What is WWOX?
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-12) and EIEE28 (Early Infantile Epileptic Encephalopathy-28) or WOREE Syndrome (WWOX-related Epileptic Encephalopathy).
Children affected by these syndromes display the following symptoms in varying severity: refractory epilepsy, profound global delay and severe cognitive impairment. Most children with WOREE Syndrome will not live through to adulthood with an average life expectancy of 4 years. At present there is no cure.
What causes WWOX deficiency and the associated SCAR12 and WOREE syndromes?
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.
To have an autosomal recessive disorder such as SCAR12 or WOREE syndrome, two mutated genes (or alleles) are inherited, one from each parent. The syndromes affecting our kids are also known as monogenic disorders because only one gene is involved.
SCAR12, the less severe of the two syndromes, typically results from a biallelic missense mutation, meaning a missense mutation is inherited from each parent. WOREE on the other hand results from a combination of nonsense mutations, missense mutations and or deletions present on both alleles. The actual combination gives rise to a phenotypic spread which is still not well classified, but varies from severe to extremely severe.
What are the symptoms of SCAR12 (Spinocerebellar Ataxia-12)?
This syndrome is typified by early-childhood onset of cerebellar ataxia which means children are unable to coordinate the movement of their muscles. This in turn causes problems with walking, speech and also abnormal eye movements. Most children also suffer from generalised tonic-clonic epilepsy and psychomotor development delay, slurred or slow speech that can be difficult to understand, gaze-evoked nystagmus where the eyes make repetitive, uncontrolled movements. All children also suffer from a learning disability. They can also have muscle weakness, tight muscles, overactive reflexes and clonus. Mild cerebellar atrophy is usually visible on a brain MRI.
What are the symptoms of WOREE Syndrome (EIEE28)?
Most affected children will present with seizures within the first two months of their lives. The seizures types vary but are typically focal or multifocal in nature. There is usually a progression to Infantile Spasms (West Syndrome) which respond poorly to the standard adrenocorticotropic hormone (ACTH), prednisone, and Vigabatrin therapies. Seizures largely remain refractory to most medications, although some children do attain a degree of seizure control after some time.
In all cases, children have profoundly delayed psychomotor development. Brain MRI's will typically show a thin corpus callosum and delayed myelination. In most cases there will be progressive cerebral atrophy, eg the child's brain will continue to shrink. This could be coupled with progressive microcephaly, meaning the child's head will not continue to grow at a normal rate.
Children with WOREE syndrome typically don't make eye contact and there have been many reports of partial to complete vision loss which can be diagnosed via an electroretinogram.
Other symptoms include axial hypotonia (abnormally low muscle tone), variable rigidity, spasticity, hyperreflexia (overresponsive reflexes), and hypokinesia (slowed muscle movement). Children have poor to no neck control, few to no voluntary movements and they are not able to sit upright unassisted. Moderate to severe scoliosis is a major co-morbidity. Metabolic problems, for instance poor calcium absorption, are also present.
Additionally, children affected by the syndrome have significant feeding issues and are at risk of aspirating liquid in to their lungs. This usually requires the introduction of a nasogastric feeding tube or gastrostomy. Pulmonary problems (apnoea and lung infections such as pneumonia) presents a significant risk to the children as a result of their profound impairment and is indeed the primary cause of mortality.