| 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. (pqac-00000002, pqac-00000003) |
| 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. (pqac-00000006, pqac-00000011, pqac-00000018) |
| 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. (pqac-00000005, pqac-00000016, pqac-00000017) |
| 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. (pqac-00000005, pqac-00000017, pqac-00000018) |
| 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. (pqac-00000001, pqac-00000005, pqac-00000018) |
| 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. (pqac-00000001, pqac-00000018) |
| 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. (pqac-00000004, pqac-00000010, pqac-00000019, pqac-00000020) |
| 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. (pqac-00000013, pqac-00000014) |
| 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. (pqac-00000015, pqac-00000022) |
| 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. (pqac-00000016, pqac-00000017) |
| 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. (pqac-00000021) |
| 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. (pqac-00000017, pqac-00000018) |
| 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. (pqac-00000003, pqac-00000019, pqac-00000020) |
| 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. (pqac-00000016, pqac-00000022) |


*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.*