WWOX: The Gene Behind WOREE and SCAR12
WWOX is an abbreviation of the name of an enzyme and associated gene called “WW domain containing oxidoreductase” located on Chromosome 16 at band 16q23.1-q23.2.
It makes the WWOX protein
The WWOX gene provides instructions for making the WWOX protein, which helps regulate cellular processes. Researchers have studied its roles in tumour suppression and brain development.
It is important for the brain
Research shows that the WWOX protein has an important role in the development and normal function of the central nervous system.
Our understanding has grown
WWOX was first studied for its role in cancer biology. In 2014, researchers reported biallelic WWOX variants causing severe neurological disease.
An extremely rare recessive mutation of the WWOX gene causes a deficiency of this protein which has a severe impact on brain development. The resultant syndromes are known as SCAR12 (Spinocerebellar Ataxia, Autosomal Recessive 12) and EIEE28 (Early Infantile Epileptic Encephalopathy-28) or WOREE Syndrome (WWOX-related Epileptic Encephalopathy).
WOREE syndrome typically involves difficult-to-control epilepsy and profound developmental impairment. SCAR12 generally has a less severe course, with features that can include balance and coordination difficulties, developmental delay, intellectual disability and seizures. Features and severity vary between individuals. WOREE Syndrome can be life-limiting. Severity and survival vary and some people live into adulthood. A child's clinical team can discuss their individual outlook. At present there is no cure.
WWOX at a Glance
Chromosome 16
WWOX is located on the long arm of chromosome 16 at band 16q23.1-q23.2
Autosomal Recessive
Changes in both copies of the WWOX gene are needed to cause disease.
WOREE & SCAR12
WWOX-related disorders include WOREE syndrome and SCAR12.
Research Underway
Scientists worldwide are working to understand WWOX and find treatments.
How is WWOX inherited?
WWOX deficiency is a direct result of autosomal recessive mutations affecting the WWOX gene. Genes come in pairs. One gene in each pair comes from the mother, and the other gene comes from the father. Recessive inheritance means both genes in a pair must be abnormal to cause disease. People with only one defective gene in the pair are called carriers. Carriers of WWOX mutations are not affected with the condition. However, they can pass the WWOX gene mutation to their children.
Unaffected (no changed copies)
Carrier (one changed copy)
Affected (two changed copies)
When both parents are carriers of a disease-causing WWOX variant, each pregnancy has a 25% chance of an affected child, a 50% chance of an unaffected carrier, and a 25% chance of an unaffected child who is not a carrier.
Understanding the Conditions
What is it?
What
causes it?
What are the symptoms?
WOREE Syndrome
WWOX-Related Epileptic Encephalopathy
WOREE syndrome is a rare, severe neurodevelopmental disorder that affects the development and function of the brain. It usually begins in infancy and is characterised by difficult-to-control epilepsy, profound developmental impairment and complex medical needs.
WOREE syndrome is caused by biallelic pathogenic variants (mutations in both copies) of the WWOX gene that result in little or no functional WWOX protein. WWOX is essential for normal brain development and function.
Symptoms often begin during the first months of life.
Severe epilepsy
Profound developmental delay
Low muscle tone (hypotonia)
Feeding difficulties
Movement disorders
Vision impairment (including cortical vision impairment)
Respiratory complications
Scoliosis
Limited or absent speech
Many children require lifelong medical care and support.
There is currently no cure for WOREE syndrome. Treatment focuses on managing symptoms and improving quality of life through multidisciplinary care. This may include anti-seizure medications, nutritional support (including feeding tubes when required), physiotherapy, occupational therapy, speech therapy, respiratory management, orthopaedic care, and vision support. Gene therapy and other potential disease-modifying treatments are under investigation. Further clinical evaluation is needed to assess their safety and effectiveness.
SCAR12
Spinocerebellar Ataxia, Autosomal Recessive 12
SCAR12 is a rare neurological disorder caused by changes in the same WWOX gene. It generally has a milder course than WOREE syndrome and primarily affects balance, coordination and movement, although the severity can vary between individuals.
SCAR12 is also caused by biallelic variants in the WWOX gene. In many cases, these variants allow the gene to retain some residual function, which is thought to contribute to the generally milder phenotype compared with WOREE syndrome.
Symptoms usually include:
Delayed motor development
Cerebellar ataxia (poor balance and coordination)
Intellectual disability (ranging from mild to severe)
Speech difficulties
Muscle weakness or spasticity
Tremor
Seizures in some individuals
The severity and progression can vary considerably.
There is currently no cure for SCAR12. Treatment is supportive and tailored to each person's symptoms. It may include physiotherapy, occupational therapy, speech therapy, seizure management when needed, mobility aids, orthopaedic care, and regular neurological follow-up. Research into therapies targeting WWOX-related disorders, including gene therapy, may also benefit individuals with SCAR12 in the future.
What are the treatments?
Important to know
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WOREE Syndrome and SCAR12 are part of the spectrum of WWOX-related disorders.
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Both conditions are caused by pathogenic variants in the WWOX gene.
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While WOREE Syndrome is generally the more severe phenotype, there can be overlap in clinical features and each individual is unique.
