WOREE syndrome

WOREE syndrome, also called WWOX-related epileptic encephalopathy or developmental and epileptic encephalopathy 28, is an autosomal recessive disorder caused by biallelic loss-of-function variants in WWOX and characterised by drug-resistant epilepsy beginning in infancy, profound global developmental delay, hypotonia, ataxia and premature death

WWOX encodes a WW domain-containing oxidoreductase that was first studied as a tumour suppressor but is also required for neuronal migration, myelination and inhibitory interneuron development, so its loss produces both a developmental and an epileptic phenotype

The disorder sits at the severe end of the WWOX-related spectrum, opposite the milder autosomal recessive spinocerebellar ataxia 12, and the same gene can produce either phenotype depending on the position and type of the biallelic variants

Terminology and classification

• The acronym WOREE stands for WWOX-related epileptic encephalopathy, and the same entity is indexed as developmental and epileptic encephalopathy 28 (DEE28) and early infantile epileptic encephalopathy 28 (EIEE28) in OMIM and the epilepsy literature
• Orphanet lists the condition as ORPHA:708171 under the name facial dysmorphism-corpus callosum hypoplasia-infantile epileptic encephalopathy, MONDO uses MONDO:0014533 and OMIM uses 616211 for the same phenotype
• It is classified among the developmental and epileptic encephalopathies, a group in which the epileptic activity itself is thought to contribute to developmental impairment beyond what the underlying genetic lesion alone would cause
• The mild counterpart is autosomal recessive spinocerebellar ataxia 12 (SCAR12), which is also caused by biallelic WWOX variants but presents with ataxia and epilepsy later in childhood and with better survival
• WWOX-related disorders also include a difference of sex development phenotype in some biallelic carriers, so the gene is pleiotropic and the epilepsy syndrome is only one part of the clinical spectrum
• The principal differentials are Dravet syndrome, West syndrome, STXBP1 encephalopathy, KCNQ2 encephalopathy, CDKL5 deficiency and MECP2-related disorders, each separated by seizure onset, electroclinical pattern, gene and inheritance

History

• WWOX was cloned in the late 1990s as a putative tumour suppressor spanning the common fragile site FRA16D, and for more than a decade its clinical interest was confined to cancer biology
• Biallelic WWOX variants were first linked to autosomal recessive spinocerebellar ataxia 12 in 2014, and the much more severe epileptic encephalopathy phenotype was recognised in the following years as exome sequencing entered paediatric neurology
• A 2019 international review added 20 patients from 18 unrelated families with WOREE syndrome and established genotype-phenotype correlations, including that truncating variants and deletions generally produce the severe end of the spectrum
• A 2021 comprehensive overview assembled 56 reported WOREE patients alongside 6 SCAR12 patients, generated the largest catalogue of WWOX pathogenic variants and highlighted the absence of any disease-specific therapy
• By 2023 the published case count had risen to about 60, and a 2024 report of an adult followed for more than 40 years showed that survival beyond early childhood is possible and that the phenotype is more heterogeneous than the earliest reports suggested
• Experimental work with patient-derived induced pluripotent stem cells and CRISPR-engineered brain organoids in 2021 provided the first human cellular model of WOREE and shifted research from descriptive genetics toward mechanism-based therapy

Epidemiology

• Only 56 patients had been reported in the comprehensive 2021 review, and the total literature comprised about 60 cases by 2023, making WOREE one of the rarest monogenic epileptic encephalopathies
• The 2019 series added 20 patients from 18 unrelated families, a ratio that reflects the high proportion of consanguineous unions and of homozygous variants in the reported population
• Onset is typically within the first year of life and often within the first months, so WOREE is classified as an early infantile epileptic encephalopathy rather than as a childhood-onset epilepsy
• Premature death occurs most often between 2 and 4 years of age in severe cases, usually from refractory seizures, aspiration, respiratory infection or central hypoventilation rather than from a single identifiable cause
• Survival is not uniformly short: the 2024 adult case followed for more than 40 years demonstrates that some compound heterozygous or hypomorphic genotypes permit survival into adulthood with severe disability
• The recurrence risk for siblings of an affected child is 25%, and the risk is higher in consanguineous families because carrier parents may share the same ancestral variant
• The condition is reported worldwide with no single founder population, but published cohorts are enriched for consanguineous families from North Africa, the Middle East and South Asia, which biases the observed variant spectrum
• Ascertainment depends on exome or genome sequencing in paediatric epilepsy cohorts, and because many cases die before testing, the published prevalence probably underestimates the true incidence

Pathophysiology

• Biallelic loss-of-function variants abolish or severely reduce WWOX protein, and the severity correlates broadly with the amount of residual protein, with null genotypes producing the WOREE phenotype and hypomorphic alleles producing SCAR12 or intermediate forms
• WWOX contains two N-terminal WW domains that mediate protein-protein interactions and a short-chain dehydrogenase/reductase domain, and loss of these domains disrupts transcriptional regulation and redox signalling in neurons
• WWOX regulates neuronal migration and cortical lamination, and knockdown or deletion in mouse cortex produces ectopic neurons, impaired dendritic arborisation and reduced cortical thickness consistent with the microcephaly seen in patients
• Loss of WWOX reduces hippocampal GABAergic inhibitory interneurons and activates microglia and astrocytes, which provides a plausible mechanism for the intractable seizures and for the neuroinflammation described in mouse models
• WWOX also regulates genes required for myelination, and neuronal Wwox deletion in mice causes myelin defects alongside epilepsy, which may explain the white-matter changes and corpus callosum hypoplasia seen on patient imaging
• The gene is a tumour suppressor and a regulator of steroid metabolism, which is why biallelic carriers can show endocrine and sex-development features in addition to the neurological phenotype

Clinical features

• Seizures begin in the first months of life and are typically drug-resistant, with epileptic spasms, tonic seizures, myoclonic seizures, focal seizures and atypical absences occurring in various combinations
• Electroencephalography usually shows multifocal epileptiform discharges, background slowing and, in some infants, a hypsarrhythmic pattern that evolves into a more disorganised tracing over time
• Global developmental delay is profound and affects motor, language and social domains, and most children never achieve independent walking or meaningful expressive speech
• Neurological examination shows axial hypotonia, appendicular hypertonia in some, ataxia, poor visual tracking, microcephaly and, in older survivors, spasticity and scoliosis
• Brain magnetic resonance imaging shows cerebral atrophy, delayed myelination, thinning of the corpus callosum and, in some cases, cerebellar vermis hypoplasia or periventricular white-matter changes
• Feeding difficulties, gastro-oesophageal reflux, aspiration, recurrent respiratory infection, sleep disturbance and autonomic instability are common and are the main proximal causes of death in severely affected infants

Diagnosis

• The diagnosis is suspected in an infant with drug-resistant seizures beginning in the first months of life, profound developmental delay, hypotonia and microcephaly, particularly when brain imaging shows atrophy or corpus callosum hypoplasia
• First-line genetic testing is exome or genome sequencing, with chromosomal microarray used in parallel to detect intragenic or whole-gene deletions that sequencing may miss
• Electroencephalography and prolonged video telemetry characterise the seizure type and distinguish WOREE from Dravet syndrome, West syndrome and other early infantile encephalopathies before genetic results are available
• Brain magnetic resonance imaging is indicated at diagnosis to document atrophy, myelination delay and malformations, and repeat imaging is useful when developmental regression or new neurological signs appear
• Parental testing confirms trans or cis configuration of the two variants, which matters because biallelic variants in cis do not cause disease and because recurrence counselling depends on carrier status
• The differential includes Dravet syndrome, West syndrome, STXBP1 encephalopathy, KCNQ2 encephalopathy, CDKL5 deficiency, MECP2-related disorder and the milder SCAR12 phenotype, each separated by seizure onset, imaging pattern, gene and inheritance
• Prenatal diagnosis is possible when both pathogenic variants have been identified in a previous child, and carrier testing of relatives allows reproductive planning in consanguineous families

Management

• Care is delivered by a paediatric neurology and palliative care team, with input from gastroenterology, respiratory medicine, orthopaedics, dietetics, physiotherapy and medical genetics, because the disorder affects multiple organ systems
• Seizures are treated with broad-spectrum antiseizure medications such as valproate, clobazam, levetiracetam or topiramate, often in combination, but complete seizure freedom is rare and the aim is to reduce seizure burden and distress
• The ketogenic diet is used in some infants with drug-resistant seizures, and cannabidiol has been tried in individual cases, but neither has been evaluated in a WOREE-specific trial
• Feeding support includes thickening, anti-reflux therapy and, when aspiration risk is high, nasogastric or gastrostomy feeding, and nutritional status should be reviewed at every admission because growth failure is common
• Respiratory surveillance includes aspiration precautions, airway clearance, vaccination and early treatment of infection, and some children require non-invasive ventilation for central hypoventilation or obstructive events
• Spasticity, scoliosis and contractures are managed with physiotherapy, positioning, orthoses and, in selected cases, botulinum toxin or orthopaedic surgery, with the goal of comfort and ease of care rather than independent walking
• Palliative care should be introduced early rather than only at the end of life, because advance care planning, symptom control and family support are central to quality of life in a disorder with high early mortality
• Genetic counselling explains the 25% recurrence risk, the difference between trans and cis variants, the availability of prenatal diagnosis and the option of carrier testing for relatives considering marriage or childbearing
• Prognosis is poor in classic null genotypes, with death usually in early childhood, but the adult case reported in 2024 shows that counselling should acknowledge a minority who survive with severe disability rather than present the diagnosis as uniformly fatal

Research and controversies

• Whether WWOX-related epilepsy is primarily a channelopathy, a myelination disorder or a neurodevelopmental migration defect remains unresolved, and the answer will determine whether antiseizure drugs, myelin-directed therapy or gene replacement is the most rational strategy
• Brain organoids derived from patient cells and from CRISPR-edited stem cells reproduced early developmental defects in 2021, providing a human platform for drug screening that avoids the limitations of mouse models
• Gene replacement is attractive in principle because loss of function is the mechanism, but the brain is a large organ, WWOX is a large gene and delivery before irreversible developmental damage would be required, so clinical translation remains distant
• Whether early diagnosis through newborn or infant epilepsy sequencing improves survival is unknown, because no disease-modifying therapy exists and earlier diagnosis mainly changes palliative and reproductive planning rather than outcome
• International registries and natural-history studies are needed to define genotype-specific survival and to identify hypomorphic alleles that might be amenable to therapies targeted at residual protein function