found in patients with intellectual disability, developmental regression and social cognition deficit but no seizures.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Four patients (4/7, 57%) also presented with developmental regression, unrelated to any seizures or specific electro-encephalographic (EEG) epileptic activity.
    explanation: Regression without concurrent seizures supports a developmental component in the wider CACNA1E spectrum, not a shared proven cellular mechanism for every allele.
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: Functional analysis revealed dramatic gain-of-function effects, indicating increased calcium inward currents that may affect neuronal excitability and synaptic transmission.
    explanation: Recombinant-channel results motivate increased calcium entry in neurons; sustained intracellular calcium overload was not measured in patients.
  - reference: PMID:38081835
    reference_title: Epilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2.3, altering inactivation kinetics and neuronal excitability.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: The percentage of cells exhibiting at least one DPP or all-or-none afterdepolarization (ADP) > 8 mV upon carbachol treatment was significantly higher in S15A mice, showing an enhanced depolarization response (Fig. 3j, k).
    explanation: S15A mouse slices show enhanced cholinergic plateau potentials/afterdepolarizations. This is a convergent engineered model, not direct evidence from a patient variant.
synonyms:
- DEE69
- EIEE69
- developmental and epileptic encephalopathy 69
- epileptic encephalopathy, early infantile, 69
experimental_models:
- name: tsA201 DII-S6 DEE Variant Channels
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Recombinant human embryonic kidney-derived cells
  description: Phe698Ser, Ile701Val and Ala702Thr in human alpha1E-1 with beta2d were tested with barium as the charge carrier. These assays establish gating effects but do not reproduce native neuronal subunit composition, developmental circuitry or the complete heterozygous state.
  publication: PMID:30343943
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The activation curve was shifted by approximately −10 mV for all three variants (Figure 2), while the time course of activation was not altered.
    explanation: The three DII-S6 variants shifted activation about -10 mV in tsA201 cells.
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Additionally, the time course of fast inactivation was significantly slowed, as indicated by an increased residual current after a 400-ms depolarizing pulse normalized to the peak current (r400) (Figures 2 and S1; Table 2).
    explanation: Slower fast inactivation was measured for the three tested DII-S6 variants.
  modeled_mechanisms:
  - target: Facilitated Cav2.3 Activation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: Recombinant variant channels shift activation.
    evidence:
    - reference: PMID:30343943
      reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: The activation curve was shifted by approximately −10 mV for all three variants (Figure 2), while the time course of activation was not altered.
      explanation: The three DII-S6 variants shifted activation about -10 mV in tsA201 cells.
  - target: Slowed Cav2.3 Inactivation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: The three tested DII-S6 variants slow fast inactivation.
    evidence:
    - reference: PMID:30343943
      reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Additionally, the time course of fast inactivation was significantly slowed, as indicated by an increased residual current after a 400-ms depolarizing pulse normalized to the peak current (r400) (Figures 2 and S1; Table 2).
      explanation: Slower fast inactivation was measured for the three tested DII-S6 variants.
- name: tsA201 Ile603Leu Channels
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Recombinant human embryonic kidney-derived cells
  description: Human alpha1E-3 Ile603Leu was expressed with beta1b and alpha2delta1; calcium and barium recordings showed increased density and facilitated activation without altered inactivation. Assay conditions differ from the DII-S6 experiments, precluding simple quantitative comparisons across the two systems.
  publication: PMID:30343943
  evidence:
  - reference: PMID:30343943
    reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: This variant resulted in a massive increase in whole-cell current density (Figures 3 and S2) to a level that in many cases precluded functional biophysical characterization. In a subset of cells where the current could be properly clamped, our analysis revealed a >10 mV hyperpolarizing shift in half activation voltage (Figures 3 and S2; Table 2). There was no significant effect on channel inactivation.
    explanation: Ile603Leu increased whole-cell current density and facilitated activation without significantly changing inactivation.
  modeled_mechanisms:
  - target: Increased Cav2.3 Current Density
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: Recombinant Ile603Leu strongly increases current density.
    evidence:
    - reference: PMID:30343943
      reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: This variant resulted in a massive increase in whole-cell current density (Figures 3 and S2) to a level that in many cases precluded functional biophysical characterization. In a subset of cells where the current could be properly clamped, our analysis revealed a >10 mV hyperpolarizing shift in half activation voltage (Figures 3 and S2; Table 2). There was no significant effect on channel inactivation.
      explanation: Ile603Leu increased whole-cell current density and facilitated activation without significantly changing inactivation.
  - target: Facilitated Cav2.3 Activation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: Activation shifts to more negative potentials.
    evidence:
    - reference: PMID:30343943
      reference_title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: This variant resulted in a massive increase in whole-cell current density (Figures 3 and S2) to a level that in many cases precluded functional biophysical characterization. In a subset of cells where the current could be properly clamped, our analysis revealed a >10 mV hyperpolarizing shift in half activation voltage (Figures 3 and S2; Table 2). There was no significant effect on channel inactivation.
      explanation: Ile603Leu increased whole-cell current density and facilitated activation without significantly changing inactivation.
- name: tsA201 Leu228Pro Channels
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Recombinant human embryonic kidney-derived cells
  description: Whole-cell patch clamp of Leu228Pro versus wild type shows hyperpolarized activation and steady-state inactivation, with an expanded window current. Peak density, inactivation kinetics and recovery were unchanged. The published abstract supports these channel findings; neuronal or treatment rescue is not demonstrated.
  publication: PMID:42392563
  evidence:
  - reference: PMID:42392563
    reference_title: Gating effects of a Cav2.3 calcium channel variant linked to developmental and epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Compared to wild-type, the L228P mutant did not present altered peak current density, inactivation kinetics, or recovery from inactivation, but showed a significant shift towards hyperpolarized voltages in both voltage-dependent activation and steady-state inactivation. This resulted in a broader window current shifted towards more hyperpolarized potentials, which predicts increased channel availability and activity at subthreshold voltages relative to wild-type channels.
    explanation: Leu228Pro changes activation and steady-state inactivation and broadens the predicted window current without changing peak density or inactivation kinetics.
  modeled_mechanisms:
  - target: Expanded Cav2.3 Window Current
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: Variant-specific gating expands the subthreshold window current.
    evidence:
    - reference: PMID:42392563
      reference_title: Gating effects of a Cav2.3 calcium channel variant linked to developmental and epileptic encephalopathy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Compared to wild-type, the L228P mutant did not present altered peak current density, inactivation kinetics, or recovery from inactivation, but showed a significant shift towards hyperpolarized voltages in both voltage-dependent activation and steady-state inactivation. This resulted in a broader window current shifted towards more hyperpolarized potentials, which predicts increased channel availability and activity at subthreshold voltages relative to wild-type channels.
      explanation: Leu228Pro changes activation and steady-state inactivation and broadens the predicted window current without changing peak density or inactivation kinetics.
- name: tsA201 Broader-Spectrum Loss-of-Function Variants
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Recombinant human embryonic kidney-derived cells
  description: H151L, M163T and R1182C were expressed in human alpha1E-3 with rat beta1b and alpha2delta1. Electrophysiology demonstrates heterogeneous loss of function; these models address broader CACNA1E neurological presentations and do not reproduce the canonical DEE69 gain-of-function mechanism. Structural predictions are not empirical surface-expression measurements.
  publication: PMID:42123681
  evidence:
  - reference: PMID:42123681
    reference_title: Characterization of Three Distinct Loss-of-Function Cav2.3 Variants.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: M163T and R1182C exhibit depolarizing shifts in the voltage-dependence of activation, whereas R1182C also shows a reduced peak current density. H151L selectively slows recovery from inactivation.
    explanation: Three experimentally characterized variants show distinct loss-of-function effects in recombinant channels; their clinical presentations span a broader spectrum than DEE69.
  modeled_mechanisms:
  - target: Facilitated Cav2.3 Activation
    relationship: PERTURBS
    fidelity: LOW
    description: M163T and R1182C shift activation in the opposite direction, demonstrating an allele-specific boundary to the DEE gain-of-function model.
    evidence:
    - reference: PMID:42123681
      reference_title: Characterization of Three Distinct Loss-of-Function Cav2.3 Variants.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: M163T and R1182C exhibit depolarizing shifts in the voltage-dependence of activation, whereas R1182C also shows a reduced peak current density. H151L selectively slows recovery from inactivation.
      explanation: Three experimentally characterized variants show distinct loss-of-function effects in recombinant channels; their clinical presentations span a broader spectrum than DEE69.
- name: Cav2.3 S15A Mouse Hippocampal Slices
  experimental_model_type: OTHER
  organism:
    preferred_term: Mus musculus
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  cell_source: Acute hippocampal slices from engineered homozygous S15A mice and wild-type littermates
  description: Somatic recordings in CA1 neurons test a phosphorylation-site mutant, not a human DEE allele. Slower R-type current inactivation and enhanced cholinergic depolarizations support mechanistic convergence. Baseline firing was unchanged; strong stimulation could cause depolarization block.
  publication: PMID:38081835
  evidence:
  - reference: PMID:38081835
    reference_title: Epilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2.3, altering inactivation kinetics and neuronal excitability.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: When compared to wild type littermates (WT), HOM S15A mice showed significantly slower inactivation τ at maximal conductance voltages, recapitulating HEK293 cell results (Fig. 3d, e). Current amplitudes at the soma did not differ (Fig. 3f).
    explanation: Native CA1 currents in engineered S15A slices inactivate more slowly without increased somatic amplitude.
  - reference: PMID:38081835
    reference_title: Epilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2.3, altering inactivation kinetics and neuronal excitability.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: firing properties were identical between WT and S15A mice under baseline conditions (Fig. 3g–i).
    explanation: Baseline firing was unchanged in S15A mouse CA1 cells; the excess depolarization emerged during cholinergic stimulation.
  - reference: PMID:38081835
    reference_title: Epilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2.3, altering inactivation kinetics and neuronal excitability.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: The percentage of cells exhibiting at least one DPP or all-or-none afterdepolarization (ADP) > 8 mV upon carbachol treatment was significantly higher in S15A mice, showing an enhanced depolarization response (Fig. 3j, k).
    explanation: S15A mouse slices show enhanced cholinergic plateau potentials/afterdepolarizations. This is a convergent engineered model, not direct evidence from a patient variant.
  modeled_mechanisms:
  - target: Slowed Cav2.3 Inactivation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: The engineered phosphorylation-site lesion prolongs native R-type currents.
    evidence:
    - reference: PMID:38081835
      reference_title: Epilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2.3, altering inactivation kinetics and neuronal excitability.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: When compared to wild type littermates (WT), HOM S15A mice showed significantly slower inactivation τ at maximal conductance voltages, recapitulating HEK293 cell results (Fig. 3d, e). Current amplitudes at the soma did not differ (Fig. 3f).
      explanation: Native CA1 currents in engineered S15A slices inactivate more slowly without increased somatic amplitude.
  - target: Altered Neuronal Excitability
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: The effect depends on cholinergic stimulation.
    evidence:
    - reference: PMID:38081835
      reference_title: Epilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2.3, altering inactivation kinetics and neuronal excitability.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: The percentage of cells exhibiting at least one DPP or all-or-none afterdepolarization (ADP) > 8 mV upon carbachol treatment was significantly higher in S15A mice, showing an enhanced depolarization response (Fig. 3j, k).
      explanation: S15A mouse slices show enhanced cholinergic plateau potentials/afterdepolarizations. This is a convergent engineered model, not direct evidence from a patient variant.
    - reference: PMID:38081835
      reference_title: Epilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2.3, altering inactivation kinetics and neuronal excitability.
      supports: REFUTE
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: firing properties were identical between WT and S15A mice under baseline conditions (Fig. 3g–i).
      explanation: Unchanged baseline firing limits this model link to the separately supported response during cholinergic stimulation.
animal_models:
- name: Cav2.3 S15A Phosphomutant Mouse
  species: Mus musculus
  genotype: Homozygous Cacna1e S15A phosphorylation-site substitution
  description: An engineered CDKL5 phosphorylation-site model, not a patient-variant knock-in. Memory, sociability and locomotor effects were observed, with some sex dependence. Female mice had enhanced kainate susceptibility; maximal seizure severity and baseline electrocorticography were unchanged, and spontaneous behavioral seizures were not observed through 40 weeks.
  publication: PMID:38081835
  evidence:
  - reference: PMID:38081835
    reference_title: Epilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2.3, altering inactivation kinetics and neuronal excitability.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Interestingly, however, female S15A mice had a reduced threshold to stage 5 behavioural seizures along with an increase in ECoG activity during KA (Fig. 5c).
    explanation: Female phosphomutants had increased kainate susceptibility; this is a small, sex-dependent provoked-seizure result.
  - reference: PMID:38081835
    reference_title: Epilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2.3, altering inactivation kinetics and neuronal excitability.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: We did not observe any spontaneous behavioural seizures in Cav2.3 S15A mice up to 40 weeks of age,
    explanation: The model did not reproduce spontaneous behavioral seizures over the observed period.
  modeled_mechanisms:
  - target: Epileptogenic Network Dysfunction
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: Provoked seizure susceptibility supports only part of the proposed human mechanism; spontaneous epilepsy was not reproduced.
    evidence:
    - reference: PMID:38081835
      reference_title: Epilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2.3, altering inactivation kinetics and neuronal excitability.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Interestingly, however, female S15A mice had a reduced threshold to stage 5 behavioural seizures along with an increase in ECoG activity during KA (Fig. 5c).
      explanation: Female phosphomutants had increased kainate susceptibility; this is a small, sex-dependent provoked-seizure result.
    - reference: PMID:38081835
      reference_title: Epilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2.3, altering inactivation kinetics and neuronal excitability.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: We did not observe any spontaneous behavioural seizures in Cav2.3 S15A mice up to 40 weeks of age,
      explanation: The model did not reproduce spontaneous behavioral seizures over the observed period.
- name: Cacna1e Knockout Mouse
  species: Mus musculus
  genotype: Constitutive or brain-specific Cacna1e knockout
  description: An inverse perturbation of the predominant DEE gain-of-function mechanism. PTZ seizure susceptibility was reduced while 4-AP sensitivity was unchanged. Kainate produced behavioral limbic seizure resistance and reduced excitotoxic injury, but hippocampal EEG seizure activity was unchanged at the tested suprathreshold dose. These results do not demonstrate neurodegeneration or drug efficacy in human DEE69.
  publication: PMID:16686648
  evidence:
  - reference: PMID:16686648
    reference_title: Altered seizure susceptibility in mice lacking the Ca(v)2.3 E-type Ca2+ channel.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Surprisingly, PTZ-induced seizure susceptibility was dramatically reduced in Ca(v)2.3-deficient mice, whereas 4-AP sensitivity remained unchanged.
    explanation: Knockout reduces PTZ susceptibility without a corresponding 4-AP effect.
  - reference: PMID:17376845
    reference_title: Hippocampal seizure resistance and reduced neuronal excitotoxicity in mice lacking the Cav2.3 E/R-type voltage-gated calcium channel.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Administration of kainic acid (30 mg/kg ip) revealed clear alteration in behavioral seizure architecture and dramatic resistance to limbic seizures in Ca(v)2.3(-/-) mice compared with controls, whereas no difference in hippocampal EEG seizure activity between both genotypes could be detected at this suprathreshold dosage.
    explanation: Behavioral limbic seizure resistance did not translate into reduced hippocampal EEG seizure activity at the tested high dose.
  modeled_mechanisms:
  - target: Epileptogenic Network Dysfunction
    relationship: PERTURBS
    fidelity: LOW
    description: Loss of the channel tests its contribution to provoked seizures in the opposite direction from most characterized DEE variants.
    evidence:
    - reference: PMID:16686648
      reference_title: Altered seizure susceptibility in mice lacking the Ca(v)2.3 E-type Ca2+ channel.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Surprisingly, PTZ-induced seizure susceptibility was dramatically reduced in Ca(v)2.3-deficient mice, whereas 4-AP sensitivity remained unchanged.
      explanation: Knockout reduces PTZ susceptibility without a corresponding 4-AP effect.
    - reference: PMID:17376845
      reference_title: Hippocampal seizure resistance and reduced neuronal excitotoxicity in mice lacking the Cav2.3 E/R-type voltage-gated calcium channel.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Administration of kainic acid (30 mg/kg ip) revealed clear alteration in behavioral seizure architecture and dramatic resistance to limbic seizures in Ca(v)2.3(-/-) mice compared with controls, whereas no difference in hippocampal EEG seizure activity between both genotypes could be detected at this suprathreshold dosage.
      explanation: Behavioral limbic seizure resistance did not translate into reduced hippocampal EEG seizure activity at the tested high dose.

📚

References & Deep Research

References

12

PMID:30343943

De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.

No top-level findings curated for this source.

PMID:31064215

Calcium Channel Dysfunction in Epilepsy: Gain of CACNA1E.

No top-level findings curated for this source.

PMID:33776624

Dystonia and Contractures are Potential Early Signs of CACNA1E-Related Epileptic Encephalopathy.

No top-level findings curated for this source.

PMID:34702355

De novo variants in CACNA1E found in patients with intellectual disability, developmental regression and social cognition deficit but no seizures.

No top-level findings curated for this source.

PMID:38081835

Epilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2.3, altering inactivation kinetics and neuronal excitability.

No top-level findings curated for this source.

PMID:38780451

Seizure and movement disorder in CACNA1E developmental and epileptic encephalopathy: Two sides of the same coin or same side of two different coins?

No top-level findings curated for this source.

PMID:41492575

A Rare Case of Dual De Novo Mutations Presenting With Infantile Spasms, Congenital Contractures, and Axial Hypotonia.

No top-level findings curated for this source.

PMID:42123681

Characterization of Three Distinct Loss-of-Function Cav2.3 Variants.

No top-level findings curated for this source.

PMID:42392563

Gating effects of a Cav2.3 calcium channel variant linked to developmental and epileptic encephalopathy.

No top-level findings curated for this source.

PMID:42615235

Efficacy of synthetic ACTH in confirmed and presumed monogenic developmental and epileptic encephalopathies.

No top-level findings curated for this source.

PMID:16686648

Altered seizure susceptibility in mice lacking the Ca(v)2.3 E-type Ca2+ channel.

No top-level findings curated for this source.

PMID:17376845

Hippocampal seizure resistance and reduced neuronal excitotoxicity in mice lacking the Cav2.3 E/R-type voltage-gated calcium channel.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Claude Code ▸

1. Disease Information

claude-haiku-4-5-20251001, claude-opus-5[1m] 21 citations 2026-07-25T17:39:33.434488

1. Disease Information

Overview

CACNA1E-related developmental and epileptic encephalopathy — formally developmental and epileptic encephalopathy 69 (DEE69) — is a severe, early-onset neurodevelopmental disorder caused by de novo heterozygous variants in CACNA1E, the gene for the pore-forming α1 subunit of the Ca_V2.3 R-type voltage-gated calcium channel.

The defining clinical picture, straight from the paper that named it:

"we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death." — Helbig et al., Am J Hum Genet 2018 (PMID:30343943) [cached & validated]

The mechanistic one-liner: most pathogenic variants sit at the cytoplasmic ends of the four S6 helices — the channel's activation gate — and they're gain-of-function. The gate gets sloppy about closing. Calcium that should trickle in on a tight schedule instead floods in early and leaves late.

Key identifiers

Resource	Identifier
MONDO	`MONDO:0032657` — developmental and epileptic encephalopathy, 69
OMIM (disease)	`#618285` DEE69
OMIM (gene)	`*601013` CACNA1E
DOID	`DOID:0112205`
MedGen / UMLS	`C4748988`
GARD	`GARD:0025714`
HGNC	`hgnc:1392` (lowercase prefix per repo convention)
NCBI Gene	`777`
Ensembl	`ENSG00000198216`
UniProt	`Q15878` (CAC1E_HUMAN)
Cytoband	1q25.3
MONDO parent	`MONDO:0100062` genetic developmental and epileptic encephalopathy

(MONDO xrefs and synonyms verified locally against sqlite:obo:mondo this session.)

Orphanet: I could not confirm a dedicated ORPHA code for the CACNA1E-specific entity. CACNA1E appears as a causal gene under Orphanet's broader early-infantile DEE grouping (ORPHA:1934), but no ORPHA_* cache file for it exists in this repo. Flag as unresolved rather than asserting a code.

ICD: no disease-specific code. Falls under ICD-10 G40.4 (other generalized epilepsy and epileptic syndromes) / ICD-11 8A61 (developmental and epileptic encephalopathies) — these are syndrome-class codes, not entity codes, so don't treat them as identifiers.

Synonyms

DEE69 · EIEE69
Epileptic encephalopathy, early infantile, 69
CACNA1E-related developmental and epileptic encephalopathy
Developmental and epileptic encephalopathy with contractures, macrocephaly, and dyskinesias
CACNA1E encephalopathy · Ca_V2.3 channelopathy (informal)

Data provenance

All disease-level knowledge here is aggregated from published individual-patient reports — GeneMatcher-assembled international cohorts, single case reports, and one video-EEG case study. There is no EHR-derived cohort, no patient registry, and no natural-history study for this disease. That's a real gap, not an oversight of my searching.

2. Etiology

Primary cause

Monogenic, essentially always de novo heterozygous missense variants in CACNA1E. No environmental, infectious, or multifactorial contribution is described anywhere in the literature I reviewed.

The variant architecture is startlingly tidy — a small mutational hotspot rather than a scatter:

"Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed CaV2.3 channel activation gate." — PMID:30343943 [cached & validated]

That S6-distal clustering isn't unique to this gene, either. It's a recurring architectural motif across the calcium-channel epilepsies — a shared soft spot, like how the same vertebra tends to go in several different back conditions:

"Disease-causing variants predominantly involve gain-of-function mechanisms, with missense variants clustering in the distal S6 segment — a mutational hotspot shared across other voltage-gated calcium channel genes." — Lauerer & Lerche, J Neurochem 2023 (PMID:37822150) [fetched this session]

Genetic risk factors

Causal: de novo GOF missense in CACNA1E. Recurrent hotspots: p.Gly352Arg (DI-S6) and p.Ala702Thr (DII-S6).
Susceptibility loci / modifier genes: none identified. No GWAS, no modifier screen exists.
Constraint: CACNA1E is a large, highly brain-expressed gene under evident missense constraint; Royer-Bertrand et al. explicitly compared the pathogenic-variant landscape against gnomAD and "identified protein regions intolerant to substitutions" (PMID:34702355). I did not retrieve the numeric gnomAD pLI/LOEUF/missense-Z values in this session (the browser is a JS app that WebFetch can't render) — fetch those directly before curating any specific number.

Environmental risk factors

None known. De novo mutation rate rises modestly with advanced paternal age as a general genomic phenomenon, but no paternal-age effect has been specifically demonstrated for CACNA1E — do not assert one.

Protective factors

None described in humans. The nearest thing is inverse-mechanistic and comes from mice: losing Ca_V2.3 function is anticonvulsant (see §15). No protective human allele is known.

Gene–environment interactions

None reported. Not applicable in any documented sense.

3. Phenotypes

The quantitative core

Almost every frequency in this disease traces back to one tabulation of the founding 30-person cohort. Here it is verbatim, because it's the single densest sentence in the whole literature:

"The 30 patients with pathogenic CACNA1E variants presented with a variable DEE characterized by refractory epilepsy (87% of patients) with median seizure onset at 4.5 months, movement disorders (60%), spastic quadriplegia (53%), congenital joint contractures (43%), macrocephaly (43%), and profound developmental impairments (ie, nonverbal and nonambulatory) (88%)." — Carvill, Epilepsy Curr 2019 (PMID:31064215) [cached & validated]

Phenotype table with HPO suggestions

Phenotype	HPO term	Freq.	Onset	Course	Type
Epileptic encephalopathy	`HP:0200134` Epileptic encephalopathy	defining	infantile	—	clinical sign
Refractory seizures	`HP:0001250` Seizure (+ temporality RECURRENT)	87% (VERY_FREQUENT)	median 4.5 months	drug-resistant, persistent	clinical sign
Profound global developmental delay	`HP:0012736`	88% (VERY_FREQUENT)	infantile	static-to-progressive impairment	clinical sign
Severe hypotonia	`HP:0001252` Hypotonia (severity SEVERE)	core feature, % not tabulated	neonatal/infantile	often evolves toward spasticity	physical sign
Movement disorder (hyperkinetic)	`HP:0002487` Hyperkinetic movements	60% (FREQUENT)	infancy–early childhood	episodic/fluctuating	clinical sign
— severe dystonia component	`HP:0001332` Dystonia	~40%	—	—	clinical sign
— other dyskinesias	`HP:0002072` Abnormality of extrapyramidal motor function	~20%	—	—	clinical sign
Spastic quadriplegia	`HP:0002510` Spastic tetraplegia	53% (FREQUENT)	infancy onward	progressive	physical sign
Congenital joint contractures	`HP:0002803` Congenital contracture	43% (FREQUENT)	congenital	fixed/progressive	physical sign
Macrocephaly	`HP:0000256` Macrocephaly	43% (FREQUENT)	congenital/infantile	—	physical sign
Absent speech	`HP:0001344` Absent speech	most (within the 88%)	—	—	clinical sign
Non-ambulatory	`HP:0002540` Inability to walk	most (within the 88%)	—	—	clinical sign
Early death	`HP:0001522` Death in infancy (approximate — timing not precisely specified in abstract)	subset	—	—	outcome
Abundant epileptiform EEG activity	`HP:0011185` EEG with focal epileptiform discharges / `HP:0002353` EEG abnormality	defining	infantile	—	lab/electrophysiology

Additional phenotypes from the non-epilepsy cohort (Royer-Bertrand 2021, PMID:34702355):

Phenotype	HPO term	Notes
Intellectual disability	`HP:0001249` Intellectual disability	7/7 in that cohort
Developmental regression	`HP:0002376` Developmental regression	variable presence
ASD-like behavioral profile	`HP:0000717` Autism	"social cognition deficit"
Severe speech/language delay	`HP:0000750` Delayed speech and language development	"marked"
Global developmental delay	`HP:0001263` Global developmental delay	shared feature
Absence of epilepsy	—	the defining negative of this subgroup

Verbatim: they found seven unrelated individuals with "intellectual disability, developmental regression and ASD-like behavioral profile, and notably without epilepsy" carrying de novo pathogenic CACNA1E variants (PMID:34702355) [fetched this session].

The seizure/movement-disorder trap — important for curation

Here's a wrinkle worth its own paragraph, because it undermines the neatness of the 60%-movement-disorder figure. When someone finally put a CACNA1E patient (p.Gly352Arg) on long-term video-EEG, some of the "movement disorder" turned out to be seizures wearing a costume:

long-term video-EEG revealed "tonic asymmetric seizures during wakefulness and mild paroxysmal dyskinesias of the trunk out of sleep which were thought to be a movement disorder and instead turned out to be focal hyperkinetic seizures." — Di Micco et al., Epileptic Disord 2024 (PMID:38780451) [fetched this session]

The authors call this the first documented description of the EEG findings in this disorder and note "a possible overlap between cortical and subcortical phenomena." So: some fraction of the reported dyskinesia burden is probably ictal, not extrapyramidal. Curate the movement-disorder phenotype with that caveat attached — it's a genuine open question, not a settled observation.

Quality of life

No EQ-5D, SF-36, PROMIS, or disease-specific QoL instrument has been applied to this population. Nothing to cite. Qualitatively, the profile — nonverbal, nonambulatory, refractory seizures, contractures, spastic quadriplegia, movement disorder — implies total dependence for all activities of daily living and a very high caregiver burden, but that inference is mine, not a published measurement. Curate it as description, not evidence.

4. Genetic / Molecular Information

The gene and its product

CACNA1E (1q25.3) encodes the ~2,251–2,270 aa, ~255–257 kDa α1E subunit — the pore-forming, voltage-sensing core of Ca_V2.3. Canonical four-domain (I–IV) architecture, each domain six transmembrane helices (S1–S6): S4s are the voltage sensors, S5–S6 line the pore, and the cytoplasmic ends of the four S6 helices form the activation gate where the disease variants live.

The channel carries the R-type current — historically "R for Resistant," since it's the high-voltage-activated current left standing after you block L, N, P, and Q types. From the abstract:

"CACNA1E is highly expressed in the CNS and is the pore-forming subunit of the voltage-gated calcium channel CaV2.3, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission." — PMID:30343943 [cached & validated]

Variant classes

Class 1 — GOF missense at the S6 activation gate (the disease-defining class). 14 partially recurring variants across 30 individuals in the founding cohort; ACMG classification pathogenic/likely pathogenic; germline de novo; absent from gnomAD.

Domain	n	Hotspot	Phenotype signature
DI-S6	10	p.Gly352Arg (9/10)	all 10 had hyperkinetic movement disorder, vs only 2/19 with variants elsewhere
DII-S6	13	p.Ala702Thr (6/13)	"the majority... presented with all clinical features" — full spectrum
DIII-S6	—	—	mildest end: 2 never developed seizures; one seizure-free 5 years, spoke single words, walked independently
DII S4–S5 linker	≥1	—	facilitated activation + increased current density

Verbatim genotype–phenotype quotes (all PMID:31064215, cached & validated):

"Ten individuals carried missense variants in the DI-S6 domain, including 9 individuals with the recurrent p.Gly352Arg variant; all 10 individuals presented with hyperkinetic movement disorders, compared with only (2/19) individuals with variants outside this domain."

"In contrast, patients with missense variants located in the DIII-S6 presented with a milder phenotype, as 2 patients never developed seizures and one has been seizure-free for 5 years, spoke single words, and walked independently."

Class 2 — truncating variants (rare, milder, mechanistically murky).

"an additional 3 individuals with truncating CACNA1E variants were identified, including 1 somatic mosaic (27% of cells), 1 inherited from an unaffected parent, and 1 with unknown inheritance. All 3 individuals presented with a much milder phenotype" — PMID:31064215 [cached & validated]

This class matters out of proportion to its size: an unaffected transmitting parent means truncating CACNA1E alleles are not straightforwardly pathogenic, and it means the disease is not simply "too much or too little Ca_V2.3" on a single dial. Curate these as a distinct, uncertain class.

Class 3 — the non-epilepsy neurodevelopmental variants. Seven de novo variants (six missense, one splice-donor c.3422+1G>A predicted to disrupt the exon 22 donor site) producing ID/regression/ASD without seizures. Functional validation was explicitly not performed — Royer-Bertrand et al. list "lacks functional validation" among their own limitations. So we don't know whether these are GOF, LOF, or something else.

Functional consequence — the biophysics

Two independent GOF flavors, both documented:

"Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation." — PMID:30343943 [cached & validated, IN_VITRO]

"Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density." — PMID:30343943 [cached & validated, IN_VITRO]

"Electrophysiological recordings showed a hyperpolarizing shift in voltage-dependent activation, slowed kinetics of inactivation, and increased current density." — PMID:31064215 [cached & validated, IN_VITRO]

Put plainly: the gate opens at voltages where it shouldn't, and then dawdles about shutting. Two independent leaks in the same faucet.

Modifier genes, epigenetics, chromosomal abnormalities

Modifiers: none identified.
Epigenetics: no methylation episignature has been reported for CACNA1E (unlike, say, several other NDD genes with published episignatures). Nothing to curate.
Chromosomal abnormalities: DEE69 is not a CNV/microdeletion syndrome. ClinGen has a dosage-sensitivity curation page for HGNC:1392 (search.clinicalgenome.org/kb/gene-dosage/HGNC:1392), but the site refused connection during this session — fetch the haploinsufficiency/triplosensitivity scores directly before curating them.
Somatic vs germline: germline de novo for the missense class; one documented somatic mosaic truncating case (27% of cells).

5. Environmental Information

Short section, honestly stated: no environmental, lifestyle, toxicological, or infectious contribution is described for this disorder. It's a de novo monogenic channelopathy. CTD/TOXNET-style exposure associations for CACNA1E as a gene exist in the general toxicogenomics literature but have no established relationship to DEE69 — don't import them.

The only environment-adjacent factor with any mechanistic footing is fever/illness as a generic seizure precipitant in DEEs, and I found no CACNA1E-specific fever-sensitivity data. (Contrast this with Timothy_Syndrome in this KB, where a fever-exacerbation hypothesis is explicitly modeled — resist the temptation to copy that pattern here without evidence.)

One genuinely interesting modulator, though, and it's ionic rather than environmental: Ca_V2.3 is the classic zinc- and copper-sensitive calcium channel, and trace-metal modulation shapes convulsive seizure behavior in mice (PMID:32068980). That's a real biological handle on the channel, but it is model-organism pharmacology, not a human risk factor.

6. Mechanism / Pathophysiology

The causal chain

Here's the pathograph as I'd model it — five nodes, molecular → organism:

CACNA1E S6-gate GOF variant          [MOLECULAR — trigger]
   ↓ DIRECT
Increased neuronal Ca²⁺ influx        [CELLULAR — central effector]
   ↓ DIRECT
Altered excitability + transmitter release   [CELLULAR — intermediate]
   ├─ DIRECT ──→ Neuronal hyperexcitability / E-I imbalance   [TISSUE — central effector]
   │                 ├─→ Developmental and epileptic encephalopathy
   │                 └─→ Refractory infantile-onset seizures
   └─ INDIRECT ─→ Impaired neurodevelopment                   [ORGANISM — outcome]
     ├─→ Profound developmental impairment
     ├─→ Hyperkinetic movement disorder
     └─→ Spastic quadriplegia

Node 1 — the leaky gate (MOLECULAR). GOF missense at the S6 activation gate: facilitated (hyperpolarized) activation + slowed inactivation, sometimes plus increased current density. GO: GO:0005245 voltage-gated calcium channel activity (INCREASED), GO:0008331 high voltage-gated calcium channel activity (INCREASED).

Node 2 — calcium overload (CELLULAR). Ca_V2.3 lives in both compartments — presynaptic terminals and the somatodendritic membrane — so a gating defect raises Ca²⁺ at both ends of the neuron simultaneously. GO: GO:0070588 calcium ion transmembrane transport (INCREASED), GO:0019722 calcium-mediated signaling. CHEBI: CHEBI:29108 calcium(2+).

Node 3 — deranged synaptic signaling (CELLULAR).

"CACNA1E encodes Cav2.3, an R-type VGCC implicated in both presynaptic neurotransmitter release and postsynaptic somatodendritic integration and long-term potentiation." — PMID:31064215 [cached & validated]

GO: GO:0007269 neurotransmitter secretion (DYSREGULATED), GO:0042391 regulation of membrane potential (ABNORMAL), GO:0060291 long-term synaptic potentiation.

Node 4 — network hyperexcitability (TISSUE). This node conforms_to the KB's existing epilepsy_excitation_inhibition_imbalance#Neuronal Hyperexcitability and Hypersynchrony module — a clean conformance target.

"We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders." — PMID:30343943 [cached & validated]

The cell-biological gearing was worked out in rodent CA1: Ca_V2.3 "triggers epileptiform activity in specialized neurons via plateau potentials and afterdepolarizations" (PMID:16686648). That's the specific machinery — R-type calcium entry sustains a depolarizing plateau after the spike, so instead of one action potential you get a burst, and instead of a burst you get a seizure. A dripping tap that never quite shuts off, and eventually the whole basin overflows in rhythm.

Node 5 — developmental encephalopathy (ORGANISM). Critically: the developmental impairment is not merely post-ictal damage. Two independent lines say so. (a) DIII-S6 patients who never seized still had disease; (b) the entire Royer-Bertrand cohort had ID/regression/ASD without epilepsy. Calcium is a developmental signaling currency — activity-dependent transcription, synapse refinement, circuit sculpting — so chronic mis-set calcium during a critical window degrades development independently of seizures. Curate the "developmental" and "epileptic" arms as parallel consequences, not as a cascade.

The CDKL5 convergence — the best mechanism news in this field

This one is genuinely elegant. Working from the other end — trying to figure out what the kinase CDKL5 actually phosphorylates — Sampedro-Castañeda et al. landed squarely on Ca_V2.3:

"We identified the voltage-gated Ca2+ channel Cav2.3 (encoded by CACNA1E) as a physiological target of CDKL5 in mice and humans. Recombinant channel electrophysiology and interdisciplinary characterization of Cav2.3 phosphomutant mice revealed that loss of Cav2.3 phosphorylation leads to channel gain-of-function via slower inactivation and enhanced cholinergic stimulation, resulting in increased neuronal excitability. Our results thus show that CDD is partly a channelopathy. The properties of unphosphorylated Cav2.3 closely resemble those described for CACNA1E gain-of-function mutations causing DEE69, a disorder sharing clinical features with CDD. We show that these two single-gene diseases are mechanistically related and could be ameliorated with Cav2.3 inhibitors." — Nat Commun 2023 (PMID:38081835) [fetched this session]

Read that again, because it's a two-gene convergence onto one channel state. In DEE69 the channel is broken open by a variant in its own gate. In CDKL5 deficiency disorder the channel is structurally fine but nobody's phosphorylating it, and unphosphorylated Ca_V2.3 behaves like a DEE69 mutant. Same phenotypic destination, two different roads — like two mutations in different enzymes of one pathway causing the same metabolite to pile up.

For this KB that suggests something concrete: a shared mechanism node ("Ca_V2.3 gain-of-function state") that both CACNA1E-Related_DEE and the existing CDKL5 entry could point at. Worth raising as a module candidate.

Additional GO terms for the CDKL5 arm: GO:0006468 protein phosphorylation, GO:0004674 protein serine/threonine kinase activity, and note the enhanced cholinergic stimulation finding (GO:0007271 synaptic transmission, cholinergic).

Protein structure

Two cryo-EM structures now anchor the mechanism in atoms:

Human Ca_V2.3 + α2δ-1 + β3, 3.1 Å — "structural and electrophysiological characterizations showed that the CH2II helix stabilizes the inactivated conformation of the channel by tightening the cytosolic juxtamembrane segments" (PMID:36446785, Nat Commun 2022; PDB entries deposited with that paper).
Human Ca_V2.3 + α2δ1 + β1 gating-mechanism structures — Nat Commun 2023, DOI 10.1038/s41467-023-36260-2.

Both papers frame Ca_V2.3 as a drug target "for pain, seizures, epilepsy, and Parkinson's disease." These structures were not available when the 2018 disease paper was written, so nobody has yet published a structure-mapped analysis of the DEE69 variant set onto the resolved gate. That's a very tractable open question and a good KNOWLEDGE_GAP candidate.

Not applicable / no data

Metabolic changes: no metabolomic or energy-metabolism data. Nothing.
Immune involvement: none described. Not an inflammatory disease.
Tissue damage mechanisms: the only relevant thread is excitotoxicity, and it comes from mice — Ca_V2.3-null mice are protected from kainate excitotoxic cell death (PMID:17376845). Whether excitotoxic neuronal loss contributes in human DEE69 is unknown; no neuropathology series exists.
Transcriptomics / proteomics / metabolomics / lipidomics / single-cell / spatial / multi-omics in patients: none published. The only omics that touched this disease is the SILAC phosphoproteomic screen in PMID:38081835 — and that was mouse/human neuronal material studying CDKL5, not patient tissue.
Functional genomics screens: no CRISPR/RNAi screen targeting CACNA1E in a disease-relevant readout.

7. Anatomical Structures Affected

Primary: the central nervous system, full stop. CACNA1E is "highly expressed in the CNS."

Level	Structure	Ontology term	Basis
Organ	brain	`UBERON:0000955`	primary site
Organ system	central nervous system	`UBERON:0001017`	—
Region	cerebral cortex	`UBERON:0000956`	seizure origin; focal hyperkinetic seizures on EEG
Region	hippocampal formation	`UBERON:0002421`	CA1 plateau-potential mechanism (rodent)
Region	basal ganglia	`UBERON:0002420`	movement-disorder substrate (inferred, not imaged)
Region	substantia nigra pars compacta	`UBERON:0002965`	high Ca_V2.3 in nigral DA neurons (mouse; PD-relevant, not DEE-demonstrated)
Tract	corticospinal / spinal cord	`UBERON:0002240`	spastic quadriplegia implies UMN involvement
Secondary	skeletal joint	`UBERON:0000982`	congenital contractures
Secondary	skeletal musculature	`UBERON:0001015`	hypotonia → spasticity
Head	cranium / head	`UBERON:0000033`	macrocephaly

Cell types:

Cell	CL term	Note
neuron (generic)	`CL:0000540`	the safe default; the founding papers don't resolve cell type
glutamatergic neuron	`CL:0000679`	inferred from excitatory network mechanism
GABAergic neuron	`CL:0000617`	inferred; E-I imbalance implies both sides — which side dominates is unknown
pyramidal neuron	`CL:0000598`	CA1 plateau-potential mechanism (rodent)
dopaminergic neuron	`CL:0000700`	Ca_V2.3-rich in SNc (mouse; relevant to channel biology, not proven in DEE69)

Subcellular (GO cellular component): - GO:0005891 voltage-gated calcium channel complex - GO:0005886 plasma membrane - GO:0043195 terminal bouton (presynaptic pool) - GO:0030425 dendrite / GO:0043197 dendritic spine (somatodendritic pool) - GO:0042995 neuron projection

Lateralization: bilateral/diffuse for the encephalopathy. Notably, Di Micco et al. recorded tonic asymmetric seizures — so ictal semiology can be asymmetric even on a diffuse substrate. No structural brain malformation is a consistent feature; no systematic neuroimaging series has been published, which is itself a notable gap given that macrocephaly is in 43% of patients and nobody has characterized what's under those large skulls.

8. Temporal Development

Onset. Congenital for the structural features (contractures are present at birth — HP:0002803); infantile for the epilepsy. Median seizure onset 4.5 months (PMID:31064215). Hypotonia is a neonatal/early-infantile finding. The onset pattern is best described as congenital-plus-early-infantile rather than acute: the machinery was mis-set before birth, and the seizures are when it becomes audible.

Progression. No staging system exists for this disease. What can be said from the cohort:

Seizures are refractory from the start — this is not a disorder with a good honeymoon period.
Development is profoundly impaired and most patients never acquire speech or ambulation (88%) — so it reads as severe static-to-slowly-worsening impairment, not a neurodegenerative course. But no longitudinal study exists, so "static vs. progressive" is genuinely unresolved. Curate with PROGRESSIVE only if the schema demands a value, and flag it.
Tone evolves: severe early hypotonia in many patients coexists with or gives way to spastic quadriplegia (53%).
Early death occurred in a subset — "often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death" (PMID:30343943). The abstract does not give a mortality rate or age distribution. Do not invent one.

Milder trajectories exist and matter. The DIII-S6 patients — some never seizing, one seizure-free five years with single words and independent walking — plus the entire truncating class ("much milder phenotype") and the whole non-epilepsy cohort together tell you this is a spectrum, not a monolith. Prognostic counseling anchored only on the severe DI/DII-S6 picture would be wrong for a meaningful minority.

Remission. Spontaneous remission not described. Treatment-induced seizure freedom is documented in five topiramate-treated participants (see §12) — that's the one bright spot in the course data.

Critical periods. No intervention-window data exist. Mechanistically, the developmental arm implies an early window (calcium-dependent circuit assembly in infancy), which would argue for early diagnosis and early mechanism-matched treatment — but this is a hypothesis, not a demonstrated therapeutic window.

9. Inheritance and Population

Inheritance: autosomal dominant, essentially always de novo. HP:0000006 Autosomal dominant inheritance.

Penetrance: for the recurrent GOF missense class, apparently complete — every reported carrier is affected. For the truncating class, penetrance is clearly incomplete: one such variant was inherited from an unaffected parent.

Expressivity: highly variable, and — unusually for a rare disease — partly predictable from variant location. DI-S6 → movement disorder in 10/10. DIII-S6 → milder, sometimes seizure-free. That domain-level genotype–phenotype correlation is one of the most curation-valuable facts in this entry.

Germline mosaicism: not reported. Somatic mosaicism is documented once (truncating variant, 27% of cells). Parental mosaicism has not been reported but cannot be excluded — relevant to recurrence-risk counseling.

Anticipation: not applicable (not a repeat-expansion disorder).

Founder effects / carrier frequency / consanguinity: all not applicable. De novo dominant disorders don't have carriers, founders, or a consanguinity signal.

Epidemiology: - Prevalence: not established. No population estimate exists. - The only defensible curation is a CASES_IN_LITERATURE measure: 30 individuals in the founding cohort, plus 7 in the non-epilepsy cohort, plus scattered case reports — on the order of 40–50 published individuals as of mid-2026. Prevalence class: ULTRA_RARE. - Incidence: unknown. - CACNA1E is a recognized contributor to the DEE gene pool but a numerically small one; it sits on the Genomics England PanelApp epileptic-encephalopathy panel and is reported as ClinGen "Definitive" for gene–disease validity with DEE69 (per ClinGen/GenCC search results this session — the ClinGen site itself refused connection, so verify the assertion ID and date before citing a CGGV reference).

Demographics: the founding cohort was an international GeneMatcher-assembled series with no reported ethnic clustering — expected, since de novo mutation doesn't respect ancestry. No sex ratio has been reported, and there's no biological reason to expect skew (autosomal, dominant, de novo). Age distribution of living patients is unstudied.

10. Diagnostics

Genetic testing — the whole ballgame

Diagnosis is molecular. There is no biochemical marker, no imaging signature, no functional test that makes this diagnosis.

"Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE" — PMID:30343943 [cached & validated]

Recommended approach, in order of yield: 1. Epilepsy/DEE gene panel or exome (WES) as first-tier for infantile-onset refractory epilepsy with developmental impairment. CACNA1E is on major DEE panels (Genomics England PanelApp panel 67, green). 2. Genome (WGS) when panel/exome is negative — better for the splice-region and non-coding space (note the c.3422+1G>A splice-donor variant class). 3. Trio testing — parental samples are essentially required, because de novo status is a major ACMG evidence line (PS2) for a gene where most missense is otherwise hard to classify. 4. Single-gene testing — only for targeted confirmation/cascade, not for discovery. 5. CMA / karyotype / FISH: appropriate as general NDD workup but not informative for this diagnosis — DEE69 is not a CNV syndrome. 6. Mitochondrial DNA testing / repeat-expansion testing: not applicable.

Variant interpretation tips specific to this gene: location is evidence. A missense at the cytoplasmic end of an S6 helix — especially at Gly352 or Ala702 — in a de novo trio configuration is a very different animal from a truncating variant, which may be benign or mildly-acting (an unaffected parent carried one). Royer-Bertrand's substitution-intolerance mapping against gnomAD provides a useful PM1-style regional argument.

MAXO: MAXO:0000533 molecular genetic testing.

EEG

"abundant epileptiform activity on EEG" — PMID:30343943 [cached & validated]

And, crucially, long-term video-EEG is not optional in this disease. Di Micco et al.'s case is the argument: routine assessment called the trunk paroxysms a movement disorder; video-EEG called them focal hyperkinetic seizures. That changes treatment. Their paper is the first published EEG characterization of the disorder — meaning the electroclinical phenotype is, at this point, an n-of-1.

MAXO: MAXO:0000932 electroencephalography.

Other modalities — status honestly reported

Laboratory / biochemical tests: no diagnostic lab abnormality. No LOINC-codeable analyte. Routine metabolic workup is normal (and is typically done to exclude mimics).
Biomarkers: none — not diagnostic, not prognostic, not pharmacodynamic. This is a real gap; a Ca_V2.3-function biomarker would be transformative for trial design.
Imaging (MRI): no consistent malformation reported; no published imaging series. Given 43% macrocephaly, the absence of a systematic neuroimaging study is conspicuous.
Biopsy / histopathology: no neuropathology series published. Not applicable clinically.
Functional/electrophysiology beyond EEG: patch-clamp of variant channels is a research assay (heterologous expression), not a clinical test — though it's how the GOF mechanism was established and how a future variant-function service could work.
Omics-based diagnostics (RNA-seq for the splice variants, proteomics, metabolomics, methylation episignature, liquid biopsy): none validated. RNA-seq is the one with a plausible near-term role, for splice-region variants like c.3422+1G>A.

Clinical criteria and differential diagnosis

No society-issued diagnostic criteria exist for DEE69 specifically. The syndrome is diagnosed as an ILAE-framework DEE plus a CACNA1E molecular result.

Differential diagnosis — the phenotype (infantile refractory seizures + profound impairment + hypotonia + movement disorder ± contractures ± macrocephaly) overlaps heavily with:

Differential	Distinguishing feature
CDKL5 deficiency disorder (CDD/DEE2)	Clinically the closest — and now known to be mechanistically related via Ca_V2.3 phosphorylation (PMID:38081835). Distinguished by gene; CDD has classic hypsarrhythmia-adjacent EEG and epileptic spasms
STXBP1 encephalopathy	Synaptic-vesicle release mechanism rather than channelopathy
CACNA1A spectrum	Ataxia/hemiplegic migraine features; different Ca_V (2.1)
CACNA1D, CACNA1G GOF encephalopathies	Other calcium channelopathies with the same S6-hotspot logic — gene-level testing separates them
SCN2A / SCN8A / KCNQ2 DEEs	Sodium/potassium channelopathies; different ASM responsiveness profiles
Arthrogryposis syndromes	When contractures dominate the neonatal picture, DEE69 can masquerade as a primary contracture syndrome
Cerebral palsy (dyskinetic/spastic quadriplegic)	The single most likely misdiagnosis — profound impairment + spastic quadriplegia + dyskinesia without a clear acquired cause should trigger genetic testing

Screening

Not applicable. No newborn screening (de novo, no treatable metabolic marker), no carrier screening (no carriers), no cascade screening (parents are unaffected non-carriers in essentially all cases). Prenatal/preimplantation testing is only relevant for the rare family with proven parental mosaicism.

11. Outcome / Prognosis

Thin evidence, plainly stated.

Mortality. "Early death" is named in the founding abstract as an outcome in a subset (PMID:30343943). No mortality rate, no median survival, no cause-of-death breakdown has been published. By analogy with other severe DEEs, SUDEP, status epilepticus, and respiratory infection are the expected contributors — but that's inference, not data. Do not curate a survival percentage.

Morbidity. This is where the picture is unambiguous and severe: 88% nonverbal and nonambulatory. Add 53% spastic quadriplegia, 43% contractures, 60% movement disorder, 87% refractory epilepsy. Functionally that's total dependence for feeding, mobility, communication, and personal care — GMFCS-V-equivalent territory, though nobody has formally scored this cohort.

Quality of life measures: none applied. No EQ-5D, PROMIS, or disease-specific instrument. Genuine gap.

Complications (expected, largely uncurated in the literature): status epilepticus, aspiration and respiratory infection, feeding difficulty/failure to thrive, orthopedic sequelae of contractures and spasticity (hip dislocation, scoliosis), and the medication burden of polytherapy.

Recovery potential: none for the developmental impairment. Seizure freedom is achievable in a minority (topiramate, n=5).

Prognostic factors — the one real signal: variant domain. - DI-S6 / p.Gly352Arg → predicts hyperkinetic movement disorder (10/10). - DII-S6 / p.Ala702Thr → predicts the full severe spectrum. - DIII-S6 → predicts a milder course, potentially seizure-free with speech and ambulation. - Truncating → "much milder phenotype."

That's an unusually clean structure-to-prognosis map for a disease this young, and it should be the headline prognostic content of the KB entry.

Prognostic biomarkers: none.

12. Treatment

Topiramate — the mechanism-matched option

This is the therapeutic centerpiece, and it's a lovely bit of pharmacological serendipity: the drug that worked is a drug that blocks the very current the mutation amplifies.

"Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels." — PMID:30343943 [cached & validated]

Corroborated independently:

"Topiramate, an antiseizure drug (ASM) acting on CaV2.3 channels, has been identified as an effective treatment option in some patients." — Lauerer & Lerche, PMID:37822150 [fetched this session]

And notably it isn't only a seizure drug here — in the non-epilepsy cohort, "one patient demonstrated clinical improvement with topiramate" (PMID:34702355), hinting that lowering R-type current might touch the developmental/behavioral arm too.

Curation pattern for this KB:

- name: Topiramate
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term: {id: NCIT:C15986, label: Pharmacotherapy}
    therapeutic_agent:
    - preferred_term: topiramate
      term: {id: CHEBI:63631, label: topiramate}
  target_mechanisms:
  - target: Increased Neuronal Calcium Influx
    treatment_effect: INHIBITS

Caveats worth stating in the entry: n=5, uncontrolled, retrospective, in a cohort where 87% had refractory epilepsy — so this is a promising signal, not an established standard of care. Topiramate is also a dirty drug pharmacologically (sodium channels, GABA-A, AMPA/kainate, carbonic anhydrase, and R-type calcium), so the R-type attribution is mechanistically plausible rather than proven.

The rest of the pharmacological picture

Nothing else has published efficacy data in this disorder. Standard DEE polytherapy applies by default (levetiracetam, valproate, benzodiazepines, vigabatrin, ketogenic diet, etc.), but I found no CACNA1E-specific response data for any of them and won't invent it. Seizures are described as pharmacoresistant as a rule.

Pharmacogenomics: none specific to this disease. Standard ASM pharmacogenetics (e.g. HLA-B*15:02 for aromatic ASMs) applies as it does to any epilepsy patient, not as a disease feature.

Advanced therapeutics — where things could go

Selective Ca_V2.3 blockade is the obvious precision-therapy target, and it now has three independent endorsements: the topiramate signal, the mouse KO anticonvulsant phenotype, and the CDKL5 paper's explicit conclusion that both diseases "could be ameliorated with Cav2.3 inhibitors" (PMID:38081835). The two cryo-EM structures (PMID:36446785 and Nat Commun 2023) provide the structural basis for rational design. But: the only well-characterized selective blocker is SNX-482, a tarantula-venom peptide gating modifier (IC₅₀ ~30 nM) — a research tool, not a drug. It's a peptide, it partitions into membranes, it isn't CNS-deliverable. There is no clinical-stage selective Ca_V2.3 antagonist.
Gene therapy / gene editing: nothing. And note the design difficulty — this is a gain-of-function dominant disorder, so the useful strategy is allele-specific knockdown (ASO or RNAi against the mutant allele), not gene replacement. No program exists.
ASO therapy: no program. Mechanistically it's a reasonable fit for the recurrent hotspot variants (p.Gly352Arg, p.Ala702Thr are shared across many patients — exactly the economics that make an allele-specific ASO feasible). Purely prospective.
Cell therapy, immunotherapy, targeted small-molecule oncology-style therapy: not applicable.

Surgical, supportive, rehabilitative

No epilepsy-surgery data (the encephalopathy is generalized/diffuse, so resective surgery is unlikely to apply; VNS/palliative approaches unreported). Orthopedic management of contractures and spasticity is expected practice, unreported in the literature.

Multidisciplinary supportive and developmental care is the practical mainstay: physical/occupational/speech therapy, spasticity and dystonia management, feeding support, seizure management, orthopedic surveillance.

MAXO suggestions: - MAXO:0000533 molecular genetic testing (diagnostic) - MAXO:0000932 electroencephalography (diagnostic) - MAXO:0000079 genetic counseling - MAXO:0000011 physical therapy - MAXO:0000950 supportive care - MAXO:0000004 surgical procedure (contracture release — inferred practice, uncited) - MAXO:0000088 dietary intervention (ketogenic diet — inferred, no CACNA1E-specific data) - NCIT:C15747 Supportive Care, NCIT:C15986 Pharmacotherapy

Clinical trials

Search result: no interventional trial specific to CACNA1E-related DEE or DEE69 was identified. Patients may be eligible for general DEE natural-history or platform studies, but no NCT identifier can be attached to this disease with confidence. Verify against ClinicalTrials.gov directly before curating any clinical_trials block.

13. Prevention

Bluntly: this section is mostly "not applicable," and saying so is more useful than padding it.

Primary prevention: not possible. De novo mutation isn't preventable by any known behavioral, nutritional, or environmental intervention.
Secondary prevention (early detection): the meaningful action is early genetic diagnosis — rapid trio exome/genome in an infant with refractory seizures and profound impairment. Earlier diagnosis buys mechanism-matched ASM selection (topiramate), stops the diagnostic odyssey, and enables accurate counseling. Whether early treatment changes the developmental trajectory is unknown but mechanistically plausible.
Tertiary prevention: seizure control, aspiration/respiratory-infection prevention, contracture and hip-dislocation surveillance, nutritional support, status-epilepticus rescue planning. Standard severe-DEE management; nothing disease-specific published.
Immunization: routine childhood schedule; no disease-specific vaccine strategy. (Standard practice for severe epilepsy applies — vaccinate, with fever management.)
Population screening: not applicable — no newborn or carrier screening rationale.
Genetic counseling: the real deliverable. Message: de novo dominant, recurrence risk low but not zero because parental gonadal mosaicism can't be excluded (and somatic mosaicism is documented in this gene). Prenatal testing available for a known familial variant. Domain-specific prognostic information (DI-S6 → movement disorder; DIII-S6 → milder) belongs in the counseling conversation.
Public health / environmental interventions: not applicable.
Prophylaxis: none established.

14. Other Species / Natural Disease

Orthologs:

Species	NCBI Taxon	Gene	Identifier
Human	`NCBITaxon:9606`	CACNA1E	HGNC:1392, NCBI Gene 777
Mouse	`NCBITaxon:10090`	Cacna1e	MGI:106217 ("calcium channel, voltage-dependent, R type, alpha 1E subunit")
Rat	`NCBITaxon:10116`	Cacna1e	RGD (ortholog exists; ID not verified this session)
Zebrafish	`NCBITaxon:7955`	cacna1e paralog(s)	ZFIN carries a human-disease page for DOID:0112205; paralog naming not verified — check ZFIN before curating

Naturally occurring disease in other species: I found no OMIA entry or veterinary case literature describing a spontaneous CACNA1E disorder in companion animals or livestock. Report as "not identified," not as "does not exist" — absence of a search hit in a rare-gene space isn't proof.

Breed (VBO): not applicable — no breed-associated natural disease known.

Comparative biology: Ca_V2.3 is deeply conserved across vertebrates in both sequence and function; the R-type current, its zinc/copper sensitivity, and its presynaptic/somatodendritic dual localization are conserved features. The knockout mouse's seizure-resistance phenotype (§15) is the mirror image of the human GOF disease — which is about as good a cross-species mechanistic validation as you get without a knock-in.

Zoonotic potential / cross-species transmission: not applicable (genetic disorder).

15. Model Organisms

Mouse — the workhorse, and the evidence is strong

Constitutive Cacna1e knockout (Ca_V2.3⁻/⁻). These mice are the inverse-mechanism proof that Ca_V2.3 activity is pro-epileptogenic:

"PTZ-induced seizure susceptibility was dramatically reduced in Ca(v)2.3-deficient mice, whereas 4-AP sensitivity remained unchanged." — Weiergräber et al., Epilepsia 2006 (PMID:16686648) [fetched this session]

"Administration of kainic acid (30 mg/kg ip) revealed clear alteration in behavioral seizure architecture and dramatic resistance to limbic seizures in Ca(v)2.3(−/−) mice compared with controls." … "excitotoxic effects after kainic acid administration are absent in Ca(v)2.3(−/−) mice, whereas Ca(v)2.3(+/+) animals exhibited clear and typical signs of excitotoxic cell death." — Weiergräber et al., J Neurophysiol 2007 (PMID:17376845) [fetched this session]

And as summarized in the disease commentary:

"Cav2.3 is also known to play a role in epileptogenesis in rodents, and its deletion reduces susceptibility to chemically induced seizures." — PMID:31064215 [cached & validated, MODEL_ORGANISM]

Note the convulsant-specific pattern: protection against PTZ and kainate, not 4-AP. That's a mechanistic fingerprint, not blanket seizure resistance — Ca_V2.3 matters for particular routes into hypersynchrony.

Knockout mice also show normal brain structure, no spontaneous seizures, and no compensatory shifts in other calcium-channel expression — so the phenotype is attributable to the channel itself.

Ca_V2.3 phosphomutant mouse (2023) — the most disease-relevant model that exists. Sampedro-Castañeda et al. made mice in which the CDKL5 phosphorylation sites on Ca_V2.3 are ablated. The result: "loss of Cav2.3 phosphorylation leads to channel gain-of-function via slower inactivation and enhanced cholinergic stimulation, resulting in increased neuronal excitability," with properties that "closely resemble those described for CACNA1E gain-of-function mutations causing DEE69" (PMID:38081835). This is currently the closest available in-vivo model of the DEE69 channel state — an indirect GOF model rather than a patient-variant knock-in.

Ca_V2.3 in nigral dopaminergic neurons. Benkert et al., Nat Commun 2019 (PMID:31704946): Ca_V2.3 transcripts are the most abundant VGCC in mouse nigral neurons and rise with age; Ca_V2.3 knockout "afforded full protection from degeneration in vivo" in a neurotoxin Parkinson's model. Relevant here for channel biology and the movement-disorder question, not as a DEE69 model — but it's the reason people care about Ca_V2.3 selective blockers beyond epilepsy.

Zinc/copper modulation: PMID:32068980 — convulsive seizures are modulated in part by zinc ions through the pharmacoresistant Ca_V2.3 channel. Useful mechanistic color; not a disease model.

The critical gap

No patient-variant knock-in mouse exists. Nobody has made a Ca_V2.3-p.Gly352Arg or -p.Ala702Thr animal. Every in-vivo statement about this disease is therefore either (a) inverse — what happens when you remove the channel — or (b) indirect, via the phosphomutant. That's the single biggest experimental gap in the field, and it's the natural KNOWLEDGE_GAP / HUMAN_MODEL_MISMATCH to record: a knockout that is protected from seizures is not a model of a disease caused by gain of the same channel, however satisfying the logic feels.

Cellular models

Heterologous expression (HEK/tsA-201 + α2δ and β subunits) with patch-clamp — the workhorse for variant functional characterization; this is how the GOF mechanism was established (PMID:30343943).
Patient-derived iPSC neurons: none published for CACNA1E. The commentary explicitly calls for them: "future studies in patient-derived iPSC are likely to shed light on pathogenic mechanisms and potential therapeutic targets" (PMID:31064215). Still true seven years on.
Organoids / MorPhiC: CACNA1E is not among the MorPhiC anchor genes (ISL1, EOMES, GCM1, NKX2-1). No cellular-phenotype data to import.
Zebrafish: ZFIN maintains a human-disease page for DOID:0112205, but I found no published cacna1e zebrafish disease model. Verify before asserting.

Model resources

MGI (MGI:106217), IMPC/KOMP (check for Cacna1e allele availability), IMSR for strain sourcing, ZFIN, Alliance of Genome Resources for ortholog/phenotype integration.

Curation notes — what I'd flag before this goes in the KB

Solid, cite-able, already validated in this repo: the founding cohort's clinical percentages, the S6-gate variant clustering, the GOF biophysics, the domain-level genotype–phenotype correlations, the truncating-variant caveat, and the topiramate signal. All of that has snippet-verified evidence in references_cache/PMID_30343943.md and PMID_31064215.md.

New material worth adding to the existing entry (all fetched this session — run just fetch-reference and re-verify each snippet before committing): 1. PMID:34702355 — the non-epilepsy neurodevelopmental phenotype. This meaningfully broadens the entry beyond "DEE" and supports an ASD/ID phenotype block plus a has_subtypes or spectrum note. 2. PMID:38081835 — the CDKL5–Ca_V2.3 convergence. Strong candidate for a cross-disease mechanism link and possibly a shared module node with the CDKL5 entry. 3. PMID:38780451 — first EEG characterization; forces a caveat on the movement-disorder phenotype (some of it is ictal). 4. PMID:37822150 — Lauerer & Lerche review; good general-mechanism citation and supports the shared distal-S6 hotspot claim across calcium-channel epilepsies. 5. PMID:16686648 / PMID:17376845 — the primary mouse KO papers behind the existing MODEL_ORGANISM evidence, currently cited only secondhand through the commentary. 6. PMID:36446785 — cryo-EM structure; enables a structural node and a variant-mapping knowledge gap.

Things to verify, not assert: the ClinGen CGGV assertion ID (site was unreachable), gnomAD constraint numbers (browser is JS-only), the Orphanet code, ClinGen dosage scores, zebrafish paralog names, and any ClinicalTrials.gov entry.

Knowledge gaps worth encoding as discussions: - No patient-variant knock-in animal exists — everything in vivo is inverse or indirect (HUMAN_MODEL_MISMATCH fits better than KNOWLEDGE_GAP here, since evidence exists but its fidelity to the human GOF disease is the open question). - No selective, CNS-deliverable Ca_V2.3 antagonist despite three converging lines of rationale (already partly captured in the existing entry's gap_cacna1e_rtype_blocker_precision_therapy). - Truncating variants: benign, hypomorphic, or a distinct milder mechanism? An unaffected transmitting parent says the simple dose model is wrong. - No structure-mapped analysis of the DEE69 variant set onto the 2022/2023 cryo-EM gate. - No natural history, no imaging series, no neuropathology, no QoL instrument, no biomarker.

Sources: - De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias — PubMed (PMID:30343943) - Calcium Channel Dysfunction in Epilepsy: Gain of CACNA1E — PubMed (PMID:31064215) - De novo variants in CACNA1E found in patients with intellectual disability, developmental regression and social cognition deficit but no seizures — PubMed (PMID:34702355) - Epilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2.3 — PubMed (PMID:38081835) - Seizure and movement disorder in CACNA1E developmental and epileptic encephalopathy — PubMed (PMID:38780451) - Voltage-gated calcium channels in genetic epilepsies (Lauerer & Lerche) — PMC11591408 (PMID:37822150) - Altered seizure susceptibility in mice lacking the Ca(v)2.3 E-type Ca2+ channel — PubMed (PMID:16686648) - Hippocampal seizure resistance and reduced neuronal excitotoxicity in mice lacking Cav2.3 — PubMed (PMID:17376845) - Structures of the R-type human Cav2.3 channel reveal conformational crosstalk — PubMed (PMID:36446785) - Molecular insights into the gating mechanisms of voltage-gated calcium channel CaV2.3 — Nature Communications 2023 - Cav2.3 channels contribute to dopaminergic neuron loss in a model of Parkinson's disease — PubMed (PMID:31704946) - Experimentally Induced Convulsive Seizures Are Modulated in Part by Zinc Ions through the Pharmacoresistant Cav2.3 Calcium Channel — PubMed (PMID:32068980) - OMIM #618285 — Developmental and Epileptic Encephalopathy 69 (403 to automated fetch; identifiers cross-verified via MONDO xrefs) - OMIM *601013 — CACNA1E gene - Genomics England PanelApp — CACNA1E (Epileptic encephalopathy panel) - GenCC — CACNA1E (HGNC:1392) submissions by classification - ClinGen dosage sensitivity — CACNA1E (connection refused during this session — verify manually) - MGI:106217 — mouse Cacna1e - ZFIN human disease page — developmental and epileptic encephalopathy 69 (DOID:0112205) - GTR — Developmental and epileptic encephalopathy, 69 (C4748988) - Orphanet — CACNA1E gene page

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OpenScientist Report

Inheritance

Subtypes

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Progression

Prevalence

Differential Diagnoses

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

Deep Research

1. Disease Information

Overview

Key identifiers

Synonyms

Data provenance

2. Etiology

Primary cause

Genetic risk factors

Environmental risk factors

Protective factors

Gene–environment interactions

3. Phenotypes

The quantitative core

Phenotype table with HPO suggestions

The seizure/movement-disorder trap — important for curation

Quality of life

4. Genetic / Molecular Information

The gene and its product

Variant classes

Functional consequence — the biophysics

Modifier genes, epigenetics, chromosomal abnormalities

5. Environmental Information

6. Mechanism / Pathophysiology

The causal chain

The CDKL5 convergence — the best mechanism news in this field

Protein structure

Not applicable / no data

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

Genetic testing — the whole ballgame

EEG

Other modalities — status honestly reported

Clinical criteria and differential diagnosis

Screening

11. Outcome / Prognosis

12. Treatment

Topiramate — the mechanism-matched option

The rest of the pharmacological picture

Advanced therapeutics — where things could go

Surgical, supportive, rehabilitative

Clinical trials

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mouse — the workhorse, and the evidence is strong

The critical gap

Cellular models

Model resources

Curation notes — what I'd flag before this goes in the KB