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Classifications

Harrison's Part

🔗

Mappings

MONDO

MONDO:0014133 developmental and epileptic encephalopathy, 16

MONDO:0014133 carries DEE16 and EIEE16 as exact synonyms and maps exactly to OMIM:615338, the TBC1D24 early-infantile epileptic encephalopathy locus.

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Inheritance

1

Autosomal recessive inheritance HP:0000007

DEE16 requires biallelic (homozygous or compound heterozygous) TBC1D24 pathogenic variants, and a separate autosomal dominant TBC1D24 phenotype exists that causes non-syndromic hearing loss rather than epilepsy. Carriers are conventionally described as asymptomatic, but that is not settled: seizures have been reported in heterozygous carriers, and the mouse work argues haploinsufficiency is clinically significant. Both positions are cited below.

Autosomal recessive inheritance

Show evidence (3 references)

PMID:25719194 SUPPORT Human Clinical

"The diagnosis of a TBC1D24-related disorder is established in an individual with suggestive findings biallelic TBC1D24 pathogenic variants when the mode of inheritance is autosomal recessive (i.e., DOORS syndrome, FIME, PME, EPRPDC, DEE, and DFNB)"

GeneReviews states that the DEE phenotype in the TBC1D24 spectrum is established by biallelic variants under autosomal recessive inheritance.

PMID:25719194 SUPPORT Human Clinical

"Heterozygotes (carriers) are typically asymptomatic."

The conventional position on carriers, stated by GeneReviews.

PMID:30335140 REFUTE INDIRECT Model Organism

"Importantly, heterozygous TBC1D24 mutation carriers have also been reported with seizures, suggesting that haploinsufficiency for TBC1D24 is significant clinically."

Contradicts the blanket claim that carriers are asymptomatic, and is the reason this entry does not assert it. Graded MODEL_ORGANISM because that classifies the cited publication, which is a mouse and cellular study; the sentence itself is background citing other reports, so the claim reaches human carriers indirectly.

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Discussions and Knowledge Gaps

3

Why does the same TBC1D24 loss-of-function lesion produce a devastating early-infantile encephalopathy in one family and a self-limiting myoclonic epilepsy with normal intellect in another?

KNOWLEDGE GAP dee16_genotype_phenotype_discordance

Attached to

pathophysiology#Biallelic TBC1D24 Loss of Function genetic#TBC1D24

Truncating variants correlate with the severe end, but the correlation is loose and does not run through the obvious mechanism. Neurite-outgrowth assays found that the variants causing the most severe clinical disease are not the ones that most disrupt the protein in culture, so residual protein function measured that way does not explain the phenotypic split. Something else - domain-specific effects, isoform usage, modifiers, or an assay that does not capture the relevant function - is doing the work. Until it is identified, DEE16 cannot be predicted from genotype at the bedside.

Does the postnatal micro-exon splicing switch that times seizure onset in the S324Tfs*3 mouse operate in human DEE16, including in patients whose variants lie outside that micro-exon?

HUMAN MODEL MISMATCH dee16_microexon_switch_human_validity

Attached to

pathophysiology#Postnatal Micro-Exon Isoform Switch animal_models#Tbc1d24 S324Tfs*3 knock-in mouse

The mouse gives an unusually clean mechanistic account of why seizures start when they do: before the developmental splicing switch the mutant allele still yields functional protein. But the account is allele-specific by construction, since it depends on the variant sitting inside the micro-exon. Human DEE16 variants are distributed across the coding sequence, and no human neuronal system has been shown to undergo the same switch. So the model may be explaining the timing of one variant rather than the timing of the disease.

Proposed experiments

Micro-exon isoform quantification in human neurons across development

dee16_human_microexon_timecourse

Quantify micro-exon-containing versus micro-exon-skipping TBC1D24 transcripts in human iPSC-derived cortical neurons across differentiation, and in post-mortem human cortex across the first year of life, to test whether the developmental switch occurs in humans.

Would support

pathophysiology#Postnatal Micro-Exon Isoform Switch

Supporting outcome

Micro-exon-containing transcripts rise sharply during a defined postnatal window in human neurons, mirroring the mouse P15 switch.

Refuting outcome

Micro-exon inclusion is constitutive or absent across human development, indicating the timing mechanism is mouse-specific.

Does loss of TLDc-domain oxidative stress protection contribute to the progressive atrophy in DEE16, or is the atrophy entirely accounted for by the developmental lesion and seizure-related injury?

KNOWLEDGE GAP dee16_tldc_oxidative_contribution

Attached to

pathophysiology#TLDc Domain Dysfunction pathophysiology#Progressive Cerebral and Cerebellar Atrophy

The question has moved but is not closed. An early purified-domain assay found no v-ATPase interaction for TBC1D24, but that negative was later overturned in mammalian brain, so read-across from OXR1 and NCOA7 was premature rather than wrong. The 2024 KIBRA interaction gives the domain a specific partner and a mechanism, and the humanized fly gives it a redox-sensor role with antioxidant rescue. But both results come from missense alleles, one of which causes a self-limiting Rolandic epilepsy, while DEE16 is enriched for truncating alleles that delete the domain outright. Nothing has measured oxidative injury or KIBRA-pathway disruption in DEE16 patient neurons or brain tissue. This matters practically: if oxidative injury contributes, it is the one arm of the mechanism with an obvious pharmacological handle, since the trafficking lesion is not currently druggable.

Proposed experiments

Antioxidant rescue tested against DEE16 truncating alleles

dee16_antioxidant_rescue_in_dee16_alleles

Repeat the N-acetylcysteine-amide and alpha-tocopherol rescue in patient-derived DEE16 neurons and in a model carrying a truncating allele, rather than the mild G501R missense allele, measuring synaptic vesicle trafficking and oxidative-stress markers.

Would support

pathophysiology#TLDc Domain Dysfunction

Supporting outcome

Antioxidant treatment restores vesicle trafficking in DEE16 neurons carrying truncating alleles, making the redox arm relevant to the severe phenotype and pointing at a treatable step.

Refuting outcome

No rescue in truncating-allele neurons, indicating the redox mechanism is specific to TLDc missense alleles and does not explain DEE16.

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Pathophysiology

14

Biallelic TBC1D24 Loss of Function

Both TBC1D24 alleles carry pathogenic variants, most severely truncating ones, that reduce or abolish protein expression and function. The protein has two separable functional modules that are lost together: a TBC (Rab-GAP) domain containing a cationic phosphoinositide-binding pocket, and a C-terminal TLDc domain implicated in oxidative-stress resistance.

Neuron CL:0000540

GTPase activator activity GO:0005096 ↓ DECREASED

Downstream

Loss of Phosphoinositide-Dependent Presynaptic Membrane Anchoring The most prevalent patient variants fall in the TBC domain's cationic pocket and abolish its binding to PI(4)P/PI(4,5)P2.

Impaired ARF6-Dependent Membrane Trafficking TBC1D24 binds and restrains ARF6; losing the protein releases that restraint.

Impaired v-ATPase Assembly and Organellar Acidification Losing TBC1D24 removes the chaperone that assists v-ATPase reassembly.

Postnatal Micro-Exon Isoform Switch For an allele inside the micro-exon, the loss of function is not expressed until that exon starts being used, which is what makes the switch a step in this chain rather than a separate observation.

TLDc Domain Dysfunction Truncating variants remove or disrupt the C-terminal TLDc domain, whose structural integrity is required for its neuroprotective activity.

Show evidence (2 references)

PMID:27281533 SUPPORT Human Clinical

"TBC1D24 encodes a protein containing a Tre2/Bub2/Cdc16 (TBC) domain, shared by Rab GTPase-activating proteins (Rab-GAPs)."

Identifies the Rab-GAP TBC domain that biallelic pathogenic variants disrupt.

PMID:27281533 SUPPORT Human Clinical

"The protein also contains a TLDc domain, putatively involved in oxidative stress resistance."

Establishes the second functional module lost when the protein is truncated.

Loss of Phosphoinositide-Dependent Presynaptic Membrane Anchoring

The TBC domain's cationic pocket binds phosphoinositides phosphorylated at the 4 and 5 positions, and that lipid binding is what tethers the protein within the presynaptic terminal and restricts its diffusion. Pathogenic variants in the pocket abolish binding, releasing the protein from the presynaptic membrane. In Drosophila the resulting synaptic-vesicle trafficking defect and seizure phenotype are rescued by raising synaptic PI(4,5)P2, which makes the lipid interaction causal rather than incidental.

Neuron CL:0000540

phosphatidylinositol-4,5-bisphosphate binding GO:0005546 ↓ DECREASED

Synapse GO:0045202

Animal models

Drosophila skywalker phosphoinositide-pocket mutants Fruit fly recapitulates Pathogenic pocket mutations abolish lipid binding and release the protein's membrane anchoring in presynaptic terminals.

Downstream

Impaired Synaptic Vesicle Endocytosis and Recycling Pocket variants produce synaptic-vesicle trafficking failure that is reversed by restoring synaptic PI(4,5)P2.

Show evidence (1 reference)

PMID:27669036 SUPPORT In Vitro

"We solved the crystal structure of the TBC domain of the Drosophila ortholog Skywalker, revealing an unanticipated cationic pocket conserved among TBC1D24 homologs. Cocrystallization and biochemistry showed that this pocket binds phosphoinositides phosphorylated at the 4 and 5 positions."

Structural and biochemical demonstration of the phosphoinositide-binding pocket whose loss this node describes.

Impaired ARF6-Dependent Membrane Trafficking

TBC1D24 normally prevents ARF6 activation. Without it, ARF6-dependent membrane exchange between the plasma membrane and endocytic compartments is dysregulated. This is the developmental arm of the mechanism: the same dysregulation that disturbs mature vesicle traffic also drives the migration and axon-specification defects below, and dominant-negative ARF6 rescues them.

Neuron CL:0000540

regulation of ARF protein signal transduction GO:0032012 ⚠ ABNORMAL

Downstream

Delayed Radial Migration and Arrested Neuronal Maturation

Postsynaptic Dendritic Spine Loss

Growth-Cone Endocytosis Failure Downgraded from DIRECT deliberately: the cited sentence says the axonal phenotype "was accompanied by" the endocytic defect and altered ARF6 activation, which is co-occurrence rather than a demonstrated causal step.

Show evidence (1 reference)

PMID:24469796 SUPPORT Model Organism

"We show that in vivo, overexpression of the dominant-negative form of ARF6 rescues the neuronal migration and dendritic outgrowth defects induced by TBC1D24 knockdown, suggesting that TBC1D24 prevents ARF6 activation."

Rescue by dominant-negative ARF6 establishes that TBC1D24 loss acts through unrestrained ARF6 activation.

TLDc Domain Dysfunction

The C-terminal TLDc domain has at least two identified activities. The domain family (OXR1, NCOA7) confers resistance to oxidative stress, and a humanized Drosophila model of a TLDc missense allele shows activity-induced vesicle-trafficking and locomotor defects that antioxidants reverse, supporting a reactive-oxygen-species sensor that sets synaptic vesicle trafficking rates. Separately, a 2024 screen identified the scaffold protein KIBRA as a specific partner of this domain, with two recessive epilepsy-associated TLDc variants disrupting the binding. A note on the v-ATPase, because the literature reads as contradictory if taken out of order. An earlier assay found no interaction between the purified TLDc domain and the v-ATPase that other TLDc proteins regulate, and that negative is still quoted as leaving the domain's function open. It has since been superseded in vivo: TBC1D24 interacts with the v-ATPase V1 subunits in mammalian brain, and its loss impairs V1/V0 association and organellar acidification. This entry models that as its own node rather than treating the purified-domain result as the settled answer. Two caveats matter for DEE16 specifically. The antioxidant-rescue work comes from a mild allele causing Rolandic epilepsy with exercise-induced dystonia, not from DEE16 patients. The KIBRA work tests two missense variants, whereas DEE16 is enriched for truncating alleles that remove the domain outright. So this arm is real biology whose contribution to the severe phenotype is inferred rather than measured.

Hippocampal neuron CL:0002608

response to oxidative stress GO:0006979 ↓ DECREASED

Animal models

Humanized TBC1D24 G501R Drosophila (TLDc allele) Fruit fly partially recapitulates Models the consequence of a TLDc missense variant, with an antioxidant rescue that identifies the pathway.

Downstream

Impaired Synaptic Vesicle Endocytosis and Recycling If the domain is a redox sensor setting vesicle trafficking rates, its loss feeds the same presynaptic failure the TBC domain lesion produces, which would explain why both domains yield overlapping phenotypes.

Progressive Cerebral and Cerebellar Atrophy Reduced oxidative-stress resistance is a plausible contributor to the progressive atrophy seen on neuroimaging, but no study has measured oxidative injury in DEE16 brain tissue.

Show evidence (3 references)

PMID:39214300 SUPPORT In Vitro

"As two epilepsy-associated recessive variants (Gly511Arg and Ala515Val) in the TLDc domain of human TBC1D24 disrupt the interaction with the human KIBRA C2 domain, this study reveals a pathogenic mechanism of TBC1D24-associated epilepsy, linking the TBC1D24 and KIBRA pathways."

Identifies a specific molecular consequence of TLDc-domain variants, giving this node a mechanism rather than an analogy.

PMID:31257402 SUPPORT INDIRECT Model Organism

"We propose that the TBC1D24/Sky TLDc domain is a reactive oxygen species sensor mediating synaptic vesicle trafficking rates that, when dysfunctional, causes a movement disorder in patients and flies."

Supports the redox-sensor role of the domain, but from a fly model of a mild human allele, so the inference to DEE16 runs through the shared domain rather than through the phenotype.

PMID:26668325 SUPPORT INDIRECT In Vitro

"TBC1D24, a protein mutated in a range of disorders characterized by seizures, hearing loss, and neurodegeneration"

Places TBC1D24 within the TLDc family whose domain integrity the same study shows is required for neuroprotection. The inference to TBC1D24's own domain is by family membership, not direct measurement.

Delayed Radial Migration and Arrested Neuronal Maturation

TBC1D24-deficient neurons fail the multipolar-to-bipolar transition, migrate late through the developing neocortex, and retain immature morphological and functional properties once they arrive. The cortex that results is populated by neurons that never fully matured, which is the developmental half of "developmental and epileptic encephalopathy".

Cortical projection neuron CL:0010012

cerebral cortex radially oriented cell migration GO:0021799 ↓ DECREASED cell morphogenesis involved in neuron differentiation GO:0048667 ⚠ ABNORMAL

Downstream

Aberrant Cortical Circuit Formation Neurons that migrate late and stay immature assemble into malformed circuits.

Show evidence (1 reference)

PMID:24469796 SUPPORT Model Organism

"Furthermore, we find that TBC1D24-knockdown neurons display an abnormal maturation and retain immature morphofunctional properties."

Direct evidence for the arrested-maturation half of this node.

Growth-Cone Endocytosis Failure

Membrane trafficking fails at the growth cone: endocytosis there is impaired and the TBC1D24 partner ARF6 is abnormally activated. This is the trafficking lesion in the growing neurite, and it is upstream of the axon-specification failure that follows from it.

Neuron CL:0000540

Growth cone GO:0030426

Downstream

Axonal Specification Failure The paper reports the axonal phenotype as accompanied by the growth-cone endocytic defect; the trafficking failure is placed upstream because that is the direction the mechanism runs.

Show evidence (1 reference)

PMID:30858606 SUPPORT In Vitro

"an impairment of endocytosis at the growth cone and an altered activation of the TBC1D24 molecular partner ADP ribosylation factor 6"

Direct evidence for the growth-cone endocytic defect and the ARF6 dysregulation accompanying it.

Axonal Specification Failure

Cortical neurons lacking TBC1D24 fail to specify an axon, mature the axon initial segment, or fire action potentials normally, and in vivo callosal projections are impaired. Critically for DEE16, the severity of this defect tracks clinical severity in patient-derived neurons: iPSC neurons from a patient with severe developmental encephalopathy show the axon defect, while neurons from a patient with mild early-onset epilepsy do not. That makes it the one cellular readout in this gene shown to separate the severe end of the spectrum from the mild end.

Cortical projection neuron CL:0010012

axonogenesis GO:0007409 ↓ DECREASED

Experimental models

Patient-derived iPSC cortical neurons (severe vs mild TBC1D24 phenotype) IPSC DERIVED MODEL Human neurons carrying patient TBC1D24 variants reproduce the axon formation defect, and do so in a severity-dependent way.

Downstream

Aberrant Cortical Circuit Formation

Neuronal Hyperexcitability and Hypersynchrony

Show evidence (2 references)

PMID:30858606 SUPPORT In Vitro

"In rat cortical primary neurons silenced for TBC1D24, we found defects in axonal specification, the maturation of axonal initial segment and action potential firing."

Direct evidence for the axonal and excitability defect this node names.

PMID:30858606 SUPPORT In Vitro

"Reprogrammed neurons from a patient with severe developmental encephalopathy show significant axon formation defect that were absent from reprogrammed neurons of a patient with mild early onset epilepsy."

Human patient-derived evidence that the axonal phenotype is specific to the severe (DEE) end of the spectrum rather than to TBC1D24 loss generally.

Impaired v-ATPase Assembly and Organellar Acidification

TBC1D24 interacts with the V1 subunits of the vacuolar ATPase in mammalian brain and behaves as a chaperone for correct v-ATPase reassembly. Without it the V1/V0 association fails, endo-lysosomal compartments and synaptic vesicles do not acidify properly, and autophagy is impaired at both the soma and the terminal. At the synapse the specific consequence is that vesicles retrieved after stimulation are not reacidified, so the reserve pool is not properly regenerated. This is the arm the sibling DOORS_Syndrome entry models as a shared endolysosomal axis with ATP6V1B2, and it is why an earlier negative result using the purified TLDc domain alone should not be read as ruling the interaction out.

Hippocampal neuron CL:0002608

Autophagy GO:0006914 ↓ DECREASED

Lysosome GO:0005764

Downstream

Impaired Synaptic Vesicle Endocytosis and Recycling Failure to reacidify retrieved vesicles is part of the same recycling defect, not a separate consequence of it.

Show evidence (2 references)

PMID:39758816 SUPPORT Model Organism

"In the present study, we reveal that TBC1D24 interacts with the V1 subunits of v-ATPase in the mammalian brain, and in its absence, the V1/V0 association is impaired in neuronal cells. This, in turn, results in defective acidification of the endo-lysosomal compartments and SVs, alongside..."

The in vivo demonstration of the interaction and of what its loss does, which is the whole content of this node.

PMID:39758816 SUPPORT Model Organism

"Taken together, these data suggest that Tbc1d24 facilitates SV reacidification and proper recycling and clearance of intra-terminal cisternae at synaptic boutons."

States the presynaptic consequence specifically, which is what connects this node to the vesicle-cycle node downstream.

Impaired Synaptic Vesicle Endocytosis and Recycling

TBC1D24 is associated with clathrin-coated vesicles and synapses of hippocampal neurons. Losing it impairs presynaptic endocytosis and the regeneration of release-ready vesicles, destabilizing neurotransmission at the terminals of an already malformed cortical network.

Hippocampal neuron CL:0002608

synaptic vesicle endocytosis GO:0048488 ↓ DECREASED synaptic vesicle cycle GO:0099504 ⚠ ABNORMAL

Clathrin-coated vesicle GO:0030136

Downstream

Neuronal Hyperexcitability and Hypersynchrony

Show evidence (2 references)

PMID:30602030 SUPPORT Model Organism

"TBC1D24 is associated with clathrin-coated vesicles and synapses of hippocampal neurons, suggesting a crucial role of TBC1D24 in vesicle trafficking important for neuronal signal transmission."

Localizes TBC1D24 to the presynaptic vesicle machinery whose failure this node describes, in the mouse model of the EIEE phenotype.

PMID:30335140 SUPPORT Model Organism

"genetic disruption of Tbc1d24 expression in the mouse leads to an impairment of endocytosis and an enlarged endosomal compartment in neurons with a decrease in spontaneous neurotransmission"

Measures the endocytic failure, the endosomal accumulation it produces, and the resulting drop in spontaneous neurotransmission.

Postnatal Micro-Exon Isoform Switch

A striking, and so far mouse-only, explanation for why DEE16 seizures begin after birth rather than in utero. The S324Tfs*3 truncating variant sits in an alternatively spliced micro-exon that is only incorporated into TBC1D24 postnatally. Before that developmental splicing switch, homozygous mutant mice make predominantly the shorter wild-type isoform that omits the micro-exon and are unaffected; seizures begin abruptly at postnatal day 15, exactly when the switch occurs. Whether this timing mechanism generalizes to human DEE16 variants outside the micro-exon is unknown.

Neuron CL:0000540

Animal models

Tbc1d24 S324Tfs*3 knock-in mouse Mouse recapitulates The model is the sole source of evidence for the micro-exon switch mechanism; the node exists because of it.

Downstream

Neuronal Hyperexcitability and Hypersynchrony Once the micro-exon is incorporated, functional TBC1D24 is lost and seizures begin.

Show evidence (2 references)

PMID:30602030 SUPPORT Model Organism

"S324Tfs*3 homozygotes show an abrupt onset of seizures at P15 that correlates with a developmental switch to utilization of the micro-exon."

Ties seizure onset timing to the postnatal micro-exon splicing switch, the claim this node makes.

PMID:30602030 SUPPORT Model Organism

"During embryonic and early postnatal development, S324Tfs*3 homozygotes produce predominantly the shorter wild-type TBC1D24 protein isoform that omits the micro-exon."

Explains the pre-switch reprieve: the mutant allele produces functional protein until the micro-exon is used.

Postsynaptic Dendritic Spine Loss

TBC1D24 is not only presynaptic. It is also present at the postsynaptic side of excitatory synapses, where inhibiting ARF6 is what maintains dendritic spines. Knocking it down in adult mouse hippocampus causes spine loss with contextual fear memory deficits, hyperactivity, and increased anxiety, and a knock-in of the disease-associated F251L substitution produces increased neuronal excitability, spontaneous seizures, and premature death in homozygotes. This arm matters because it makes the cognitive impairment of DEE16 partly independent of the seizures rather than purely their consequence.

Hippocampal excitatory neuron CL:0002608

Dendritic spine GO:0043197

Animal models

Tbc1d24 F251L knock-in mouse Mouse recapitulates The heterozygous arm isolates spine loss and memory impairment without the confound of ongoing seizures.

Downstream

Aberrant Cortical Circuit Formation

Neuronal Hyperexcitability and Hypersynchrony

Show evidence (2 references)

PMID:32004315 SUPPORT Model Organism

"we report that TBC1D24 is present at the postsynaptic sites of excitatory synapses, where it is required for the maintenance of dendritic spines through inhibition of the small GTPase ARF6"

Establishes the postsynaptic localization and the ARF6-dependent spine maintenance function this node describes.

PMID:32004315 SUPPORT Model Organism

"Mice subjected to viral-mediated knockdown of TBC1D24 in the adult hippocampus display dendritic spine loss, deficits in contextual fear memory, as well as abnormal behaviors including hyperactivity and increased anxiety."

Measures the spine loss and its behavioural consequences after TBC1D24 knockdown.

Aberrant Cortical Circuit Formation

The combined migration, maturation, and axon-specification defects yield a neocortex whose circuitry never assembled correctly. This is the substrate on which the presynaptic release defect acts, and it accounts for the developmental impairment being present from the outset rather than being purely a consequence of seizures.

Cerebral cortex UBERON:0000956

Downstream

Neuronal Hyperexcitability and Hypersynchrony

Global developmental delay

Developmental regression

Hypotonia Hypotonia is the commonest neurologic sign in this gene, but no source traces it to a specific step, so the intermediates are not named.

Decelerating head growth Postnatal brain growth failure follows the developmental lesion, though the relative contribution of ongoing seizures is not established.

Extrapyramidal signs No source traces the movement findings to a specific step in this chain, so the intermediates are not named.

Show evidence (1 reference)

PMID:23526554 SUPPORT In Vitro

"Mutations severely impaired TBC1D24 expression and function, which is critical for maturation of neuronal circuits."

States that the DEE16-causing variants impair a function required for neuronal circuit maturation.

Neuronal Hyperexcitability and Hypersynchrony

Excitation and inhibition are pushed out of balance by the combination of a malformed cortical network and unstable presynaptic release, producing hypersynchronous discharges. In DEE16 these discharges characteristically fail to stay put: they migrate from one cortical region to another, giving the prolonged unilateral clonic activity that wanders between arm, leg, and face, and the ictal pattern of epilepsy of infancy with migrating focal seizures.

modulation of chemical synaptic transmission GO:0050804 ⚠ ABNORMAL

Cerebral cortex UBERON:0000956

Animal models

Tbc1d24 S324Tfs*3 knock-in mouse Mouse recapitulates Homozygotes show abrupt-onset spontaneous seizures recapitulating human EIEE, from the human-equivalent allele.

Tbc1d24 F251L knock-in mouse Mouse recapitulates

Downstream

Migrating focal seizures

Focal clonic seizures

Myoclonic seizures

Epilepsia partialis continua

Infantile spasms

Febrile seizures

Super-refractory status epilepticus

Multifocal epileptiform EEG abnormality

Drug-resistant epilepsy Antiseizure drugs act on the network, not on the trafficking lesion that keeps regenerating the hyperexcitable state, which is why the seizures in this entity are refractory rather than merely severe.

Death in childhood

Show evidence (1 reference)

PMID:20727515 SUPPORT INDIRECT Human Clinical

"unveiled the involvement of ARF6-dependent molecular pathway in brain hyperexcitability and seizures"

Connects the TBC1D24-ARF6 axis to brain hyperexcitability, the state this node describes. Indirect on two counts: it is an author conclusion resting on linkage genetics plus neurite assays rather than a measurement of human cortical excitability, and the family studied had the mild, drug-responsive phenotype rather than DEE16.

Progressive Cerebral and Cerebellar Atrophy

Cerebral or cerebellar atrophy, delayed myelination, and in some patients hippocampal sclerosis develop over time. Whether this reflects the underlying neurodevelopmental lesion, cumulative seizure-related injury, loss of TLDc-dependent oxidative stress resistance, or all three is unresolved; the imaging findings did not correlate with phenotype or prognosis in the largest cohort.

Brain UBERON:0000955

Downstream

Cerebral atrophy

Cerebellar atrophy

Ataxia Cerebellar involvement is the obvious substrate for the ataxia, but no cited source reports the two in the same patients, so the link is not claimed as direct.

Delayed myelination

Show evidence (2 references)

PMID:27281533 SUPPORT Human Clinical

"Neuroimaging revealed cerebral or cerebellar atrophy in 16 patients. Five patients had delayed myelination; 3 others had hippocampal sclerosis."

Documents the atrophy, myelination delay, and hippocampal sclerosis this node describes, in the 48-patient TBC1D24 cohort.

PMID:27281533 NO_EVIDENCE Human Clinical

"There was no specific association among neuroimaging findings, phenotypic features, or prognosis."

Records that the cohort found no imaging-phenotype correlation, so these findings are not used here to grade severity.

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Pathograph

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Phenotypes

21

Ear 1

Sensorineural hearing impairment HP:0000407

The 3/48 count covers only patients without DOORS syndrome, so it is neither a DEE16 frequency nor a whole-cohort one. No `frequency:` is recorded.

Show evidence (1 reference)

PMID:27281533 SUPPORT Human Clinical

"Three patients without DOORS (17a, 17b, 18) had bilateral sensorineural hearing loss or deafness."

Documents sensorineural hearing loss in TBC1D24 patients outside the DOORS phenotype.

Eye 1

Visual impairment HP:0000505

The only count available is from the pooled 48-patient TBC1D24 series, so it is a spectrum figure and not a DEE16 frequency. No `frequency:` is recorded for that reason, following the same rule this entry applies to the neuroimaging phenotypes.

Show evidence (1 reference)

PMID:27281533 SUPPORT Human Clinical

"Thirteen patients (27%), including 6 patients with DOORS, had signs of visual impairment."

Quantifies visual impairment at 13/48 across the TBC1D24 cohort.

Musculoskeletal 1

Hypotonia HP:0001252

No `frequency:` recorded. The cited cohort calls hypotonia "the most frequent neurologic sign" but gives no count for it, and counts the signs it ranks below (ataxia 7/48, extrapyramidal 8/48) low enough that "most frequent" is compatible with OCCASIONAL. A ranking is not a frequency.

Show evidence (2 references)

PMID:27281533 SUPPORT Human Clinical

"The most frequent neurologic sign was muscle hypotonia."

Identifies hypotonia as the commonest neurologic sign in the 48-patient cohort.

PMID:27502353 SUPPORT Human Clinical

"TBC1D24-related epilepsy can manifest with hypotonia, developmental delays, and a variety of focal-onset seizures"

Independent confirmation of hypotonia in the TBC1D24 epilepsy phenotype.

Nervous System 16

Migrating focal seizures FREQUENT HP:0032786

Show evidence (3 references)

PMID:35350397 SUPPORT Other

"The most commonly reported type of seizures is migrating focal ones (17/30), followed by migrating clonic ones (9/30), myoclonic ones (9/30), generalized tonic-clonic ones (4/30), epileptic spasm (4/30), tonic ones (3/30), and apnea attacks (1/30)"

In a 30-patient TBC1D24-DEE compilation, restricted to the DEE phenotype rather than the whole spectrum, migrating focal seizures are the commonest type at 17/30, supporting FREQUENT.

PMID:25719194 SUPPORT Human Clinical

"developmental and epileptic encephalopathy (DEE), including epilepsy of infancy with migrating focal seizures (EIMFS)"

GeneReviews places EIMFS within the DEE phenotype of the TBC1D24 spectrum.

PMID:23526554 SUPPORT Human Clinical

"Here, we describe a familial form of MMPSI due to mutation in TBC1D24, revealing a devastating epileptic phenotype associated with TBC1D24 dysfunction."

The index report establishing the migrating-seizure phenotype as TBC1D24-caused.

Focal clonic seizures HP:0002266

Show evidence (1 reference)

PMID:27502353 SUPPORT Human Clinical

"All patients had seizure semiologies consisting of prolonged, unilateral, focal clonic activity of the arm, leg or face, in addition to generalized clonic or myoclonic seizures."

Describes the focal clonic semiology in all four patients of the TBC1D24 drug-resistant epilepsy series.

Myoclonic seizures FREQUENT HP:0032794

Show evidence (2 references)

PMID:35350397 SUPPORT Other

"The most commonly reported type of seizures is migrating focal ones (17/30), followed by migrating clonic ones (9/30), myoclonic ones (9/30), generalized tonic-clonic ones (4/30), epileptic spasm (4/30), tonic ones (3/30), and apnea attacks (1/30)"

In the DEE-restricted 30-patient compilation myoclonic seizures are 9/30, which is what sets FREQUENT here. The pan-spectrum figure below is higher because that cohort includes the myoclonic-epilepsy phenotypes at the mild end of the gene.

PMID:27281533 SUPPORT Human Clinical

"Myoclonic or clonic seizures were the most frequent seizure types (29/48, 60%), often unresponsive to medication."

The pan-TBC1D24 figure, recorded for contrast. It describes the whole spectrum, not DEE16, and should not be read as a DEE16 frequency.

Epilepsia partialis continua HP:0012847

Show evidence (1 reference)

PMID:27502353 SUPPORT Human Clinical

"Ictal EEG characteristics included epilepsia partialis continua, epilepsy of infancy with migrating focal seizures, and other focal seizures with indiscrete interictal-ictal transitions."

Lists epilepsia partialis continua among the ictal EEG patterns in the TBC1D24 series.

Super-refractory status epilepticus HP:0032868

Show evidence (2 references)

PMID:27502353 SUPPORT Human Clinical

"Two seemingly unrelated Navajo patients with identical variations experienced super-refractory status epilepticus at 9 months of age, with one achieving resolution with ketogenic diet therapy."

Documents super-refractory status epilepticus in TBC1D24-related epilepsy, including its response to ketogenic diet in one patient.

PMID:27281533 SUPPORT Human Clinical

"Thirty-eight (79%) individuals had had status epilepticus, either convulsive or nonconvulsive, or prolonged seizures (>5 minutes). In 19 patients, seizures or status episodes were precipitated by fever or infections."

Quantifies status epilepticus across the cohort and identifies fever and infection as precipitants.

Infantile spasms HP:0012469

Show evidence (1 reference)

PMID:27281533 SUPPORT Human Clinical

"Seizure types included infantile spasms and febrile convulsive, myoclonic, clonic, tonic, absence, tonic-clonic with or without apparent focal onset, and focal seizures with retained or impaired awareness."

Lists infantile spasms among the seizure types observed in the TBC1D24 cohort.

Febrile seizures Febrile seizure (within the age range of 3 months to 6 years) HP:0002373

Show evidence (2 references)

PMID:27281533 SUPPORT Human Clinical

"In 19 patients, seizures or status episodes were precipitated by fever or infections."

Quantifies fever and infection as seizure precipitants in 19 of the 48 patients.

PMID:27281533 SUPPORT Human Clinical

"In some patients, they were triggered by fatigue, drowsiness, intense and persistent stimulation (acoustic stimuli or variations in light intensity), repetitive movements, feeding, febrile episodes, constipation, or delayed medication."

Enumerates the broader set of activity- and state-dependent triggers described in this phenotype.

Drug-resistant epilepsy VERY_FREQUENT Seizure HP:0001250

Show evidence (3 references)

PMID:27281533 SUPPORT Human Clinical

"At least one such mutation occurred in 17 patients. Of these, 15 had drug-resistant epilepsy and 8 of them died by the age of 7 years."

In the loss-of-function subgroup that corresponds to DEE16, 15 of 17 patients had drug-resistant epilepsy, supporting VERY_FREQUENT.

PMID:27502353 SUPPORT Human Clinical

"We report four patients with novel variants of TBC1D24 demonstrating drug-resistant focal epilepsy, developmental delays, and head growth deceleration."

Independent series reporting drug-resistant focal epilepsy in TBC1D24-related disease.

PMID:35350397 SUPPORT Other

"All patients developed a drug-resistant epileptic encephalopathy"

In the DEE-restricted 30-patient compilation drug resistance is universal, which is the strongest basis for VERY_FREQUENT here.

Multifocal epileptiform EEG abnormality Multifocal epileptiform discharges HP:0010841

Show evidence (1 reference)

PMID:27281533 SUPPORT Human Clinical

"Various features, including slow background activity and multifocal paroxysmal abnormalities, were described in 35 patients."

Documents multifocal paroxysmal EEG abnormalities in 35 of the 48 patients.

Global developmental delay VERY_FREQUENT HP:0001263

Show evidence (2 references)

PMID:27281533 SUPPORT Human Clinical

"Thirty-nine individuals had intellectual disability or developmental delay, from mild to profound."

39 of 48 patients had intellectual disability or developmental delay, supporting VERY_FREQUENT.

PMID:27502353 SUPPORT Human Clinical

"Our series suggests that TBC1D24-related epilepsy can manifest with hypotonia, developmental delays, and a variety of focal-onset seizures prone to electroclinical dissociation."

Independent series reporting developmental delay with the focal-onset seizure phenotype.

Developmental regression HP:0002376

Regression is named in the MONDO definition of MONDO:0014133 ("delayed or regression of psychomotor development") and is documented in an individual patient, but no cohort quantifies it, so no `frequency:` is recorded. The DEE-restricted series reports developmental delay or intellectual disability in all 30 patients without separating regression from delay.

Show evidence (1 reference)

PMID:27502353 SUPPORT Human Clinical

"At 8 months, she experienced motor and lan- guage regression."

A TBC1D24 patient losing acquired motor and language skills, which is the claim this phenotype makes.

Cerebral atrophy HP:0002059

Show evidence (1 reference)

PMID:27281533 SUPPORT Human Clinical

"Neuroimaging revealed cerebral or cerebellar atrophy in 16 patients."

Documents cerebral atrophy on neuroimaging in the TBC1D24 cohort.

Cerebellar atrophy HP:0001272

Show evidence (1 reference)

PMID:27281533 SUPPORT Human Clinical

"Eleven patients had cerebellar abnormalities: signal hyperintensity, especially in T2-weighted images (11, 14, 19, 25), atrophy (4, 5c, 5d, 7c, 10, 11, 13, 19), or mild vermian hypoplasia (29)."

Enumerates the cerebellar abnormalities including atrophy in the cohort.

Delayed myelination HP:0012448

Show evidence (1 reference)

PMID:27281533 SUPPORT Human Clinical

"Five patients had delayed myelination; 3 others had hippocampal sclerosis."

Documents delayed myelination on neuroimaging in the TBC1D24 cohort.

Ataxia HP:0001251

The only count available is from the pooled 48-patient TBC1D24 series, so it is a spectrum figure and not a DEE16 frequency. No `frequency:` is recorded for that reason, following the same rule this entry applies to the neuroimaging phenotypes.

Show evidence (1 reference)

PMID:27281533 SUPPORT Human Clinical

"The most frequent neurologic sign was muscle hypotonia. Seven patients had ataxia. Eight patients had extrapyramidal signs (table e-3)."

Quantifies ataxia at 7/48 across the TBC1D24 cohort.

Extrapyramidal signs Abnormality of extrapyramidal motor function HP:0002071

The only count available is from the pooled 48-patient TBC1D24 series, so it is a spectrum figure and not a DEE16 frequency. No `frequency:` is recorded for that reason, following the same rule this entry applies to the neuroimaging phenotypes.

Show evidence (1 reference)

PMID:27281533 SUPPORT Human Clinical

"The most frequent neurologic sign was muscle hypotonia. Seven patients had ataxia. Eight patients had extrapyramidal signs (table e-3)."

Quantifies extrapyramidal signs at 8/48 across the TBC1D24 cohort.

Other 2

Decelerating head growth

Left unbound deliberately. HP:0000253 "Progressive microcephaly" was the obvious binding and is wrong: PMID:27502353 describes each patient as normocephalic (for example "She was normocephalic (OFC: 43.0 cm; 20%) with decelerating head growth"), and no cited source reports microcephaly in TBC1D24 disease at all. HPO's nearest alternatives, HP:0004485 "Cessation of head growth" and HP:0040195 "Decreased head circumference", both assert more than the source does for a normocephalic child on a falling centile. No term beats a wrong one; an HPO new-term request is the right route.

Show evidence (1 reference)

PMID:27502353 SUPPORT Human Clinical

"We report four patients with novel variants of TBC1D24 demonstrating drug-resistant focal epilepsy, developmental delays, and head growth deceleration."

Reports head growth deceleration, the postnatal pattern this phenotype term captures.

Death in childhood FREQUENT

Left unbound deliberately. HP:0003819 "Death in childhood" sits under HP:0012823 Clinical modifier rather than HP:0000118 Phenotypic abnormality, so it is outside the PhenotypeTerm dynamic enum; the same applies to HP:0001522. No phenotypic-abnormality term names early mortality, and binding a substitute would misstate the claim.

Show evidence (3 references)

PMID:27281533 SUPPORT Human Clinical

"Nine individuals (19%) were deceased (average age at death 37 months, range 6-96 months)."

Quantifies mortality across the pan-TBC1D24 cohort. This 19% is the spectrum figure and understates DEE16, where the DEE-restricted series below reports 13/30.

PMID:35350397 SUPPORT Other

"Overall, 13 patients (13/30) died at a very young age (ranging from 3 months to 9"

In the DEE-restricted 30-patient compilation 13/30 died in early childhood, which is the figure this entry uses for DEE16 and the basis for FREQUENT.

PMID:27281533 SUPPORT Human Clinical

"The other reported causes of death were infectious episode (7a, 7c, 17a, 17b), respiratory failure (6a), status epilepticus associated with a pulmonary infection (7b), and unknown (26, 28)."

Enumerates the causes of death described in this phenotype.

🧬

Genetic Associations

1

TBC1D24

Gene: TBC1D24 hgnc:29203 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:23526554 SUPPORT Human Clinical

"We identified two inherited novel mutations in TBC1D24 in two affected siblings."

Establishes biallelic TBC1D24 variants as the cause of the severe early-onset epileptic encephalopathy phenotype that defines DEE16. The functional-assay half of this paper is cited separately, on the cortical-circuit node, so each item carries a single evidence_source.

PMID:20727515 SUPPORT Model Organism

"In situ hybridization analysis revealed that Tbc1d24 is mainly expressed at the level of the cerebral cortex and the hippocampus."

Localizes TBC1D24 expression to the cortical and hippocampal regions from which the seizures of DEE16 arise.

Variants (1)

Truncating (frameshift, nonsense, splice-site) TBC1D24 variants

Gene: TBC1D24 hgnc:29203

Predicted loss-of-function alleles concentrate at the severe end of the TBC1D24 spectrum, where DEE16 lies. The correlation is a trend rather than a rule: variant position and in-vitro severity do not cleanly predict the clinical phenotype, and the cohort records one positional exception, truncating variants falling in the last exon, where escape from nonsense-mediated decay leaves a milder course.

Show evidence (2 references)

PMID:27281533 SUPPORT Human Clinical

"We noted an unfavorable outcome associated with frameshift, nonsense, or splice-site mutations, indicating that loss of function produces more severe disease. At least one such mutation occurred in 17 patients. Of these, 15 had drug-resistant epilepsy and 8 of them died by the age of 7 years."

Directly links loss-of-function alleles to drug resistance and early death, the outcome profile of DEE16.

PMID:27281533 REFUTE In Vitro

"Neuronal outgrowth assays showed that some TBC1D24 mutations, associated with the most severe TBC1D24-associated disorders, are not necessarily the most disruptive to this gene function."

Contradicts a simple dose-of-residual-function model: the variants causing the most severe clinical disease are not the ones that most disrupt neurite outgrowth in vitro.

💊

Medical Actions

5

Antiseizure pharmacotherapy

Action: anticonvulsant agent therapy Ontology label: Anticonvulsant Therapy NCIT:C64172

Agent: zonisamide CHEBI:10127 topiramate CHEBI:63631 valproate CHEBI:39867 phenobarbital CHEBI:8069

Platform: Small molecule

Symptomatic pharmacologic management of seizures. No regimen is established for DEE16 and seizures are usually drug-resistant; across the wider TBC1D24 spectrum individual patients have responded to zonisamide, topiramate, valproate, or phenobarbital, but those responders sit at the milder end.

Mechanism Target:

Neuronal Hyperexcitability and Hypersynchrony — Antiseizure medications act on the hyperexcitable network rather than on the TBC1D24 trafficking lesion upstream of it, which is one reason control is so often incomplete.

Show evidence (2 references)

PMID:25719194 SUPPORT Human Clinical

"symptomatic pharmacologic management for seizures"

GeneReviews recommends symptomatic pharmacologic seizure management for TBC1D24-related disorders.

PMID:27281533 REFUTE Human Clinical

"In 30 patients, epilepsy was drug-resistant24; 18 patients responded well to treatment."

Refutes any claim of reliable pharmacologic control: the majority of the cohort was drug-resistant, and the responders were concentrated at the mild end of the spectrum rather than in DEE16.

Ketogenic diet therapy

Action: ketogenic diet therapy Ontology label: Dietary Intervention NCIT:C15447

Platform: Behavioral / lifestyle

Two reported responses, both single cases. In one patient with TBC1D24-related drug-resistant epilepsy it resolved super-refractory status epilepticus; in another it produced a long seizure-free period that did not hold, with epilepsy recurring later. That second case is the useful one to know, because it sets the expectation: this is a lead worth trying in refractory status, not established or durable therapy.

Mechanism Target:

Super-refractory status epilepticus — Applied to break refractory status rather than to correct the underlying trafficking lesion.

Show evidence (2 references)

PMID:27502353 SUPPORT INDIRECT Human Clinical

"Two seemingly unrelated Navajo patients with identical variations experienced super-refractory status epilepticus at 9 months of age, with one achieving resolution with ketogenic diet therapy."

A single patient's response supports the diet as a candidate for refractory status; one of two patients with the same variant responded, so the inference to general efficacy is indirect.

PMID:35350397 SUPPORT INDIRECT Other

"In addition, another one obtained the absence of epileptic episodes for a long time following a ketogenic diet, although epilepsy recurred later"

A second reported response in the DEE-restricted series, and the reason this entry does not present the diet as durable: the benefit was lost.

Early intervention therapies

Action: physical, occupational and speech therapy Ontology label: Rehabilitation NCIT:C15315

Platform: Behavioral / lifestyle

Early educational intervention with physical, occupational, and speech therapy for the developmental delay, which is present from the outset rather than only after seizures begin.

Mechanism Target:

Global developmental delay — Supportive rather than disease-modifying; it addresses function, not the cortical circuit lesion.

Show evidence (1 reference)

PMID:25719194 SUPPORT Human Clinical

"early educational intervention and physical, occupational, and speech therapy for developmental delay"

GeneReviews recommends this bundle of early interventions for developmental delay in TBC1D24-related disorders.

Genetic counseling

Action: Genetic Counseling NCIT:C15240

Counseling for the 25% autosomal recessive recurrence risk. Once both familial variants are identified, prenatal and preimplantation genetic testing are available, and testing at-risk sibs allows seizures to be treated as early as possible.

Show evidence (2 references)

PMID:25719194 SUPPORT Human Clinical

"Once the TBC1D24 pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible."

GeneReviews describes the reproductive testing options that follow genetic counseling.

PMID:25719194 SUPPORT Human Clinical

"Molecular genetic testing for the familial TBC1D24 pathogenic variant(s) in older and younger sibs of a proband is appropriate in order to identify as early as possible those who would benefit from early treatment of seizures and/or hearing loss."

GeneReviews recommends testing at-risk sibs to enable early treatment.

Neurologic surveillance with EEG

Action: neurologic surveillance Ontology label: Supportive Care NCIT:C15747

Serial neurologic evaluation with EEG, at a frequency set by seizure burden and progression.

Show evidence (1 reference)

PMID:25719194 SUPPORT Human Clinical

"Neurologic evaluations with EEGs depending on seizure frequency and/or progression"

GeneReviews surveillance recommendation for TBC1D24-related disorders.

🔬

Diagnosis

4

Molecular confirmation of biallelic TBC1D24 variants

The diagnosis rests on finding two pathogenic TBC1D24 variants in trans. Phase matters and is the step most often skipped: two variants reported on one report do not establish a recessive diagnosis until parental segregation shows they are on opposite alleles.

Because TBC1D24 causes a continuum, the molecular result does not by itself assign which phenotype a patient has. DEE16 is a clinical call made on onset, seizure pattern, drug resistance, and developmental course.

Show evidence (1 reference)

PMID:25719194 SUPPORT Human Clinical

"The diagnosis of a TBC1D24-related disorder is established in an individual with suggestive findings biallelic TBC1D24 pathogenic variants when the mode of inheritance is autosomal recessive"

States the molecular criterion for a recessive TBC1D24 diagnosis.

Video EEG

Ictal recording is what distinguishes DEE16 from other early-infantile epilepsies, since the migrating focal pattern and epilepsia partialis continua are electroclinical diagnoses. Seizures in this gene are also prone to electroclinical dissociation, so semiology alone under-reads the burden.

Show evidence (2 references)

PMID:27502353 SUPPORT Human Clinical

"Ictal EEG characteristics included epilepsia partialis continua, epilepsy of infancy with migrating focal seizures, and other focal seizures with indiscrete interictal-ictal transitions."

Establishes what ictal EEG contributes to the diagnosis in this gene.

PMID:27502353 SUPPORT Human Clinical

"a variety of focal-onset seizures prone to electroclinical dissociation"

The reason EEG rather than observation is needed to count seizures here.

Brain MRI

Imaging supports the diagnosis by exclusion more than by a positive sign. It may be normal early; later it may show cerebral or cerebellar atrophy, delayed myelination, or hippocampal sclerosis. None of these predicts phenotype or prognosis, so MRI should not be used to grade severity.

Show evidence (2 references)

PMID:27281533 SUPPORT Human Clinical

"Neuroimaging revealed cerebral or cerebellar atrophy in 16 patients. Five patients had delayed myelination; 3 others had hippocampal sclerosis."

Lists the imaging findings this diagnostic step looks for.

PMID:27281533 NO_EVIDENCE Human Clinical

"There was no specific association among neuroimaging findings, phenotypic features, or prognosis."

Records that imaging carries no prognostic information here, which is the caveat on this diagnostic step.

Audiologic assessment

Hearing loss runs through the whole TBC1D24 spectrum and can be progressive, so audiology belongs in the diagnostic workup and in follow-up rather than only when hearing loss is suspected.

Show evidence (1 reference)

PMID:25719194 SUPPORT Human Clinical

"annual audiologic evaluations to assess for possible progression of hearing loss"

GeneReviews surveillance recommendation for TBC1D24-related disorders.

📈

Progression

3

Early-infantile seizure onset

Seizures begin in the first weeks to months of life. Across the whole TBC1D24 spectrum mean onset is 7 months with a wide range; the DEE16 end sits at the early extreme of that distribution, within weeks of birth.

Show evidence (2 references)

PMID:27281533 SUPPORT Human Clinical

"The average age at seizure onset was 7 months (range from within 1 hour after birth to 8 years; SD 15 months)."

The pan-TBC1D24 age-at-onset distribution, recorded for contrast. The DEE-restricted figure below is the one that describes DEE16.

PMID:35350397 SUPPORT Other

"All patients presented a history of early onset of seizures, ranging from 20 minutes after birth to 8 months of life: in the majority of the patients (28/30), the onset was within 3 months of life, and, among them, 6/30 individuals developed seizures within the first week"

Measures onset in the DEE subset rather than inferring it from the spectrum: 28/30 within three months, 6/30 in the first week.

Drug-resistant course with recurrent status epilepticus

Seizures fail to respond to sequential antiseizure medications; prolonged seizures and status epilepticus recur, frequently triggered by fever or intercurrent infection.

Show evidence (1 reference)

PMID:27281533 SUPPORT Human Clinical

"In 30 patients, epilepsy was drug-resistant24; 18 patients responded well to treatment."

Records drug resistance in the majority of the TBC1D24 cohort.

Early death or profound disability

Children either die in early childhood, most within the first seven years, or survive with profound developmental impairment.

Show evidence (1 reference)

PMID:27281533 SUPPORT Human Clinical

"TBC1D24-related epilepsy syndromes show marked phenotypic pleiotropy, with multisystem involvement and severity spectrum ranging from isolated deafness (not studied here), benign myoclonic epilepsy restricted to childhood with complete seizure control and normal intellect, to early-onset..."

Places the early-onset epileptic encephalopathy phenotype, DEE16, at the severe-developmental-delay-and-early-death end of the spectrum.

🧫

Experimental Models

1

Patient-derived iPSC cortical neurons (severe vs mild TBC1D24 phenotype) IPSC_DERIVED_MODEL

Reprogrammed neurons from a patient with severe developmental encephalopathy compared against neurons from a patient with mild early-onset epilepsy. The comparison is the point: the axon-formation defect is present only in the severe line, so it is a candidate cellular correlate of what separates DEE16 from the mild end of the same gene's spectrum.

Pathograph links

Axonal Specification Failure recapitulates fidelity: moderate observes: cellular Human neurons carrying patient TBC1D24 variants reproduce the axon formation defect, and do so in a severity-dependent way.

Limitations: Two patient lines with no isogenic control, so the difference between them cannot be attributed to the variants alone. iPSC-derived neurons are developmentally immature and lack the cortical circuit context in which the human phenotype arises.

Readouts

Axon formation in patient-derived neurons

Direction: DECREASED

Interpretation: Axon formation is impaired in the severe-phenotype line and unaffected in the mild-phenotype line.

Show evidence (1 reference)

PMID:30858606 SUPPORT In Vitro

"Reprogrammed neurons from a patient with severe developmental encephalopathy show significant axon formation defect that were absent from reprogrammed neurons of a patient with mild early onset epilepsy."

Reports the axon-formation measurement and its direction in each line.

Show evidence (1 reference)

PMID:30858606 SUPPORT In Vitro

"Our data reveal that alterations of membrane trafficking at the growth cone induced by TBC1D24 loss of function cause axonal and excitability defects."

Supports treating these human neurons as informative for the axonal node.

🐁

Animal Models

4

Tbc1d24 S324Tfs*3 knock-in mouse

A CRISPR-engineered mouse carrying the exact equivalent of a human truncating TBC1D24 variant associated with early infantile epileptic encephalopathy. Hearing and vestibular function are normal, so the model isolates the epilepsy phenotype from the deafness phenotypes of the same gene.

Species

Mouse

Genotype

Tbc1d24 S324Tfs*3 homozygous (CRISPR-Cas9 knock-in)

Publication

PMID:30602030

Pathograph links

Neuronal Hyperexcitability and Hypersynchrony recapitulates fidelity: moderate observes: organism Homozygotes show abrupt-onset spontaneous seizures recapitulating human EIEE, from the human-equivalent allele.

Limitations: The onset timing depends on a micro-exon splicing switch specific to this allele's position, so the model's developmental course may not generalize to DEE16 variants elsewhere in the gene. Seizure semiology in the mouse is convulsive rather than the migrating focal pattern that characterizes human DEE16.

Readouts

Spontaneous seizure onset at postnatal day 15

Direction: INCREASED

Interpretation: Abrupt appearance of spontaneous seizures in homozygotes, absent before P15.

Show evidence (1 reference)

PMID:30602030 SUPPORT Model Organism

"Homozygous S324Tfs*3 mice have normal auditory and vestibular functions but show an abrupt onset of spontaneous seizures at postnatal day 15 recapitulating human EIEE."

Reports the seizure measurement and its direction in the model.

Show evidence (1 reference)

PMID:30602030 SUPPORT Model Organism

"Using CRISPR-Cas9 genome editing, we engineered a mouse with a premature translation stop codon equivalent to human S324Tfs*3, a recessive mutation of TBC1D24 associated with early infantile epileptic encephalopathy (EIEE)."

Establishes that the model carries the human EIEE-associated allele, which is what makes it informative for this node.

Postnatal Micro-Exon Isoform Switch recapitulates fidelity: high observes: molecular The model is the sole source of evidence for the micro-exon switch mechanism; the node exists because of it.

Limitations: The switch has not been demonstrated in human neurons, and it can only apply to human variants that fall within the same micro-exon.

Show evidence (1 reference)

PMID:30602030 SUPPORT Model Organism

"The S324Tfs*3 variant is located in an alternatively spliced micro-exon encoding six perfectly conserved amino acids incorporated postnatally into TBC1D24 protein due to a micro-exon utilization switch."

Describes the micro-exon mechanism the model demonstrates.

Drosophila skywalker phosphoinositide-pocket mutants

Flies carrying the fly orthologue's equivalent of the most prevalent human TBC1D24 pocket variants. The value of the model is the rescue arm: the defects are reversed by genetically raising synaptic PI(4,5)P2, which establishes the lipid interaction as the causal node rather than a correlate.

Species

Fruit fly

Genotype

skywalker (sky) alleles carrying human-equivalent TBC1D24 pocket mutations

Publication

PMID:27669036

Pathograph links

Loss of Phosphoinositide-Dependent Presynaptic Membrane Anchoring recapitulates fidelity: moderate observes: molecular Pathogenic pocket mutations abolish lipid binding and release the protein's membrane anchoring in presynaptic terminals.

Limitations: Drosophila Skywalker is an orthologue, not the human protein, and the fly has no TLDc-domain-dependent phenotype to compare. The seizure phenotype in flies is not the migrating focal seizure of human DEE16.

Readouts

Synaptic-vesicle trafficking and seizure defects, PI(4,5)P2 rescue

Direction: RESTORED

Interpretation: Defects caused by pocket mutations are reversed when synaptic PI(4,5)P2 is raised, establishing the lipid interaction as causal.

Show evidence (1 reference)

PMID:27669036 SUPPORT Model Organism

"these defects are reversed by genetically increasing synaptic PI(4,5)P2 concentrations through synaptojanin mutations"

Reports the rescue measurement behind this readout.

Show evidence (1 reference)

PMID:27669036 SUPPORT Model Organism

"the pathogenic mutations cause severe neurological defects in flies, including impaired synaptic-vesicle trafficking and seizures"

Supports treating the fly pocket mutants as informative for the human membrane-anchoring lesion.

Tbc1d24 F251L knock-in mouse

A knock-in of a disease-associated missense substitution that destabilizes the protein. Homozygotes seize spontaneously and die prematurely; heterozygotes survive to adulthood but have dendritic spine defects and impaired memory, which is the cleanest available separation of the cognitive phenotype from the seizure phenotype in this gene.

Species

Mouse

Genotype

Tbc1d24 F251L knock-in (homozygous and heterozygous)

Publication

PMID:32004315

Pathograph links

Postsynaptic Dendritic Spine Loss recapitulates fidelity: moderate observes: cellular The heterozygous arm isolates spine loss and memory impairment without the confound of ongoing seizures.

Limitations: F251L is a missense allele in the TBC domain; DEE16 is enriched for truncating alleles, so the model tests a protein-destabilization mechanism rather than complete loss. Heterozygous mice model a carrier state, not the biallelic human genotype.

Readouts

Dendritic spine density and contextual fear memory

Direction: DECREASED

Interpretation: Spine defects and impaired memory in heterozygotes surviving to adulthood.

Show evidence (1 reference)

PMID:32004315 SUPPORT Model Organism

"the heterozygous F251L knock-in mice survive into adulthood but display dendritic spine defects and impaired memory"

Reports the spine and memory measurements behind this readout.

Show evidence (1 reference)

PMID:32004315 SUPPORT Model Organism

"we show that the protein stability of TBC1D24 is diminished by the disease-associated missense mutation that leads to F251L amino acid substitution"

Establishes that the modelled allele acts by destabilizing the protein, which is what makes it informative for a loss-of-function node.

Neuronal Hyperexcitability and Hypersynchrony recapitulates fidelity: moderate observes: organism

Limitations: Spontaneous seizures in the homozygote are not shown to be the migrating focal seizures that characterize human DEE16, and the allele is missense rather than truncating.

Show evidence (1 reference)

PMID:32004315 SUPPORT Model Organism

"the homozygous mutants show increased neuronal excitability, spontaneous seizure and pre-mature death"

Supports treating the homozygous knock-in as informative for the hyperexcitability node.

Humanized TBC1D24 G501R Drosophila (TLDc allele)

A fly expressing the human protein carrying a TLDc-domain variant. The informative arm is pharmacological: the activity-induced trafficking and locomotor defects are reversed by N-acetylcysteine amide or alpha-tocopherol, which is the only antioxidant-rescue result in this gene and the strongest argument that the TLDc domain acts as a redox sensor.

Species

Fruit fly

Genotype

Drosophila neuronally expressing human TBC1D24 p.Gly501Arg

Publication

PMID:31257402

Pathograph links

TLDc Domain Dysfunction partially recapitulates fidelity: low observes: molecular Models the consequence of a TLDc missense variant, with an antioxidant rescue that identifies the pathway.

Limitations: G501R causes Rolandic epilepsy with exercise-induced dystonia in humans, a self-limiting phenotype at the opposite end of the spectrum from DEE16. The fly is a heterologous expression system, and the antioxidant rescue has not been tested against a DEE16 allele or in any human system. The result is a therapeutic lead for the gene, not evidence about DEE16 treatment.

Readouts

Synaptic vesicle trafficking and sustained activity under antioxidant treatment

Direction: RESTORED

Interpretation: Antioxidant treatment restores trafficking and behavioural activity in the mutant, implicating oxidative stress as the mediating step.

Show evidence (1 reference)

PMID:31257402 SUPPORT Model Organism

"which is rescued by treating TBC1D24G501R mutant animals with antioxidants N-acetylcysteine amide or alpha-tocopherol as indicated by restored synaptic vesicle trafficking levels and sustained behavioural activity"

Reports the rescue measurement and its direction.

Show evidence (1 reference)

PMID:31257402 SUPPORT INDIRECT Model Organism

"The neuronal phenotypes of the TBC1D24G501R mutation are consistent with exacerbated oxidative stress sensitivity"

Supports treating this fly as informative for TLDc-domain dysfunction. Indirect for DEE16 because the modelled allele causes a mild human phenotype.

{ }

Source YAML

click to show

name: Developmental And Epileptic Encephalopathy 16
creation_date: "2026-09-07T00:00:00Z"
category: Mendelian
description: >-
  The severe end of the TBC1D24 spectrum. A baby with biallelic loss-of-function
  variants in TBC1D24 begins seizing in the first weeks or months of life, often
  with prolonged unilateral clonic activity that wanders from one body part to
  another as the discharge migrates across the cortex, the picture that used to be
  called malignant migrating partial seizures of infancy and is now epilepsy of
  infancy with migrating focal seizures. The seizures do not respond to drugs,
  status epilepticus is the rule rather than the exception, development stalls or
  regresses, and a substantial minority of children die in early childhood.

  What makes the entry interesting is that the same gene also causes a
  self-limiting infantile myoclonic epilepsy in people with normal intelligence,
  and non-syndromic deafness with no epilepsy at all. TBC1D24 is a presynaptic
  protein with two functional halves: a TBC domain whose phosphoinositide-binding
  pocket anchors it to the presynaptic membrane and regulates ARF6-dependent
  vesicle traffic, and a TLDc domain that confers resistance to oxidative
  stress. Truncating variants, which abolish both, sit at the severe end
  where DEE16 lives; the correlation is real but loose, and neurite-outgrowth
  assays show the variants causing the worst disease are not always the ones that
  disrupt the protein most in a dish. The disorder is therefore both a
  synaptopathy and a neurodevelopmental one: the same trafficking lesion that
  destabilizes mature neurotransmission also derails radial migration and axon
  specification before birth.
parents:
  - Genetic Developmental and Epileptic Encephalopathy
  - Epilepsy
  - Neurodevelopmental Disorder
  - Neurological Disease
  - Genetic Disease
synonyms:
  - DEE16
  - EIEE16
  - epileptic encephalopathy, early infantile, 16
  - epileptic encephalopathy, early infantile, type 16
  - developmental and epileptic encephalopathy 16
  - TBC1D24-related developmental and epileptic encephalopathy
classifications:
  harrisons_chapter:
    - classification_value: NEUROLOGIC
      notes: >-
        A monogenic early-infantile epilepsy syndrome, diagnosed and managed
        neurologically.
disease_term:
  preferred_term: developmental and epileptic encephalopathy, 16
  term:
    id: MONDO:0014133
    label: developmental and epileptic encephalopathy, 16
mappings:
  mondo_mappings:
    - term:
        id: MONDO:0014133
        label: developmental and epileptic encephalopathy, 16
      mapping_predicate: skos:exactMatch
      mapping_source: MONDO
      mapping_justification: >-
        MONDO:0014133 carries DEE16 and EIEE16 as exact synonyms and maps
        exactly to OMIM:615338, the TBC1D24 early-infantile epileptic
        encephalopathy locus.
references:
  - reference: PMID:25719194
    title: TBC1D24-Related Disorders.
    tags:
      - GeneReviews
  - reference: PMID:27281533
    title: "TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features."
  - reference: PMID:23526554
    title: >-
      Novel compound heterozygous mutations in TBC1D24 cause familial malignant
      migrating partial seizures of infancy.
  - reference: PMID:39237642
    title: Developmental and epileptic encephalopathies.
  - reference: PMID:39214300
    title: >-
      Interaction between the TBC1D24 TLDc domain and the KIBRA C2 domain is
      disrupted by two epilepsy-associated TBC1D24 missense variants.
inheritance:
  - name: Autosomal recessive inheritance
    description: >-
      DEE16 requires biallelic (homozygous or compound heterozygous) TBC1D24
      pathogenic variants, and a separate autosomal dominant TBC1D24 phenotype
      exists that causes non-syndromic hearing loss rather than epilepsy.
      Carriers are conventionally described as asymptomatic, but that is not
      settled: seizures have been reported in heterozygous carriers, and the
      mouse work argues haploinsufficiency is clinically significant. Both
      positions are cited below.
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
      - reference: PMID:25719194
        reference_title: "TBC1D24-Related Disorders."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "The diagnosis of a TBC1D24-related disorder is established in \nan individual with suggestive findings biallelic TBC1D24 pathogenic variants \nwhen the mode of inheritance is autosomal recessive (i.e., DOORS syndrome, FIME, \nPME, EPRPDC, DEE, and DFNB)"
        explanation: >-
          GeneReviews states that the DEE phenotype in the TBC1D24 spectrum is
          established by biallelic variants under autosomal recessive inheritance.
      - reference: PMID:25719194
        reference_title: "TBC1D24-Related Disorders."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Heterozygotes \n(carriers) are typically asymptomatic."
        explanation: >-
          The conventional position on carriers, stated by GeneReviews.
      - reference: PMID:30335140
        reference_title: "The epilepsy-associated protein TBC1D24 is required for normal development, survival and vesicle trafficking in mammalian neurons."
        supports: REFUTE
        directness: INDIRECT
        evidence_source: MODEL_ORGANISM
        snippet: "Importantly, heterozygous TBC1D24 mutation carriers have also been reported with seizures, suggesting that haploinsufficiency for TBC1D24 is significant clinically."
        explanation: >-
          Contradicts the blanket claim that carriers are asymptomatic, and is
          the reason this entry does not assert it. Graded MODEL_ORGANISM because
          that classifies the cited publication, which is a mouse and cellular
          study; the sentence itself is background citing other reports, so the
          claim reaches human carriers indirectly.
genetic:
  - name: TBC1D24
    notes: >-
      TBC1D24 (16p13.3) encodes a Rab-GTPase-activating-protein-domain protein
      that also carries a TLDc domain. It is most highly expressed in cerebral
      cortex and hippocampus. Biallelic pathogenic variants cause the whole
      TBC1D24 disease continuum; DEE16 sits at its severe extreme.
    gene_term:
      preferred_term: TBC1D24
      term:
        id: hgnc:29203
        label: TBC1D24
    relationship_type: CAUSATIVE
    variant_origin: GERMLINE
    evidence:
      - reference: PMID:23526554
        reference_title: "Novel compound heterozygous mutations in TBC1D24 cause familial malignant migrating partial seizures of infancy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "We identified two inherited novel mutations in TBC1D24 in two affected siblings."
        explanation: >-
          Establishes biallelic TBC1D24 variants as the cause of the severe
          early-onset epileptic encephalopathy phenotype that defines DEE16. The
          functional-assay half of this paper is cited separately, on the
          cortical-circuit node, so each item carries a single evidence_source.
      - reference: PMID:20727515
        reference_title: "TBC1D24, an ARF6-interacting protein, is mutated in familial infantile myoclonic epilepsy."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "In situ hybridization analysis revealed that Tbc1d24 is mainly expressed at the level of the cerebral cortex and the hippocampus."
        explanation: >-
          Localizes TBC1D24 expression to the cortical and hippocampal regions
          from which the seizures of DEE16 arise.
    variants:
      - name: Truncating (frameshift, nonsense, splice-site) TBC1D24 variants
        description: >-
          Predicted loss-of-function alleles concentrate at the severe end of the
          TBC1D24 spectrum, where DEE16 lies. The correlation is a trend rather
          than a rule: variant position and in-vitro severity do not cleanly
          predict the clinical phenotype, and the cohort records one positional
          exception, truncating variants falling in the last exon, where escape
          from nonsense-mediated decay leaves a milder course.
        gene:
          preferred_term: TBC1D24
          term:
            id: hgnc:29203
            label: TBC1D24
        evidence:
          - reference: PMID:27281533
            reference_title: "TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "We noted an unfavorable outcome associated with frameshift, nonsense, or splice-site mutations, indicating that loss of function produces more severe disease. At least one such mutation occurred in 17 patients. Of these, 15 had drug-resistant epilepsy and 8 of them died by the age of 7 years."
            explanation: >-
              Directly links loss-of-function alleles to drug resistance and
              early death, the outcome profile of DEE16.
          - reference: PMID:27281533
            reference_title: "TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features."
            supports: REFUTE
            evidence_source: IN_VITRO
            snippet: "Neuronal outgrowth assays showed that some TBC1D24 mutations, associated with the most severe TBC1D24-associated disorders, are not necessarily the most disruptive to this gene function."
            explanation: >-
              Contradicts a simple dose-of-residual-function model: the variants
              causing the most severe clinical disease are not the ones that most
              disrupt neurite outgrowth in vitro.
pathophysiology:
  - name: Biallelic TBC1D24 Loss of Function
    description: >-
      Both TBC1D24 alleles carry pathogenic variants, most severely truncating
      ones, that reduce or abolish protein expression and function. The protein
      has two separable functional modules that are lost together: a TBC
      (Rab-GAP) domain containing a cationic phosphoinositide-binding pocket, and
      a C-terminal TLDc domain implicated in oxidative-stress resistance.
    biological_scale: MOLECULAR
    cell_types:
      - preferred_term: Neuron
        term:
          id: CL:0000540
          label: neuron
    molecular_functions:
      - preferred_term: GTPase activator activity
        term:
          id: GO:0005096
          label: GTPase activator activity
        modifier: DECREASED
    evidence:
      - reference: PMID:27281533
        reference_title: "TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "TBC1D24 encodes a protein containing a Tre2/Bub2/Cdc16 (TBC) domain, shared by Rab GTPase-activating proteins (Rab-GAPs)."
        explanation: >-
          Identifies the Rab-GAP TBC domain that biallelic pathogenic variants
          disrupt.
      - reference: PMID:27281533
        reference_title: "TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "The protein also contains a TLDc domain, putatively involved in oxidative stress resistance."
        explanation: >-
          Establishes the second functional module lost when the protein is
          truncated.
    downstream:
      - target: Loss of Phosphoinositide-Dependent Presynaptic Membrane Anchoring
        causal_link_type: DIRECT
        description: >-
          The most prevalent patient variants fall in the TBC domain's cationic
          pocket and abolish its binding to PI(4)P/PI(4,5)P2.
        evidence:
          - reference: PMID:27669036
            reference_title: "Skywalker-TBC1D24 has a lipid-binding pocket mutated in epilepsy and required for synaptic function."
            supports: SUPPORT
            evidence_source: IN_VITRO
            snippet: "The most prevalent patient mutations affect the phosphoinositide-binding pocket and inhibit lipid binding."
            explanation: >-
              States that pathogenic variants act by abolishing phosphoinositide
              binding, which is the step this edge asserts.
      - target: Impaired ARF6-Dependent Membrane Trafficking
        causal_link_type: DIRECT
        description: >-
          TBC1D24 binds and restrains ARF6; losing the protein releases that
          restraint.
        evidence:
          - reference: PMID:20727515
            reference_title: "TBC1D24, an ARF6-interacting protein, is mutated in familial infantile myoclonic epilepsy."
            supports: SUPPORT
            evidence_source: IN_VITRO
            snippet: "By coimmunoprecipitation assay we found that TBC1D24 binds ARF6, a Ras-related family of small GTPases regulating exo-endocytosis dynamics."
            explanation: >-
              Establishes the physical TBC1D24-ARF6 interaction that this edge
              claims is lost.
      - target: Impaired v-ATPase Assembly and Organellar Acidification
        causal_link_type: DIRECT
        description: >-
          Losing TBC1D24 removes the chaperone that assists v-ATPase reassembly.
        evidence:
          - reference: PMID:39758816
            reference_title: TBC1D24 interacts with the v-ATPase and regulates intraorganellar pH in neurons.
            supports: SUPPORT
            evidence_source: MODEL_ORGANISM
            snippet: "we suggest that TBC1D24 acts as a chaperone assisting the correct assembly of the v-ATPase proton pump during SV recycling"
            explanation: >-
              Names the function lost when TBC1D24 is absent, which is the step
              this edge asserts.
      - target: Postnatal Micro-Exon Isoform Switch
        causal_link_type: DIRECT
        description: >-
          For an allele inside the micro-exon, the loss of function is not
          expressed until that exon starts being used, which is what makes the
          switch a step in this chain rather than a separate observation.
      - target: TLDc Domain Dysfunction
        causal_link_type: DIRECT
        description: >-
          Truncating variants remove or disrupt the C-terminal TLDc domain, whose
          structural integrity is required for its neuroprotective activity.
        evidence:
          - reference: PMID:26668325
            reference_title: "The Evolutionarily Conserved Tre2/Bub2/Cdc16 (TBC), Lysin Motif (LysM), Domain Catalytic (TLDc) Domain Is Neuroprotective against Oxidative Stress."
            supports: SUPPORT
            directness: INDIRECT
            evidence_source: IN_VITRO
            snippet: "Our data demonstrate that the integrity of the TLDc domain is essential for conferring neuroprotection"
            explanation: >-
              Shows that disrupting the TLDc domain removes its neuroprotective
              function. Indirect for TBC1D24: the in vivo demonstration in this
              paper uses an Oxr1 mutant mouse, so the step reaches TBC1D24's own
              domain by family membership.

  - name: Loss of Phosphoinositide-Dependent Presynaptic Membrane Anchoring
    description: >-
      The TBC domain's cationic pocket binds phosphoinositides phosphorylated at
      the 4 and 5 positions, and that lipid binding is what tethers the protein
      within the presynaptic terminal and restricts its diffusion. Pathogenic
      variants in the pocket abolish binding, releasing the protein from the
      presynaptic membrane. In Drosophila the resulting synaptic-vesicle
      trafficking defect and seizure phenotype are rescued by raising synaptic
      PI(4,5)P2, which makes the lipid interaction causal rather than incidental.
    biological_scale: MOLECULAR
    conforms_to: "synaptic_vesicle_cycle#Synaptic Vesicle Cycle Protein Deficiency"
    cell_types:
      - preferred_term: Neuron
        term:
          id: CL:0000540
          label: neuron
    molecular_functions:
      - preferred_term: phosphatidylinositol-4,5-bisphosphate binding
        term:
          id: GO:0005546
          label: phosphatidylinositol-4,5-bisphosphate binding
        modifier: DECREASED
    cellular_components:
      - preferred_term: Synapse
        term:
          id: GO:0045202
          label: synapse
    evidence:
      - reference: PMID:27669036
        reference_title: "Skywalker-TBC1D24 has a lipid-binding pocket mutated in epilepsy and required for synaptic function."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "We solved the crystal structure of the TBC domain of the Drosophila ortholog Skywalker, revealing an unanticipated cationic pocket conserved among TBC1D24 homologs. Cocrystallization and biochemistry showed that this pocket binds phosphoinositides phosphorylated at the 4 and 5 positions."
        explanation: >-
          Structural and biochemical demonstration of the phosphoinositide-binding
          pocket whose loss this node describes.
    downstream:
      - target: Impaired Synaptic Vesicle Endocytosis and Recycling
        causal_link_type: DIRECT
        description: >-
          Pocket variants produce synaptic-vesicle trafficking failure that is
          reversed by restoring synaptic PI(4,5)P2.
        evidence:
          - reference: PMID:27669036
            reference_title: "Skywalker-TBC1D24 has a lipid-binding pocket mutated in epilepsy and required for synaptic function."
            supports: SUPPORT
            evidence_source: MODEL_ORGANISM
            snippet: "the pathogenic mutations cause severe neurological defects in flies, including impaired synaptic-vesicle trafficking and seizures, and these defects are reversed by genetically increasing synaptic PI(4,5)P2 concentrations through synaptojanin mutations"
            explanation: >-
              Establishes the causal step from loss of lipid binding to
              synaptic-vesicle trafficking failure, with a rescue experiment.

  - name: Impaired ARF6-Dependent Membrane Trafficking
    description: >-
      TBC1D24 normally prevents ARF6 activation. Without it, ARF6-dependent
      membrane exchange between the plasma membrane and endocytic compartments is
      dysregulated. This is the developmental arm of the mechanism: the same
      dysregulation that disturbs mature vesicle traffic also drives the
      migration and axon-specification defects below, and dominant-negative ARF6
      rescues them.
    biological_scale: MOLECULAR
    cell_types:
      - preferred_term: Neuron
        term:
          id: CL:0000540
          label: neuron
    biological_processes:
      - preferred_term: regulation of ARF protein signal transduction
        term:
          id: GO:0032012
          label: regulation of ARF protein signal transduction
        modifier: ABNORMAL
    evidence:
      - reference: PMID:24469796
        reference_title: "TBC1D24 regulates neuronal migration and maturation through modulation of the ARF6-dependent pathway."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "We show that in vivo, overexpression of the dominant-negative form of ARF6 rescues the neuronal migration and dendritic outgrowth defects induced by TBC1D24 knockdown, suggesting that TBC1D24 prevents ARF6 activation."
        explanation: >-
          Rescue by dominant-negative ARF6 establishes that TBC1D24 loss acts
          through unrestrained ARF6 activation.
    downstream:
      - target: Delayed Radial Migration and Arrested Neuronal Maturation
        causal_link_type: DIRECT
        evidence:
          - reference: PMID:24469796
            reference_title: "TBC1D24 regulates neuronal migration and maturation through modulation of the ARF6-dependent pathway."
            supports: SUPPORT
            evidence_source: MODEL_ORGANISM
            snippet: "in utero TBC1D24 knockdown in the rat developing neocortex affects the multipolar-bipolar transition of neurons leading to delayed radial migration"
            explanation: >-
              Directly links loss of TBC1D24 to the radial-migration delay this
              edge asserts.
      - target: Postsynaptic Dendritic Spine Loss
        causal_link_type: DIRECT
        evidence:
          - reference: PMID:32004315
            reference_title: "The epilepsy and intellectual disability-associated protein TBC1D24 regulates the maintenance of excitatory synapses and animal behaviors."
            supports: SUPPORT
            evidence_source: MODEL_ORGANISM
            snippet: "it is required for the maintenance of dendritic spines through inhibition of the small GTPase ARF6"
            explanation: >-
              States that spine maintenance runs through ARF6 inhibition, which
              is the mechanism this edge claims.
      - target: Growth-Cone Endocytosis Failure
        causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
        description: >-
          Downgraded from DIRECT deliberately: the cited sentence says the axonal
          phenotype "was accompanied by" the endocytic defect and altered ARF6
          activation, which is co-occurrence rather than a demonstrated causal
          step.
        evidence:
          - reference: PMID:30858606
            reference_title: "TBC1D24 regulates axonal outgrowth and membrane trafficking at the growth cone in rodent and human neurons."
            supports: SUPPORT
            evidence_source: IN_VITRO
            snippet: "The axonal phenotype was accompanied by an impairment of endocytosis at the growth cone and an altered activation of the TBC1D24 molecular partner ADP ribosylation factor 6."
            explanation: >-
              Ties the axonal and growth-cone endocytic defect to altered ARF6
              activation, the mechanism this edge runs through.

  - name: TLDc Domain Dysfunction
    description: >-
      The C-terminal TLDc domain has at least two identified activities. The
      domain family (OXR1, NCOA7) confers resistance to oxidative stress, and a
      humanized Drosophila model of a TLDc missense allele shows
      activity-induced vesicle-trafficking and locomotor defects that
      antioxidants reverse, supporting a reactive-oxygen-species sensor that
      sets synaptic vesicle trafficking rates. Separately, a 2024 screen
      identified the scaffold protein KIBRA as a specific partner of this
      domain, with two recessive epilepsy-associated TLDc variants disrupting
      the binding.

      A note on the v-ATPase, because the literature reads as contradictory if
      taken out of order. An earlier assay found no interaction between the
      purified TLDc domain and the v-ATPase that other TLDc proteins regulate,
      and that negative is still quoted as leaving the domain's function open.
      It has since been superseded in vivo: TBC1D24 interacts with the v-ATPase
      V1 subunits in mammalian brain, and its loss impairs V1/V0 association and
      organellar acidification. This entry models that as its own node rather
      than treating the purified-domain result as the settled answer.

      Two caveats matter for DEE16 specifically. The antioxidant-rescue work
      comes from a mild allele causing Rolandic epilepsy with exercise-induced
      dystonia, not from DEE16 patients. The KIBRA work tests two missense
      variants, whereas DEE16 is enriched for truncating alleles that remove the
      domain outright. So this arm is real biology whose contribution to the
      severe phenotype is inferred rather than measured.
    biological_scale: MOLECULAR
    cell_types:
      - preferred_term: Hippocampal neuron
        term:
          id: CL:0002608
          label: hippocampal neuron
    biological_processes:
      - preferred_term: response to oxidative stress
        term:
          id: GO:0006979
          label: response to oxidative stress
        modifier: DECREASED
    evidence:
      - reference: PMID:39214300
        reference_title: "Interaction between the TBC1D24 TLDc domain and the KIBRA C2 domain is disrupted by two epilepsy-associated TBC1D24 missense variants."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "As two epilepsy-associated recessive variants (Gly511Arg and Ala515Val) in the TLDc domain of human TBC1D24 disrupt the interaction with the human KIBRA C2 domain, this study reveals a pathogenic mechanism of TBC1D24-associated epilepsy, linking the TBC1D24 and KIBRA pathways."
        explanation: >-
          Identifies a specific molecular consequence of TLDc-domain variants,
          giving this node a mechanism rather than an analogy.
      - reference: PMID:31257402
        reference_title: "TBC1D24-TLDc-related epilepsy exercise-induced dystonia: rescue by antioxidants in a disease model."
        supports: SUPPORT
        directness: INDIRECT
        evidence_source: MODEL_ORGANISM
        snippet: "We propose that the TBC1D24/Sky TLDc domain is a reactive oxygen species sensor mediating synaptic vesicle trafficking rates that, when dysfunctional, causes a movement disorder in patients and flies."
        explanation: >-
          Supports the redox-sensor role of the domain, but from a fly model of a
          mild human allele, so the inference to DEE16 runs through the shared
          domain rather than through the phenotype.
      - reference: PMID:26668325
        reference_title: "The Evolutionarily Conserved Tre2/Bub2/Cdc16 (TBC), Lysin Motif (LysM), Domain Catalytic (TLDc) Domain Is Neuroprotective against Oxidative Stress."
        supports: SUPPORT
        directness: INDIRECT
        evidence_source: IN_VITRO
        snippet: "TBC1D24, a protein mutated in a range of disorders characterized by seizures, hearing loss, and neurodegeneration"
        explanation: >-
          Places TBC1D24 within the TLDc family whose domain integrity the same
          study shows is required for neuroprotection. The inference to TBC1D24's
          own domain is by family membership, not direct measurement.
    downstream:
      - target: Impaired Synaptic Vesicle Endocytosis and Recycling
        causal_link_type: DIRECT
        description: >-
          If the domain is a redox sensor setting vesicle trafficking rates, its
          loss feeds the same presynaptic failure the TBC domain lesion produces,
          which would explain why both domains yield overlapping phenotypes.
        evidence:
          - reference: PMID:31257402
            reference_title: "TBC1D24-TLDc-related epilepsy exercise-induced dystonia: rescue by antioxidants in a disease model."
            supports: SUPPORT
            evidence_source: MODEL_ORGANISM
            snippet: "we demonstrated that the TBC1D24G501R TLDc mutation causes activity-induced locomotion and synaptic vesicle trafficking defects, while TBC1D24R360H is benign"
            explanation: >-
              Shows a TLDc-domain variant producing synaptic vesicle trafficking
              defects, the step this edge asserts.
      - target: Progressive Cerebral and Cerebellar Atrophy
        causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
        description: >-
          Reduced oxidative-stress resistance is a plausible contributor to the
          progressive atrophy seen on neuroimaging, but no study has measured
          oxidative injury in DEE16 brain tissue.

  - name: Delayed Radial Migration and Arrested Neuronal Maturation
    description: >-
      TBC1D24-deficient neurons fail the multipolar-to-bipolar transition,
      migrate late through the developing neocortex, and retain immature
      morphological and functional properties once they arrive. The cortex that
      results is populated by neurons that never fully matured, which is the
      developmental half of "developmental and epileptic encephalopathy".
    biological_scale: CELLULAR
    cell_types:
      - preferred_term: Cortical projection neuron
        term:
          id: CL:0010012
          label: cerebral cortex neuron
    biological_processes:
      - preferred_term: cerebral cortex radially oriented cell migration
        term:
          id: GO:0021799
          label: cerebral cortex radially oriented cell migration
        modifier: DECREASED
      - preferred_term: cell morphogenesis involved in neuron differentiation
        term:
          id: GO:0048667
          label: cell morphogenesis involved in neuron differentiation
        modifier: ABNORMAL
    evidence:
      - reference: PMID:24469796
        reference_title: "TBC1D24 regulates neuronal migration and maturation through modulation of the ARF6-dependent pathway."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Furthermore, we find that TBC1D24-knockdown neurons display an abnormal maturation and retain immature morphofunctional properties."
        explanation: >-
          Direct evidence for the arrested-maturation half of this node.
    downstream:
      - target: Aberrant Cortical Circuit Formation
        causal_link_type: DIRECT
        description: >-
          Neurons that migrate late and stay immature assemble into malformed
          circuits.

  - name: Growth-Cone Endocytosis Failure
    description: >-
      Membrane trafficking fails at the growth cone: endocytosis there is
      impaired and the TBC1D24 partner ARF6 is abnormally activated. This is the
      trafficking lesion in the growing neurite, and it is upstream of the
      axon-specification failure that follows from it.
    biological_scale: CELLULAR
    cell_types:
      - preferred_term: Neuron
        term:
          id: CL:0000540
          label: neuron
    cellular_components:
      - preferred_term: Growth cone
        term:
          id: GO:0030426
          label: growth cone
    evidence:
      - reference: PMID:30858606
        reference_title: "TBC1D24 regulates axonal outgrowth and membrane trafficking at the growth cone in rodent and human neurons."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "an impairment of endocytosis at the growth cone and an altered activation of the TBC1D24 molecular partner ADP ribosylation factor 6"
        explanation: >-
          Direct evidence for the growth-cone endocytic defect and the ARF6
          dysregulation accompanying it.
    downstream:
      - target: Axonal Specification Failure
        causal_link_type: DIRECT
        description: >-
          The paper reports the axonal phenotype as accompanied by the
          growth-cone endocytic defect; the trafficking failure is placed
          upstream because that is the direction the mechanism runs.

  - name: Axonal Specification Failure
    description: >-
      Cortical neurons lacking TBC1D24 fail to specify an axon, mature the axon
      initial segment, or fire action potentials normally, and in vivo callosal
      projections are impaired. Critically for DEE16, the severity of this defect
      tracks clinical severity in patient-derived neurons: iPSC neurons from a
      patient with severe developmental encephalopathy show the axon defect,
      while neurons from a patient with mild early-onset epilepsy do not. That
      makes it the one cellular readout in this gene shown to separate the severe
      end of the spectrum from the mild end.
    biological_scale: CELLULAR
    cell_types:
      - preferred_term: Cortical projection neuron
        term:
          id: CL:0010012
          label: cerebral cortex neuron
    biological_processes:
      - preferred_term: axonogenesis
        term:
          id: GO:0007409
          label: axonogenesis
        modifier: DECREASED
    evidence:
      - reference: PMID:30858606
        reference_title: "TBC1D24 regulates axonal outgrowth and membrane trafficking at the growth cone in rodent and human neurons."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "In rat cortical primary neurons silenced for TBC1D24, we found defects in axonal specification, the maturation of axonal initial segment and action potential firing."
        explanation: >-
          Direct evidence for the axonal and excitability defect this node names.
      - reference: PMID:30858606
        reference_title: "TBC1D24 regulates axonal outgrowth and membrane trafficking at the growth cone in rodent and human neurons."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Reprogrammed neurons from a patient with severe developmental encephalopathy show significant axon formation defect that were absent from reprogrammed neurons of a patient with mild early onset epilepsy."
        explanation: >-
          Human patient-derived evidence that the axonal phenotype is specific to
          the severe (DEE) end of the spectrum rather than to TBC1D24 loss
          generally.
    downstream:
      - target: Aberrant Cortical Circuit Formation
        causal_link_type: DIRECT
      - target: Neuronal Hyperexcitability and Hypersynchrony
        causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
        intermediate_mechanisms:
          - axon initial segment maturation failure
          - altered action potential firing

  - name: Impaired v-ATPase Assembly and Organellar Acidification
    description: >-
      TBC1D24 interacts with the V1 subunits of the vacuolar ATPase in mammalian
      brain and behaves as a chaperone for correct v-ATPase reassembly. Without
      it the V1/V0 association fails, endo-lysosomal compartments and synaptic
      vesicles do not acidify properly, and autophagy is impaired at both the
      soma and the terminal. At the synapse the specific consequence is that
      vesicles retrieved after stimulation are not reacidified, so the reserve
      pool is not properly regenerated.

      This is the arm the sibling DOORS_Syndrome entry models as a shared
      endolysosomal axis with ATP6V1B2, and it is why an earlier negative result
      using the purified TLDc domain alone should not be read as ruling the
      interaction out.
    biological_scale: MOLECULAR
    cell_types:
      - preferred_term: Hippocampal neuron
        term:
          id: CL:0002608
          label: hippocampal neuron
    biological_processes:
      - preferred_term: Autophagy
        term:
          id: GO:0006914
          label: autophagy
        modifier: DECREASED
    cellular_components:
      - preferred_term: Lysosome
        term:
          id: GO:0005764
          label: lysosome
    evidence:
      - reference: PMID:39758816
        reference_title: TBC1D24 interacts with the v-ATPase and regulates intraorganellar pH in neurons.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "In the present study, we reveal that TBC1D24 interacts with the V1 subunits of v-ATPase in the mammalian brain, and in its absence, the V1/V0 association is impaired in neuronal cells. This, in turn, results in defective acidification of the endo-lysosomal compartments and SVs, alongside autophagic impairment at neuronal soma and synaptic terminals."
        explanation: >-
          The in vivo demonstration of the interaction and of what its loss does,
          which is the whole content of this node.
      - reference: PMID:39758816
        reference_title: TBC1D24 interacts with the v-ATPase and regulates intraorganellar pH in neurons.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Taken together, these data suggest that Tbc1d24 facilitates SV reacidification and proper recycling and clearance of intra-terminal cisternae at synaptic boutons."
        explanation: >-
          States the presynaptic consequence specifically, which is what connects
          this node to the vesicle-cycle node downstream.
    downstream:
      - target: Impaired Synaptic Vesicle Endocytosis and Recycling
        causal_link_type: DIRECT
        description: >-
          Failure to reacidify retrieved vesicles is part of the same recycling
          defect, not a separate consequence of it.
        evidence:
          - reference: PMID:39758816
            reference_title: TBC1D24 interacts with the v-ATPase and regulates intraorganellar pH in neurons.
            supports: SUPPORT
            evidence_source: MODEL_ORGANISM
            snippet: "This implies the need of correct v-ATPase reassembly upon SV endocytosis to allow SV reacidification and recycling."
            explanation: >-
              States that correct v-ATPase reassembly is required for vesicle
              recycling, which is the causal step this edge asserts.

  - name: Impaired Synaptic Vesicle Endocytosis and Recycling
    description: >-
      TBC1D24 is associated with clathrin-coated vesicles and synapses of
      hippocampal neurons. Losing it impairs presynaptic endocytosis and the
      regeneration of release-ready vesicles, destabilizing neurotransmission at
      the terminals of an already malformed cortical network.
    biological_scale: CELLULAR
    conforms_to: "synaptic_vesicle_cycle#Impaired Synaptic Vesicle Endocytosis and Recycling"
    cell_types:
      - preferred_term: Hippocampal neuron
        term:
          id: CL:0002608
          label: hippocampal neuron
    biological_processes:
      - preferred_term: synaptic vesicle endocytosis
        term:
          id: GO:0048488
          label: synaptic vesicle endocytosis
        modifier: DECREASED
      - preferred_term: synaptic vesicle cycle
        term:
          id: GO:0099504
          label: synaptic vesicle cycle
        modifier: ABNORMAL
    cellular_components:
      - preferred_term: Clathrin-coated vesicle
        term:
          id: GO:0030136
          label: clathrin-coated vesicle
    evidence:
      - reference: PMID:30602030
        reference_title: "The phenotypic landscape of a Tbc1d24 mutant mouse includes convulsive seizures resembling human early infantile epileptic encephalopathy."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "TBC1D24 is associated with \nclathrin-coated vesicles and synapses of hippocampal neurons, suggesting a \ncrucial role of TBC1D24 in vesicle trafficking important for neuronal signal \ntransmission."
        explanation: >-
          Localizes TBC1D24 to the presynaptic vesicle machinery whose failure
          this node describes, in the mouse model of the EIEE phenotype.
      - reference: PMID:30335140
        reference_title: "The epilepsy-associated protein TBC1D24 is required for normal development, survival and vesicle trafficking in mammalian neurons."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "genetic disruption of Tbc1d24 expression in the mouse leads to an impairment of endocytosis and an enlarged endosomal compartment in neurons with a decrease in spontaneous neurotransmission"
        explanation: >-
          Measures the endocytic failure, the endosomal accumulation it produces,
          and the resulting drop in spontaneous neurotransmission.
    downstream:
      - target: Neuronal Hyperexcitability and Hypersynchrony
        causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
        intermediate_mechanisms:
          - destabilized neurotransmitter release
        evidence:
          - reference: PMID:35350397
            reference_title: "Synaptopathies in Developmental and Epileptic Encephalopathies: A Focus on Pre-synaptic Dysfunction."
            supports: SUPPORT
            directness: INDIRECT
            evidence_source: OTHER
            snippet: "This process is coordinated by several GTPases: Tbc1d24 regulates Rab35, while Rbns5 interacts with Rab4 and Rab5 to lead the empty synaptic vesicle toward the endosome for recycling."
            explanation: >-
              Places TBC1D24 at the endocytic recycling step of the presynaptic
              cycle whose failure this edge routes through. Indirect because the
              review describes the normal step rather than measuring its failure
              in DEE16.

  - name: Postnatal Micro-Exon Isoform Switch
    description: >-
      A striking, and so far mouse-only, explanation for why DEE16 seizures begin
      after birth rather than in utero. The S324Tfs*3 truncating variant sits in
      an alternatively spliced micro-exon that is only incorporated into TBC1D24
      postnatally. Before that developmental splicing switch, homozygous mutant
      mice make predominantly the shorter wild-type isoform that omits the
      micro-exon and are unaffected; seizures begin abruptly at postnatal day 15,
      exactly when the switch occurs. Whether this timing mechanism generalizes
      to human DEE16 variants outside the micro-exon is unknown.
    biological_scale: MOLECULAR
    cell_types:
      - preferred_term: Neuron
        term:
          id: CL:0000540
          label: neuron
    evidence:
      - reference: PMID:30602030
        reference_title: "The phenotypic landscape of a Tbc1d24 mutant mouse includes convulsive seizures resembling human early infantile epileptic encephalopathy."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "S324Tfs*3 homozygotes show an abrupt onset of seizures at P15 that \ncorrelates with a developmental switch to utilization of the micro-exon."
        explanation: >-
          Ties seizure onset timing to the postnatal micro-exon splicing switch,
          the claim this node makes.
      - reference: PMID:30602030
        reference_title: "The phenotypic landscape of a Tbc1d24 mutant mouse includes convulsive seizures resembling human early infantile epileptic encephalopathy."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "During \nembryonic and early postnatal development, S324Tfs*3 homozygotes produce \npredominantly the shorter wild-type TBC1D24 protein isoform that omits the \nmicro-exon."
        explanation: >-
          Explains the pre-switch reprieve: the mutant allele produces functional
          protein until the micro-exon is used.
    downstream:
      - target: Neuronal Hyperexcitability and Hypersynchrony
        causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
        description: >-
          Once the micro-exon is incorporated, functional TBC1D24 is lost and
          seizures begin.
        intermediate_mechanisms:
          - loss of functional TBC1D24 protein

  - name: Postsynaptic Dendritic Spine Loss
    description: >-
      TBC1D24 is not only presynaptic. It is also present at the postsynaptic
      side of excitatory synapses, where inhibiting ARF6 is what maintains
      dendritic spines. Knocking it down in adult mouse hippocampus causes spine
      loss with contextual fear memory deficits, hyperactivity, and increased
      anxiety, and a knock-in of the disease-associated F251L substitution
      produces increased neuronal excitability, spontaneous seizures, and
      premature death in homozygotes. This arm matters because it makes the
      cognitive impairment of DEE16 partly independent of the seizures rather
      than purely their consequence.
    biological_scale: CELLULAR
    cell_types:
      - preferred_term: Hippocampal excitatory neuron
        term:
          id: CL:0002608
          label: hippocampal neuron
    cellular_components:
      - preferred_term: Dendritic spine
        term:
          id: GO:0043197
          label: dendritic spine
    evidence:
      - reference: PMID:32004315
        reference_title: "The epilepsy and intellectual disability-associated protein TBC1D24 regulates the maintenance of excitatory synapses and animal behaviors."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "we report that TBC1D24 is present at the postsynaptic sites of excitatory synapses, where it is required for the maintenance of dendritic spines through inhibition of the small GTPase ARF6"
        explanation: >-
          Establishes the postsynaptic localization and the ARF6-dependent spine
          maintenance function this node describes.
      - reference: PMID:32004315
        reference_title: "The epilepsy and intellectual disability-associated protein TBC1D24 regulates the maintenance of excitatory synapses and animal behaviors."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Mice subjected to viral-mediated knockdown of TBC1D24 in the adult hippocampus display dendritic spine loss, deficits in contextual fear memory, as well as abnormal behaviors including hyperactivity and increased anxiety."
        explanation: >-
          Measures the spine loss and its behavioural consequences after
          TBC1D24 knockdown.
    downstream:
      - target: Aberrant Cortical Circuit Formation
        causal_link_type: DIRECT
      - target: Neuronal Hyperexcitability and Hypersynchrony
        causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
        intermediate_mechanisms:
          - excitatory synapse loss
        evidence:
          - reference: PMID:32004315
            reference_title: "The epilepsy and intellectual disability-associated protein TBC1D24 regulates the maintenance of excitatory synapses and animal behaviors."
            supports: SUPPORT
            evidence_source: MODEL_ORGANISM
            snippet: "We further generate the F251L knock-in mice, and the homozygous mutants show increased neuronal excitability, spontaneous seizure and pre-mature death."
            explanation: >-
              A disease-associated allele acting through this postsynaptic
              function produces the hyperexcitability this edge asserts.

  - name: Aberrant Cortical Circuit Formation
    description: >-
      The combined migration, maturation, and axon-specification defects yield a
      neocortex whose circuitry never assembled correctly. This is the substrate
      on which the presynaptic release defect acts, and it accounts for the
      developmental impairment being present from the outset rather than being
      purely a consequence of seizures.
    biological_scale: TISSUE
    locations:
      - preferred_term: Cerebral cortex
        term:
          id: UBERON:0000956
          label: cerebral cortex
    evidence:
      - reference: PMID:23526554
        reference_title: "Novel compound heterozygous mutations in TBC1D24 cause familial malignant migrating partial seizures of infancy."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Mutations severely impaired TBC1D24 expression and function, which is critical for maturation of neuronal circuits."
        explanation: >-
          States that the DEE16-causing variants impair a function required for
          neuronal circuit maturation.
    downstream:
      - target: Neuronal Hyperexcitability and Hypersynchrony
        causal_link_type: DIRECT
      - target: Global developmental delay
        causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
        intermediate_mechanisms:
          - malformed cortical circuitry
        evidence:
          - reference: PMID:35350397
            reference_title: "Synaptopathies in Developmental and Epileptic Encephalopathies: A Focus on Pre-synaptic Dysfunction."
            supports: SUPPORT
            evidence_source: OTHER
            snippet: "In those patients presenting with pre-existing DD, the effect of the epileptic activity causes a worsening of the developmental consequences arising directly from the genetic mutation"
            explanation: >-
              States the two-source model of developmental impairment in DEE that
              this edge and the entry as a whole assert: the genetic lesion
              impairs development directly, and seizures compound it.
      - target: Developmental regression
        causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
        intermediate_mechanisms:
          - malformed cortical circuitry
          - recurrent seizures
      - target: Hypotonia
        causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
        description: >-
          Hypotonia is the commonest neurologic sign in this gene, but no source
          traces it to a specific step, so the intermediates are not named.
      - target: Decelerating head growth
        causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
        description: >-
          Postnatal brain growth failure follows the developmental lesion, though
          the relative contribution of ongoing seizures is not established.
      - target: Extrapyramidal signs
        causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
        description: >-
          No source traces the movement findings to a specific step in this
          chain, so the intermediates are not named.

  - name: Neuronal Hyperexcitability and Hypersynchrony
    description: >-
      Excitation and inhibition are pushed out of balance by the combination of a
      malformed cortical network and unstable presynaptic release, producing
      hypersynchronous discharges. In DEE16 these discharges characteristically
      fail to stay put: they migrate from one cortical region to another, giving
      the prolonged unilateral clonic activity that wanders between arm, leg, and
      face, and the ictal pattern of epilepsy of infancy with migrating focal
      seizures.
    biological_scale: TISSUE
    conforms_to: "epilepsy_excitation_inhibition_imbalance#Neuronal Hyperexcitability and Hypersynchrony"
    locations:
      - preferred_term: Cerebral cortex
        term:
          id: UBERON:0000956
          label: cerebral cortex
    biological_processes:
      - preferred_term: modulation of chemical synaptic transmission
        term:
          id: GO:0050804
          label: modulation of chemical synaptic transmission
        modifier: ABNORMAL
    evidence:
      - reference: PMID:20727515
        reference_title: "TBC1D24, an ARF6-interacting protein, is mutated in familial infantile myoclonic epilepsy."
        supports: SUPPORT
        directness: INDIRECT
        evidence_source: HUMAN_CLINICAL
        snippet: "unveiled the involvement of ARF6-dependent molecular pathway in brain hyperexcitability and seizures"
        explanation: >-
          Connects the TBC1D24-ARF6 axis to brain hyperexcitability, the state
          this node describes. Indirect on two counts: it is an author
          conclusion resting on linkage genetics plus neurite assays rather than
          a measurement of human cortical excitability, and the family studied
          had the mild, drug-responsive phenotype rather than DEE16.
    downstream:
      - target: Migrating focal seizures
        causal_link_type: DIRECT
      - target: Focal clonic seizures
        causal_link_type: DIRECT
      - target: Myoclonic seizures
        causal_link_type: DIRECT
      - target: Epilepsia partialis continua
        causal_link_type: DIRECT
      - target: Infantile spasms
        causal_link_type: DIRECT
      - target: Febrile seizures
        causal_link_type: DIRECT
      - target: Super-refractory status epilepticus
        causal_link_type: DIRECT
      - target: Multifocal epileptiform EEG abnormality
        causal_link_type: DIRECT
      - target: Drug-resistant epilepsy
        causal_link_type: DIRECT
        description: >-
          Antiseizure drugs act on the network, not on the trafficking lesion
          that keeps regenerating the hyperexcitable state, which is why the
          seizures in this entity are refractory rather than merely severe.
      - target: Death in childhood
        causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
        intermediate_mechanisms:
          - refractory status epilepticus
          - respiratory failure and intercurrent infection

  - name: Progressive Cerebral and Cerebellar Atrophy
    description: >-
      Cerebral or cerebellar atrophy, delayed myelination, and in some patients
      hippocampal sclerosis develop over time. Whether this reflects the
      underlying neurodevelopmental lesion, cumulative seizure-related injury,
      loss of TLDc-dependent oxidative stress resistance, or all three is
      unresolved; the imaging findings did not correlate with phenotype or
      prognosis in the largest cohort.
    biological_scale: TISSUE
    locations:
      - preferred_term: Brain
        term:
          id: UBERON:0000955
          label: brain
    evidence:
      - reference: PMID:27281533
        reference_title: "TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Neuroimaging revealed cerebral or cerebellar atrophy in 16 patients. Five patients had delayed myelination; 3 others had hippocampal sclerosis."
        explanation: >-
          Documents the atrophy, myelination delay, and hippocampal sclerosis
          this node describes, in the 48-patient TBC1D24 cohort.
      - reference: PMID:27281533
        reference_title: "TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features."
        supports: NO_EVIDENCE
        evidence_source: HUMAN_CLINICAL
        snippet: "There was no specific association among neuroimaging findings, phenotypic features, or prognosis."
        explanation: >-
          Records that the cohort found no imaging-phenotype correlation, so
          these findings are not used here to grade severity.
    downstream:
      - target: Cerebral atrophy
        causal_link_type: DIRECT
      - target: Cerebellar atrophy
        causal_link_type: DIRECT
      - target: Ataxia
        causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
        description: >-
          Cerebellar involvement is the obvious substrate for the ataxia, but no
          cited source reports the two in the same patients, so the link is not
          claimed as direct.
      - target: Delayed myelination
        causal_link_type: DIRECT

phenotypes:
  - name: Migrating focal seizures
    category: Neurological
    description: >-
      The defining electroclinical signature of the severe TBC1D24 phenotype:
      focal seizures whose ictal discharge migrates from one cortical region to
      another, historically called malignant migrating partial seizures of
      infancy (MMPSI) and now epilepsy of infancy with migrating focal seizures
      (EIMFS).
    phenotype_term:
      preferred_term: Migrating focal seizure
      term:
        id: HP:0032786
        label: Migrating focal seizure
    frequency: FREQUENT
    evidence:
      - reference: PMID:35350397
        reference_title: "Synaptopathies in Developmental and Epileptic Encephalopathies: A Focus on Pre-synaptic Dysfunction."
        supports: SUPPORT
        evidence_source: OTHER
        snippet: "The most commonly reported type of seizures is migrating focal ones (17/30), followed by migrating clonic ones (9/30), myoclonic ones (9/30), generalized tonic-clonic ones (4/30), epileptic spasm (4/30), tonic ones (3/30), and apnea attacks (1/30)"
        explanation: >-
          In a 30-patient TBC1D24-DEE compilation, restricted to the DEE
          phenotype rather than the whole spectrum, migrating focal seizures are
          the commonest type at 17/30, supporting FREQUENT.
      - reference: PMID:25719194
        reference_title: "TBC1D24-Related Disorders."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "developmental and epileptic encephalopathy (DEE), including epilepsy of infancy \nwith migrating focal seizures (EIMFS)"
        explanation: >-
          GeneReviews places EIMFS within the DEE phenotype of the TBC1D24
          spectrum.
      - reference: PMID:23526554
        reference_title: "Novel compound heterozygous mutations in TBC1D24 cause familial malignant migrating partial seizures of infancy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Here, we describe a familial form of MMPSI due to mutation in TBC1D24, revealing a devastating epileptic phenotype associated with TBC1D24 dysfunction."
        explanation: >-
          The index report establishing the migrating-seizure phenotype as
          TBC1D24-caused.

  - name: Focal clonic seizures
    category: Neurological
    description: >-
      Prolonged unilateral clonic activity of an arm, leg, or face, often lasting
      far beyond an ordinary seizure and shifting body part as the discharge
      migrates.
    phenotype_term:
      preferred_term: Focal clonic seizure
      term:
        id: HP:0002266
        label: Focal clonic seizure
    evidence:
      - reference: PMID:27502353
        reference_title: "Electroclinical phenotypes and outcomes in TBC1D24-related epilepsy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "All patients had seizure semiologies consisting of prolonged, unilateral, focal clonic activity of the arm, leg or face, in addition to generalized clonic or myoclonic seizures."
        explanation: >-
          Describes the focal clonic semiology in all four patients of the
          TBC1D24 drug-resistant epilepsy series.

  - name: Myoclonic seizures
    category: Neurological
    description: >-
      Myoclonic or clonic seizures are the commonest seizure type across the
      TBC1D24 spectrum and occur in DEE16 alongside the focal seizures, often in
      prolonged clusters and often unresponsive to medication.
    phenotype_term:
      preferred_term: Myoclonic seizure
      term:
        id: HP:0032794
        label: Myoclonic seizure
    frequency: FREQUENT
    evidence:
      - reference: PMID:35350397
        reference_title: "Synaptopathies in Developmental and Epileptic Encephalopathies: A Focus on Pre-synaptic Dysfunction."
        supports: SUPPORT
        evidence_source: OTHER
        snippet: "The most commonly reported type of seizures is migrating focal ones (17/30), followed by migrating clonic ones (9/30), myoclonic ones (9/30), generalized tonic-clonic ones (4/30), epileptic spasm (4/30), tonic ones (3/30), and apnea attacks (1/30)"
        explanation: >-
          In the DEE-restricted 30-patient compilation myoclonic seizures are
          9/30, which is what sets FREQUENT here. The pan-spectrum figure below
          is higher because that cohort includes the myoclonic-epilepsy
          phenotypes at the mild end of the gene.
      - reference: PMID:27281533
        reference_title: "TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Myoclonic or clonic seizures were the most frequent seizure types (29/48, 60%), often unresponsive to medication."
        explanation: >-
          The pan-TBC1D24 figure, recorded for contrast. It describes the whole
          spectrum, not DEE16, and should not be read as a DEE16 frequency.

  - name: Epilepsia partialis continua
    category: Neurological
    description: >-
      Continuous focal motor seizure activity, recorded as an ictal EEG pattern in
      TBC1D24-related drug-resistant epilepsy.
    phenotype_term:
      preferred_term: Epilepsia partialis continua
      term:
        id: HP:0012847
        label: Epilepsia partialis continua
    evidence:
      - reference: PMID:27502353
        reference_title: "Electroclinical phenotypes and outcomes in TBC1D24-related epilepsy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Ictal EEG characteristics included epilepsia partialis continua, epilepsy of infancy with migrating focal seizures, and other focal seizures with indiscrete interictal-ictal transitions."
        explanation: >-
          Lists epilepsia partialis continua among the ictal EEG patterns in the
          TBC1D24 series.

  - name: Super-refractory status epilepticus
    category: Neurological
    description: >-
      Status epilepticus that continues or recurs despite 24 hours of anaesthesia.
      Prolonged seizures or status of some kind occur in the large majority of
      patients across the TBC1D24 spectrum, and are frequently precipitated by
      fever or intercurrent infection.
    phenotype_term:
      preferred_term: Super-refractory status epilepticus
      term:
        id: HP:0032868
        label: Super-refractory status epilepticus
    evidence:
      - reference: PMID:27502353
        reference_title: "Electroclinical phenotypes and outcomes in TBC1D24-related epilepsy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Two seemingly unrelated Navajo patients with identical variations experienced super-refractory status epilepticus at 9 months of age, with one achieving resolution with ketogenic diet therapy."
        explanation: >-
          Documents super-refractory status epilepticus in TBC1D24-related
          epilepsy, including its response to ketogenic diet in one patient.
      - reference: PMID:27281533
        reference_title: "TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Thirty-eight (79%) individuals had had status epilepticus, either convulsive or nonconvulsive, or prolonged seizures (>5 minutes). In 19 patients, seizures or status episodes were precipitated by fever or infections."
        explanation: >-
          Quantifies status epilepticus across the cohort and identifies fever and
          infection as precipitants.

  - name: Infantile spasms
    category: Neurological
    description: >-
      Epileptic spasms occur within the wide seizure repertoire of the TBC1D24
      spectrum, alongside the focal and myoclonic types that dominate.
    phenotype_term:
      preferred_term: Infantile spasms
      term:
        id: HP:0012469
        label: Infantile spasms
    evidence:
      - reference: PMID:27281533
        reference_title: "TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Seizure types included infantile spasms and febrile convulsive, myoclonic, clonic, tonic, absence, tonic-clonic with or without apparent focal onset, and focal seizures with retained or impaired awareness."
        explanation: >-
          Lists infantile spasms among the seizure types observed in the
          TBC1D24 cohort.

  - name: Febrile seizures
    category: Neurological
    description: >-
      Fever and intercurrent infection are the commonest precipitants of seizures
      and status in this gene. Other reported triggers are unusually varied for an
      epilepsy - fatigue, drowsiness, acoustic or light stimulation, repetitive
      movement, feeding, constipation, and a delayed medication dose - which is
      consistent with an activity-dependent presynaptic lesion rather than a
      fixed structural focus.
    phenotype_term:
      preferred_term: Febrile seizure (within the age range of 3 months to 6 years)
      term:
        id: HP:0002373
        label: Febrile seizure (within the age range of 3 months to 6 years)
    evidence:
      - reference: PMID:27281533
        reference_title: "TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "In 19 patients, seizures or status episodes were precipitated by fever or infections."
        explanation: >-
          Quantifies fever and infection as seizure precipitants in 19 of the 48
          patients.
      - reference: PMID:27281533
        reference_title: "TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "In some patients, they were triggered by fatigue, drowsiness, intense and persistent stimulation (acoustic stimuli or variations in light intensity), repetitive movements, feeding, febrile episodes, constipation, or delayed medication."
        explanation: >-
          Enumerates the broader set of activity- and state-dependent triggers
          described in this phenotype.

  - name: Drug-resistant epilepsy
    category: Neurological
    description: >-
      Seizures fail to come under control with adequate trials of appropriate
      antiseizure medications. Drug resistance is the norm in the DEE16 end of
      the spectrum and is what distinguishes it from the drug-responsive
      TBC1D24 phenotypes.
    phenotype_term:
      preferred_term: Drug-resistant epilepsy
      term:
        id: HP:0001250
        label: Seizure
      qualifiers:
        - predicate:
            preferred_term: drug resistance status
            term:
              id: NCIT:C102626
              label: Drug Resistance Status
          value:
            preferred_term: refractory drug response
            term:
              id: HP:0020174
              label: Refractory drug response
    frequency: VERY_FREQUENT
    evidence:
      - reference: PMID:27281533
        reference_title: "TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "At least one such mutation occurred in 17 patients. Of these, 15 had drug-resistant epilepsy and 8 of them died by the age of 7 years."
        explanation: >-
          In the loss-of-function subgroup that corresponds to DEE16, 15 of 17
          patients had drug-resistant epilepsy, supporting VERY_FREQUENT.
      - reference: PMID:27502353
        reference_title: "Electroclinical phenotypes and outcomes in TBC1D24-related epilepsy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "We report four patients with novel variants of TBC1D24 demonstrating drug-resistant focal epilepsy, developmental delays, and head growth deceleration."
        explanation: >-
          Independent series reporting drug-resistant focal epilepsy in
          TBC1D24-related disease.
      - reference: PMID:35350397
        reference_title: "Synaptopathies in Developmental and Epileptic Encephalopathies: A Focus on Pre-synaptic Dysfunction."
        supports: SUPPORT
        evidence_source: OTHER
        snippet: "All patients developed a drug-resistant epileptic encephalopathy"
        explanation: >-
          In the DEE-restricted 30-patient compilation drug resistance is
          universal, which is the strongest basis for VERY_FREQUENT here.

  - name: Multifocal epileptiform EEG abnormality
    category: Neurological
    description: >-
      Interictal EEG shows background slowing with multifocal paroxysmal
      abnormalities, consistent with the multifocal cortical origin of the
      migrating seizures.
    phenotype_term:
      preferred_term: Multifocal epileptiform discharges
      term:
        id: HP:0010841
        label: Multifocal epileptiform discharges
    evidence:
      - reference: PMID:27281533
        reference_title: "TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Various features, including slow background activity and multifocal paroxysmal abnormalities, were described in 35 patients."
        explanation: >-
          Documents multifocal paroxysmal EEG abnormalities in 35 of the 48
          patients.

  - name: Global developmental delay
    category: Neurological
    description: >-
      Development is delayed from the outset in DEE16 rather than being lost only
      after seizures begin, reflecting the prenatal migration and axon-formation
      defect. Severity across the TBC1D24 spectrum ranges from mild to profound;
      the DEE16 end is at the severe extreme.
    phenotype_term:
      preferred_term: Global developmental delay
      term:
        id: HP:0001263
        label: Global developmental delay
    frequency: VERY_FREQUENT
    evidence:
      - reference: PMID:27281533
        reference_title: "TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Thirty-nine individuals had intellectual disability or developmental delay, from mild to profound."
        explanation: >-
          39 of 48 patients had intellectual disability or developmental delay,
          supporting VERY_FREQUENT.
      - reference: PMID:27502353
        reference_title: "Electroclinical phenotypes and outcomes in TBC1D24-related epilepsy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Our series suggests that TBC1D24-related epilepsy can manifest with hypotonia, developmental delays, and a variety of focal-onset seizures prone to electroclinical dissociation."
        explanation: >-
          Independent series reporting developmental delay with the focal-onset
          seizure phenotype.

  - name: Developmental regression
    category: Neurological
    description: >-
      Loss of previously acquired milestones. The MONDO concept definition for
      DEE16 names delayed or regressed psychomotor development as a defining
      feature alongside early seizure onset.
    phenotype_term:
      preferred_term: Developmental regression
      term:
        id: HP:0002376
        label: Developmental regression
    evidence:
      - reference: PMID:27502353
        reference_title: Electroclinical phenotypes and outcomes in TBC1D24-related epilepsy.
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "At 8 months, she experienced motor and lan-\nguage regression."
        explanation: >-
          A TBC1D24 patient losing acquired motor and language skills, which is
          the claim this phenotype makes.
    notes: >-
      Regression is named in the MONDO definition of MONDO:0014133 ("delayed or
      regression of psychomotor development") and is documented in an individual
      patient, but no cohort quantifies it, so no `frequency:` is recorded. The
      DEE-restricted series reports developmental delay or intellectual
      disability in all 30 patients without separating regression from delay.

  - name: Hypotonia
    category: Neurological
    description: >-
      Muscle hypotonia is the most frequent neurologic sign across the TBC1D24
      spectrum.
    phenotype_term:
      preferred_term: Hypotonia
      term:
        id: HP:0001252
        label: Hypotonia
    notes: >-
      No `frequency:` recorded. The cited cohort calls hypotonia "the most
      frequent neurologic sign" but gives no count for it, and counts the signs
      it ranks below (ataxia 7/48, extrapyramidal 8/48) low enough that "most
      frequent" is compatible with OCCASIONAL. A ranking is not a frequency.
    evidence:
      - reference: PMID:27281533
        reference_title: "TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "The most frequent neurologic sign was muscle hypotonia."
        explanation: >-
          Identifies hypotonia as the commonest neurologic sign in the 48-patient
          cohort.
      - reference: PMID:27502353
        reference_title: "Electroclinical phenotypes and outcomes in TBC1D24-related epilepsy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "TBC1D24-related epilepsy can manifest with hypotonia, developmental delays, and a variety of focal-onset seizures"
        explanation: >-
          Independent confirmation of hypotonia in the TBC1D24 epilepsy
          phenotype.

  - name: Decelerating head growth
    category: Neurological
    description: >-
      Head circumference falls across centiles after birth. Note what this is
      not: the reported patients were normocephalic on absolute measurement, so
      this is a falling growth trajectory rather than microcephaly, and the
      source paper records it as head-circumference regression.
    phenotype_term:
      preferred_term: Decelerating head growth
    notes: >-
      Left unbound deliberately. HP:0000253 "Progressive microcephaly" was the
      obvious binding and is wrong: PMID:27502353 describes each patient as
      normocephalic (for example "She was normocephalic (OFC: 43.0 cm; 20%) with
      decelerating head growth"), and no cited source reports microcephaly in
      TBC1D24 disease at all. HPO's nearest alternatives, HP:0004485 "Cessation
      of head growth" and HP:0040195 "Decreased head circumference", both assert
      more than the source does for a normocephalic child on a falling centile.
      No term beats a wrong one; an HPO new-term request is the right route.
    evidence:
      - reference: PMID:27502353
        reference_title: "Electroclinical phenotypes and outcomes in TBC1D24-related epilepsy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "We report four patients with novel variants of TBC1D24 demonstrating drug-resistant focal epilepsy, developmental delays, and head growth deceleration."
        explanation: >-
          Reports head growth deceleration, the postnatal pattern this phenotype
          term captures.

  - name: Cerebral atrophy
    category: Neurological
    phenotype_term:
      preferred_term: Cerebral atrophy
      term:
        id: HP:0002059
        label: Cerebral atrophy
    evidence:
      - reference: PMID:27281533
        reference_title: "TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Neuroimaging revealed cerebral or cerebellar atrophy in 16 patients."
        explanation: >-
          Documents cerebral atrophy on neuroimaging in the TBC1D24 cohort.

  - name: Cerebellar atrophy
    category: Neurological
    description: >-
      Cerebellar involvement is common and can be progressive, with signal
      hyperintensity, hemispheric atrophy, or vermian hypoplasia.
    phenotype_term:
      preferred_term: Cerebellar atrophy
      term:
        id: HP:0001272
        label: Cerebellar atrophy
    evidence:
      - reference: PMID:27281533
        reference_title: "TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Eleven patients had cerebellar abnormalities: signal hyperintensity, especially in T2-weighted images (11, 14, 19, 25), atrophy (4, 5c, 5d, 7c, 10, 11, 13, 19), or mild vermian hypoplasia (29)."
        explanation: >-
          Enumerates the cerebellar abnormalities including atrophy in the
          cohort.

  - name: Delayed myelination
    category: Neurological
    phenotype_term:
      preferred_term: Delayed myelination
      term:
        id: HP:0012448
        label: Delayed myelination
    evidence:
      - reference: PMID:27281533
        reference_title: "TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Five patients had delayed myelination; 3 others had hippocampal sclerosis."
        explanation: >-
          Documents delayed myelination on neuroimaging in the TBC1D24 cohort.

  - name: Visual impairment
    category: Neurological
    description: >-
      Signs of visual impairment are the commonest non-epilepsy neurologic
      finding reported across the TBC1D24 series, more frequent than the
      cerebellar atrophy also curated here.
    phenotype_term:
      preferred_term: Visual impairment
      term:
        id: HP:0000505
        label: Visual impairment
    notes: >-
      The only count available is from the pooled 48-patient TBC1D24 series, so
      it is a spectrum figure and not a DEE16 frequency. No `frequency:` is
      recorded for that reason, following the same rule this entry applies to
      the neuroimaging phenotypes.
    evidence:
      - reference: PMID:27281533
        reference_title: "TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Thirteen patients (27%), including 6 patients with DOORS, had signs of visual impairment."
        explanation: >-
          Quantifies visual impairment at 13/48 across the TBC1D24 cohort.

  - name: Ataxia
    category: Neurological
    description: >-
      Ataxia occurs in a minority and sits alongside the cerebellar atrophy seen
      on imaging, though no source links the two in the same patients.
    phenotype_term:
      preferred_term: Ataxia
      term:
        id: HP:0001251
        label: Ataxia
    notes: >-
      The only count available is from the pooled 48-patient TBC1D24 series, so
      it is a spectrum figure and not a DEE16 frequency. No `frequency:` is
      recorded for that reason, following the same rule this entry applies to
      the neuroimaging phenotypes.
    evidence:
      - reference: PMID:27281533
        reference_title: "TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "The most frequent neurologic sign was muscle hypotonia. Seven patients had ataxia. Eight patients had extrapyramidal signs (table e-3)."
        explanation: >-
          Quantifies ataxia at 7/48 across the TBC1D24 cohort.

  - name: Extrapyramidal signs
    category: Neurological
    description: >-
      Extrapyramidal signs are reported as a category rather than as specific
      movement phenotypes, so this entry binds the category term rather than
      naming a movement disorder the source does not name.
    phenotype_term:
      preferred_term: Extrapyramidal signs
      term:
        id: HP:0002071
        label: Abnormality of extrapyramidal motor function
    notes: >-
      The only count available is from the pooled 48-patient TBC1D24 series, so
      it is a spectrum figure and not a DEE16 frequency. No `frequency:` is
      recorded for that reason, following the same rule this entry applies to
      the neuroimaging phenotypes.
    evidence:
      - reference: PMID:27281533
        reference_title: "TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "The most frequent neurologic sign was muscle hypotonia. Seven patients had ataxia. Eight patients had extrapyramidal signs (table e-3)."
        explanation: >-
          Quantifies extrapyramidal signs at 8/48 across the TBC1D24 cohort.

  - name: Sensorineural hearing impairment
    category: Neurological
    description: >-
      Hearing loss is the phenotype that unites the whole TBC1D24 spectrum, and
      it occurs in patients who do not have DOORS syndrome. Its presence is one
      reason audiologic assessment sits in this entry's diagnostic workup rather
      than being reserved for suspected hearing loss.
    phenotype_term:
      preferred_term: Sensorineural hearing impairment
      term:
        id: HP:0000407
        label: Sensorineural hearing impairment
    notes: >-
      The 3/48 count covers only patients without DOORS syndrome, so it is
      neither a DEE16 frequency nor a whole-cohort one. No `frequency:` is
      recorded.
    evidence:
      - reference: PMID:27281533
        reference_title: "TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Three patients without DOORS (17a, 17b, 18) had bilateral sensorineural hearing loss or deafness."
        explanation: >-
          Documents sensorineural hearing loss in TBC1D24 patients outside the
          DOORS phenotype.

  - name: Death in childhood
    category: Neurological
    description: >-
      Early death is a defining outcome at the loss-of-function end of the
      TBC1D24 spectrum. Reported causes include intercurrent infection,
      respiratory failure, status epilepticus with pneumonia, and probable sudden
      unexpected death in epilepsy.
    phenotype_term:
      preferred_term: Death in childhood
    frequency: FREQUENT
    notes: >-
      Left unbound deliberately. HP:0003819 "Death in childhood" sits under
      HP:0012823 Clinical modifier rather than HP:0000118 Phenotypic
      abnormality, so it is outside the PhenotypeTerm dynamic enum; the same
      applies to HP:0001522. No phenotypic-abnormality term names early
      mortality, and binding a substitute would misstate the claim.
    evidence:
      - reference: PMID:27281533
        reference_title: "TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Nine individuals (19%) were deceased (average age at death 37 months, range 6-96 months)."
        explanation: >-
          Quantifies mortality across the pan-TBC1D24 cohort. This 19% is the
          spectrum figure and understates DEE16, where the DEE-restricted series
          below reports 13/30.
      - reference: PMID:35350397
        reference_title: "Synaptopathies in Developmental and Epileptic Encephalopathies: A Focus on Pre-synaptic Dysfunction."
        supports: SUPPORT
        evidence_source: OTHER
        snippet: "Overall, 13 patients (13/30) died at a very young age (ranging from 3 months to 9"
        explanation: >-
          In the DEE-restricted 30-patient compilation 13/30 died in early
          childhood, which is the figure this entry uses for DEE16 and the basis
          for FREQUENT.
      - reference: PMID:27281533
        reference_title: "TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "The other reported causes of death were infectious episode (7a, 7c, 17a, 17b), respiratory failure (6a), status epilepticus associated with a pulmonary infection (7b), and unknown (26, 28)."
        explanation: >-
          Enumerates the causes of death described in this phenotype.

progression:
  - phase: Early-infantile seizure onset
    notes: >-
      Seizures begin in the first weeks to months of life. Across the whole
      TBC1D24 spectrum mean onset is 7 months with a wide range; the DEE16 end
      sits at the early extreme of that distribution, within weeks of birth.
    evidence:
      - reference: PMID:27281533
        reference_title: "TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "The average age at seizure onset was 7 months (range from within 1 hour after birth to 8 years; SD 15 months)."
        explanation: >-
          The pan-TBC1D24 age-at-onset distribution, recorded for contrast. The
          DEE-restricted figure below is the one that describes DEE16.
      - reference: PMID:35350397
        reference_title: "Synaptopathies in Developmental and Epileptic Encephalopathies: A Focus on Pre-synaptic Dysfunction."
        supports: SUPPORT
        evidence_source: OTHER
        snippet: "All patients presented a history of early onset of seizures, ranging from 20 minutes after birth to 8 months of life: in the majority of the patients (28/30), the onset was within 3 months of life, and, among them, 6/30 individuals developed seizures within the first week"
        explanation: >-
          Measures onset in the DEE subset rather than inferring it from the
          spectrum: 28/30 within three months, 6/30 in the first week.

  - phase: Drug-resistant course with recurrent status epilepticus
    notes: >-
      Seizures fail to respond to sequential antiseizure medications; prolonged
      seizures and status epilepticus recur, frequently triggered by fever or
      intercurrent infection.
    evidence:
      - reference: PMID:27281533
        reference_title: "TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "In 30 patients, epilepsy was drug-resistant24; 18 patients responded well to treatment."
        explanation: >-
          Records drug resistance in the majority of the TBC1D24 cohort.

  - phase: Early death or profound disability
    notes: >-
      Children either die in early childhood, most within the first seven years,
      or survive with profound developmental impairment.
    evidence:
      - reference: PMID:27281533
        reference_title: "TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "TBC1D24-related epilepsy syndromes show marked phenotypic pleiotropy, with multisystem involvement and severity spectrum ranging from isolated deafness (not studied here), benign myoclonic epilepsy restricted to childhood with complete seizure control and normal intellect, to early-onset epileptic encephalopathy with severe developmental delay and early death."
        explanation: >-
          Places the early-onset epileptic encephalopathy phenotype, DEE16, at
          the severe-developmental-delay-and-early-death end of the spectrum.

animal_models:
  - name: Tbc1d24 S324Tfs*3 knock-in mouse
    species: Mouse
    genotype: Tbc1d24 S324Tfs*3 homozygous (CRISPR-Cas9 knock-in)
    description: >-
      A CRISPR-engineered mouse carrying the exact equivalent of a human
      truncating TBC1D24 variant associated with early infantile epileptic
      encephalopathy. Hearing and vestibular function are normal, so the model
      isolates the epilepsy phenotype from the deafness phenotypes of the same
      gene.
    publication: PMID:30602030
    modeled_mechanisms:
      - target: Neuronal Hyperexcitability and Hypersynchrony
        relationship: RECAPITULATES
        fidelity: MODERATE
        model_scale: ORGANISM
        description: >-
          Homozygotes show abrupt-onset spontaneous seizures recapitulating human
          EIEE, from the human-equivalent allele.
        limitations: >-
          The onset timing depends on a micro-exon splicing switch specific to
          this allele's position, so the model's developmental course may not
          generalize to DEE16 variants elsewhere in the gene. Seizure semiology in
          the mouse is convulsive rather than the migrating focal pattern that
          characterizes human DEE16.
        readouts:
          - name: Spontaneous seizure onset at postnatal day 15
            target: Neuronal Hyperexcitability and Hypersynchrony
            direction: INCREASED
            interpretation: >-
              Abrupt appearance of spontaneous seizures in homozygotes, absent
              before P15.
            evidence:
              - reference: PMID:30602030
                reference_title: "The phenotypic landscape of a Tbc1d24 mutant mouse includes convulsive seizures resembling human early infantile epileptic encephalopathy."
                supports: SUPPORT
                evidence_source: MODEL_ORGANISM
                snippet: "Homozygous S324Tfs*3 mice have normal auditory and vestibular functions \nbut show an abrupt onset of spontaneous seizures at postnatal day 15 \nrecapitulating human EIEE."
                explanation: >-
                  Reports the seizure measurement and its direction in the model.
        evidence:
          - reference: PMID:30602030
            reference_title: "The phenotypic landscape of a Tbc1d24 mutant mouse includes convulsive seizures resembling human early infantile epileptic encephalopathy."
            supports: SUPPORT
            evidence_source: MODEL_ORGANISM
            snippet: "Using CRISPR-Cas9 genome editing, we engineered a mouse with a \npremature translation stop codon equivalent to human S324Tfs*3, a recessive \nmutation of TBC1D24 associated with early infantile epileptic encephalopathy \n(EIEE)."
            explanation: >-
              Establishes that the model carries the human EIEE-associated allele,
              which is what makes it informative for this node.
      - target: Postnatal Micro-Exon Isoform Switch
        relationship: RECAPITULATES
        fidelity: HIGH
        model_scale: MOLECULAR
        description: >-
          The model is the sole source of evidence for the micro-exon switch
          mechanism; the node exists because of it.
        limitations: >-
          The switch has not been demonstrated in human neurons, and it can only
          apply to human variants that fall within the same micro-exon.
        evidence:
          - reference: PMID:30602030
            reference_title: "The phenotypic landscape of a Tbc1d24 mutant mouse includes convulsive seizures resembling human early infantile epileptic encephalopathy."
            supports: SUPPORT
            evidence_source: MODEL_ORGANISM
            snippet: "The S324Tfs*3 variant is located in an alternatively \nspliced micro-exon encoding six perfectly conserved amino acids incorporated \npostnatally into TBC1D24 protein due to a micro-exon utilization switch."
            explanation: >-
              Describes the micro-exon mechanism the model demonstrates.

  - name: Drosophila skywalker phosphoinositide-pocket mutants
    species: Fruit fly
    genotype: skywalker (sky) alleles carrying human-equivalent TBC1D24 pocket mutations
    description: >-
      Flies carrying the fly orthologue's equivalent of the most prevalent human
      TBC1D24 pocket variants. The value of the model is the rescue arm: the
      defects are reversed by genetically raising synaptic PI(4,5)P2, which
      establishes the lipid interaction as the causal node rather than a
      correlate.
    publication: PMID:27669036
    modeled_mechanisms:
      - target: Loss of Phosphoinositide-Dependent Presynaptic Membrane Anchoring
        relationship: RECAPITULATES
        fidelity: MODERATE
        model_scale: MOLECULAR
        description: >-
          Pathogenic pocket mutations abolish lipid binding and release the
          protein's membrane anchoring in presynaptic terminals.
        limitations: >-
          Drosophila Skywalker is an orthologue, not the human protein, and the
          fly has no TLDc-domain-dependent phenotype to compare. The seizure
          phenotype in flies is not the migrating focal seizure of human DEE16.
        readouts:
          - name: Synaptic-vesicle trafficking and seizure defects, PI(4,5)P2 rescue
            target: Loss of Phosphoinositide-Dependent Presynaptic Membrane Anchoring
            direction: RESTORED
            interpretation: >-
              Defects caused by pocket mutations are reversed when synaptic
              PI(4,5)P2 is raised, establishing the lipid interaction as causal.
            evidence:
              - reference: PMID:27669036
                reference_title: "Skywalker-TBC1D24 has a lipid-binding pocket mutated in epilepsy and required for synaptic function."
                supports: SUPPORT
                evidence_source: MODEL_ORGANISM
                snippet: "these defects are reversed by genetically increasing synaptic PI(4,5)P2 concentrations through synaptojanin mutations"
                explanation: >-
                  Reports the rescue measurement behind this readout.
        evidence:
          - reference: PMID:27669036
            reference_title: "Skywalker-TBC1D24 has a lipid-binding pocket mutated in epilepsy and required for synaptic function."
            supports: SUPPORT
            evidence_source: MODEL_ORGANISM
            snippet: "the pathogenic mutations cause severe neurological defects in flies, including impaired synaptic-vesicle trafficking and seizures"
            explanation: >-
              Supports treating the fly pocket mutants as informative for the
              human membrane-anchoring lesion.

  - name: Tbc1d24 F251L knock-in mouse
    species: Mouse
    genotype: Tbc1d24 F251L knock-in (homozygous and heterozygous)
    description: >-
      A knock-in of a disease-associated missense substitution that destabilizes
      the protein. Homozygotes seize spontaneously and die prematurely;
      heterozygotes survive to adulthood but have dendritic spine defects and
      impaired memory, which is the cleanest available separation of the
      cognitive phenotype from the seizure phenotype in this gene.
    publication: PMID:32004315
    modeled_mechanisms:
      - target: Postsynaptic Dendritic Spine Loss
        relationship: RECAPITULATES
        fidelity: MODERATE
        model_scale: CELLULAR
        description: >-
          The heterozygous arm isolates spine loss and memory impairment without
          the confound of ongoing seizures.
        limitations: >-
          F251L is a missense allele in the TBC domain; DEE16 is enriched for
          truncating alleles, so the model tests a protein-destabilization
          mechanism rather than complete loss. Heterozygous mice model a carrier
          state, not the biallelic human genotype.
        readouts:
          - name: Dendritic spine density and contextual fear memory
            target: Postsynaptic Dendritic Spine Loss
            direction: DECREASED
            interpretation: >-
              Spine defects and impaired memory in heterozygotes surviving to
              adulthood.
            evidence:
              - reference: PMID:32004315
                reference_title: "The epilepsy and intellectual disability-associated protein TBC1D24 regulates the maintenance of excitatory synapses and animal behaviors."
                supports: SUPPORT
                evidence_source: MODEL_ORGANISM
                snippet: "the heterozygous F251L knock-in mice survive into adulthood but display dendritic spine defects and impaired memory"
                explanation: >-
                  Reports the spine and memory measurements behind this readout.
        evidence:
          - reference: PMID:32004315
            reference_title: "The epilepsy and intellectual disability-associated protein TBC1D24 regulates the maintenance of excitatory synapses and animal behaviors."
            supports: SUPPORT
            evidence_source: MODEL_ORGANISM
            snippet: "we show that the protein stability of TBC1D24 is diminished by the disease-associated missense mutation that leads to F251L amino acid substitution"
            explanation: >-
              Establishes that the modelled allele acts by destabilizing the
              protein, which is what makes it informative for a loss-of-function
              node.
      - target: Neuronal Hyperexcitability and Hypersynchrony
        relationship: RECAPITULATES
        fidelity: MODERATE
        model_scale: ORGANISM
        limitations: >-
          Spontaneous seizures in the homozygote are not shown to be the
          migrating focal seizures that characterize human DEE16, and the allele
          is missense rather than truncating.
        evidence:
          - reference: PMID:32004315
            reference_title: "The epilepsy and intellectual disability-associated protein TBC1D24 regulates the maintenance of excitatory synapses and animal behaviors."
            supports: SUPPORT
            evidence_source: MODEL_ORGANISM
            snippet: "the homozygous mutants show increased neuronal excitability, spontaneous seizure and pre-mature death"
            explanation: >-
              Supports treating the homozygous knock-in as informative for the
              hyperexcitability node.

  - name: Humanized TBC1D24 G501R Drosophila (TLDc allele)
    species: Fruit fly
    genotype: Drosophila neuronally expressing human TBC1D24 p.Gly501Arg
    description: >-
      A fly expressing the human protein carrying a TLDc-domain variant. The
      informative arm is pharmacological: the activity-induced trafficking and
      locomotor defects are reversed by N-acetylcysteine amide or
      alpha-tocopherol, which is the only antioxidant-rescue result in this
      gene and the strongest argument that the TLDc domain acts as a redox
      sensor.
    publication: PMID:31257402
    modeled_mechanisms:
      - target: TLDc Domain Dysfunction
        relationship: PARTIALLY_RECAPITULATES
        fidelity: LOW
        model_scale: MOLECULAR
        description: >-
          Models the consequence of a TLDc missense variant, with an antioxidant
          rescue that identifies the pathway.
        limitations: >-
          G501R causes Rolandic epilepsy with exercise-induced dystonia in
          humans, a self-limiting phenotype at the opposite end of the spectrum
          from DEE16. The fly is a heterologous expression system, and the
          antioxidant rescue has not been tested against a DEE16 allele or in any
          human system. The result is a therapeutic lead for the gene, not
          evidence about DEE16 treatment.
        readouts:
          - name: Synaptic vesicle trafficking and sustained activity under antioxidant treatment
            target: TLDc Domain Dysfunction
            direction: RESTORED
            interpretation: >-
              Antioxidant treatment restores trafficking and behavioural activity
              in the mutant, implicating oxidative stress as the mediating step.
            evidence:
              - reference: PMID:31257402
                reference_title: "TBC1D24-TLDc-related epilepsy exercise-induced dystonia: rescue by antioxidants in a disease model."
                supports: SUPPORT
                evidence_source: MODEL_ORGANISM
                snippet: "which is rescued by treating TBC1D24G501R mutant animals with antioxidants N-acetylcysteine amide or alpha-tocopherol as indicated by restored synaptic vesicle trafficking levels and sustained behavioural activity"
                explanation: >-
                  Reports the rescue measurement and its direction.
        evidence:
          - reference: PMID:31257402
            reference_title: "TBC1D24-TLDc-related epilepsy exercise-induced dystonia: rescue by antioxidants in a disease model."
            supports: SUPPORT
            directness: INDIRECT
            evidence_source: MODEL_ORGANISM
            snippet: "The neuronal phenotypes of the TBC1D24G501R mutation are consistent with exacerbated oxidative stress sensitivity"
            explanation: >-
              Supports treating this fly as informative for TLDc-domain
              dysfunction. Indirect for DEE16 because the modelled allele causes a
              mild human phenotype.

experimental_models:
  - name: Patient-derived iPSC cortical neurons (severe vs mild TBC1D24 phenotype)
    experimental_model_type: IPSC_DERIVED_MODEL
    description: >-
      Reprogrammed neurons from a patient with severe developmental
      encephalopathy compared against neurons from a patient with mild
      early-onset epilepsy. The comparison is the point: the axon-formation
      defect is present only in the severe line, so it is a candidate cellular
      correlate of what separates DEE16 from the mild end of the same gene's
      spectrum.
    modeled_mechanisms:
      - target: Axonal Specification Failure
        relationship: RECAPITULATES
        fidelity: MODERATE
        model_scale: CELLULAR
        description: >-
          Human neurons carrying patient TBC1D24 variants reproduce the axon
          formation defect, and do so in a severity-dependent way.
        limitations: >-
          Two patient lines with no isogenic control, so the difference between
          them cannot be attributed to the variants alone. iPSC-derived neurons
          are developmentally immature and lack the cortical circuit context in
          which the human phenotype arises.
        readouts:
          - name: Axon formation in patient-derived neurons
            target: Axonal Specification Failure
            direction: DECREASED
            interpretation: >-
              Axon formation is impaired in the severe-phenotype line and
              unaffected in the mild-phenotype line.
            evidence:
              - reference: PMID:30858606
                reference_title: "TBC1D24 regulates axonal outgrowth and membrane trafficking at the growth cone in rodent and human neurons."
                supports: SUPPORT
                evidence_source: IN_VITRO
                snippet: "Reprogrammed neurons from a patient with severe developmental encephalopathy show significant axon formation defect that were absent from reprogrammed neurons of a patient with mild early onset epilepsy."
                explanation: >-
                  Reports the axon-formation measurement and its direction in
                  each line.
        evidence:
          - reference: PMID:30858606
            reference_title: "TBC1D24 regulates axonal outgrowth and membrane trafficking at the growth cone in rodent and human neurons."
            supports: SUPPORT
            evidence_source: IN_VITRO
            snippet: "Our data reveal that alterations of membrane trafficking at the growth cone induced by TBC1D24 loss of function cause axonal and excitability defects."
            explanation: >-
              Supports treating these human neurons as informative for the axonal
              node.

diagnosis:
  - name: Molecular confirmation of biallelic TBC1D24 variants
    description: >-
      The diagnosis rests on finding two pathogenic TBC1D24 variants in trans.
      Phase matters and is the step most often skipped: two variants reported on
      one report do not establish a recessive diagnosis until parental
      segregation shows they are on opposite alleles.
    evidence:
      - reference: PMID:25719194
        reference_title: TBC1D24-Related Disorders.
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "The diagnosis of a TBC1D24-related disorder is established in \nan individual with suggestive findings biallelic TBC1D24 pathogenic variants \nwhen the mode of inheritance is autosomal recessive"
        explanation: >-
          States the molecular criterion for a recessive TBC1D24 diagnosis.
    notes: >-
      Because TBC1D24 causes a continuum, the molecular result does not by itself
      assign which phenotype a patient has. DEE16 is a clinical call made on
      onset, seizure pattern, drug resistance, and developmental course.

  - name: Video EEG
    description: >-
      Ictal recording is what distinguishes DEE16 from other early-infantile
      epilepsies, since the migrating focal pattern and epilepsia partialis
      continua are electroclinical diagnoses. Seizures in this gene are also
      prone to electroclinical dissociation, so semiology alone under-reads the
      burden.
    evidence:
      - reference: PMID:27502353
        reference_title: Electroclinical phenotypes and outcomes in TBC1D24-related epilepsy.
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Ictal EEG characteristics included epilepsia partialis continua, epilepsy of infancy with migrating focal seizures, and other focal seizures with indiscrete interictal-ictal transitions."
        explanation: >-
          Establishes what ictal EEG contributes to the diagnosis in this gene.
      - reference: PMID:27502353
        reference_title: Electroclinical phenotypes and outcomes in TBC1D24-related epilepsy.
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "a variety of focal-onset seizures prone to electroclinical dissociation"
        explanation: >-
          The reason EEG rather than observation is needed to count seizures
          here.

  - name: Brain MRI
    description: >-
      Imaging supports the diagnosis by exclusion more than by a positive sign.
      It may be normal early; later it may show cerebral or cerebellar atrophy,
      delayed myelination, or hippocampal sclerosis. None of these predicts
      phenotype or prognosis, so MRI should not be used to grade severity.
    evidence:
      - reference: PMID:27281533
        reference_title: "TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Neuroimaging revealed cerebral or cerebellar atrophy in 16 patients. Five patients had delayed myelination; 3 others had hippocampal sclerosis."
        explanation: >-
          Lists the imaging findings this diagnostic step looks for.
      - reference: PMID:27281533
        reference_title: "TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features."
        supports: NO_EVIDENCE
        evidence_source: HUMAN_CLINICAL
        snippet: "There was no specific association among neuroimaging findings, phenotypic features, or prognosis."
        explanation: >-
          Records that imaging carries no prognostic information here, which is
          the caveat on this diagnostic step.

  - name: Audiologic assessment
    description: >-
      Hearing loss runs through the whole TBC1D24 spectrum and can be progressive,
      so audiology belongs in the diagnostic workup and in follow-up rather than
      only when hearing loss is suspected.
    evidence:
      - reference: PMID:25719194
        reference_title: TBC1D24-Related Disorders.
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "annual audiologic evaluations to assess for possible \nprogression of hearing loss"
        explanation: >-
          GeneReviews surveillance recommendation for TBC1D24-related disorders.

treatments:
  - name: Antiseizure pharmacotherapy
    description: >-
      Symptomatic pharmacologic management of seizures. No regimen is established
      for DEE16 and seizures are usually drug-resistant; across the wider TBC1D24
      spectrum individual patients have responded to zonisamide, topiramate,
      valproate, or phenobarbital, but those responders sit at the milder end.
    therapeutic_modality: SMALL_MOLECULE
    treatment_term:
      preferred_term: anticonvulsant agent therapy
      term:
        id: NCIT:C64172
        label: Anticonvulsant Therapy
      therapeutic_agent:
        - preferred_term: zonisamide
          term:
            id: CHEBI:10127
            label: zonisamide
        - preferred_term: topiramate
          term:
            id: CHEBI:63631
            label: topiramate
        - preferred_term: valproate
          term:
            id: CHEBI:39867
            label: valproic acid
        - preferred_term: phenobarbital
          term:
            id: CHEBI:8069
            label: phenobarbital
    target_mechanisms:
      - target: Neuronal Hyperexcitability and Hypersynchrony
        description: >-
          Antiseizure medications act on the hyperexcitable network rather than on
          the TBC1D24 trafficking lesion upstream of it, which is one reason
          control is so often incomplete.
    evidence:
      - reference: PMID:25719194
        reference_title: "TBC1D24-Related Disorders."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "symptomatic \npharmacologic management for seizures"
        explanation: >-
          GeneReviews recommends symptomatic pharmacologic seizure management for
          TBC1D24-related disorders.
      - reference: PMID:27281533
        reference_title: "TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features."
        supports: REFUTE
        evidence_source: HUMAN_CLINICAL
        snippet: "In 30 patients, epilepsy was drug-resistant24; 18 patients responded well to treatment."
        explanation: >-
          Refutes any claim of reliable pharmacologic control: the majority of the
          cohort was drug-resistant, and the responders were concentrated at the
          mild end of the spectrum rather than in DEE16.

  - name: Ketogenic diet therapy
    description: >-
      Two reported responses, both single cases. In one patient with
      TBC1D24-related drug-resistant epilepsy it resolved super-refractory status
      epilepticus; in another it produced a long seizure-free period that did not
      hold, with epilepsy recurring later. That second case is the useful one to
      know, because it sets the expectation: this is a lead worth trying in
      refractory status, not established or durable therapy.
    therapeutic_modality: BEHAVIORAL
    treatment_term:
      preferred_term: ketogenic diet therapy
      term:
        id: NCIT:C15447
        label: Dietary Intervention
    target_mechanisms:
      - target: Super-refractory status epilepticus
        description: >-
          Applied to break refractory status rather than to correct the
          underlying trafficking lesion.
    evidence:
      - reference: PMID:27502353
        reference_title: "Electroclinical phenotypes and outcomes in TBC1D24-related epilepsy."
        supports: SUPPORT
        directness: INDIRECT
        evidence_source: HUMAN_CLINICAL
        snippet: "Two seemingly unrelated Navajo patients with identical variations experienced super-refractory status epilepticus at 9 months of age, with one achieving resolution with ketogenic diet therapy."
        explanation: >-
          A single patient's response supports the diet as a candidate for
          refractory status; one of two patients with the same variant responded,
          so the inference to general efficacy is indirect.
      - reference: PMID:35350397
        reference_title: "Synaptopathies in Developmental and Epileptic Encephalopathies: A Focus on Pre-synaptic Dysfunction."
        supports: SUPPORT
        directness: INDIRECT
        evidence_source: OTHER
        snippet: "In addition, another one obtained the absence of epileptic episodes for a long time following a ketogenic diet, although epilepsy recurred later"
        explanation: >-
          A second reported response in the DEE-restricted series, and the reason
          this entry does not present the diet as durable: the benefit was lost.

  - name: Early intervention therapies
    description: >-
      Early educational intervention with physical, occupational, and speech
      therapy for the developmental delay, which is present from the outset
      rather than only after seizures begin.
    therapeutic_modality: BEHAVIORAL
    treatment_term:
      preferred_term: physical, occupational and speech therapy
      term:
        id: NCIT:C15315
        label: Rehabilitation
    target_mechanisms:
      - target: Global developmental delay
        description: >-
          Supportive rather than disease-modifying; it addresses function, not the
          cortical circuit lesion.
    evidence:
      - reference: PMID:25719194
        reference_title: "TBC1D24-Related Disorders."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "early educational intervention and physical, \noccupational, and speech therapy for developmental delay"
        explanation: >-
          GeneReviews recommends this bundle of early interventions for
          developmental delay in TBC1D24-related disorders.

  - name: Genetic counseling
    description: >-
      Counseling for the 25% autosomal recessive recurrence risk. Once both
      familial variants are identified, prenatal and preimplantation genetic
      testing are available, and testing at-risk sibs allows seizures to be
      treated as early as possible.
    treatment_term:
      preferred_term: Genetic Counseling
      term:
        id: NCIT:C15240
        label: Genetic Counseling
    evidence:
      - reference: PMID:25719194
        reference_title: "TBC1D24-Related Disorders."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Once the TBC1D24 pathogenic variant(s) have been identified in an affected \nfamily member, prenatal and preimplantation genetic testing are possible."
        explanation: >-
          GeneReviews describes the reproductive testing options that follow
          genetic counseling.
      - reference: PMID:25719194
        reference_title: "TBC1D24-Related Disorders."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Molecular genetic testing for the \nfamilial TBC1D24 pathogenic variant(s) in older and younger sibs of a proband is \nappropriate in order to identify as early as possible those who would benefit \nfrom early treatment of seizures and/or hearing loss."
        explanation: >-
          GeneReviews recommends testing at-risk sibs to enable early treatment.

  - name: Neurologic surveillance with EEG
    description: >-
      Serial neurologic evaluation with EEG, at a frequency set by seizure burden
      and progression.
    treatment_term:
      preferred_term: neurologic surveillance
      term:
        id: NCIT:C15747
        label: Supportive Care
    evidence:
      - reference: PMID:25719194
        reference_title: "TBC1D24-Related Disorders."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Neurologic evaluations with EEGs depending on seizure frequency \nand/or progression"
        explanation: >-
          GeneReviews surveillance recommendation for TBC1D24-related disorders.

discussions:
  - discussion_id: dee16_genotype_phenotype_discordance
    kind: KNOWLEDGE_GAP
    prompt: >-
      Why does the same TBC1D24 loss-of-function lesion produce a devastating
      early-infantile encephalopathy in one family and a self-limiting myoclonic
      epilepsy with normal intellect in another?
    attaches_to:
      - pathophysiology#Biallelic TBC1D24 Loss of Function
      - genetic#TBC1D24
    rationale: >-
      Truncating variants correlate with the severe end, but the correlation is
      loose and does not run through the obvious mechanism. Neurite-outgrowth
      assays found that the variants causing the most severe clinical disease are
      not the ones that most disrupt the protein in culture, so residual protein
      function measured that way does not explain the phenotypic split. Something
      else - domain-specific effects, isoform usage, modifiers, or an assay that
      does not capture the relevant function - is doing the work. Until it is
      identified, DEE16 cannot be predicted from genotype at the bedside.

  - discussion_id: dee16_microexon_switch_human_validity
    kind: HUMAN_MODEL_MISMATCH
    prompt: >-
      Does the postnatal micro-exon splicing switch that times seizure onset in
      the S324Tfs*3 mouse operate in human DEE16, including in patients whose
      variants lie outside that micro-exon?
    attaches_to:
      - pathophysiology#Postnatal Micro-Exon Isoform Switch
      - animal_models#Tbc1d24 S324Tfs*3 knock-in mouse
    rationale: >-
      The mouse gives an unusually clean mechanistic account of why seizures
      start when they do: before the developmental splicing switch the mutant
      allele still yields functional protein. But the account is allele-specific
      by construction, since it depends on the variant sitting inside the
      micro-exon. Human DEE16 variants are distributed across the coding
      sequence, and no human neuronal system has been shown to undergo the same
      switch. So the model may be explaining the timing of one variant rather
      than the timing of the disease.
    proposed_experiments:
      - experiment_id: dee16_human_microexon_timecourse
        name: Micro-exon isoform quantification in human neurons across development
        description: >-
          Quantify micro-exon-containing versus micro-exon-skipping TBC1D24
          transcripts in human iPSC-derived cortical neurons across
          differentiation, and in post-mortem human cortex across the first year
          of life, to test whether the developmental switch occurs in humans.
        would_support:
          - pathophysiology#Postnatal Micro-Exon Isoform Switch
        supporting_outcome:
          - >-
            Micro-exon-containing transcripts rise sharply during a defined
            postnatal window in human neurons, mirroring the mouse P15 switch.
        refuting_outcome:
          - >-
            Micro-exon inclusion is constitutive or absent across human
            development, indicating the timing mechanism is mouse-specific.

  - discussion_id: dee16_tldc_oxidative_contribution
    kind: KNOWLEDGE_GAP
    prompt: >-
      Does loss of TLDc-domain oxidative stress protection contribute to the
      progressive atrophy in DEE16, or is the atrophy entirely accounted for by
      the developmental lesion and seizure-related injury?
    attaches_to:
      - pathophysiology#TLDc Domain Dysfunction
      - pathophysiology#Progressive Cerebral and Cerebellar Atrophy
    rationale: >-
      The question has moved but is not closed. An early purified-domain assay
      found no v-ATPase interaction for TBC1D24, but that negative was later
      overturned in mammalian brain, so read-across from OXR1 and NCOA7 was
      premature rather than wrong. The 2024 KIBRA
      interaction gives the domain a specific partner and a mechanism, and the
      humanized fly gives it a redox-sensor role with antioxidant rescue. But
      both results come from missense alleles, one of which causes a
      self-limiting Rolandic epilepsy, while DEE16 is enriched for truncating
      alleles that delete the domain outright. Nothing has measured oxidative
      injury or KIBRA-pathway disruption in DEE16 patient neurons or brain
      tissue. This matters practically: if oxidative injury contributes, it is
      the one arm of the mechanism with an obvious pharmacological handle, since
      the trafficking lesion is not currently druggable.
    proposed_experiments:
      - experiment_id: dee16_antioxidant_rescue_in_dee16_alleles
        name: Antioxidant rescue tested against DEE16 truncating alleles
        description: >-
          Repeat the N-acetylcysteine-amide and alpha-tocopherol rescue in
          patient-derived DEE16 neurons and in a model carrying a truncating
          allele, rather than the mild G501R missense allele, measuring synaptic
          vesicle trafficking and oxidative-stress markers.
        would_support:
          - pathophysiology#TLDc Domain Dysfunction
        supporting_outcome:
          - >-
            Antioxidant treatment restores vesicle trafficking in DEE16 neurons
            carrying truncating alleles, making the redox arm relevant to the
            severe phenotype and pointing at a treatable step.
        refuting_outcome:
          - >-
            No rescue in truncating-allele neurons, indicating the redox
            mechanism is specific to TLDc missense alleles and does not explain
            DEE16.

notes: >-
  Relationship to the other TBC1D24 entries in this knowledge base. DOORS
  syndrome, myoclonic epilepsy in infancy, DFNB93, and DFNA65 are separate
  entries for separate MONDO concepts in the same gene's spectrum; GeneReviews
  treats all of them as one continuum. DEE16 is kept separate because MONDO
  keeps it separate (MONDO:0014133, OMIM:615338) and because the phenotype
  distinctions are clinically load-bearing: drug resistance, early death, and
  the migrating focal seizure pattern do not occur at the mild end.

  A consequence of that continuum, and the main sourcing rule in this entry: the
  large TBC1D24 series pool all epilepsy phenotypes, so frequencies quoted from
  PMID:27281533 describe the whole spectrum, not DEE16 alone. Three things follow.
  Where that paper reports its loss-of-function subgroup separately, the subgroup
  is cited instead. Where a DEE-restricted source exists, it takes precedence:
  PMID:35350397 carries a 30-patient TBC1D24-DEE compilation, and its figures
  drive onset, mortality, migrating-seizure frequency and drug resistance here.
  Where both are cited on one phenotype, the pan-spectrum figure is kept for
  contrast and its explanation says so, because the two genuinely disagree -
  mortality is 19% across the spectrum and 13/30 in the DEE subset, and myoclonic
  seizures are commoner in the spectrum than in DEE because the mild myoclonic
  phenotypes sit in that denominator.

  What that rule does not do is license dropping a finding because its only
  count is pan-spectrum. Where no DEE-restricted figure exists, the phenotype is
  still curated with the pooled count quoted and `frequency:` omitted, and the
  omission is explained in that phenotype's `notes:`. That is how the
  neuroimaging findings, hypotonia, and the associated findings (visual
  impairment, ataxia, extrapyramidal signs, hearing loss) are handled.

  Prevalence is deliberately absent. No population estimate exists for DEE16 as
  a distinct entity; the published denominators are TBC1D24 patient series
  ascertained through epilepsy gene panels, which cannot support a rate.

📚

References & Deep Research

References

5

PMID:25719194

TBC1D24-Related Disorders.

No top-level findings curated for this source.

PMID:27281533

TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features.

No top-level findings curated for this source.

PMID:23526554

Novel compound heterozygous mutations in TBC1D24 cause familial malignant migrating partial seizures of infancy.

No top-level findings curated for this source.

PMID:39237642

Developmental and epileptic encephalopathies.

No top-level findings curated for this source.

PMID:39214300

Interaction between the TBC1D24 TLDc domain and the KIBRA C2 domain is disrupted by two epilepsy-associated TBC1D24 missense variants.

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.

Evaluations and curation notes (1)

Create: Developmental And Epileptic Encephalopathy 16 (TBC1D24) · 2026-09-07T04:01:16Z · View source

De novo curation of DEE16 (MONDO:0014133, OMIM:615338, biallelic TBC1D24). Deep research: falcon (Edison Scientific), 731s, report at research/Developmental_And_Epileptic_Encephalopathy_16-deep-research-falcon.md plus citations sidecar and one markdown artifact. The run's own validation reported 11/11 references resolved (confabulation_rate 0.0), 28/28 CURIEs resolved, 0 off-topic. Its needs_review flag was set by a single mislabelled-term entry naming MONDO:0014133 'if available' -- that is the research template's literal '(MONDO ID) (if available)' text being parsed as a label, not a bad binding, and was disregarded on that basis. The report carried no PMIDs (falcon cites by author-year key), so its 12 DOIs were swept from the body and converted via the PMC ID converter; all resolved except the Nature Reviews primer and a PhD thesis, and 10.1093/brain/awz175 turned out to be a paper already cited (PMID:31257402). Literature: 16 cited references, all PMID-keyed and cached. Core clinical basis is the GeneReviews TBC1D24 chapter (PMID:25719194, tagged GeneReviews in top-level references) plus the 48-patient pan-TBC1D24 cohort (PMID:27281533), the index MMPSI family report (PMID:23526554), and an independent drug-resistant series (PMID:27502353). Mechanism rests on the ARF6 interaction (PMID:20727515, PMID:24469796), the Skywalker phosphoinositide pocket (PMID:27669036), growth-cone and axonal work including patient iPSC neurons (PMID:30858606), presynaptic endocytosis in mouse (PMID:30335140, PMID:30602030), postsynaptic spine maintenance (PMID:32004315), and the TLDc domain (PMID:26668325, PMID:31257402, PMID:39214300). Curation decisions worth recording. Spectrum conflation is the main risk for this gene, so every pooled cohort figure is attributed to the pan-TBC1D24 series rather than to DEE16, and where PMID:27281533 reports its loss-of-function subgroup separately that subgroup is cited instead. Prevalence was left absent: no DEE16-specific denominator exists. The falcon artifact table offered a DEE16-specific onset figure (28 of 30 cases by 3 months) that could not be traced to a resolvable citation, so it was not used. Two evidence items are deliberately REFUTE. PMID:27281533's neurite-outgrowth result contradicts a simple residual-function model of the genotype-phenotype correlation, and PMID:39214300 reports no V-ATPase interaction for the TBC1D24 TLDc domain, contradicting read-across from OXR1/NCOA7. A third REFUTE on PMID:30335140 records that heterozygous carriers have been reported with seizures, against the GeneReviews statement that carriers are typically asymptomatic; both are cited on the inheritance block rather than one being suppressed. Death in childhood is curated with an unbound preferred_term. HP:0003819 and HP:0001522 both sit under Clinical modifier rather than Phenotypic abnormality, so they fall outside the PhenotypeTerm dynamic enum; the reason is recorded in the phenotype's notes. This follows existing KB practice. Conformance: three nodes declare conforms_to against synaptic_vesicle_cycle (Synaptic Vesicle Cycle Protein Deficiency, Impaired Synaptic Vesicle Endocytosis and Recycling) and epilepsy_excitation_inhibition_imbalance (Neuronal Hyperexcitability and Hypersynchrony). Validation: just validate-disorders passed (schema, terms, references; 85/85 snippets verified against cached references). Also green: check-entity-refs, check-causal-targets, check-enum-values, check-duplicate-keys, check-qualifier-terms, check-title-snippets, check-snippet-length, check-snippet-grading, check-folded-hyphens, check-stubs. Two self-inflicted gate failures were found and fixed before commit: line-ending hyphens in the folded description scalar, and one PMID:23526554 quote graded both HUMAN_CLINICAL and IN_VITRO, resolved by splitting the snippet so the human-genetics sentence and the functional-assay sentence are separate items. reference_title backfilled with just backfill-reference-titles. Side effects: fetching refreshed three existing cache files (PMID_25719194, PMID_30602030 cosmetically; PMID_39758816 upgraded from abstract to full text). Content was only added, and DOORS_Syndrome, the other entry citing PMID:39758816, was re-validated and still passes 34/34. The stub stubs/Developmental_And_Epileptic_Encephalopathy_16.yaml was deleted.

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Developmental and Epileptic Encephalopathy 16: Disease-Characteristics Report

Edison Scientific Literature 28 citations 2026-09-07T03:01:58.290315

Developmental and Epileptic Encephalopathy 16: Disease-Characteristics Report

Executive summary and evidence boundaries

Developmental and epileptic encephalopathy 16 (DEE16), formerly early-infantile epileptic encephalopathy 16 (EIEE16), is an ultrarare, usually autosomal-recessive neurodevelopmental disorder caused by biallelic pathogenic variants in TBC1D24. It is characterized by neonatal or early-infantile seizures—often multiple, prolonged, fever-sensitive, and drug-resistant—together with severe developmental impairment. DEE16 is the severe end of a much broader allelic spectrum that also includes familial infantile myoclonic epilepsy, focal epilepsy, progressive myoclonus phenotypes, DOORS syndrome, and dominant or recessive nonsyndromic hearing loss. Findings from those other phenotypes should not automatically be assigned to DEE16. (tona2019thephenotypiclandscape pages 2-3, spoto2022synaptopathiesindevelopmental pages 11-13, balestrini2016tbc1d24genotype–phenotypecorrelation pages 1-2)

The evidence base is small and consists predominantly of individual cases, literature-assembled cohorts, patient-derived neurons, and animal models. Consequently, many quoted frequencies below are from a 48-person pan-TBC1D24 epilepsy cohort, not a population-based DEE16 cohort. Disease-specific prevalence, survival curves, treatment-response rates, and quality-of-life scores are unavailable. The retrieval system supplied DOI records but generally did not expose PubMed identifiers; PMIDs are therefore not invented or inferred.

Domain	Curated finding	Ontology or identifier suggestions	Evidence scope and limitations
Identity	Developmental and epileptic encephalopathy 16, or DEE16, was formerly called early-infantile epileptic encephalopathy 16, or EIEE16. It is a severe early-onset epilepsy and neurodevelopmental disorder within the TBC1D24-related disorder spectrum.	OMIM: 615338; MONDO: MONDO:0014133, supplied by user; synonyms: DEE16, EIEE16, TBC1D24-associated early-infantile epileptic encephalopathy	DEE16 must not be conflated with milder TBC1D24 epilepsies, dominant or recessive nonsyndromic deafness, or DOORS syndrome. (tona2019thephenotypiclandscape pages 2-3, tona2019thephenotypiclandscape pages 1-2)
Etiology and inheritance	Classic DEE16 is caused by germline biallelic pathogenic variants in TBC1D24, usually homozygous or compound heterozygous, and follows autosomal-recessive inheritance.	Gene: TBC1D24; NCBI Gene: 57465; inheritance: autosomal recessive	A broad 48-person epilepsy cohort was almost entirely biallelic. Isolated heterozygous variants and multigene 16p13.3 deletions have been associated with other epilepsy phenotypes but do not establish classic DEE16. (finelli2019theepilepsyassociatedprotein pages 5-6, balestrini2016tbc1d24genotype–phenotypecorrelation pages 3-4)
Onset and seizures	DEE-focused literature reports onset from approximately 20 minutes after birth to 8 months, with 28 of 30 reported DEE cases beginning by 3 months. Seizures may be myoclonic, clonic, tonic, focal, multifocal, migrating focal, generalized tonic-clonic, epileptic spasms, or prolonged status episodes.	HPO: HP:0001250 Seizure; HP:0002123 Generalized myoclonic seizure; HP:0002069 Bilateral tonic-clonic seizure; HP:0012469 Infantile spasms; HP:0002133 Status epilepticus	The 30-case figures derive from a literature-compiled TBC1D24-DEE table, not a prospective DEE16 registry. In the broader 48-person TBC1D24 epilepsy cohort, onset averaged 7 months, range less than 1 hour to 8 years; 60% had myoclonic or clonic seizures and 79% had prolonged seizures or status epilepticus. (spoto2022synaptopathiesindevelopmental pages 11-13, balestrini2016tbc1d24genotype–phenotypecorrelation pages 1-2, balestrini2016tbc1d24genotype–phenotypecorrelation pages 2-3)
Triggers and EEG	Fever or infection may precipitate seizures or status. Fatigue, repetitive movement, feeding, sensory stimulation, drowsiness, constipation, and delayed medication have also been reported as triggers. EEG may show background slowing, multifocal or generalized epileptiform discharges, or hypsarrhythmia.	HPO: HP:0002373 Febrile seizures; HP:0011182 EEG abnormality; HP:0010841 Multifocal epileptiform discharges; HP:0002521 Hypsarrhythmia	Evidence largely comes from the broader TBC1D24 epilepsy spectrum: fever or infection precipitated episodes in 19 of 48 patients, whereas 13 of 48 had a normal interictal EEG. Clinical photosensitivity was absent in that cohort. (spoto2022synaptopathiesindevelopmental pages 11-13, balestrini2016tbc1d24genotype–phenotypecorrelation pages 2-3, balestrini2016tbc1d24genotype–phenotypecorrelation pages 3-4)
Neurodevelopment and neurologic phenotype	Severe or profound global developmental delay or intellectual disability, psychomotor stagnation or regression, hypotonia, impaired speech, and major motor disability are characteristic. Ataxia, dystonia or other extrapyramidal signs, visual impairment, and sensorineural hearing loss occur variably.	HPO: HP:0001263 Global developmental delay; HP:0001249 Intellectual disability; HP:0001252 Hypotonia; HP:0001251 Ataxia; HP:0001332 Dystonia; HP:0000407 Sensorineural hearing impairment; HP:0000505 Visual impairment	In the broader cohort, 39 of 48 had developmental delay or intellectual disability, but eight relatives with benign familial infantile myoclonic epilepsy had normal development. Spectrum-level frequencies therefore should not be treated as DEE16-specific estimates. (balestrini2016tbc1d24genotype–phenotypecorrelation pages 2-3, spoto2022synaptopathiesindevelopmental pages 11-13, balestrini2016tbc1d24genotype–phenotypecorrelation pages 3-4)
Neuroimaging and anatomy	Imaging may initially be normal or may show cerebral or cerebellar atrophy, delayed myelination, cerebellar signal abnormalities or hypoplasia, and occasionally hippocampal sclerosis. The central nervous system is primarily affected, particularly the cerebral cortex, hippocampus, cerebellum, axons, and synapses.	HPO: HP:0002059 Cerebral atrophy; HP:0001272 Cerebellar atrophy; HP:0012448 Delayed myelination; HP:0001321 Cerebellar hypoplasia; UBERON suggestions: cerebral cortex, hippocampus, cerebellum	In the broader 48-person cohort, 16 had cerebral or cerebellar atrophy, five had delayed myelination, three had hippocampal sclerosis, and 11 had cerebellar abnormalities. No imaging feature consistently predicted phenotype or prognosis. (balestrini2016tbc1d24genotype–phenotypecorrelation pages 2-3, balestrini2016tbc1d24genotype–phenotypecorrelation pages 3-4)
Molecular mechanism	Pathogenic variants generally reduce or disrupt TBC1D24 function. Defects involving its TBC lipid-binding and TLDc domains disturb ARF6- and Rab-related membrane trafficking, growth-cone endocytosis, synaptic-vesicle recycling, neuronal migration, axon formation, dendritic-spine maintenance, and oxidative-stress resistance. These defects alter neuronal connectivity and excitability, leading to seizures and developmental impairment.	GO suggestions: synaptic vesicle endocytosis; endosomal transport; regulation of ARF protein signal transduction; axon development; neuron migration; dendritic spine maintenance; response to oxidative stress. CL suggestions: neuron; cortical neuron; hippocampal neuron	ARF6, axonal, and synaptic findings are demonstrated in rodent neurons, patient-derived induced pluripotent stem-cell neurons, and mice. The complete causal chain to human DEE16 remains partly inferred. Severe patient-derived neurons showed axon-formation defects absent from a milder epilepsy line. (pepe2023arolein pages 14-17, finelli2019theepilepsyassociatedprotein pages 13-14, lin2020theepilepsyand pages 1-2, aprile2019tbc1d24regulatesaxonal pages 1-2)
2024 mechanistic development	The TBC1D24 TLDc domain specifically binds the C2 domain of KIBRA, encoded by WWC1. Recessive epilepsy-associated variants p.Gly511Arg and p.Ala515Val abolished or weakened this interaction, linking TBC1D24 dysfunction to a synaptic and cognition-related scaffold pathway.	Genes and proteins: TBC1D24 and WWC1 or KIBRA; candidate pathways: Hippo signaling, scaffold organization, and synaptic signaling	Demonstrated using yeast two-hybrid and nanoscale pull-down assays, with hippocampal co-expression supporting biological plausibility. Necessity of the interaction in human DEE16 and its therapeutic tractability remain unproven. Published online 28 August 2024. (tona2024interactionbetweenthe pages 13-14, tona2024interactionbetweenthe pages 1-2)
Diagnosis	Diagnosis combines seizure and developmental history, video EEG, brain MRI, hearing, vision, and neurologic assessments, plus molecular confirmation of pathogenic or likely pathogenic variants on opposite TBC1D24 alleles. Trio whole-exome or whole-genome sequencing, or a comprehensive epilepsy panel with deletion and duplication analysis, is preferred. Parental segregation is essential.	Suggested tests: trio WES; trio WGS; epilepsy multigene panel; copy-number analysis; ACMG and AMP variant classification	A 2024 general DEE cohort found pathogenic variants in 35 of 82 WES tests, a 43% diagnostic yield, supporting first-line WES; this is not a DEE16-specific yield. Chromosomal microarray is useful when a copy-number variant is suspected. (vetri2024wholeexomesequencing pages 1-2, scheffer2024developmentalandepileptic pages 1-4)
Treatment status	No approved TBC1D24- or DEE16-specific disease-modifying treatment exists. Management is individualized with antiseizure polytherapy and rescue treatment for prolonged seizures, plus feeding, respiratory, hearing, vision, physical, occupational, speech, developmental, and psychosocial support.	NCIT suggestions: Anticonvulsant Therapy; Electroencephalography; Physical Therapy; Occupational Therapy; Speech Therapy; Genetic Counseling	In the broader cohort, 30 of 48 had drug-resistant epilepsy and 18 responded well. Benefits were reported with valproate, phenobarbital, phenytoin plus clobazam, zonisamide, topiramate, and other combinations, but uncontrolled observations do not establish a preferred DEE16 regimen. (balestrini2016tbc1d24genotype–phenotypecorrelation pages 1-2, balestrini2016tbc1d24genotype–phenotypecorrelation pages 2-3)
Experimental treatment	N-acetylcysteine amide and alpha-tocopherol restored vesicle trafficking and sustained activity in a humanized TBC1D24 p.Gly501Arg fly model, suggesting oxidative-stress modulation as a research direction.	CHEBI suggestions: N-acetylcysteine amide; alpha-tocopherol; antioxidant	Rescue was demonstrated in Drosophila modeling a milder TLDc-associated epilepsy and dystonia phenotype, not in humans or a DEE16 clinical trial. No relevant interventional DEE16 trial was identified in the search. (luthy2019tbc1d24tldcrelatedepilepsyexerciseinduced pages 1-2)
Prognosis	DEE16 is chronic and may cause profound lifelong disability, persistent drug-resistant seizures, and childhood death. Respiratory failure, infection-associated status epilepticus, and sudden unexpected death in epilepsy are recognized risks across severe TBC1D24 epilepsies.	HPO: HP:0001250 Seizure; HP:0001263 Global developmental delay; HP:0003811 Lethal infantile encephalopathy	In the broader cohort, 9 of 48 patients, or 19%, were deceased; mean age at death was 37 months, range 6 to 96 months, including one probable SUDEP. Among 17 individuals with a truncating or splice variant, 15 had drug-resistant epilepsy and eight died by age seven. These are retrospective spectrum-level data, not DEE16 survival estimates. (balestrini2016tbc1d24genotype–phenotypecorrelation pages 2-3, balestrini2016tbc1d24genotype–phenotypecorrelation pages 3-4)
Models	Models include patient-derived induced pluripotent stem-cell neurons, TBC1D24-silenced rodent cortical neurons, Drosophila skywalker mutants and humanized flies, and several mice. Homozygous S324Tfs*3 mice develop abrupt spontaneous seizures at postnatal day 15; homozygous F251L mice show hyperexcitability, spontaneous seizures, and premature death.	Taxa: Homo sapiens NCBITaxon:9606; Mus musculus NCBITaxon:10090; Rattus norvegicus NCBITaxon:10116; Drosophila melanogaster NCBITaxon:7227. Model types: knock-in; knockdown; humanized transgenic; induced pluripotent stem-cell-derived neuron	S324Tfs*3 seizure onset coincides with a developmentally regulated micro-exon switch. F251L destabilizes TBC1D24 and impairs excitatory-synapse maintenance. Models reproduce selected seizure, survival, trafficking, axonal, or cognitive features, but not the full human multisystem phenotype. (tona2019thephenotypiclandscape pages 1-2, lin2020theepilepsyand pages 1-2, aprile2019tbc1d24regulatesaxonal pages 1-2)
Epidemiologic evidence gap	DEE16 is ultrarare, but no reliable disease-specific prevalence, incidence, carrier frequency, ethnic enrichment, founder effect, or sex ratio has been established.	MONDO: MONDO:0014133, supplied by user	The 48-person spectrum cohort included 28 males and 20 females, but non-population-based ascertainment precludes estimation of a sex ratio. General DEE incidence estimates must not be assigned to DEE16. (balestrini2016tbc1d24genotype–phenotypecorrelation pages 1-2, scheffer2024developmentalandepileptic pages 1-4)

Table: Concise curation of DEE16 identity, genetics, phenotype, mechanism, diagnosis, management, prognosis, and experimental models. Evidence boundaries distinguish DEE16-specific observations from broader TBC1D24-spectrum findings.

1. Disease information

Definition. DEE16 is a genetic developmental and epileptic encephalopathy in which the underlying TBC1D24 defect impairs neurodevelopment and synaptic function, while recurrent seizures and epileptiform activity may add further developmental burden. This conforms to the modern ILAE concept of DEE, which recognizes contributions from both the primary etiology and epileptic activity. (vetri2024wholeexomesequencing pages 1-2, scheffer2024developmentalandepileptic pages 1-4)

Identifiers and synonyms. The principal identifiers are OMIM 615338 and the user-specified MONDO:0014133. Common names are “developmental and epileptic encephalopathy 16,” “DEE16,” “early-infantile epileptic encephalopathy 16,” “EIEE16,” and “TBC1D24-associated early-infantile epileptic encephalopathy.” No dedicated MeSH, ICD-10, or ICD-11 code was verified; clinically it is ordinarily represented under broader epilepsy/epileptic-encephalopathy and developmental-disability codes. EIEE16 can occur with or without hearing loss. (tona2019thephenotypiclandscape pages 2-3, tona2019thephenotypiclandscape pages 1-2)

Data provenance. Available knowledge is aggregated from published patients and families rather than EHR-derived population surveillance. The largest detailed source examined assembled 11 newly characterized and 37 previously published individuals with TBC1D24-related epilepsy. Its abstract states: “TBC1D24-related epilepsy syndromes show marked phenotypic pleiotropy,” ranging from benign epilepsy to early-onset encephalopathy with severe delay and early death. (balestrini2016tbc1d24genotype–phenotypecorrelation pages 1-2)

2. Etiology, risk, protection, and environment

Classic DEE16 results from germline biallelic TBC1D24 pathogenic variants, either homozygous or compound heterozygous. Consanguinity increases the probability that both parents carry the same rare allele, but affected children also occur in nonconsanguineous families. Segmental uniparental isodisomy is a rare alternative route to biallelic disease. Heterozygous TBC1D24 variants and multigene 16p13.3 deletions can produce other epilepsy phenotypes, but these do not define classic recessive DEE16. (finelli2019theepilepsyassociatedprotein pages 5-6, balestrini2016tbc1d24genotype–phenotypecorrelation pages 2-3, balestrini2016tbc1d24genotype–phenotypecorrelation pages 3-4)

No validated environmental cause, lifestyle risk factor, infectious cause, genetic protective allele, or human protective exposure is known. Fever and infection can trigger seizures/status epilepticus in an affected individual but do not cause the Mendelian disease: 19 of 48 individuals in the broad cohort had fever- or infection-precipitated episodes. Fatigue, drowsiness, repetitive movement, feeding, sensory stimulation, constipation, and delayed medication were additional reported seizure precipitants. (balestrini2016tbc1d24genotype–phenotypecorrelation pages 1-2, balestrini2016tbc1d24genotype–phenotypecorrelation pages 2-3)

A plausible gene–environment interaction is reduced cellular tolerance of activity-associated reactive oxygen species: TLDc-domain dysfunction increased oxidative-stress sensitivity in a fly model. This is mechanistic/preclinical evidence, not proof that environmental oxidants alter human penetrance. (luthy2019tbc1d24tldcrelatedepilepsyexerciseinduced pages 1-2)

3. Phenotypes

Core neurologic phenotype

A DEE-focused literature compilation identified seizure onset from approximately 20 minutes after birth to 8 months, with 28/30 cases beginning by 3 months. Reported seizure types include myoclonic and clonic seizures, tonic seizures, focal and multifocal seizures, migrating focal seizures, generalized tonic–clonic seizures, epileptic spasms, absence seizures, and convulsive or nonconvulsive status epilepticus. Suggested terms include HP:0001250 Seizure, HP:0002123 generalized myoclonic seizure, HP:0012469 infantile spasms, HP:0002069 bilateral tonic-clonic seizure, and HP:0002133 status epilepticus. (spoto2022synaptopathiesindevelopmental pages 11-13)

In the broader cohort, onset averaged 7 months but ranged from under 1 hour to 8 years; 29/48 (60%) had myoclonic or clonic seizures and 38/48 (79%) had status epilepticus or seizures lasting over five minutes. Myoclonus could be segmental or generalized, unilateral or bilateral, migrating, alternating, rhythmic or pseudorhythmic, and could persist in clusters for days. These spectrum-wide figures likely underestimate the severity and earlier onset of DEE16. (balestrini2016tbc1d24genotype–phenotypecorrelation pages 1-2, balestrini2016tbc1d24genotype–phenotypecorrelation pages 2-3)

EEG. Findings include slow background, multifocal or generalized epileptiform abnormalities, focal discharges, and hypsarrhythmia; suggested terms are HP:0011182 EEG abnormality, HP:0010841 multifocal epileptiform discharges, and HP:0002521 hypsarrhythmia. Thirteen of 48 spectrum patients had a normal interictal recording, illustrating that a normal single EEG does not exclude a TBC1D24 disorder. Only two had a photoparoxysmal response, and none showed clinical photosensitivity. (spoto2022synaptopathiesindevelopmental pages 11-13, balestrini2016tbc1d24genotype–phenotypecorrelation pages 3-4)

Development, motor function, behavior, and sensory findings

Severe global developmental delay or intellectual disability, psychomotor stagnation/regression, hypotonia, absent or very limited speech, and marked motor disability are typical of DEE16. Relevant terms include HP:0001263 global developmental delay, HP:0001249 intellectual disability, HP:0001252 hypotonia, and HP:0001344 absent speech. Across the broader cohort, 39/48 had developmental delay or intellectual disability, whereas eight relatives with benign familial infantile myoclonic epilepsy had normal development—an important demonstration of allelic pleiotropy. (spoto2022synaptopathiesindevelopmental pages 11-13, balestrini2016tbc1d24genotype–phenotypecorrelation pages 3-4)

Variable associated findings include ataxia (HP:0001251), dystonia (HP:0001332), other extrapyramidal signs, visual impairment (HP:0000505), and sensorineural hearing impairment (HP:0000407). In the spectrum cohort, seven had ataxia, eight had extrapyramidal signs, 13/48 (27%) had visual impairment, and three non-DOORS patients had bilateral sensorineural deafness. Acral, nail, and bone abnormalities instead suggest overlapping DOORS syndrome and should not be considered obligatory DEE16 manifestations. (balestrini2016tbc1d24genotype–phenotypecorrelation pages 2-3, balestrini2016tbc1d24genotype–phenotypecorrelation pages 3-4)

Quality of life. No DEE16-specific EQ-5D, SF-36, PROMIS, or caregiver-burden study was found. Severe epilepsy, nonverbal status, dependence for mobility and activities of daily living, sensory impairment, feeding/respiratory risks, and repeated emergency care imply profound patient and caregiver burden. Contemporary experts emphasize that DEEs require substantial lifelong support and impose high psychosocial burden on families and communities. (scheffer2024developmentalandepileptic pages 1-4)

4. Genetic and molecular information

Gene. TBC1D24 encodes a 559-amino-acid protein in its longest cited isoform, containing an N-terminal TBC region and C-terminal TLDc domain. TBC1D24 is expressed broadly but is particularly relevant in neurons and is found at the trans-Golgi network, clathrin-coated vesicles, growth cones, and pre- and postsynaptic sites. Suggested identifiers are HGNC symbol TBC1D24 and NCBI Gene 57465. (pepe2023arolein pages 14-17, tona2024interactionbetweenthe pages 1-2, aprile2019tbc1d24regulatesaxonal pages 1-2)

Variant classes and interpretation. Reported disease alleles include missense, nonsense, frameshift, splice-site, small insertion/deletion, and larger copy-number variants. Examples in DEE-focused compilations include p.Ser45Arg, p.Gly139Val, p.Pro144Leu, p.Lys206Glu, p.Arg237Trp, p.Arg266Cys, p.Gly346Val, p.Gly359Arg, and p.Glu373Lys. Classification should follow current ACMG/AMP criteria and require phenotype concordance, population rarity, segregation, phase confirmation, predicted loss of function where applicable, and functional evidence. No single list should be treated as permanently pathogenic without checking the current ClinVar record and transcript. (spoto2022synaptopathiesindevelopmental pages 11-13)

All well-supported patients in the 2016 epilepsy cohort had biallelic mutations except one clinically typical DOORS case in whom only one variant was detected. Frameshift, nonsense, or splice variants generally predicted worse outcome: among 17 carriers of at least one such allele, 15 had drug-resistant epilepsy and eight died by age seven. Nevertheless, missense effects are heterogeneous, and no reliable position-only genotype–phenotype rule exists. Variants associated with the severest disease were not always the most disruptive in neurite-outgrowth assays. (balestrini2016tbc1d24genotype–phenotypecorrelation pages 1-2, balestrini2016tbc1d24genotype–phenotypecorrelation pages 3-4)

DEE16 alleles are expected to be absent or extremely rare in population databases; an exact gnomAD frequency must be reported variant by variant. They are germline, not recognized somatic cancer drivers. No validated modifier gene, disease-specific episignature, methylation abnormality, repeat expansion, aneuploidy, or recurrent balanced rearrangement is established. Multigene 16p13.3 deletions involving TBC1D24 can cause epilepsy, microcephaly, and developmental delay but represent a contiguous-gene disorder rather than canonical DEE16. (finelli2019theepilepsyassociatedprotein pages 5-6)

5. Environmental information

DEE16 is not caused by toxins, radiation, pollution, diet, smoking, alcohol, occupation, or an infectious agent. Fever/infection may lower seizure threshold and precipitate prolonged episodes. Accordingly, rapid treatment of intercurrent illness, hydration, avoidance of missed antiseizure doses, and an individualized rescue plan are clinically relevant, although they do not alter the inherited lesion. No disease-specific dietary or exercise intervention has proven preventive efficacy. (balestrini2016tbc1d24genotype–phenotypecorrelation pages 2-3)

6. Mechanism and pathophysiology

Ordered causal chain

Biallelic pathogenic TBC1D24 variants lead to reduced protein abundance, stability, or domain function; this is demonstrated for several alleles but inferred for variants lacking functional assays. (finelli2019theepilepsyassociatedprotein pages 13-14, lin2020theepilepsyand pages 1-2)
TBC/TLDc dysfunction leads to disturbed phosphoinositide-membrane association, ARF6/Rab-related signaling, oxidative-stress handling, and—in two 2024-tested alleles—loss or weakening of TBC1D24–KIBRA binding. (tona2024interactionbetweenthe pages 1-2, aprile2019tbc1d24regulatesaxonal pages 1-2, luthy2019tbc1d24tldcrelatedepilepsyexerciseinduced pages 1-2)
Abnormal small-GTPase and membrane regulation leads to defective growth-cone endocytosis, enlarged endosomal compartments, and impaired synaptic-vesicle sorting/recycling. (pepe2023arolein pages 14-17, finelli2019theepilepsyassociatedprotein pages 13-14, aprile2019tbc1d24regulatesaxonal pages 1-2)
Defective trafficking leads to impaired neuronal migration, axonal specification/callosal projection, neurite growth, dendritic-spine maintenance, and pre- and postsynaptic dysfunction. (lin2020theepilepsyand pages 1-2, aprile2019tbc1d24regulatesaxonal pages 1-2)
Altered neuronal connectivity and vesicle cycling lead to abnormal neurotransmission and increased network excitability; direct links are demonstrated in models and inferred in human cortex. (tona2019thephenotypiclandscape pages 1-2, lin2020theepilepsyand pages 1-2)
Network hyperexcitability results in neonatal/infantile multifocal seizures, spasms, and status epilepticus. In parallel, primary developmental wiring defects result in developmental encephalopathy; recurrent epileptic activity may further worsen development. (spoto2022synaptopathiesindevelopmental pages 11-13, vetri2024wholeexomesequencing pages 1-2, scheffer2024developmentalandepileptic pages 1-4)
Severe, prolonged epilepsy plus neurologic dysfunction leads to profound disability and risks of aspiration/respiratory failure, infection-associated status, and premature death. (balestrini2016tbc1d24genotype–phenotypecorrelation pages 2-3, balestrini2016tbc1d24genotype–phenotypecorrelation pages 3-4)

Mechanistic detail and annotations

TBC1D24 binds ARF6 through its TBC region and appears to restrain active ARF6-GTP, although it lacks canonical residues expected of a conventional GAP. Knockdown causes migration, neurite, axonal-specification, action-potential, and dendritic-spine defects; dominant-negative ARF6 rescues several model phenotypes. Patient iPSC-derived neurons from a severe developmental encephalopathy showed axon-formation defects that were absent in neurons from a milder epilepsy case. (pepe2023arolein pages 14-17, aprile2019tbc1d24regulatesaxonal pages 1-2)

Presynaptically, reduced TBC1D24 slows vesicle endocytosis and produces enlarged endosomal accumulations; postsynaptically, TBC1D24 inhibits ARF6 and maintains excitatory dendritic spines. Suggested GO terms include synaptic vesicle endocytosis, endosomal transport, regulation of ARF protein signal transduction, neuron migration, axon development, dendritic spine maintenance, chemical synaptic transmission, and response to oxidative stress. Suggested cell types include CL:0000540 neuron, cortical projection neurons, hippocampal neurons, and excitatory neurons. (pepe2023arolein pages 14-17, finelli2019theepilepsyassociatedprotein pages 13-14, lin2020theepilepsyand pages 1-2)

The TLDc domain has a neuroprotective/oxidative-stress role. In a humanized p.Gly501Arg fly, activity-induced locomotor and vesicle-trafficking defects were associated with oxidative-stress sensitivity and rescued by N-acetylcysteine amide or alpha-tocopherol. This supports a redox-sensitive synaptic mechanism but derives from a milder epilepsy/dystonia allele, not DEE16 patients. (luthy2019tbc1d24tldcrelatedepilepsyexerciseinduced pages 1-2)

Latest mechanistic development, 2024. Tona et al., published online 28 August 2024, identified a specific interaction between the TBC1D24 TLDc domain and the C2 domain of KIBRA/WWC1. Recessive epilepsy-associated p.Gly511Arg and p.Ala515Val disrupted the human interaction. The abstract states that this finding “reveals a pathogenic mechanism of TBC1D24-associated epilepsy, linking the TBC1D24 and KIBRA pathways.” Hippocampal coexpression supports in-vivo plausibility, but necessity in human DEE16 and therapeutic tractability remain unproven. DOI: https://doi.org/10.1016/j.jbc.2024.107725. (tona2024interactionbetweenthe pages 13-14, tona2024interactionbetweenthe pages 1-2)

No replicated DEE16-specific transcriptomic, proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic, or integrated multi-omics signature was identified. Available “omics” primarily consist of genomic sequencing and patient-derived neuronal modeling.

7. Anatomical structures affected

The nervous system is primary. Relevant sites are the cerebral cortex and developing corticocortical projections, hippocampus, cerebellum, and synapses. Suggested UBERON concepts include cerebral cortex, hippocampus, cerebellum, corpus callosum, and central nervous system; relevant subcellular GO components include synapse, presynaptic active zone, postsynaptic density, dendritic spine, growth cone, clathrin-coated vesicle, endosome, and trans-Golgi network. (tona2019thephenotypiclandscape pages 1-2, tona2024interactionbetweenthe pages 1-2, lin2020theepilepsyand pages 1-2, aprile2019tbc1d24regulatesaxonal pages 1-2)

MRI may be initially nonspecific or normal. In the broader cohort, 16/48 had cerebral or cerebellar atrophy, five delayed myelination, three hippocampal sclerosis, and 11 cerebellar signal, atrophy, or hypoplasia abnormalities. No consistent relationship linked imaging to prognosis. Abnormalities are generally bilateral/diffuse rather than characteristically lateralized. The cochlea/auditory pathway can be secondarily relevant in patients with hearing loss. (balestrini2016tbc1d24genotype–phenotypecorrelation pages 3-4)

8. Temporal development

Onset is congenital-developmental at the molecular level and usually neonatal or early infantile clinically. Seizures may begin abruptly in the first hours or weeks and evolve into multiple seizure types, prolonged clusters, or status. Development may already be abnormal because of the genetic lesion and may plateau or regress with severe epileptic activity. (spoto2022synaptopathiesindevelopmental pages 11-13, scheffer2024developmentalandepileptic pages 1-4)

The course is chronic and highly variable. Severe DEE16 commonly remains drug-resistant with profound disability; milder TBC1D24 epilepsies can remit, so remission data from those disorders cannot be generalized. The period from fetal cortical development through the first postnatal years is probably the principal window of vulnerability. A mouse S324Tfs*3 model illustrates temporal biology: seizures appeared abruptly at postnatal day 15 as use of a conserved alternatively spliced micro-exon increased. (tona2019thephenotypiclandscape pages 1-2)

9. Inheritance and population

Inheritance is predominantly autosomal recessive. For two confirmed carrier parents, each pregnancy has a 25% probability of an affected child, 50% probability of an unaffected carrier, and 25% probability of inheriting neither familial allele, subject to confirmation of phase and parental status. Penetrance for two severe pathogenic alleles appears high, but expressivity is broad across the TBC1D24 spectrum. No anticipation mechanism is known. Parental germline mosaicism is theoretically possible but not quantified; uniparental isodisomy is documented as an unusual mechanism.

DEE16-specific incidence, prevalence, carrier frequency, founder effects, ethnic enrichment, and sex ratio are unknown. The 48-person cohort contained 28 males and 20 females, but referral ascertainment makes this unsuitable for estimating sex bias. General DEEs have cumulative childhood incidence estimates around 169/100,000 in one New Zealand study, but that statistic must not be assigned to DEE16. (balestrini2016tbc1d24genotype–phenotypecorrelation pages 1-2, scheffer2024developmentalandepileptic pages 1-4)

10. Diagnostics

Clinical evaluation. Obtain pregnancy/birth and three-generation family history, precise seizure semiology and triggers, serial video-EEG including sleep, brain MRI with epilepsy protocol, developmental and neurologic assessment, growth measurements, audiology, ophthalmology, feeding/swallowing and respiratory evaluation, and screening for movement disorder. Basic metabolic testing is useful when presentation is undiagnosed because treatable metabolic epilepsies can mimic DEE16, but no enzyme, metabolite, blood, urine, biopsy, or liquid-biopsy marker diagnoses TBC1D24 disease.

Molecular testing. Trio WES or WGS is preferred for an unexplained neonatal/infantile DEE; a comprehensive epilepsy/DEE panel including TBC1D24 with copy-number analysis is also appropriate. Confirm candidate variants by orthogonal testing where required, establish that biallelic variants are in trans, and test parents. WGS can detect noncoding, structural, and copy-number lesions missed by WES. CMA is useful when microcephaly, dysmorphism, congenital anomalies, or a contiguous-gene deletion is suspected. Karyotype/FISH, mitochondrial sequencing, and repeat-expansion assays are not routine DEE16 tests unless another diagnosis is suspected.

A 2024 first-line WES study of 82 unselected DEE cases found 35 pathogenic variants, a 43% yield; 66% were de novo. This supports early genomic testing but is not a TBC1D24-specific yield. DOI: https://doi.org/10.3390/ijms25021146; published 17 January 2024. (vetri2024wholeexomesequencing pages 1-2)

Differential diagnosis. Consider other neonatal/infantile DEEs—including STXBP1-, KCNQ2-, SCN2A-, SCN8A-, KCNT1-, CDKL5-, PCDH19-, GNAO1-, TUBA1A-, and metabolic/vitamin-responsive epilepsies—plus epilepsy of infancy with migrating focal seizures, infantile epileptic spasms syndrome, progressive myoclonus epilepsies, mitochondrial disorders, and structural cortical malformations. Within TBC1D24 disease, distinguish DEE16 from DOORS syndrome and milder epilepsy/hearing-loss phenotypes.

No population newborn screen is available. Targeted familial testing, cascade carrier testing, prenatal diagnosis, and preimplantation genetic testing are feasible after both causal alleles are established.

11. Outcome and prognosis

No valid DEE16-specific five- or ten-year survival rate or life-expectancy estimate exists. In the broader cohort, 9/48 (19%) had died at a mean 37 months (range 6–96 months). Causes included infection, respiratory failure, infection-associated status epilepticus, unknown causes, and one probable SUDEP at 18 months. These retrospective spectrum-wide observations should not be interpreted as a DEE16 mortality rate. (balestrini2016tbc1d24genotype–phenotypecorrelation pages 2-3)

Poor prognostic indicators include neonatal onset, frequent prolonged seizures/status, drug resistance, profound early developmental impairment, respiratory/feeding complications, and truncating or splice-disrupting alleles. Among 17 cohort members with at least one frameshift, nonsense, or splice variant, 15 had drug-resistant epilepsy and eight died by age seven. Recovery to typical development is unlikely in severe DEE16, although seizure burden may improve. No validated molecular or circulating prognostic biomarker exists. (balestrini2016tbc1d24genotype–phenotypecorrelation pages 3-4)

12. Treatment and applications

There is no approved TBC1D24-directed or disease-modifying therapy. Treatment is individualized by seizure type and EEG syndrome, with prompt management of prolonged seizures and intercurrent illness. The 2016 spectrum cohort reported 30/48 with drug-resistant epilepsy and 18 with good treatment response. Observational benefits occurred with valproate or phenobarbital, phenytoin plus clobazam, zonisamide, topiramate, and other combinations; these uncontrolled data do not establish a preferred DEE16 algorithm. (balestrini2016tbc1d24genotype–phenotypecorrelation pages 1-2, balestrini2016tbc1d24genotype–phenotypecorrelation pages 2-3)

A practical strategy is: (1) classify seizure types and EEG syndrome; (2) select standard antiseizure therapy accordingly; (3) provide a home rescue plan and status protocol; (4) monitor sedation, respiration, feeding, hepatic/hematologic toxicity, and drug interactions; (5) reassess polytherapy regularly; and (6) integrate developmental, physical, occupational, speech/augmentative-communication, nutritional, hearing, vision, orthopedic, sleep, respiratory, and palliative-care expertise as needed. Suggested NCIT concepts include Anticonvulsant Therapy, Electroencephalography, Physical Therapy, Occupational Therapy, Speech Therapy, and Genetic Counseling.

No relevant interventional ClinicalTrials.gov study for DEE16/TBC1D24 was identified. Antioxidant rescue with N-acetylcysteine amide and alpha-tocopherol is preclinical and must not be used as evidence of human efficacy. Likewise, the 2024 KIBRA result identifies a possible target network but not a treatment. No gene replacement, editing, ASO, siRNA, mRNA, cell therapy, immunotherapy, or validated pharmacogenomic regimen is currently established. (tona2024interactionbetweenthe pages 1-2, luthy2019tbc1d24tldcrelatedepilepsyexerciseinduced pages 1-2)

13. Prevention

The de novo occurrence of symptoms cannot be prevented by vaccination, lifestyle, or environmental modification once a child has biallelic pathogenic variants. Primary reproductive prevention consists of genetic counseling, parental carrier confirmation, cascade testing, preimplantation genetic testing, or prenatal diagnosis. Secondary prevention consists of early genomic diagnosis, seizure recognition, EEG monitoring, and rapid initiation of appropriate therapy to reduce avoidable epileptic burden. Tertiary prevention includes rescue medication, fever/illness plans, aspiration and respiratory precautions, nutrition and bone-health support, injury prevention, SUDEP counseling, and rehabilitation.

Routine immunization remains appropriate unless an individual clinical contraindication exists; vaccines do not cause DEE16. Because fever can trigger seizures, vaccination planning and fever management should be individualized without withholding the protection against infections that can themselves provoke status.

14. Other species and natural disease

No well-established naturally occurring veterinary disease equivalent to human DEE16 was identified. There is no zoonotic transmission or cross-species infectious susceptibility because this is a germline Mendelian disorder. Relevant orthologous systems include Mus musculus (NCBITaxon:10090), Rattus norvegicus (10116), and Drosophila melanogaster (7227; ortholog skywalker/sky). Conservation of the TBC and TLDc functions supports comparative modeling, but species-specific isoforms and auditory biology limit direct extrapolation. (tona2019thephenotypiclandscape pages 2-3, tona2024interactionbetweenthe pages 1-2)

15. Model organisms and experimental systems

Mouse S324Tfs*3. Homozygous mice have abrupt spontaneous seizures beginning at postnatal day 15, coincident with a developmental switch that incorporates a conserved six-amino-acid micro-exon. Hippocampal TBC1D24 localizes to synapses and clathrin-coated vesicles. Auditory and vestibular function were normal, demonstrating incomplete recapitulation of human multisystem disease. DOI: https://doi.org/10.1093/hmg/ddy445; published online 2 January 2019. (tona2019thephenotypiclandscape pages 1-2)

Mouse F251L. This missense allele destabilizes TBC1D24. Homozygous knock-in mice develop neuronal hyperexcitability, spontaneous seizures, and premature death; heterozygotes survive but exhibit dendritic-spine and memory defects. Hippocampal knockdown similarly causes spine loss, impaired contextual fear memory, hyperactivity, and anxiety. DOI: https://doi.org/10.1371/journal.pgen.1008587; published 31 January 2020. (lin2020theepilepsyand pages 1-2)

Rodent and human neurons. TBC1D24-silenced rat cortical neurons show impaired axonal specification, growth-cone endocytosis, axon-initial-segment maturation, action-potential firing, and callosal projection. Patient iPSC-derived neurons from severe developmental encephalopathy reproduced axon-formation defects, whereas a milder epilepsy line did not. DOI: https://doi.org/10.1038/s41418-019-0313-x; published online 11 March 2019. (aprile2019tbc1d24regulatesaxonal pages 1-2)

Drosophila. skywalker models are efficient for synaptic-vesicle trafficking and oxidative-stress experiments. Humanized p.Gly501Arg flies showed activity-induced behavioral and vesicle-transport abnormalities rescued by antioxidants. Limitations include invertebrate circuitry, variant-specific phenotypes, and uncertain human dosing or safety. DOI: https://doi.org/10.1093/brain/awz175; advance publication 29 June 2019. (luthy2019tbc1d24tldcrelatedepilepsyexerciseinduced pages 1-2)

Overall assessment

Current expert understanding places DEE16 among presynaptic/postsynaptic trafficking disorders rather than a primary ion-channel disorder. The strongest disease model is biallelic TBC1D24 loss or dysfunction producing convergent defects in neuronal development, ARF6/Rab-associated membrane trafficking, synaptic-vesicle recycling, dendritic-spine maintenance, and cellular stress resistance. The 2024 discovery of variant-sensitive TBC1D24–KIBRA binding adds a specific molecular interaction to this framework, but clinical care remains symptomatic. Priorities are a disease-specific natural-history registry, standardized variant curation, longitudinal EEG/developmental outcomes, quantitative patient/caregiver measures, human-neuron validation of KIBRA and redox mechanisms, and carefully designed genotype-stratified therapeutic studies. (tona2024interactionbetweenthe pages 13-14, tona2024interactionbetweenthe pages 1-2, scheffer2024developmentalandepileptic pages 1-4)

References

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(tona2019thephenotypiclandscape pages 1-2): Risa Tona, Wenqian Chen, Yoko Nakano, Laura D Reyes, Ronald S Petralia, Ya-Xian Wang, Matthew F Starost, Talah T Wafa, Robert J Morell, Kevin D Cravedi, Johann du Hoffmann, Takushi Miyoshi, Jeeva P Munasinghe, Tracy S Fitzgerald, Yogita Chudasama, Koichi Omori, Carlo Pierpaoli, Botond Banfi, Lijin Dong, Inna A Belyantseva, and Thomas B Friedman. The phenotypic landscape of a tbc1d24 mutant mouse includes convulsive seizures resembling human early infantile epileptic encephalopathy. Human Molecular Genetics, 28:1530–1547, Jan 2019. URL: https://doi.org/10.1093/hmg/ddy445, doi:10.1093/hmg/ddy445. This article has 41 citations and is from a domain leading peer-reviewed journal.
(finelli2019theepilepsyassociatedprotein pages 5-6): Mattéa J Finelli, Davide Aprile, Enrico Castroflorio, Alexander Jeans, Matteo Moschetta, Lauren Chessum, Matteo T Degiacomi, Julia Grasegger, Alexis Lupien-Meilleur, Andrew Bassett, Elsa Rossignol, Philippe M Campeau, Michael R Bowl, Fabio Benfenati, Anna Fassio, and Peter L Oliver. The epilepsy-associated protein tbc1d24 is required for normal development, survival and vesicle trafficking in mammalian neurons. Human Molecular Genetics, 28:584-597, Oct 2019. URL: https://doi.org/10.1093/hmg/ddy370, doi:10.1093/hmg/ddy370. This article has 73 citations and is from a domain leading peer-reviewed journal.
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(balestrini2016tbc1d24genotype–phenotypecorrelation pages 2-3): Simona Balestrini, Mathieu Milh, Claudia Castiglioni, Kevin Lüthy, Mattea J. Finelli, Patrik Verstreken, Aaron Cardon, Barbara Gnidovec Stražišar, J. Lloyd Holder, Gaetan Lesca, Maria M. Mancardi, Anne L. Poulat, Gabriela M. Repetto, Siddharth Banka, Leonilda Bilo, Laura E. Birkeland, Friedrich Bosch, Knut Brockmann, J. Helen Cross, Diane Doummar, Temis M. Félix, Fabienne Giuliano, Mutsuki Hori, Irina Hüning, Hulia Kayserili, Usha Kini, Melissa M. Lees, Girish Meenakshi, Leena Mewasingh, Alistair T. Pagnamenta, Silvio Peluso, Antje Mey, Gregory M. Rice, Jill A. Rosenfeld, Jenny C. Taylor, Matthew M. Troester, Christine M. Stanley, Dorothee Ville, Magdalena Walkiewicz, Antonio Falace, Anna Fassio, Johannes R. Lemke, Saskia Biskup, Jessica Tardif, Norbert F. Ajeawung, Aslihan Tolun, Mark Corbett, Jozef Gecz, Zaid Afawi, Katherine B. Howell, Karen L. Oliver, Samuel F. Berkovic, Ingrid E. Scheffer, Fabrizio A. de Falco, Peter L. Oliver, Pasquale Striano, Federico Zara, Phillipe M. Campeau, and S.M. Sisodiya. Tbc1d24 genotype–phenotype correlation. Neurology, 87:77-85, Jul 2016. URL: https://doi.org/10.1212/wnl.0000000000002807, doi:10.1212/wnl.0000000000002807. This article has 163 citations and is from a highest quality peer-reviewed journal.
(pepe2023arolein pages 14-17): SARA PEPE. A role in ph homeostasis regulation by genes related to neurodevelopmental disorders: tbc1d24 and atp6v1a. May 2023. URL: https://doi.org/10.15167/pepe-sara_phd2023-05-15, doi:10.15167/pepe-sara_phd2023-05-15. This article has 0 citations.
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(luthy2019tbc1d24tldcrelatedepilepsyexerciseinduced pages 1-2): Kevin Lüthy, Davide Mei, Baptiste Fischer, Maurizio De Fusco, Jef Swerts, Jone Paesmans, Elena Parrini, Naomi Lubarr, Inge A Meijer, Katherine M Mackenzie, Wang-Tso Lee, Davide Cittaro, Paolo Aridon, Nils Schoovaerts, Wim Versées, Patrik Verstreken, Giorgio Casari, and Renzo Guerrini. Tbc1d24-tldc-related epilepsy exercise-induced dystonia: rescue by antioxidants in a disease model. Brain : a journal of neurology, 142:2319-2335, Jun 2019. URL: https://doi.org/10.1093/brain/awz175, doi:10.1093/brain/awz175. This article has 73 citations.

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