AMPD2 regulates GTP synthesis and is mutated in a potentially treatable neurodegenerative brainstem disorder.

Purine biosynthesis and metabolism, conserved in all living organisms, is essential for cellular energy homeostasis and nucleic acid synthesis. The de novo synthesis of purine precursors is under tight negative feedback regulation mediated by adenosine and guanine nucleotides. We describe a distinct early-onset neurodegenerative condition resulting from mutations in the adenosine monophosphate deaminase 2 gene (AMPD2). Patients have characteristic brain imaging features of pontocerebellar hypoplasia (PCH) due to loss of brainstem and cerebellar parenchyma. We found that AMPD2 plays an evolutionary conserved role in the maintenance of cellular guanine nucleotide pools by regulating the feedback inhibition of adenosine derivatives on de novo purine synthesis. AMPD2 deficiency results in defective GTP-dependent initiation of protein translation, which can be rescued by administration of purine precursors. These data suggest AMPD2-related PCH as a potentially treatable early-onset neurodegenerative disease.

The role of ketogenic diet in controlling epileptic seizures.

OBJECTIVES: To study the role of the ketogenic diet (KD) in controlling seizures in children with medically resistant epilepsy in Saudi Arabia. METHODS: This retrospective study was conducted in the Pediatric Neurology Clinic at a tertiary care epilepsy center. Thirty-one patients with medically resistant epilepsy were enrolled from 2013 to 2018. The seizure reduction variables were evaluated at 6, 12, 18 and 24 months after enrollment. RESULTS: Of the 31 patients, 14 (45.2%) were males and 17 (54.8%) were females. The most common types of seizures were myoclonic seizures and mixed seizures, both of which occurred in 9 (29%) of the participants. Of the participants, 15 (48.4%) had seizures one to 5 times per day. Six months after starting a KD, 2 (6.45%) of participants were seizure-free; 6 (19.35%) were seizure-free after 12 months of treatment. CONCLUSION: The present study highlighted the effectiveness of KD in medically resistant epilepsy children to local population. A larger cohort is warrant to confirm these findings.

Epilepsy and school in the Middle East and North Africa (MENA) region: The current situation, challenges, and solutions.

Education is a human right that plays a key role in social and economic development. Children having active epilepsy may not be properly schooled in ordinary school structures. Students with epilepsy (SWE) are often faced with academic barriers. The lack of information about the current status of special education for SWE obliged the researchers to try to describe the existing reality of the special education practices in the Middle East and North Africa (MENA) region. We disseminated a simple self-administered questionnaire via email to main healthcare professionals involved in epilepsy care in the MENA region, and we also did a literature search on the PubMed, Google Scholar, and Embase engines. We ranked the countries in terms of their educational system. The 1st group contains the most advanced educational system, including specialized schools for SWE. The 2nd group contains an educational system with specialized but less structured schools. The 3rd group includes countries using integrated classes or classes mixing many children with cognitive disabilities. The 4th group includes countries with ordinary classes for SWE, and finally, the 5th group with no schooling for children with epilepsy (CWE). This study indicates that 60% of the countries in the MENA region belong to the 3rd group; there is only one country in each of the first two groups. This work highlights the need to develop structured environments for schooling for SWE in the MENA region.

Diagnosis and management of cerebral folate deficiency. A form of folinic acid-responsive seizures.

Folinic acid-responsive seizures (FARS) are a rare treatable cause of neonatal epilepsy. They have characteristic peaks on CSF monoamine metabolite analysis, and have mutations in the ALDH7A1 gene, characteristically found in pyridoxine-dependent epilepsy. There are case reports of patients presenting with seizures at a later age, and with folate deficiency due to different mechanisms with variable response to folinic acid supplementation. Here, we report 2 siblings who presented with global developmental delay and intractable seizures who responded clinically to folinic acid therapy. Their work-up included metabolic and genetic testing. The DNA sequencing was carried out for the ALDH7A1 gene, and the folate receptor 1 (FOLR1) gene. They had very low 5-methyltetrahydrofolate (5-MTHF) in CSF with no systemic folate deficiency and no characteristic peaks on neurotransmitter metabolite chromatogram. A novel mutation in the FOLR1 gene was found. The mutation in this gene is shown to affect CSF folate transport leading to cerebral folate deficiency. The response to treatment with folinic acid was dramatic with improvement in social interaction, mobility, and complete seizure control. We should consider the possibility of this treatable condition in appropriate clinical circumstances early, as diagnosis with favorable outcome depends on the specialized tests.

Diagnosis and management of infantile epileptic spasms syndrome (IESS) in Gulf Cooperation Council (GCC) countries: Expert consensus statement.

Despite the availability of international recommendations for the management of Infantile Epileptic Spasms Syndrome (IESS), there is a lack of recommendations adapted to the local context of clinical practice of pediatric neurology in the Gulf Cooperation Council (GCC) countries. By an initiative from the Saudi Pediatric Neurology Society (SPNS), a literature review was performed and an expert panel comprised of 13 pediatric neurologists from all GCC countries (Saudi Arabia, Kuwait, Bahrain, Oman, Qatar, and the United Arab Emirates) was subsequently convened to discuss all issues related to the management and diagnosis practices of IESS in the GCC. The overall aim of this consensus document was to develop practical recommendations to support the care of patients with IESS in the GCC and to reflect on how clinical management approaches compare with those adopted internationally.

Evaluating the Potential of Light Exposure on Reducing the Frequency of Epileptic Seizures.

Epilepsy is one of the most common and devastating neurological disorders that causes unprovoked, recurrent seizures arising from excessive synchronized neuronal discharging. Although antiepileptic drugs (AEDs) reduce the frequency of epilepsy seizures, drug-refractory epileptic patients exert resistance to AEDs, resulting in treatment difficulty. Moreover, pharmacological treatments do not show satisfactory results in response to photosensitive epilepsy. In the recent era, light therapy emerged as a potential non-pharmacological approach for treating various diseases, including depression, seasonal affective disorders, migraine, pain, and others. Several studies have also shown the potential of light therapy in treating epilepsy. In addition, Red light evokes epilepsy seizures. Blue lenses filter the red light and significantly suppress the frequency of epilepsy seizures. However, the effects of green light on the frequency of epileptic seizures are not studied yet. In addition, light-activated gene therapy or optogenetics also emerged as a possible option for epilepsy treatment. Animal models have shown the therapeutic possibilities of optogenetics and light therapy; however, human studies addressing this possibility are still vague. This review provides the beneficial effects of light in reducing seizure frequency in epilepsy patients. A limited number of studies have been reported so far; therefore, light therapy for treating epilepsy requires more studies on animal models to provide precise results of light effects on seizures.

Dravet syndrome, what is new?

Dravet syndrome (DS) is one of the most severe genetic epilepsies of childhood. Charlotte Dravet described severe myoclonic epilepsy in infancy in 1978. Shortly after the initial report, many cases were published. Most of the cases have the SCN1A mutation. A variant of DS called borderline severe myoclonic epilepsy in infancy has similar clinical and electrographic features without myoclonus. The prevalence of DS is 3-6% of epilepsy cases in infancy, and the incidence is less than one per 40,000 infants. Also, there is a rare mutation in the GABARG2 and SCN1B genes. Usually, affected patients have normal developmental milestones during infancy. Then after 1-4 years of age, they start to develop refractory mixed seizure types (tonic seizures are exceptional) and psychomotor retardation, ataxia, and hyperkinesias. The EEG reveals focal or multifocal epileptic discharges and it commonly shows photosensitivity. The treatment of the seizures is challenging. The combination of stiripentol, valproic acid, clobazam, and topiramate is promising.

Pediatric awake epilepsy surgery: Intraoperative language mapping utilizing digital video gaming and electrocorticography.

Intraoperative functional language mapping is vital to minimize the risks associated with surgical removal of the seizure onset zone in selected patients with epilepsy. In children, this method has been reported extraoperatively by the placement of invasive electrodes to map the language area and monitor epileptic activity. It is difficult from a technical standpoint to perform an awake craniotomy and language mapping in young children under 10 years of age. Here we report a 9-year-old boy suffering from drug-resistant non-lesional epilepsy who underwent extraoperative and intraoperative electrical stimulation with successful identification of Broca's language area. Electrocorticography (ECOG) was applied intraoperatively in a continuous manner utilizing grid electrodes before the skin opening. We found that the use of visual digital video games facilitated extraoperative and intraoperative cortical mapping. Cortical language inhibition by electrical stimulation was elicited at an amplitude of 7 mA (100 µs single-phase duration and 50 Hz pulse width). Resection of the seizure onset zone was completed safely. The post-resection ECOG revealed the disappearance of epileptogenic electrographic discharges at the seizure onset contacts and at other involved contacts in the epileptogenic zone. After surgery, the child recovered well with no language deficits and remained seizure-free. The child remembered only the video game test that was performed intraoperatively. This report highlights safety strategies for awake language mapping in pediatrics and the importance of the perioperative use of a visual digital video game and continuous ECOG, in addition to the use of targeted language cortex stimulation to facilitate faster and safer intraoperative language mapping under awake conditions in this age group.

Epilepsy in patients with WWOX-related epileptic encephalopathy (WOREE) syndrome

Objective: Epileptic encephalopathy (EE) is difficult to diagnose and manage. It can be caused by a variety of disorders, and its aetiology may guide management and prognosis. The human gene for WW domain-containing oxidoreductase (WWOX) has been associated with epileptic encephalopathy, which presents in infancy with seizures, psychomotor delay, microcephaly, and optic atrophy. Methods: We report nine patients with WWOX-related EE from six families. We provide detailed descriptions of clinical presentations, imaging findings, neurophysiological manifestations, and related mutations. Whole-exome sequencing (WES) was used to identify the mutations in the WWOX gene. Results: We established correlations between genotype and phenotype in our cases and previously reported cases. Significance: Our data support previously reported findings regarding WWOX-related EE, indicating the importance of the human WWOX gene in brain development and the association between WWOX mutations and EE. Our study also highlights the power of WES, particularly in clinically challenging cases.

West syndrome, can topiramate be on top?

OBJECTIVE: To determine Topiramate efficacy on treatment of infantile spasms and ancillary seizures, and whether there were any improvements on EEG. METHODS: A retrospective study of 18 patients with infantile spasms recruited from the Pediatric Unit at King Fahd Hospital of the University, Dammam University, Saudi Arabia was carried out between January 2004 and December 2008. Topiramate was used as treatment in 7 males and 11 females aged 2-14 months. The maximum dose was 12 mg/kg/day. RESULTS: The etiology in 9 (50%) patients was cryptogenic, 6 (33%) symptomatic, and 3 (17%) idiopathic. After Topiramate treatment 6 (33%) were spasm free, 8 (44%) had ≥50% reduction, 2 (11%) had no change, and one (6%) had worsening of their spasms. Eight patients had ancillary seizures, 2 (25%) were seizure free, 2 (25%) had ≥50% seizure reduction, and 4 (50%) had no change in the ancillary seizure. The EEG showed hypsarrhythmia in 14 (78%). Post Topiramate, the EEG was normal in one (5%), improved in 3 (17%), showed persistent hypsarrhythmia in 8 (44%), and evolved to other features in 3 (17%). Three patients developed side effects such as weight loss and irritability, for which 2 patients stopped the medication. CONCLUSION: Topiramate has a good effect on the clinical features of West syndrome, but not on the EEG. It was tolerated with minimal side effects.

Quality of Life and the Perceived Impact of Epilepsy in Children and Adolescents in the Eastern Province of the Kingdom of Saudi Arabia.

Objectives This cross-sectional study aimed to assess the perceived impact of epilepsy on children and adolescents and analyze its aspects. Materials and methods The study included patients with epilepsy aged between and two and 19 years old in three major hospitals in the Eastern Province of Saudi Arabia. Data were collected through an online survey. Results The mean score percentage of the quality of life (QOL) assessment was 65.6. This study showed better mean score QOL percentages in males (67), adolescents (65), patients with higher family income and socioeconomic status (64), and those living in Al Jubail (71). QOL was negatively associated with seizure frequency, the number of fears, problems, and concerns, and longer treatment duration. The most common concerns in children and adolescents with epilepsy are having/starting a relationship with others and what people at school will think if they have a seizure. The most common problems were lack of concentration and feeling short-tempered or grumpy. Continuing with education was the most common fear for the future. The most common concern of parents/caregivers was their ability to keep up with schoolwork. The QOL of participants who preferred to keep their epilepsy a secret (69) and those who used magazines and books (71) as one of the sources of information was better than that of those who did not. Conclusion Better QOL was found in males, adolescents, patients with higher family income, those living in Al Jubail, who preferred to keep their epilepsy a secret, and those who used magazines and books as sources of information. However, the QOL was negatively associated with seizure frequency, the number of fears, problems, and concerns that the patients/caregivers had, and longer treatment duration.

Can Doppler sonography be used to diagnose neonatal cerebral infarction caused by portal vein thrombosis.

Neonatal cerebral infarction is a serious and disabling condition. It is extremely rare if it occurs in association with portal vein thrombosis. We are reporting 2 cases of neonatal cerebral infarction with this etiology. The unique mechanism of cerebral infarction will be discussed. We propose that in the absence of any identifiable cause for the cerebral infarction, portal vein thrombosis should be considered and a Doppler sonography for the portal system is worth carrying out to confirm the diagnosis.

3-M Syndrome: A Local Case Report.

BACKGROUND 3-M syndrome is an uncommon disease characterized by severe growth retardation, dysmorphic features, and skeletal abnormalities. Radiographic images may show delayed bone maturation long slender tubular bones, and tall vertebral bodies. Due to the inheritance mode of 3-M syndrome disease, early diagnosis is vital for genetic counseling. CASE REPORT In this case report, we present the case of a 3-year-old male patient who was referred to our clinic for development assessment due to delayed development, particularly speech, who had clinical outcomes of 3-M syndrome. CONCLUSIONS The aim of the case report is to add this new patient to the literature on 3-M syndrome.

Generic substitution of anti-epileptic drugs. A needed battle?

The clinical and economic consequences of generic antiepileptic drug (AED) substitution are not yet fully understood. Generic substitution may increase pharmacy utilization, but it may not always save health care costs for AEDs. The AEDs are relatively cheap, but high volumes of prescriptions mean that substantial drug-budget savings may be possible by switching from innovator brands to cheaper generic drugs. Such savings have been achieved in many other treatment areas. However, more caution may be needed for epilepsy because of the narrow therapeutic index, low solubility, and non-linear pharmacokinetics of some AEDs. This means that the ranges of bioequivalence that are authorized for generic formulations do not offer the same results regarding effectiveness and safety as those obtained by brand name drugs. This is why seizure control should not be sacrificed on the basis of cost alone, as the major endpoint in treating epilepsy with AEDs is seizure control without adverse effects. Switching to the cheapest generic AED may offer drug-budget savings that outweigh any risk to patient safety. But to date, this cost-benefit analysis has not been carried out. We propose that all changes to established principles of treating epilepsy are evidence based and that the risks of switching are clearly defined.

Ataxia-telangiectasia: future prospects.

Ataxia-telangiectasia (A-T) is an autosomal recessive multi-system disorder caused by mutation in the ataxia-telangiectasia mutated gene (ATM). ATM is a large serine/threonine protein kinase, a member of the phosphoinositide 3-kinase-related protein kinase (PIKK) family whose best-studied function is as master controller of signal transduction for the DNA damage response (DDR) in the event of double strand breaks (DSBs). The DDR rapidly recognizes DNA lesions and initiates the appropriate cellular programs to maintain genome integrity. This includes the coordination of cell-cycle checkpoints, transcription, translation, DNA repair, metabolism, and cell fate decisions, such as apoptosis or senescence. DSBs can be generated by exposure to ionizing radiation (IR) or various chemical compounds, such as topoisomerase inhibitors, or can be part of programmed generation and repair of DSBs via cellular enzymes needed for the generation of the antibody repertoire as well as the maturation of germ cells. AT patients have immunodeficiency, and are sterile with gonadal dysgenesis as a result of defect in meiotic recombination. In the cells of nervous system ATM has additional role in vesicle dynamics as well as in the maintenance of the epigenetic code of histone modifications. Moderate levels of ATM are associated with prolonged lifespan through resistance to oxidative stress. ATM inhibitors are being viewed as potential radiosensitizers as part of cancer radiotherapy. Though there is no cure for the disease at present, glucocorticoids have been shown to induce alternate splicing site in the gene for ATM partly restoring its activity, but their most effective timing in the disease natural history is not yet known. Gene therapy is promising but large size of the gene makes it technically difficult to be delivered across the blood-brain barrier at present. As of now, apart from glucocorticoids, use of histone deacetylase inhibitors/EZH2 to minimize effect of the absence of ATM, looks more promising.