Early infantile epileptic encephalopathy (EIEE), also called Ohtahara syndrome, is a rare disorder characterized by infantile spasms. It has an early onset and symptoms generally occur before the age of one, with seizures often beginning before the tenth day of life. Spasms usually occur just after waking and involve bending at the waist and neck and stretching the arms and legs.
The spasms can happen as an isolated event or in clusters lasting minutes, sometimes over a hundred times a day. It is a severely progressive syndrome and some children with EIEE may go on to develop other epileptic disorders later in life.
Prof. Ingrid Scheffer - What are the genetic epileptic encephalopathies?
Causes of Early Infantile Epileptic Encephalopathy
The exact causes for EIEE are not fully understood. H owever, there is evidence to suggest that the onset of EIEE can lie in both genetic and nongenetic causes.
EIEE can be caused by mutations in the ARX gene. This is a regulatory gene involved in brain development, and it is thought that a reduction in the protein produced by the ARX gene is the main effect of the ARX mutation. Changes in genes not located on the X chromosome can also cause infantile spasms in rare cases.
There are a number of nongenetic causes that have been observed in patients with EIEE, including:
- Brain damage
- Brain malformations
- Metabolic disorders
- Other disorders affecting brain function
Some possible metabolic causes of EIEE include:
- Cytochrome C oxidase deficiency
- Carnitine palmitoyl transferase II deficiency
ARX Gene Mutations and EIEE
The ARX gene produces proteins that regulate the activity of other genes. ARX genes are part of a larger group of homeobox genes that are active during early embryonic development and control the development of a number of structures. The ARX gene is thought to be mainly involved in the development of the:
- Skeletal muscles (used for movement).
In the brain, the ARX protein is involved in the communication and migration of nerve cells. In a normal ARX gene, there are four regions where the amino acid alanine is repeated. The most common ARX gene mutations show extra alanine repetitions. This is believed to reduce the amount of ARX protein in cells . A shortage of ARX function is thought to underlie the main characteristics of early infantile epileptic encephalopathy by affecting the normal migration and development of interneurons.
Other genes with mutations associated with the onset of EIEE include the following:
- CDKL5 (Xp22)
- SL25A22 (11p15.5)
- STXBP1 (9q34.1)
Signs and Symptoms of EIEE
Signs of EIEE show on electroencephalogram (EEG), which measures the electrical activity of the brain. The EEG will show an irregular pattern of suppression-bursts, progressing to hypsarrhythmia. Burst suppression is present in EEG tests during both wakefulness and sleep. EEG tests can help in diagnosing infantile spasms and rule out other types of infantile seizures.
EIEE is characterized by the following symptoms:
- Generalized or lateralized tonic spasms
- Developmental delay or regression
- Intellectual disabilities
Brain imaging is the main method for diagnosis of EIEE. Both CT and MRI scans can show anomalies from the first presentation of clinical symptoms.
EIEE was first identified in 1978. I t affects 1 to 1.6 in 100,000 individuals worldwide and is considered a very rare condition. This number includes types of spasms other than those seen in EIEE.
Early mortality is common in children severely affected by EIEE, often due to seizures, chest infections and pneumonia. Due to recurring seizures, children experience developmental regression and lose skills they have learned. Those who are significantly affected by EIEE are likely to have intellectual disability throughout life.
Around 75% of EIEE patients will continue to develop another age-dependent encephalopathy called West syndrome. EIEE and West syndrome have common characteristics including tonic spasms, severe and continuous epileptic activity and severe mental delay. West syndrome typically occurs after three months of life.
There is currently no cure for EIEE. Patients with EIEE require constant supervision. Treatment for EIEE is not very responsive to antiepileptic drugs
Some success has been observed in controlling seizures by implementing a ketogenic diet, which is a low in carbohydrates and high in fats. This forces the body to burn fat instead of carbohydrates. Some surgical interventions can lead to improvements in those with certain structural abnormalities.