Insight into Genetic Mutations of SZT2: Is It a Syndrome?

BACKGROUND: The seizure threshold 2 (SZT2) gene encodes a protein of unknown function, which is widely expressed, confers a low seizure threshold, and enhances epileptogenesis. It also comprises the KICSTOR protein complex, which inhibits the mTORC1 pathway. A pathogenic variant in the SZT2 gene could result in hyperactive mTORC1 signaling, which can lead to several neurological disorders. AIM OF THE STUDY: To review every reported case and present two novel cases to expand the current knowledge and understanding of the mutation. METHODS: Whole exome sequencing (WES) was used to identify the novel cases and present their clinical and radiological findings. A detailed revision of the literature was conducted to illustrate and compare findings. The clinical, genetical, neuroimaging, and electrophysiological data were extracted. RESULTS: The study included 16 female patients and 13 male patients in addition to the 2 novel male cases. Eighteen patients had heterozygous mutations; others were homozygous. The majority presented with facial dysmorphism (n = 22). Seizures were noted as the predominant hallmark (n = 26). Developmental delay and hypotonia were reported in 27 and 15 patients, respectively. The majority of patients had multifocal epileptiform discharges on the electroencephalogram (EEG) and short and thick corpus callosum on the magnetic resonance imaging (MRI). CONCLUSION: Several promising features are becoming strongly linked to patients with SZT2 mutations. High variability among the cases was observed. Developmental delay and facial dysmorphism can be investigated as potential hallmarks; aiding clinicians in diagnosing the condition and optimizing management plans.

Next generation sequencing reveals novel homozygous frameshift in PUS7 and splice acceptor variants in AASS gene leading to intellectual disability, developmental delay, dysmorphic feature and microcephaly.

Intellectual developmental disorder with abnormal behavior, microcephaly and short stature (IDDABS), (OMIM# 618342) is an autosomal recessive condition described as developmental delay, poor or absent speech, intellectual disability, short stature, mild to progressive microcephaly, delayed psychomotor development, hyperactivity, seizure, along with mild to swear aggressive behavior. Homozygous frameshift mutation in Pseudouridine Synthase 7, Putative; (PUS7) OMIM# 616,261 NM_019042.3 and splice acceptor variants in Alpha-Aminoadipic Semialdehyde Synthase; (AASS) OMIM# 605,113 NM_005763.3 was funded. Whole exome sequencing (WES) technique was used as tool to identify the molecular diagnostic test. Different bioinformatics analysis done for WES data and we identified two novel mutations one as frameshift mutation c.606_607delGA, p.Ser282CysfsTer9 in the PUS7 gene and splice acceptor variants c.1767-1 G > A in the AASS gene has been reported. The pattern of family segregation maintained the pathogenicity of this variation associated with abnormal behavior, intellectual developmental disorder, microcephaly along with short stature IDDABS. Further, the WES data was validated in the family having other affected individuals and healthy controls (n = 100) was done using Sanger sequencing. Finally, our results further explained the role of WES in the disease diagnosis and elucidated that the mutation in PUS7 and AASS genes may lead an important role for the development of IDDABS in Saudi family.

Parental perceptions of dental health and need for treatment in children with epilepsy: a multicenter cross-sectional study.

BACKGROUND: Epilepsy is a common neurological disorder in childhood. However, there have been limited studies on its impact on the oral health of affected children. Our study aimed to assess the oral health of children with epilepsy in the city of Jeddah, Saudi Arabia, as perceived by their mothers. METHODS: We conducted a cross-sectional study in three hospitals. We included children 2-18 years old with physician-confirmed epilepsy diagnosis. We assessed parental perception of dental status and need for dental care using a standardized questionnaire that was completed by the mothers. To adjust for potential confounding variables, we used univariate and multivariate logistic regression. RESULTS: We included 96 children with epilepsy in our study. Their mean age was 6.4±3.4 years. In 55.2% (n=53), dental status was rated as bad, and in 84.4% (n=81) a need for dental care was expressed. Cerebral palsy (OR 5.06, 95% CI 1.28-19.99; P=0.021), motor disability (OR 6.41, 95% CI 1.12-36.73; P=0.037), referral from a pediatric neurology clinic to a dentist (OR 10.755, 95% CI 3.290-35.151; P<0.001), and irregular brushing of teeth (OR 5.397, 95% CI 1.536-18.961; P=0.009) were significantly associated with increased risk of perceived bad dental status. Perception of the child as being overweight (OR 0.117, 95% CI 0.034-0.400; P=0.001) was significantly associated with decreased risk of perceived bad dental status. Motor disability (OR 5.73, 95% CI 1.64-20.04; P=0.006) was significantly associated with increased parental expression of need for dental care. CONCLUSION: In most children with epilepsy, perceived dental status was bad and there was a high expressed need for dental care. Interventions to improve the dental health of children with epilepsy should focus on those with cerebral palsy and motor disability.

Treatment of infantile spasms in Saudi Arabia.

OBJECTIVE: To evaluate the treatment approach and compliance of pediatric neurologists with evidence-based guidelines across Kingdom of Saudi Arabia (KSA). These guidelines that clarify the optimal management of infantile spasms (IS) are not widely followed for various practical reasons. METHODS: Physicians practicing in the field of pediatric neurology in KSA were contacted from the database of national societies. A cross-sectional study was conducted using a structured 20-item on-line survey designed to examine their clinical experience with IS and their treatment choices. RESULTS: A total of 52 pediatric neurologists completed the survey (69% estimated capture rate). They received their formal training within KSA (40%), North America (33%), or Europe (14%). The majority practiced in 2 major cities, Riyadh (46%) or Jeddah (19%). Vigabatrin was favored over adrenocorticotropic hormone (ACTH) as first line drug for patients without tuberous sclerosis complex (48% vs. 21%). Several factors correlated with correctly selecting ACTH as first line including western training (33% vs. 5%, p=0.001), practicing in the city of Riyadh (25% vs. 14%, p=0.001), or having >10 years of clinical experience (25% vs. 5%, p=0.017). Reasons for not complying with the recommended treatment guidelines included lack of availability of ACTH (42%), side effect profile of steroids (29%), and personal preferences (14%). Only 4% admitted lack of awareness of the currently published management guidelines. CONCLUSION: Many pediatric neurologists in KSA are not following the published IS management guidelines. Using ACTH as first line correlated with their training, practice location, and years of experience. Lack of drug availability and side effect profile were common reasons for not complying with the management guidelines.

The Impact of Pediatric Epilepsy on Children and Families: A Multicenter Cross-Sectional Study.

BACKGROUND AND OBJECTIVES: Epilepsy is considered one of the most prevalent causes of morbidity in children. The aim of this study is to determine how epilepsy impacts the lives of children with epilepsy and their families. METHODS: A translated version of the "Impact of Pediatric Epilepsy Scale" (IPES) questionnaire was completed by the 80 mothers of children with epilepsy, recruited at three hospitals in Jeddah, Saudi Arabia This is a validated self-administered questionnaire used to assess the impact of epilepsy on the lives of the child and family, as well as the quality of life (QoL) of the child. RESULTS: The mean age of children epilepsy was 6.32 years (SD = 3.22). The mean IPES score was 6.28 (SD = 8.42) and the mean child's QoL was 2.85 (SD= 0.83). 87.5% of the mothers rated their child's QoL as low. IPES score was significantly associated with cause of seizure (ß=0.259; 95%-CI= 0.263 - 10.334; p = 0.039). Child's QoL was significantly associated with frequency of seizure (ß=0.251; 95%-CI= 0.016 - 0.568; p= 0.039) and child's nationality (ß=-0.270; 95%-CI -0.252, -0.013; p= 0.031). CONCLUSIONS: Pediatric epilepsy may have a greater impact on the lives of the child and the family when it is not comorbid with cerebral palsy. Quality of life tends to be lower for non-Saudi children, and children with more frequent seizures. Therefore, these groups may need more support in managing the impact that epilepsy has on their daily functioning and quality of life.

Publications pattern of clinical epilepsy research in Saudi Arabia.

OBJECTIVE: To assess the progress in the field clinical epilepsy in Saudi Arabia, by analyzing in depth the research output productivity and publication pattern, and to identify the current situation of epilepsy research and offer solutions. METHODS: Literature search strategy was designed to retrieve accessible articles that are related to epilepsy utilizing PubMed, Google Scholar, and Embase. The retrieved articles were analyzed with several parameters, then evaluated using Oxford Center of Evidence Based Medicine level of evidence scale. RESULTS: Of all identified articles, 90 were conducted in Kingdom of Saudi Arabia and therefore were included. The included articles had a frequency of only 3.5 publications per year, and growth of 24.4% between the periods of 1990-2003 and 2004-2016. Only 13.3% of the articles were related to surgical epilepsy but the majority (86.7%) were related to medical epilepsy. Many articles (53.3%) were level III studies. The most common study design was retrospective studies in 35.6%, and the citations number ranged from 1-289 (Mean=7). CONCLUSION: Pattern of publications in clinical epilepsy researches revealed a slow growth rate in the frequency and a lower significance in the quality throughout the past 26 years. Active institutional and national promotion of clinical research is needed to help assess and therefore improve the quality of the provided epilepsy services.

Public awareness of autism spectrum disorder.

OBJECTIVE: Examine the awareness of autism spectrum disorders (ASD) in our community which would help in early recognition and improved support of affected families. METHODS: A focused 20-item questionnaire was designed to survey the public awareness and knowledge of ASD. Personal interviews were conducted during an ASD awareness day, which was organized in a major shopping mall on February 20, 2015 in Jeddah, Kingdom of Saudi Arabia. RESULTS: A total of 259 individuals participated in the study with 47% being <30 years of age and 57% being females. Most participants (60%) were married, educated (68% university level), and employed (54%). When asked if they knew what autism is, 88% responded positively. However, when asked to rate their degree of knowledge, 41% felt that it is weak. Females and those older than 30 years of age were more likely to feel knowledgeable (p=0.04 for females and p=0.013 for those >30 years of age). Females were more likely to think that autistic children can be employed in the future (p=0.008), whereas males were more likely to think that autism is similar to mental retardation (p=0.005). CONCLUSION: The public awareness of ASD needs improvement. Areas for targeted education were identified to help improve the quality of life of autistic children and their families.

A novel mutation in PGAP2 gene causes developmental delay, intellectual disability, epilepsy and microcephaly in consanguineous Saudi family.

PGAP2 (Post-GPI Attachment to Proteins 2) gene is involved in lipid remodeling steps of Glycosylphosphatidylinositol (GPI)-anchor maturation. At the surface of the cell this gene is required for proper expression of GPI-anchored proteins. Hyperphosphatasia with mental retardation syndrome-3 is an autosomal recessive disorder usually characterized by severe mental retardation. Mutations in the PGAP2 gene cause hyperphosphatasia mental retardation syndrome-3. We have identified a large consanguineous family from Saudi origin segregating developmental delay, intellectual disability, epilepsy and microcephaly. Whole exome sequencing with 100× coverage was performed on two affected siblings of the family. Data analysis in the patient revealed a novel missense mutation c.191C>T in PGAP2 gene resulting in Alanine to Valine substitution (Ala64Val). The mutation was reconfirmed and validated by subsequent Sanger sequencing method. The mutation was ruled out in 100 unrelated healthy controls. We suggest that this pathogenic mutation disrupts the proper function of the gene proteins resulting in the disease state.

Copy number variations in Saudi family with intellectual disability and epilepsy.

BACKGROUND: Epilepsy is genetically complex but common brain disorder of the world affecting millions of people with almost of all age groups. Novel Copy number variations (CNVs) are considered as important reason for the numerous neurodevelopmental disorders along with intellectual disability and epilepsy. DNA array based studies contribute to explain a more severe clinical presentation of the disease but interoperation of many detected CNVs are still challenging. RESULTS: In order to study novel CNVs with epilepsy related genes in Saudi family with six affected and two normal individuals with several forms of epileptic seizures, intellectual disability (ID), and minor dysmorphism, we performed the high density whole genome Agilent sure print G3 Hmn CGH 2x 400 K array-CGH chips analysis. Our results showed de novo deletions, duplications and deletion plus duplication on differential chromosomal regions in the affected individuals that were not shown in the normal fathe and normal kids by using Agilent CytoGenomics 3.0.6.6 softwear. Copy number gain were observed in the chromosome 1, 16 and 22 with LCE3C, HPR, GSTT2, GSTTP2, DDT and DDTL genes respectively whereas the deletions observed in the chromosomal regions 8p23-p21 (4303127-4337759) and the potential gene in this region is CSMD1 (OMIM: 612279). Moreover, the array CGH results deletions and duplication were also validated by using primer design of deleted regions utilizing the flanked SNPs using simple PCR and also by using quantitative real time PCR. CONCLUSIONS: We found some of the de novo deletions and duplication in our study in Saudi family with intellectual disability and epilepsy. Our results suggest that array-CGH should be used as a first line of genetic test for epilepsy except there is a strong indication for a monogenic syndrome. The advanced high through put array-CGH technique used in this study aim to collect the data base and to identify new mechanisms describing epileptic disorder, may help to improve the clinical management of individual cases in decreasing the burden of epilepsy in Saudi Arabia.

Dental health of children with cerebral palsy.

Cerebral palsy (CP) is a common chronic motor disorder with associated cognitive, communicative, and seizure disorders. Children with CP have a higher risk of dental problems creating significant morbidity that can further affect their wellbeing and negatively impact their quality of life. Screening for dental disease should be part of the initial assessment of any child with CP. The objective of this article is to present an updated overview of dental health issues in children with CP and outline important preventative and practical strategies to the management of this common comorbidity. Providing adequate oral care requires adaptation of special dental skills to help families manage the ongoing health issues that may arise. As oral health is increasingly recognized as a foundation for general wellbeing, caregivers for CP patients should be considered an important component of the oral health team and must become knowledgeable and competent in home oral health practices.

The availability of services for children with autism spectrum disorder in a Saudi population.

OBJECTIVE: To assess the perceived availability of various services provided by Autism centers in our region. METHODS: A cross sectional study was conducted from March to May 2015 involving health care workers at various governmental and private autism centers in Jeddah, Kingdom of Saudi Arabia. A structured 30-item questionnaire was designed to assess their demographics, training, experience, and the availability of various services at their centers. RESULTS: Twelve autism centers were included and 136 employees participated in the study. Seventy-eight (57%) participants indicated that their center lacked important and essential services. These included programs for home care and outreach (59%), family recognition incentives and rewards (51%), integrative educational programs (39%), and occupational therapy (16%). Access for outside referral for these services was available in only 24% of cases. They cited several major obstacles in providing adequate service including; family involvement (24%), child`s behavioral problems (13%), increased number of students (9%), and work environment and space (5%). CONCLUSION: Significant deficiencies exist in the availability of autism services in our region. Access for referrals for important services is also limited. We identified several areas that can be targeted to help develop, promote, and improve the provided services for children with autism spectrum disorder.

Reflex Seizures Triggered by Diaper Change in Dravet Syndrome.

Dravet syndrome (DS) is a severe epilepsy syndrome characterized by early onset of multiple types of seizures. We report the first case of reflex seizures triggered by diaper change in a girl at 9 months old and 2 years old with a mutation in the SCN1A gene causing DS. Reflex seizures have been reported in patients with DS provoked by increased body temperature or visual stimulation. The case we report widens the spectrum of triggers causing reflex seizures in children with DS. Cortical hyperexcitability resulting from the genetic defect explains the tendency to experience such reflex seizures.

Maternal knowledge of acute seizures.

OBJECTIVE: To study maternal knowledge -of, and behavior during acute seizures. METHODS: A cross sectional study conducted from September 2013 to January 2014 included consecutive mothers presenting at the Pediatric Neurology Clinics of King Abdulaziz University Hospital, Jeddah, Kingdom of Saudi Arabia. A structured 30-item questionnaire was designed to examine their demographics, knowledge, and behavior on acute seizures. RESULTS: A total of 92 mothers were interviewed and 41% witnessed at least one acute seizure in their affected child (range 1-15 years, mean 4.5). Up to 26% felt not knowledgeable at all regarding the acute care and management of seizure. Mothers with higher education (college or university degree) were more likely to feel very knowledgeable (19% versus 11%, p=0.02). Only 10% were aware of an antiepileptic drug that could be used at home to stop prolonged seizures, and 35% mentioned that they would wait for 15 minutes before taking the child to the emergency department. Most mothers (93%) wanted more information. Those who felt strongly regarding that (66%), were more likely to be younger (<27 years) (p=0.01), and have at least 3 out of 7 mismanagement decisions (p=0.003). CONCLUSION: Maternal level of knowledge and behavior during acute seizures needs improvement. Many mothers have significant misinformation, negative behavior, and poor management practices. Increased awareness and educational programs are needed.

Lennox-Gastaut syndrome. Management update.

Lennox-Gastaut syndrome (LGS) is a severe pediatric epilepsy syndrome characterized by mixed seizures, cognitive decline, and generalized slow (<3 Hz) spike wave discharges on electroencephalography. Atonic seizures result in dangerous drop attacks with risks of injury and impairment of the quality of life. The seizures are frequently resistant to multiple antiepileptic (AED) drugs. Newer AEDs, such as rufinamide, are now available. When multiple AED trials fail, non-pharmacological treatments such as the ketogenic diet, vagus nerve stimulation, and epilepsy surgery, should be considered. The aim of this review is to present an updated outline of LGS and the available treatments. Although the prognosis for complete seizure control remains poor, the addition of newer therapies provides an improved hope for some of these patients and their families. Further long term randomized controlled trials are required to compare different therapeutic interventions in terms of efficacy and tolerability.

Genome wide analysis of novel copy number variations duplications/deletions of different epileptic patients in Saudi Arabia.

BACKGROUND: Epilepsy is genetically complex neurological disorder affecting millions of people of different age groups varying in its type and severity. Copy number variants (CNVs) are key players in the genetic etiology of numerous neurodevelopmental disorders and prior findings also revealed that chromosomal aberrations are more susceptible against the pathogenesis of epilepsy. Novel technologies, such as array comparative genomic hybridization (array-CGH), may help to uncover the pathogenic CNVs in patients with epilepsy. RESULTS: This study was carried out by high density whole genome array-CGH analysis with blood DNA samples from a cohort of 22 epilepsy patients to search for CNVs associated with epilepsy. Pathogenic rearrangements which include 6p12.1 microduplications in 5 patients covering a total region of 99.9kb and 7q32.3 microdeletions in 3 patients covering a total region of 63.9kb were detected. Two genes BMP5 and PODXL were located in the predicted duplicated and deleted regions respectively. Furthermore, these CNV findings were confirmed by qPCR. CONCLUSION: We have described, for the first time, several novel CNVs/genes implicated in epilepsy in the Saudi population. These findings enable us to better describe the genetic variations in epilepsy, and could provide a foundation for understanding the critical regions of the genome which might be involved in the development of epilepsy.

The impact of maternal iron deficiency and iron deficiency anemia on child's health.

Iron deficiency anemia is extremely common, particularly in the developing world, reaching a state of global epidemic. Iron deficiency during pregnancy is one of the leading causes of anemia in infants and young children. Many women go through the entire pregnancy without attaining the minimum required intake of iron. This review aims to determine the impact of maternal iron deficiency and iron deficiency anemia on infants and young children. Extensive literature review revealed that iron deficiency is a global nutritional problem affecting up to 52% of pregnant women. Many of these women are symptomatic. Lack of proper weight gain during pregnancy is an important predictor of iron deficiency.

Metabolic syndrome in the survivors of childhood acute lymphoblastic leukaemia.

Metabolic syndrome is a common complication encountered in children surviving acute lymphoblastic leukaemia (ALL). Affected patients develop obesity, insulin resistance, hypertension, and hyperlipidemia. Metabolic syndrome is a consequence of multiple factors, particularly hormonal imbalance induced by various ALL treatments. This review aims to evaluate the risk factors and mechanisms leading to the development of metabolic syndrome. Further research is needed to improve our understanding of the mechanisms leading to insulin resistance and the associated endothelial and adipose tissue dysfunction. Future studies should also examine other possible contributing factors, such as environmental and genetic factors. Understanding these factors will help in guiding modifications of the current ALL treatment protocols in order to prevent the development of this syndrome and hence improve the quality of life of ALL survivors. Until this is achieved, clinicians should continue to identify patients at risk early and use a therapeutic approach that combines dietary restrictions and enhanced physical activity.

Public awareness and attitudes toward epilepsy in Saudi Arabia is improving.

OBJECTIVE: To examine public awareness and attitudes toward epilepsy in Riyadh, the capital city of Saudi Arabia. METHODS: A focused 10-item questionnaire was designed to survey public awareness and attitudes toward epilepsy. Personal interviews were conducted randomly by one author in preselected public places in Riyadh, Saudi Arabia during March and April 2011. RESULTS: Seven hundred and forty-nine interviews were completed during the study period. Most participants (77.4%) had prior knowledge of epilepsy, and 52% believed that epilepsy is an organic disease. This correlated with their educational level, as those with higher levels of education were more likely to link epilepsy to organic causes (p=0.008). However, 15% also linked epilepsy to evil spirit possession, and up to 37% preferred spiritual rituals and religious healing to medical treatments. Although most respondents (61%) would accept an epileptic patient in a regular job, 71% (particularly males) reported reservations in marrying someone with epilepsy (p=0.001). CONCLUSION: The awareness and attitudes of the Saudi public toward epilepsy are showing some improvement. However, it is still thought to be linked to evil spirit possession by some, and spiritual rituals and religious healing are commonly believed to be effective treatments. Targeted areas for focused education were identified.