What is Ohtahara Syndrome?
Ohtahara Syndrome in medical terms is also identified as early infantile epileptic encephalopathy (EIEE). This is very severe and uncommon epilepsy observed in infants. In this disorder, the seizure begins before age of 3 months in the form of epileptic seizures and they are regarded as hard to control seizures with developmental delays (Shields 2008). Even before seizures develop, babies often have developmental disabilities difficulties and abnormal neurological assessment. As the number of seizures increases, motor and cognitive deficits might deteriorate. Boys and girls are both susceptible to Ohtahara syndrome. The seizures either occur alone or in clusters.
The main symptoms among infants having primarily tonic seizures include upward eye gazing, muscle stiffening, dilated pupils, and alteration in breathing. Focal seizures are also experienced in infants including only side or one area of the brain as well as myoclonic seizures having muscles jerks (Bayat et al., 2021). The symptoms are also characterised by very aberrant brain structure, which can result from trauma or atypical growth. It could also be caused by metabolic diseases or hereditary epilepsy syndromes, albeit in many cases, the reason or causes are unknown (Djukic et al., 2006). As per recent research, Ohtahara syndrome is frequently caused by a genetic mutation. Electroencephalography observations of brain activity in new-borns with Ohtahara syndrome show a distinct pattern of high voltage aberrant brain activity followed by intervals of relatively low activity. “Burst suppression” is the term for this pattern (Djukic et al., 2006).
In Japan, the incidence is estimated to be 1 in every 100,000 births, while in the United Kingdom, it is 1 in every 50,000 births. There have been about 100 instances recorded in all; however this number could be overstated. Because OS new-borns who die early might even go undiagnosed by clinico-EEG Male instances somewhat exceed female cases (Bastos et al., 2008).
There are many genes that cause Ohtahara syndrome and one such gene is ARX. The ARX gene, which is found on the X chromosome’s short arm, has been linked to a variety of syndromes and non-syndrome mental retardation since its discovery in 2002 (Khan and Al Baradie 2012). ARX expression is high in the foetal brain as well as some areas of the adult brain, according to limited human and substantial mouse gene-expression research. Many researches reveal that Ohtahara syndrome is directly related to mutations in ARX.
However, genetic disorders are also related with development of Ohtahara syndrome. Ohtahara syndrome is characterised by a very unusual brain structure that can be caused by trauma or improper growth. It can also be caused by metabolic diseases or hereditary epilepsy syndromes, although in several cases, the reason or origins are unknown (Von Deimling, Helbig and Marsh 2017).
Ohtahara syndrome is a disease which progresses rapidly. Seizures grow more frequent and are associated with deficits in physical and cognitive development if epilepsy surgery is not possible. Several kids will die in early stages, while others will live but with serious disabilities (Shields 2008). Some kids develop additional epilepsy syndromes as they mature, including such West syndrome and Lennox-Gastaut syndrome.
Symptoms of Ohtahara Syndrome
The prognosis in babies with Ohtahara syndrome is very poor and it can be described by seizure control, secondary symptom implications, and shorter life duration (up to three years of age). Survivors suffer from significant psychomotor deficits and are totally reliant on on their caregiver for assistance. Whenever symptoms worsen or develop, family members of new-borns with OS must meet with a palliative care team (Beal, Cherian and Moshe 2012). Seizures, pneumonia, and other consequences from motor limitations are common causes of death. Patients experiencing “catch up” in development after hemispherectomy surgery have demonstrated to have a good chance of recovering from OS (Malik et al., 2013).
The report aims at examining Ohtahara syndrome, its causes, genetic mutations, as well as current and new treatments.
Current evidence and theories of pathogenesis in Ohtahara syndrome
According to Yamamoto, Okumura and Fukuda (2011) the ARX gene encodes a protein which modulates the activation of other genes. The ARX protein is classified as a transcription factor because of this activity. The ARX gene belongs to the homeobox gene family, which regulates the formation of various body structures during early embryonic development. The ARX protein, in particular, is known to play a part in the growth of the brain, pancreas, testes, and movement muscles (skeletal muscles). A range of diseases affecting brain function can be triggered by mutations in the ARX gene. Certain ARX gene mutations cause mental retardation but no other neurological issues.
As per the research conducted by Friocourt and Parnavelas (2010), the first polyalanine tract of ARX has been reported to extend in numerous pathogenic variants. X-linked West syndrome, IEDE, and Ohtahara disease have all been linked to an increase of seven residues. Ohtahara syndrome is caused by the greatest recorded expansion, which adds eleven alanines. It’s important to note that, although having a short growth of seven alanine residues, the patient defined in the report had Ohtahara syndrome, which causes progressive and severe neuro-degeneration and leads to death within the first year of life due to mutation caused by ASX.
Absoud et al., (2010) conducted a research about Initial irregular neurodevelopment, a sophisticated movement condition, and initial infantile epileptic encephalopathy with a suppression-burst pattern is all symptoms of a novel neurodegenerative phenotype linked to a known ARX mutation (Ohtahara syndrome). At the age of five months, a male new born appeared with a dyskinetic movement problem that has been initially classified as infantile spasms. Scientific deterioration was supplemented by increasing cortical atrophy, which resulted in a decrease in white matter volume and death in the first year of lifetime; such a fast progressing and severe phenotype has never been recorded before.
Both clinical care and research are affected by this report. This emphasises the necessity of ARX mutation testing in males with a mobility problem and an early infantile epileptic encephalopathy (Absoud et al., 2010). Researchers also recommend ARX testing for new-borns with apparent neurotoxicity, continuous white matter loss, or cerebral atrophy.
Likewise, according to the research of Kato et al., (2010), extended extension of ARX’s initial polyalanine tract has been linked to Ohtahara syndrome without brain deformity, whereas ARX premature termination mutations have been linked to severe brain deformities including lissencephaly and hydranencephaly. ARX-related interneuronopathies are the names given to both of these conditions. Two families suffering from Ohtahara syndrome were studied by the researchers. In two patients from both families, new point mutation variants in the ARX gene’s terminal exon were discovered. Two of the patients acquired West syndrome, including one developing Lennox-Gastaut syndrome later.
Causes of Ohtahara Syndrome
Hence, Detecting ARX mutations in new-borns with the stated phenotype is critical for prognosis, and doctors must be aware that accelerated neuro-degeneration and mortality could happen during the first year of life (Ek?io?lu, Pong and Takeoka 2011).
Figure: Neuro-images of Ohtahara syndrome
Source: (Sekar et al., 2021)
Research has been conducted by Kato et al., (2007) about the genetic mutation and it’s associated with Ohtahara syndrome. The study reveals that Early Infantile Epileptic Encephalopathy (EIEE) with suppression-burst configuration is caused by a longer polyalanine growth mutation in the ARX gene. Initial infantile epileptic encephalopathy with suppression-burst pattern (EIEE), also identified as “Ohtahara syndrome,” is one of the utmost severe and early forms of epilepsy. ARX, the aristaless-related homeobox gene, is found on human chromosome Xp22 and is required for the formation of cerebral interneurons as a transcription factor. ARX mutations induce a variety of symptoms, ranging from severe brain deformities including such hydranencephaly or lissencephaly (lissencephaly without nonpyramidal or GABAergic inter-neurons) to non – syndromic mental disabilities, with a clear link among phenotypic features (Saneto and Sotero de Menezes 2007).
Kato et al., (2007) in order to identify the link between ARX and EIEE or Ohtahara syndrome, ARX mutation was carried out on male patients having EIEE. The patients have suppression burst pattern and very brief tonic seizures. As even the null mutation of ARX generates fewer severe symptoms than West syndrome, female individuals were excluded from the research. It was found that patients showed signs of shifting from EIEE to West syndrome, as well as significant developmental problems. The following is clinical information on the people who had the ARX mutation:
- Patient 1 was the first kid of two healthy parents who were unrelated. He was born healthy and deprived of asphyxia at full term. He had his first seizure 40 minutes after being born. He had his first seizure 40 minutes after being born (Kato et al., 2007). With unconsciousness, his eyes diverged to the left, followed by transient clonic movement, primarily of the left leg and arm. The seizure lasted about a minute and then repeated four times. Although an EEG showed a change to hypsarrhythmia, indicating West syndrome, adrenocorticotropic hormone (ACTH) therapy was unsuccessful.
- Patient 2 had a healthy older sister and was the second kid of distinct healthy parents. Without asphyxia, he was born at full term. He had blinking of the left eyelid and sudden flexion of the right arm and left leg after birth, which indicated seizures (Kato et al., 2007). Cavum septi pellucidi defect and hypo plastic corpus callosum were discovered on his brain MRI scan.
Fullston et al., (2010) carried their research on a family with Ohtahara syndrome with an ARX protein mutation. It was observed that at all stages of development, ARX protein is strong in the germinal matrix and ventricular zone neuronal precursors. The caudate nucleus, corpus callosum, amygdala, putamen, substantia nigra and hippocampus all have high levels of expression as well. ARX thought to play a vital part in developing brain because of its activity throughout initial development and preference for neuronal tissue.
The research includes two male cousins who were diagnosed with Ohtahara syndrome. A family background of stillbirth, infant death, and seizure disorders in men is also present, which is consistent with X-linked heredity. Both cousins and their parents were found to have the ARX mutation c.81C>G in exon 1. This is the first non-malformation condition associated with an ARX protein shortening mutation (Fullston et al., 2010). The re-start of translation from p.M41, which allowed an N-terminally truncated, mostly functional ARX protein to be generated, is most likely responsible for the failure of a severe deformity. A new nucleotide mutation in ARX was found in the patients and both of them were found to be hemizygous for the mutation.
Ohtahara syndrome is not curable; however, there are various treatments available for the syndrome. The treatments are helpful in reducing the frequency as well as cruelty of seizures, however, they are not considered that effective in handling developmental issues. Some of the current treatments for Ohtahara syndrome are as follows:
Genetic Mutations and Ohtahara Syndrome
Steroids are frequently used to treat encephalopathy. Ohtahara syndrome has been cured with high-dose steroids like adrenocorticotrophic hormone (ACTH) or methylprednisone. Since steroids and AEDs function in different ways, it’s feasible for kids to get both. Corticosteroids have traditionally been used to treat a range of epileptic disorders in children (Esmaeeli Nieh and Sherr 2014). Corticosteroids, including such adrenocorticotropic hormone, have been used to treat infantile spasms in one large multicentre experiment.
Other types of adolescent epilepsies are treated with corticosteroids. Since there is a scarcity of information about which corticosteroid to be using, how much it will be using, and how long to use it, doctors have relied on skilled consensus declarations and tiny case studies within certain epilepsy disorders to guide their treatment. Corticosteroids have been used to treat non-convulsive status epilepticus in LKS, Ohtahara syndrome, and LGS.
According to Ishii et al., (2010), this diet includes high fat, low protein and carbohydrate. This assists in preventing seizures by inducing ketosis in the patient which is a metabolic state triggered by this food combination. Since the kid might not have been able to swallow or eat, the diet might well be given in liquid form. If a child’s seizures are resistant to medication and he or she is no suitable for epilepsy surgery, a ketogenic diet could be tried. This diet is water soluble and can easily transport to the brain. The brain is not capable to use fatty acid but it can use ketones for energy requirements.
After determination of amount of protein intake in patients, the diet is structured into fat grams to protein grams as well as carbohydrate grams. The ratio of 4:1 is taken and it is fluid and calorie limited (Ishii et al., 2010). The diet has anti-inflammatory and anti-oxidant characteristics that seem to modify the expression of some epilepsy-related genes.
A vagus nerve stimulator (VNS) might well be considered whenever a kid is in the early stages of schooling. VNS assist in preventing seizures through transmission of mild electric signals into the brain with the help of vagus nerve. This is often termed as pacemaker for the brain. This is a device which is transplanted under the skin of the chest and device is supposed to wound about the vagus nerve present in the neckline (Wheless, Gienapp and Ryvlin 2018). The device is configured to deliver pulses or stimulation at regular times in the outpatient clinic. This device works without the user having to do anything. If a person understands that they are having a seizure, they could glide a magnet over the transmitter in their left chest to transmit an extra oomph of stimuli to the brain. This could effectively deter seizures in some patients. Improving blood flow to critical brain locations and increasing levels of certain brain chemicals (called neurotransmitters) which are essential for seizure regulation.
These drugs are used to supress seizures; however they are rarely helpful in treating this illness. To assist control the child’s seizures, doctors could use a variety of drugs. Topamax (topiramate), Zonegran (zonisamide), Sabril (vigabatrin), and Felbatol (felbamate) are some of the AEDs suggested for the treatment of Ohtahara syndrome (Aneja and Sharma 2013). The medicines might be administered in runny or injectable formula because the infant is younger that may not be able to swallow it.
Prognosis and Treatment of Ohtahara Syndrome
A further method is elevated transcutaneous electrical nerve stimulation (HD-tDCS), which is a non-invasive technique of stimulating the central nervous system using electrodes placed superficially on the skull (Hallett 2007). Regular rounds of stimulation are often used in trials to cure Ohtahara syndrome, but they are not now employed as a standard treatment.
Epilepsy which does not react to medical treatment is known as refractory epilepsy. Refractory epilepsy can sometimes be treated with surgery. Cortical transection, that entails severing a piece of the brain to stop the spread of confused nerve activity, should be used to control epilepsy in Ohtahara syndrome (Wu and Sharan 2013). Surgical treatment, including like lobectomy, hemispherotomy, or hemispherectomy, might alleviate severe occurrences with regional or hemispheres lesions; with better outcomes the sooner the surgery is performed. Callosotomy could help patients with LGS and drop attacks. The usage of vagus nerve stimulation (VNS) before callosotomy is advocated in the most recent protocols.
The power to make almost every cell type from generated Pluripotent Stem Cells has been made possible because to advances in cellular reprogramming (iPSCs). When accessibility to real humanoid tissue appropriate for culture is very limited, iPSCs offer such a particularly appealing model for neurologic illness. iPSCs have been used to model epileptic pathways in Dravet syndrome in a few recent research. Such findings indicate that epilepsy syndrome-specific iPSC-derived neurons could be used to imitate epileptic-like activation, giving a basis for testing new drug therapies (Esmaeeli Nieh and Sherr 2014). The example of Rett syndrome is another indication of how programming technologies might be used. Rett syndrome is a neurodevelopmental condition that causes one in each 10,000–15,000 normal female birth.
Zebrafish larvae have evolved as a unique model system for drug screening. Recent times, a zebrafish mutant was characterised as a simple vertebrate model of a potassium channels mutation which matched crucial parts of Neuropathic pain. Clemizole was discovered as a effective treatment for Dravet syndrome (Basnet at al., 2019). This research is a new route in juvenile epilepsy modelling, and it will likely be employed more in the future to find new therapies for other genetically inherited epilepsy.
This is a mouse model wherein a gene of interest could be eliminated in specialized cell types in a specific part of the body while remaining functional in other cell types and tissues (Dulla 2018). The phenotype could also be more consistently linked to the target gene’s inactivation. DLX5/6-expressing lymphocytes were genetically stripped of ARX in this model. ARX activity in sensory neurons eminence-derived cells, like cortical GABAergic interneurons, is thereby eliminated.
Conclusion
The above discussion is about Ohtahara Syndrome which is a brain disorder in infants. The Ohtahara Syndrome is able to develop poor nutrition status, stress and infections among patients. As a result, controlling such variables assists in seizure prevention. Since this condition has no cure or treatment, the prognosis and characteristics of the condition must be thoroughly explained to the patient’s parents/guardians. The patient’s parents/guardians must be informed about the patient’s trigger factors and danger indicators so that catastrophic seizures could be avoided or treated quickly. In developing countries, especially in resource-poor areas, managing such a patient might be challenging.
The ARX Gene and Ohtahara Syndrome
References
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