| Topic | Key information | Citations |
|---|---|---|
| Definition / acronym | DOORS syndrome = **D**eafness, **O**nychodystrophy, **O**steodystrophy, intellectual disability/developmental delay, and **S**eizures; classically described as a rare multisystem Mendelian disorder. | (pqac-00000001, pqac-00000002, pqac-00000006) |
| Key identifiers | Disease OMIM/MIM: **220500**; major causal gene: **TBC1D24** (gene MIM **613577**), chromosome 16p13. | (pqac-00000001, pqac-00000038) |
| Core genetic architecture | Best-established cause is **biallelic TBC1D24** pathogenic variation with **autosomal recessive** inheritance; diagnosis in classic cases is supported by identifying biallelic pathogenic variants. Genetic heterogeneity is likely. | (pqac-00000001, pqac-00000004, pqac-00000006, pqac-00000038) |
| Additional causal gene | **ATP6V1B2** is an additional DOORS-spectrum gene; a recurrent truncating **c.1516C>T (p.Arg506\*)** variant was identified in multiple unrelated families/individuals with DOORS-like presentations, typically in the **heterozygous** state. | (pqac-00000002, pqac-00000009, pqac-00000015) |
| Cohort-level genetics | In a 46-family DOORS cohort, reported etiologies included **TBC1D24 in 13 families (28%)**, **ATP6V1B2 in 8 families (17%)**, and **6 families (13%)** remained unsolved; broader heterogeneity included other genes in some families. | (pqac-00000000, pqac-00000002) |
| Hallmark phenotype spectrum | Typical findings include **sensorineural deafness**, **small/absent nails**, **hypoplastic/absent terminal phalanges**, **intellectual disability/developmental delay**, and **seizures**; deafness, onychodystrophy, and abnormal digits were present in all reported ATP6V1B2-DOORS individuals in one cohort. | (pqac-00000000, pqac-00000001, pqac-00000002, pqac-00000006) |
| Frequency statements | Reported recurring phenotype frequencies: **triphalangeal thumb ~one third**, **microcephaly ~one third**, **narrow bifrontal diameter ~two thirds** of affected individuals. | (pqac-00000005, pqac-00000006) |
| Seizure timing / severity | Seizures occur in most affected individuals and **usually start in the first year of life**; seizure types include generalized tonic-clonic, complex partial, focal clonic, and infantile spasms; some cases are drug-resistant and may progress to status epilepticus or early death. | (pqac-00000001, pqac-00000005, pqac-00000006, pqac-00000035) |
| Other reported findings | Additional manifestations reported across cases include **visual impairment/optic neuropathy**, **peripheral neuropathy**, **MRI abnormalities**, and occasional congenital anomalies (e.g., cardiac defects in case reports). | (pqac-00000001, pqac-00000005, pqac-00000040) |
| Diagnostic clues | Highest diagnostic yield is in individuals with all five classic features; recommended testing starts with **TBC1D24 sequence analysis**, then deletion/duplication analysis and/or broader exome/genome or multigene-panel testing; audiology, EEG, radiographs, and systemic evaluation are useful adjuncts. | (pqac-00000004, pqac-00000036, pqac-00000038, pqac-00000040) |
| Mechanistic theme: vesicle trafficking / endocytosis | TBC1D24 is linked to **Rab/ARF6-related vesicle trafficking**, presynaptic **endocytosis**, synaptic vesicle recycling/rejuvenation, and phosphoinositide-mediated membrane binding; deficiency causes presynaptic endocytic defects and impaired spontaneous neurotransmission. | (pqac-00000009, pqac-00000012, pqac-00000013, pqac-00000015, pqac-00000023) |
| Mechanistic theme: v-ATPase / lysosome | ATP6V1B2 encodes a **V-ATPase** subunit; DOORS-associated ATP6V1B2 variants are linked to impaired **lysosomal acidification**. TBC1D24 also physically/functionally interfaces with the **v-ATPase**, supporting a shared endolysosomal disease axis. | (pqac-00000009, pqac-00000010, pqac-00000014) |
| Mechanistic theme: mitochondria / ER contact sites | Emerging evidence links TBC1D24 deficiency to **fragmented mitochondria**, **decreased ATP**, **reduced mitochondrial membrane potential**, and altered **ER–mitochondria contact sites (ERMCS)**, expanding pathophysiology beyond synaptic trafficking. | (pqac-00000008, pqac-00000011) |
| 2024 development: mitochondria | **Benhammouda 2024** reported that patient fibroblasts and TBC1D24-deficient cells show mitochondrial dysfunction and altered ERMCS, nominating mitochondrial homeostasis as a new disease mechanism. | (pqac-00000008, pqac-00000011) |
| 2024 development: cochlea | **Defourny 2024** localized TBC1D24 in early postnatal mouse cochlea mainly to **glia-like non-sensory/supporting epithelial cells**, with little to no signal in adjacent hair cells and loss of epithelial signal around hearing onset, suggesting a supporting-cell vesicle-trafficking role in hearing biology. | (pqac-00000027, pqac-00000028, pqac-00000029) |
| Model-organism support | Mouse and invertebrate models support neuronal/synaptic roles: Drosophila DOORS-equivalent variants impair synaptic vesicle trafficking and cause seizures; a CRISPR mouse **Tbc1d24 S324Tfs\*3** model shows abrupt spontaneous seizures at **P15** and death by ~3 weeks, with hippocampal localization of TBC1D24 at clathrin-coated vesicles/synapses. | (pqac-00000016, pqac-00000018, pqac-00000019, pqac-00000023) |
| Management snapshot | No disease-modifying therapy is established; management is **symptomatic and multidisciplinary**: antiseizure medications, hearing aids or **cochlear implantation** in selected patients, developmental therapies (PT/OT/speech/AAC), and routine surveillance (neurology/EEG, audiology, dental, ophthalmology, other specialty assessments). | (pqac-00000033, pqac-00000034, pqac-00000036, pqac-00000038) |


*Table: This table condenses the highest-yield clinical, genetic, mechanistic, and diagnostic facts about DOORS syndrome, including classic frequencies and recent 2024 mechanistic updates. It is designed for direct reuse in a disease knowledge-base report with row-level citation IDs.*