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.

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

1. 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)
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)
3. 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)
4. 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)
5. 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)
6. 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)
7. 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)

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4. (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.

5. (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.

6. (balestrini2016tbc1d24genotype–phenotypecorrelation pages 3-4): 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.

7. (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.

8. (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.

9. (finelli2019theepilepsyassociatedprotein pages 13-14): 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.

10. (lin2020theepilepsyand pages 1-2): Lianfeng Lin, Quanwei Lyu, Pui-Yi Kwan, Junjun Zhao, Ruolin Fan, Anping Chai, Cora Sau Wan Lai, Ying-Shing Chan, Xuting Shen, and Kwok-On Lai. The epilepsy and intellectual disability-associated protein tbc1d24 regulates the maintenance of excitatory synapses and animal behaviors. PLOS Genetics, 16:e1008587, Jan 2020. URL: https://doi.org/10.1371/journal.pgen.1008587, doi:10.1371/journal.pgen.1008587. This article has 28 citations and is from a domain leading peer-reviewed journal.

11. (aprile2019tbc1d24regulatesaxonal pages 1-2): Davide Aprile, Floriana Fruscione, Simona Baldassari, Manuela Fadda, Daniele Ferrante, Antonio Falace, Emmanuelle Buhler, Jacopo Sartorelli, Alfonso Represa, Pietro Baldelli, Fabio Benfenati, Federico Zara, and Anna Fassio. Tbc1d24 regulates axonal outgrowth and membrane trafficking at the growth cone in rodent and human neurons. Cell Death & Differentiation, 26:2464-2478, Mar 2019. URL: https://doi.org/10.1038/s41418-019-0313-x, doi:10.1038/s41418-019-0313-x. This article has 57 citations and is from a domain leading peer-reviewed journal.

12. (tona2024interactionbetweenthe pages 13-14): Risa Tona, Sayaka Inagaki, Yasuko Ishibashi, Rabia Faridi, Rizwan Yousaf, Isabelle Roux, Elizabeth Wilson, Cristina Fenollar-Ferrer, Wade W. Chien, Inna A. Belyantseva, and Thomas B. Friedman. Interaction between the tbc1d24 tldc domain and the kibra c2 domain is disrupted by two epilepsy-associated tbc1d24 missense variants. Journal of Biological Chemistry, 300:107725, Sep 2024. URL: https://doi.org/10.1016/j.jbc.2024.107725, doi:10.1016/j.jbc.2024.107725. This article has 8 citations and is from a domain leading peer-reviewed journal.

13. (tona2024interactionbetweenthe pages 1-2): Risa Tona, Sayaka Inagaki, Yasuko Ishibashi, Rabia Faridi, Rizwan Yousaf, Isabelle Roux, Elizabeth Wilson, Cristina Fenollar-Ferrer, Wade W. Chien, Inna A. Belyantseva, and Thomas B. Friedman. Interaction between the tbc1d24 tldc domain and the kibra c2 domain is disrupted by two epilepsy-associated tbc1d24 missense variants. Journal of Biological Chemistry, 300:107725, Sep 2024. URL: https://doi.org/10.1016/j.jbc.2024.107725, doi:10.1016/j.jbc.2024.107725. This article has 8 citations and is from a domain leading peer-reviewed journal.

14. (vetri2024wholeexomesequencing pages 1-2): Luigi Vetri, Francesco Calì, Salvatore Saccone, Mirella Vinci, Natalia Valeria Chiavetta, Marco Carotenuto, Michele Roccella, Carola Costanza, and Maurizio Elia. Whole exome sequencing as a first-line molecular genetic test in developmental and epileptic encephalopathies. International Journal of Molecular Sciences, 25:1146, Jan 2024. URL: https://doi.org/10.3390/ijms25021146, doi:10.3390/ijms25021146. This article has 25 citations.

15. (scheffer2024developmentalandepileptic pages 1-4): Ingrid E. Scheffer, Sameer Zuberi, Heather C. Mefford, Renzo Guerrini, and Amy McTague. Developmental and epileptic encephalopathies. Nature Reviews Disease Primers, Sep 2024. URL: https://doi.org/10.1038/s41572-024-00546-6, doi:10.1038/s41572-024-00546-6. This article has 175 citations.

16. (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.

Artifacts

• Edison artifact artifact-00

Reference Validation

Checked with linkml-reference-validator 0.2.1.

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

• MONDO:0014133 (4 mentions) - the report calls it "if available"; MONDO calls it developmental and epileptic encephalopathy, 16