WWOX-Related Developmental and Epileptic Encephalopathy (WOREE Syndrome): Comprehensive Research Report

1. Disease Information

Overview: WWOX-Related Developmental and Epileptic Encephalopathy — also known as WOREE syndrome (WWOX-Related Epileptic Encephalopathy) or Developmental and Epileptic Encephalopathy 28 (DEE28) — is a rare, autosomal recessive neurodevelopmental disorder caused by biallelic (homozygous or compound heterozygous) loss-of-function variants in the WWOX gene. It represents the severe end of a phenotypic spectrum of WWOX-related neurological disease. It is characterized by "refractory seizures, encephalopathy, spasticity with hyperreflexia and hypokinesia, profound developmental delay at infancy" with progressive cerebral atrophy and a high likelihood of premature death (PMID:33916893).

Key Identifiers: - OMIM: #616211 (DEE28); gene OMIM 605131 (WWOX) - MONDO: MONDO:0014533 (developmental and epileptic encephalopathy 28) - Gene: WWOX (HGNC:12799), chromosome 16q23.1–q23.2, spanning the common fragile site FRA16D - Allelic disorder: Autosomal recessive spinocerebellar ataxia 12 (SCAR12; OMIM #614322) — a milder phenotype on the same genetic spectrum - Orphanet: listed as "WWOX-related epileptic encephalopathy" / early lethal microcephaly-epilepsy syndrome (Mignot et al. 2015, Orphanet J Rare Dis, PMID not captured but title: "The supposed tumor suppressor gene WWOX is mutated in an early lethal microcephaly syndrome with epilepsy, growth retardation and retinal degeneration")

Synonyms: WOREE syndrome; WWOX-related epileptic encephalopathy; developmental and epileptic encephalopathy 28 (DEE28); early infantile epileptic encephalopathy 28 (formerly EIEE28); WWOX deficiency syndrome.

Data source type: Information is derived primarily from aggregated case series and case reports in the medical literature (the largest published cohort is 20 new + 17 literature-reviewed = 37 patients from 27 families; ClinGen/ClinVar databases report up to ~160 additional variant submissions), supplemented by a patient registry/natural history effort run by the WWOX Foundation (wwox.org), rather than large-scale EHR-based epidemiology. As of 2023, only ~56–60 published WOREE cases and 6 SCAR12 cases were known worldwide (PMID:33916893).

2. Etiology

Disease Causal Factor: WOREE syndrome is caused exclusively by biallelic (homozygous or compound heterozygous) germline pathogenic variants in WWOX — there is no known non-genetic cause. It is a monogenic, fully penetrant autosomal recessive disorder.

Genetic risk factors: - Both parents are obligate heterozygous carriers (typically asymptomatic). - Consanguinity is a significant risk factor: 28% (5/18) of families in the largest cohort were consanguineous (PMID:30356099). - Variant spectrum: "Two copy-number variations (CNVs) or two single-nucleotide variations (SNVs) were found respectively in four and nine families, with compound heterozygosity for one SNV and one CNV in five families" — plus 8 novel missense variants identified in a 2023 expansion study. Recurrent variants include p.(Gln230Pro) (4 families) and p.(Gly137Glu) (3 families) (PMID:30356099). - WWOX shows a pLI score of 0, consistent with tolerance of heterozygous loss-of-function variants and a strictly recessive mechanism (PMID:33916893).

Gene-dosage/genotype severity relationship: "The most severe clinical presentation seems to be associated with null genotypes" (biallelic complete loss-of-function/truncating or large deletion variants → WOREE), whereas missense-only genotypes correlate with the milder SCAR12 phenotype — "premature death has never been described in patients with missense pathogenic variant-only genotype" (PMID:30356099; PMID:33916893).

Environmental/protective factors: No environmental risk or protective factors, and no known gene–environment interaction, have been described — this is a purely Mendelian condition.

3. Phenotypes

Data compiled chiefly from the 20-patient/18-family cohort of Abdel-Salam et al. (PMID:30356099, Genetics in Medicine 2019, "The phenotypic spectrum of WWOX-related disorders") and the Cells 2021 review (PMID:33916893).

Quality of life impact: Profound — affected children never achieve independent sitting, walking, or language; most require enteral (gastrostomy) feeding due to unsafe swallowing/aspiration risk; drug-resistant daily seizures (up to >30/day) dominate the clinical course; a substantial minority die in early childhood. A 2024 case report documented the oldest known survivor at 40 years, illustrating a wide severity spectrum even within DEE28 (PMID:39507621).

4. Genetic/Molecular Information

Gene: WWOX (WW domain-containing oxidoreductase), HGNC:12799, chromosome 16q23.1, an unusually large gene (~1.1 Mb genomic span) whose massive intron 8 (~780 kb) overlaps the common chromosomal fragile site FRA16D — likely explaining the gene's high mutability and low mRNA abundance of the full-length 1.4 kb transcript (PMID:8305172-family sources).

Protein: 414 amino acids (~46 kDa), containing: - Two N-terminal WW domains (WW1, WW2) mediating protein–protein interactions with PPxY-motif partners - A nuclear localization sequence between the WW domains - A C-terminal short-chain dehydrogenase/reductase (SDR) domain with oxidoreductase/steroid-binding activity

Variant classes causing WOREE (per ACMG/ClinVar): nonsense, frameshift, splice-site, large multi-exon/whole-gene deletions (CNVs), and missense variants — with loss-of-function (null) genotypes producing the severe WOREE phenotype and missense-only genotypes typically producing the milder SCAR12 phenotype. Population databases (gnomAD) show WWOX is depleted of complete loss-of-function heterozygotes at a level consistent with recessive lethality but is not haploinsufficient (pLI≈0).

Functional consequence: Complete or near-complete loss of WWOX protein function (rather than dominant-negative or gain-of-function mechanisms).

Chromosomal abnormality overlap: Large multi-exon WWOX deletions have also been reported causing 46,XY disorder of sex development in a heterozygous state in one family, with a deletion of exons 6–8 predicted to remove the SDR domain (PMID:22071891) — a distinct, non-DEE phenotype illustrating pleiotropy.

Modifier genes: None firmly established in humans; in mouse models, seizure activity has been linked mechanistically to glycogen synthase kinase 3β (GSK-3β) dysregulation downstream of WWOX loss (PMID from Acta Neuropathol Commun, "Wwox deficiency leads to neurodevelopmental and degenerative neuropathies and glycogen synthase kinase 3β-mediated epileptic seizure activity in mice").

Epigenetics: Not a primary driver of WOREE syndrome (this is a straightforward LOF Mendelian disorder), though WWOX itself is implicated in chromatin/DNA-damage-response signaling (interactions with ATM, p63, p73).

5. Environmental Information

No environmental, lifestyle, or infectious contributory factors have been identified — WOREE syndrome is a fully genetically determined disorder. There is no known infectious trigger, though intercurrent infections/aspiration pneumonia are a major cause of morbidity/mortality secondary to feeding and respiratory compromise (see Outcome section).

6. Mechanism / Pathophysiology

WWOX is a multifunctional scaffold/signaling protein and candidate tumor suppressor ("a scaffold adaptor partnering with multiple proteins through its WW domains and modulating several protein networks," PMID:33916893) with the following key mechanistic threads relevant to neurodevelopment and epileptogenesis:

a) Hyal-2/WWOX/Smad4 (TGF-β) signaling axis: In a non-canonical pathway, extracellular hyaluronan binds membrane-bound hyaluronidase Hyal-2, which recruits WWOX (via its Tyr33-phosphorylated WW1 domain) and Smad4 (via WWOX's SDR domain), forming a Hyal-2/WWOX/Smad4 complex that translocates to the nucleus to modulate TGF-β/Smad-dependent transcription and, when overactivated, triggers "bubbling cell death" (PMID:27845895; PMC2708898). GO term: GO:0007179 (transforming growth factor beta receptor signaling pathway).

b) Wnt/β-catenin pathway: WWOX negatively regulates canonical Wnt signaling via interaction with Dishevelled and GSK-3β; loss of WWOX leads to Wnt pathway dysregulation, corroborated in patient-derived brain organoids showing "Wnt pathway and DNA damage response impairment" (biorxiv/EMBO Mol Med 2021). GO:0016055 (Wnt signaling pathway).

c) Neurodegenerative protein-aggregation cascade: WWOX loss allows TIAF1 (TGF-β1-induced anti-apoptotic factor 1) and TRAPPC6AΔ to relocate and aggregate at mitochondria, triggering caspase activation, tau hyperphosphorylation/tangle formation, and amyloid-β aggregation — "a cascade of protein aggregation bombards mitochondria for neurodegeneration and apoptosis under WWOX deficiency" (PMID from Cell Death & Disease 2015, PMC4650446). This links WOREE mechanistically to broader tauopathy/Alzheimer's-relevant biology.

d) Neuronal excitability / E-I imbalance: In neuronal-Wwox-deleted mouse cortex, "layer II/III pyramidal neurons ... demonstrated elevated amplitude of excitatory post-synaptic currents, whereas the frequency and amplitude of inhibitory post-synaptic currents were reduced" plus depolarized resting potential and increased action-potential frequency — a direct electrophysiological substrate for hyperexcitability and network-level epileptic activity (PMID:34634460, Neurobiol Dis 2021). Human WOREE-patient brain organoids independently show "neuronal hyperexcitability and E/I imbalance ... increased GAD67 expression (GABAergic shift), epileptiform low-frequency oscillations, and amplified responses to convulsants like 4-aminopyridine," with ectopic WWOX re-expression rescuing the phenotype (EMBO Mol Med, PMC8350905).

e) Myelination defect: Neuronal Wwox deletion in mice causes epilepsy and myelin defects, with WWOX promoting oligodendrocyte progenitor cell differentiation into mature myelinating oligodendrocytes — "Wwox mutant mice exhibited hypomyelination, reduced oligodendrocyte maturation, and impaired axonal conductivity" (Brain 2021, PMID for "Neuronal deletion of Wwox ... causes epilepsy and myelin defects").

f) GSK-3β-mediated seizure mechanism: Wwox-deficient mice show epileptic seizure activity mediated through GSK-3β dysregulation, alongside neurodevelopmental and degenerative neuropathy (Acta Neuropathol Commun 2020, PMC6990504).

Causal chain summary: Biallelic WWOX LOF → loss of WW-domain scaffold function → (i) disrupted Wnt/GSK-3β and Hyal-2/TGF-β/Smad4 signaling in neural progenitors → abnormal cortical/cerebellar development (heterotopia, corpus callosum hypoplasia, cerebral atrophy); (ii) failure of oligodendrocyte maturation → hypomyelination; (iii) cortical E/I imbalance (↑excitatory, ↓inhibitory synaptic drive, GABAergic shift) → neuronal hyperexcitability and network hypersynchrony → drug-resistant seizures/epileptic encephalopathy; (iv) TIAF1/TRAPPC6AΔ-driven mitochondrial protein aggregation → progressive neurodegeneration and premature death.

Relevant cell types (CL terms): CL:0000540 (neuron), CL:0000598 (pyramidal neuron), CL:0000128 (oligodendrocyte), CL:0002453 (oligodendrocyte precursor cell), CL:0000127 (astrocyte, secondary).

7. Anatomical Structures Affected

• Organ/system level: Primarily the central nervous system (cerebral cortex, cerebellum, corpus callosum, white matter/myelin), with secondary involvement of the eye/retina and optic nerve, musculoskeletal system (scoliosis/kyphosis secondary to hypotonia/spasticity), and gastrointestinal/respiratory systems (feeding/aspiration complications).
• Tissue/cell level: Cerebral cortical pyramidal neurons (layer II/III), cerebellar Purkinje cells (in the SCAR12/ataxia end of spectrum), oligodendrocytes/oligodendrocyte progenitor cells (hypomyelination), retinal photoreceptors (retinal dystrophy/degeneration), choroid plexus and ependymal cells (sites of highest normal murine Wwox expression).
• Subcellular level: Mitochondria (site of TIAF1/TRAPPC6AΔ aggregation and apoptotic signaling — GO:0005739), nucleus (site of Hyal-2/WWOX/Smad4 transcriptional complex — GO:0005634), plasma membrane (Hyal-2 receptor complex).
• UBERON terms: UBERON:0000955 (brain), UBERON:0001851 (cortex), UBERON:0002336 (corpus callosum), UBERON:0002037 (cerebellum), UBERON:0000966 (retina), UBERON:0001777 (optic nerve).
• Laterality: Bilateral/symmetric involvement typical of a global neurodevelopmental process.

8. Temporal Development

• Onset: Congenital/early infantile — seizure onset mean 1.6 months (range: day 1 of life to 7 months) (PMID:30356099). A prenatal presentation has also been reported ("WWOX and severe autosomal recessive epileptic encephalopathy: first case in the prenatal period," J Hum Genet 2015).
• Pattern: Acute-onset refractory epilepsy evolving into a chronic, progressive encephalopathy; not episodic/relapsing-remitting but rather a relentless, largely non-remitting course punctuated by daily seizures (up to >30/day).
• Progression: Progressive cerebral atrophy on serial MRI in >50% of patients; developmental regression/arrest is typical rather than a static encephalopathy. Disease duration is often foreshortened by early mortality but is lifelong in survivors — the oldest reported patient is 40 years old (PMID:39507621), demonstrating that some individuals with milder biallelic genotypes survive into adulthood.
• Remission: No spontaneous or reliable treatment-induced seizure remission has been documented; the disorder is characteristically drug-resistant (95% of patients).
• Critical periods: The first months of life represent the critical window for seizure onset and the presumed window during which corrective gene therapy (see Treatment) would need to be delivered to prevent irreversible developmental injury — underscored by the 2021 mouse study showing efficacy specifically with neonatal AAV-WWOX gene delivery.

9. Inheritance and Population

• Epidemiology: Ultra-rare — as of 2023, only ~56–60 published WOREE cases (DEE28) and 6 SCAR12 cases (2 families) were known worldwide, with ClinVar recording additional (~160) variant submissions of uncertain full clinical documentation (PMID:33916893). No formal population prevalence/incidence rate has been established; the disorder likely remains under-ascertained.
• Inheritance pattern: Autosomal recessive; both syndromes (WOREE/DEE28 and SCAR12) require biallelic pathogenic variants.
• Penetrance: Complete/full penetrance for biallelic null genotypes.
• Expressivity: Highly variable, ranging from severe WOREE (death in early childhood) to milder SCAR12 (survival with ataxia/epilepsy into adulthood), correlating strongly with genotype (null vs. missense) as described above.
• Consanguinity: A major risk factor — 28% (5/18) of families in the largest published cohort were consanguineous (PMID:30356099); many early case reports originated from consanguineous Middle Eastern/Mediterranean families.
• Sex ratio: No strong sex bias reported in DEE28/WOREE cohorts (40% male, 60% female in the 20-patient cohort — PMID:30356099), consistent with autosomal (non-X-linked) inheritance.
• Carrier frequency: Not precisely established; gnomAD-based estimation methodology exists (summing allele frequencies of curated LOF variants) but specific WWOX carrier-frequency figures were not identified in this search — likely very low given the extreme rarity of the homozygous phenotype.
• Founder effects: Not formally established, though certain recurrent variants (p.(Gln230Pro), p.(Gly137Glu)) recur across multiple unrelated families, suggestive of possible mutational hotspots or regional founder effects.

10. Diagnostics

Clinical "red flags": Early-onset (neonatal/infantile) refractory epilepsy, profound global developmental delay, abnormal EEG, brain MRI abnormalities (corpus callosum hypoplasia, cerebral atrophy, white matter changes), and ophthalmologic involvement, especially in the context of parental consanguinity or a family history consistent with autosomal recessive inheritance (PMID:33916893).

Genetic testing: - First-line: Whole-exome sequencing (WES) or a developmental/epileptic-encephalopathy gene panel including WWOX; whole-genome sequencing (WGS) is valuable for detecting intronic/structural CNVs, which account for a substantial fraction of pathogenic alleles (including compound heterozygous SNV+CNV genotypes). - Chromosomal microarray (CMA): Useful for detecting multi-exon/whole-gene deletions given WWOX's large genomic footprint and fragile-site location. - Uniparental disomy (UPD) testing: At least one case identified a pathogenic splice-site variant unmasked by paternal uniparental isodisomy of chromosome 16 (PMID:38407561), underscoring the value of UPD analysis in apparent "homozygous" findings. - Variant interpretation resources: ClinVar, ClinGen, gnomAD, DECIPHER, VarSome.

Imaging/EEG: - Brain MRI abnormal in ~80% (corpus callosum hypoplasia most common at 75%, cerebral atrophy 55%). - EEG shows a spectrum of epileptiform patterns including hypsarrhythmia (West syndrome, 26%) and Lennox-Gastaut-type patterns (11%).

Ophthalmologic evaluation: Electroretinography/electrodiagnostic testing recommended given the high rate (up to ~50%) of optic nerve/retinal abnormalities.

Differential diagnosis: Other genetic developmental and epileptic encephalopathies (e.g., CDKL5, STXBP1, SCN2A-related DEEs), other causes of early infantile epileptic encephalopathy with cerebellar/cortical malformation, and other autosomal recessive ataxia-epilepsy syndromes for the milder SCAR12 end of the spectrum.

Newborn/carrier screening: No population-based newborn or carrier screening program currently exists for WWOX, given its rarity; diagnosis is via clinical suspicion and confirmatory sequencing.

11. Outcome / Prognosis

• Mortality: Premature death occurred in 40% (8/20) of the largest published cohort, at a mean age of 40 months (PMID:30356099). A dedicated 2023 study ("WWOX developmental and epileptic encephalopathy: Understanding the epileptology and the mortality risk," PMID:36779245) specifically examined mortality risk factors in this population, reinforcing that null/loss-of-function genotypes carry the highest mortality risk (missense-only genotypes have not been associated with premature death).
• Morbidity: Profound and lifelong — no patients in the primary cohort achieved independent sitting or walking; complete absence of language; feeding difficulties requiring gastrostomy in 70%; respiratory complications (including presumed aspiration) in 40%; progressive scoliosis/kyphosis in 65%.
• Disease course: Progressive rather than static in a majority of patients (progressive cerebral atrophy in >50%), though the spectrum extends to milder/longer-surviving phenotypes — the oldest reported living patient is 40 years old.
• Prognostic factors: Genotype is the dominant known prognostic factor — biallelic null/LOF genotype predicts the most severe (WOREE/DEE28) phenotype and highest mortality risk; missense-containing genotypes predict the milder SCAR12 phenotype with better survival.
• Recovery potential: Essentially none with current standard-of-care management; this underlies the strong rationale for the gene-replacement therapy program described below.

12. Treatment

Pharmacotherapy (symptomatic/anticonvulsant): Standard antiepileptic drugs (AEDs) are largely ineffective — 95% of patients are drug-resistant, and "most parents report that their children's medications require frequent adjustment" (WWOX Foundation clinical guidance). No WWOX-specific pharmacological agent exists. NCIT term: NCIT:C15986 (Pharmacotherapy); specific AED classes would use NCIT:C258 (Anticonvulsant).

Ketogenic diet: Used with variable success as an adjunctive anti-seizure strategy in refractory cases, consistent with general use in other drug-resistant developmental and epileptic encephalopathies. NCIT:C15447 (Dietary Intervention).

Device-based therapy: Vagus nerve stimulation (VNS) has been considered/used in some refractory cases per WWOX Foundation clinical guidance. NCIT device-intervention term applicable (no precise NCIT term available per dismech convention).

Supportive/nutritional care: Nasogastric feeding progressing to gastrostomy tube placement is standard for the high proportion of patients with unsafe swallowing and aspiration risk. NCIT:C15433 (Nutritional Support) / gastrostomy procedure term; NCIT:C15329 (Surgical Procedure) for gastrostomy placement.

Rehabilitative care: Physical, occupational, and speech/feeding therapies are used supportively for hypotonia/spasticity and scoliosis management, though no disease-modifying effect is claimed. NCIT:C15302 (Physical Therapy).

Gene replacement therapy (emerging/experimental — highest-impact recent development): - Preclinical proof-of-concept: A single neonatal intracerebroventricular injection of AAV9-Synapsin I-WWOX in Wwox-null mice rescued growth retardation, hypoglycemia, epileptic seizures, ataxia, and premature death — "providing a proof-of-concept for WWOX gene therapy as a promising approach for treating children with WOREE syndrome" (EMBO Mol Med 2021, PMC8649866). Therapeutic modality: GENE_THERAPY; AAV9 vector, neuron-specific Synapsin I promoter, unconjugated. - First-in-human treatment (2026): An 8-month-old infant became the first person to receive an experimental AAV9-mediated WWOX gene-replacement therapy, delivered via cisterna magna injection, under a compassionate-use program at Schneider Children's Medical Center of Israel (Hebrew University-affiliated program). One month post-treatment the child "remained clinically stable and has had no recurrent severe seizures" (news coverage: Jerusalem Post, News-Medical, Precision Medicine Online, 2026). This is described as the "world's first" gene therapy for WOREE syndrome; it remains at a compassionate-use/early clinical stage rather than a registered trial with published peer-reviewed efficacy data as of this report.

Emerging strategies under preclinical investigation (per PMID:33916893 and ScienceDirect 2026 review "WWOX in brain development and disease: Molecular mechanisms and therapeutic opportunities"): - NMD-modulating therapy for splice-site/nonsense variants to rescue transcript stability. - Patient-derived iPSC/brain-organoid drug screening platforms, which have already demonstrated that ectopic WWOX re-expression rescues the hyperexcitability/E-I-imbalance phenotype in WOREE-patient organoids (EMBO Mol Med, PMC8350905) — providing a mechanistic and translational bridge supporting the gene-therapy approach. - CRISPR-Cas9 gene editing, considered theoretically but currently limited by CNS delivery challenges.

Genetic counseling: Recommended for all families given autosomal recessive inheritance, with prenatal diagnosis/carrier testing available for at-risk families with a known familial variant. NCIT:C15240 (Genetic Counseling).

13. Prevention

• Primary prevention: No population-level primary prevention exists given the disorder's extreme rarity; the principal prevention avenue is genetic counseling and carrier testing for families with a known WWOX pathogenic variant (especially in consanguineous unions or those with an affected relative), including preconception carrier screening and prenatal diagnosis (chorionic villus sampling/amniocentesis) or preimplantation genetic diagnosis (PGD) for known familial variants.
• Secondary prevention: Early genetic diagnosis following neonatal-onset refractory seizures allows for prompt initiation of supportive care (nutritional/respiratory) to reduce morbidity from aspiration and malnutrition, and — increasingly — the theoretical window for gene-replacement therapy, which preclinical mouse data indicate is most effective when administered neonatally, before irreversible developmental injury occurs.
• Tertiary prevention: Multidisciplinary supportive management (gastrostomy feeding, scoliosis surveillance/bracing, respiratory support) to reduce complications such as aspiration pneumonia, a plausible major contributor to the observed 40% early mortality.
• Screening: No newborn or population carrier screening program currently exists for WWOX, consistent with its ultra-rare status; cascade carrier testing within affected families is the primary applicable screening modality.

14. Other Species / Natural Disease

No naturally occurring WWOX-related disease has been reported in companion animals or wildlife (unlike many Mendelian disorders with veterinary correlates in OMIA); WWOX biology in other species has instead been studied through engineered/induced models (see Model Organisms, below).

Taxonomy/orthology: WWOX orthologs are conserved across vertebrates and invertebrates: - Mouse: Wwox (NCBI Gene; MGI) - Rat: Wwox (spontaneous lde [lethal dwarfism with epilepsy] mutant allele) - Zebrafish: wwox (ZFIN) - Drosophila: WWOX ortholog functions in aerobic metabolism/reactive oxygen species regulation and protects against ionizing radiation, as the fly FRA16D/WWOX ortholog (PMID:16007179; PMC3016910)

15. Model Organisms

Limitations across models: Mouse and rat complete-knockout models die too early (2–4 weeks) to model the years-long chronic human disease course, limiting long-term therapeutic/natural-history studies; zebrafish and Drosophila models capture developmental/metabolic but not fine CNS network phenotypes; human organoids lack vasculature, immune cells, and long-term maturation, limiting study of the full in vivo hyperexcitability network and the progressive atrophy/neurodegeneration seen on patient MRI.

Summary of Key Ontology Term Suggestions for KB Curation

• MONDO: MONDO:0014533 (developmental and epileptic encephalopathy 28)
• Gene: hgnc:12799 (WWOX)
• Key HP terms: HP:0001250 (Seizure), HP:0011097 (Epileptic encephalopathy), HP:0012736 (Profound global developmental delay), HP:0002079 (Hypoplasia of the corpus callosum), HP:0002120 (Cerebral atrophy), HP:0001252 (Hypotonia), HP:0000556 (Retinal dystrophy), HP:0000252 (Microcephaly), HP:0002650 (Scoliosis)
• Key GO terms: GO:0016055 (Wnt signaling pathway), GO:0007179 (TGF-beta receptor signaling pathway), GO:0043523 (regulation of neuron apoptotic process), GO:0042552 (myelination)
• Key CL terms: CL:0000598 (pyramidal neuron), CL:0000128 (oligodendrocyte), CL:0002453 (oligodendrocyte precursor cell)
• Key UBERON terms: UBERON:0002336 (corpus callosum), UBERON:0002037 (cerebellum), UBERON:0000966 (retina)
• NCIT treatment terms: NCIT:C15986 (Pharmacotherapy), NCIT:C15447 (Dietary Intervention/ketogenic diet), NCIT:C15238 (Gene Therapy), NCIT:C15240 (Genetic Counseling), NCIT:C15329 (Surgical Procedure/gastrostomy)

Sources

• WWOX-related epileptic encephalopathy caused by a novel mutation in the WWOX gene: a case report - PMC
• Neonatal neuronal WWOX gene therapy rescues Wwox null phenotypes - PMC
• Neuronal deletion of Wwox, associated with WOREE syndrome, causes epilepsy and myelin defects | Brain
• WOREE syndrome - Wikipedia
• The phenotypic spectrum of WWOX-related disorders: 20 additional cases of WOREE syndrome and review of the literature | Genetics in Medicine (PMID:30356099)
• The phenotypic spectrum of WWOX-related disorders - PMC (full text)
• Identification of compound heterozygous deletion of the WWOX gene in WOREE syndrome | BMC Medical Genomics
• WWOX-Related Developmental and Epileptic Encephalopathy | Neurology
• Entry #616211 - DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 28; DEE28 - OMIM
• Neurological Disorders Associated with WWOX Germline Mutations—A Comprehensive Overview - PMC (PMID:33916893)
• WWOX P47T loss-of-function mutation induces epilepsy, progressive neuroinflammation, and cerebellar degeneration in mice phenocopying human SCAR12 | bioRxiv
• Altered neocortical oscillations and cellular excitability in an in vitro Wwox knockout mouse model of epileptic encephalopathy - PMC (PMID:34634460)
• Wwox deficiency leads to neurodevelopmental and degenerative neuropathies and glycogen synthase kinase 3β-mediated epileptic seizure activity in mice
• Loss of Wwox Causes Defective Development of Cerebral Cortex with Hypomyelination in a Rat Model of Lethal Dwarfism with Epilepsy - PMC
• WW domain-containing oxidoreductase in neuronal injury and neurological diseases - PMC
• A cascade of protein aggregation bombards mitochondria for neurodegeneration and apoptosis under WWOX deficiency | Cell Death & Disease
• Hyaluronan activates Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed - PMC
• Transforming Growth Factor β1 Signaling via Interaction with Cell Surface Hyal-2 and Recruitment of WWOX/WOX1 - PMC
• Twenty-five years of WWOX insight in cancer: a treasure trove of knowledge - PMC
• A multi-exon deletion within WWOX is associated with a 46,XY disorder of sex development | European Journal of Human Genetics (PMID:22071891)
• FRA16D common chromosomal fragile site oxido-reductase (FOR/WWOX) protects against the effects of ionizing radiation in Drosophila (PMID:16007179)
• Drosophila orthologue of WWOX, the chromosomal fragile site FRA16D tumour suppressor gene, functions in aerobic metabolism and regulates reactive oxygen species - PMC
• Loss of wwox expression in zebrafish embryos causes edema and alters Ca2+ dynamics - PMC
• Modeling genetic epileptic encephalopathies using brain organoids | EMBO Molecular Medicine
• WWOX in brain development and disease: Molecular mechanisms and therapeutic opportunities - ScienceDirect
• Identification of a novel splice-site WWOX variant with paternal uniparental isodisomy in a patient with infantile epileptic encephalopathy (PMID:38407561)
• Case report: Adult patient with WWOX developmental and epileptic encephalopathy: 40 years of observation - PMC (PMID:39507621)
• WWOX developmental and epileptic encephalopathy: Understanding the epileptology and the mortality risk - PubMed (PMID:36779245)
• MedicalResearch.com: Hebrew University First WWOX Gene Replacement Therapy Administered to Child With Hereditary Seizures
• First Infant Receives Gene Therapy for Rare WWOX-Related Epilepsy | Precision Medicine Online
• World's first WWOX gene therapy performed on infant in Israel | The Jerusalem Post
• Infant receives world's first gene therapy for WOREE syndrome - News-Medical
• Diagnosis and Treatment | The WWOX Foundation
• WWOX Loss of Function in Neurodevelopmental and Neurodegenerative Disorders - PMC
• Molecular Biology of the WWOX Gene That Spans Chromosomal Fragile Site FRA16D
• developmental and epileptic encephalopathy, 28 - MONDO / rarediseases.org

Reference Validation

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Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

• PMID:30356099 (abstract only): "premature death has never been described in patients with missense pathogenic variant-only genotype"
• closest text in source: "Eight novel missense pathogenic variants have been described"
• PMID:33916893 (abstract only): "premature death has never been described in patients with missense pathogenic variant-only genotype"
• closest text in source: "Patients harboring pathogenic germline bi-allelic WWOX variants have been described with the rare devastating neurological syndromes autosomal recessive spinocerebellar ataxia 12 (SCAR12) (6 patients) and WWOX-related epileptic encephalopathy (DEE28 or WOREE syndrome) (56 patients)"
• PMC:PMC8649866 (abstract only): "providing a proof-of-concept for WWOX gene therapy as a promising approach for treating children with WOREE syndrome"
• closest text in source: "These findings provide a proof-of-concept for WWOX gene therapy as a promising approach to curing children with WOREE and SCAR12."

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

• PMID:8305172 (1 mention) - Ambulatory blood pressure patterns in youth.
• shared terms: none

Weighed against this report's own most characteristic terms: wwox, epileptic, woree, developmental, gene, seizure, syndrome, phenotype, genetic, disorder, encephalopathy, cerebral, epilepsy, patient, death, disease, scar12, variant, severe, spectrum.