Efficacy and tolerability of perampanel in pediatric patients with Dravet syndrome.

Background: In 1978, Charlotte Dravet first described a form of epilepsy termed Dravet syndrome (DS). It is a form of genetic epilepsy with early-onset, intractable epilepsy episodes, and neurodevelopmental delay. In children, DS can lead to refractory seizures that are resistant to standard therapy. Recently, perampanel (PER) was approved as an antiepileptic drug for patients as young as 4 years old. Methods: The medical records were retrospectively reviewed and patients with DS who used PER were included in this study. The diagnosis was established using whole-exome sequencing, and the collected data included the patients' demographic characteristics, seizure pattern, PER dosage, laboratory and imaging findings. Results: This study included 18 pediatric patients with a clinical diagnosis of DS. The mean age of PER initiation was 7.67±3.865. Most patients had two types of seizures (61.1%) followed by three types (22.2%), with generalized tonic-clonic being the most frequently reported type of seizure. The mean efficacy of PER was 29.17%±29.368%, and only one patient had an efficacy of 100%. Moreover, patients aged 8 years and younger presented with higher efficacy than those who were older (49.17%±34.120% vs. 19.17%±21.829%, P=0.03). Conclusions: This study presented supporting evidence of the promising therapeutic effect of PER among patients with DS. PER can be considered one of the treatment options for this group of patients. However, several patients presented with unfavorable side effects that led to medication cessation. Future multicenter studies are required to explore further treatment options for patients with DS.

Current Concepts in the Management of Sanfilippo Syndrome (MPS III): A Narrative Review.

Sanfilippo syndrome is a childhood-onset (1-4 years) autosomal recessive lysosomal storage disease that presents as a neurodegenerative disease by targeting the brain and spinal cord. It is also known as mucopolysaccharidosis III. Mucopolysaccharidosis III is divided into four subtypes (A, B, C, or D). It can cause delayed speech, behavior problems, and features of autism spectrum disorder. Sanfilippo syndrome is of a higher prevalence within consanguineous families that carry its gene alteration. If both parents have a nonfunctional copy of a gene linked to this condition, their children will have a 25% (1 in 4) chance of developing the disease. In Saudi Arabia, the incidence rate is estimated at 2 per 100,000 live births. Recent research focused on promising treatment approaches, such as gene therapy, modified enzyme replacement therapy, and stem cells. These approaches work by exogenous administration of the proper version of the mutant enzyme (enzyme replacement therapy), cleaning the defective enzyme in individuals with glycolipid storage disorders (substrate reduction therapy), or using a pharmacological chaperone to target improperly folded proteins. However, there is currently no approved curative medication for Sanfilippo syndrome that can effectively halt or reverse the disorder.

Epilepsia partialis continua: A review.

Epilepsia partialis continua (EPC) is a rare type of focal motor seizure characterized by continuous, involuntary muscle contractions in a specific part of the body. These contractions usually involve rhythmic, twitching movements and can last for several hours to days. The seizures are usually limited to one part of the body and can be clonic or dystonic. EPC can affect people of all ages but is more common in children and adolescents. The pathophysiology of EPC is complex and depends on the cause. There are several possible causes of EPC including structural brain abnormalities, infections, metabolic and genetic disorders, inflammatory conditions, traumatic brain injury, and vascular causes. The work-up of EPC includes electroencephalography (EEG), magnetic resonance imaging (MRI) of the brain, position emission tomography (PET) scan of the brain, autoimmune antibodies, infection work-up, and metabolic and genetic work-up. The management of EPC can be challenging. Antiseizure medications (ASDs) including benzodiazepines are an integral part of the management of EPC. Immunotherapy trials are recommended in resistant cases. Epilepsy surgery is one of the effective modalities in some surgically amenable cases. This article reviews the topic of EPC and summarizes diagnostic and .treatment recommendations.

Giant Axonal Neuropathy: A Case Report of Subclinical Childhood Manifestations.

Giant axonal neuropathy (GAN) is a rare, inherited neurodegenerative disease that affects both the central and peripheral nervous systems. It is mostly characterized by a progressive loss of motor and sensory function, which can begin in early childhood. GAN is thought to be caused by a mutation in the GAN gene on chromosome 16q24.1. We report a seven-year-old Saudi male child with GAN who was diagnosed using whole-exome sequencing. The child presented with a history of progressive weakness and muscle wasting in the arms and legs as well as difficulty walking. The sequencing identified a mutation in the GAN gene (NM_022041.3: c.1456G>A). Electrodiagnostic studies showed evidence of diffuse axonal motor and sensory polyneuropathy involving cranial nerves. This case report adds to the growing evidence that whole-exome sequencing can be a useful tool for diagnosing rare inherited neuromuscular disorders. It also highlights the importance of early diagnosis and intervention for this condition.

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.

Parkinsonism-dystonia-2: Case-series study from Saudi Arabia.

Parkinsonism-dystonia-2 PKDYS2 is an autosomal-recessive disorder, caused by pathogenic biallelic variants in SLC18A2 which encodes the vesicular monoamine transporter (VMAT2) protein. PKDYS2 is a treatable neurotransmitter disease, and the rate of diagnosis of this disorder has increased significantly with the advance of genomic technologies. Our report highlights a novel pathologic variant in one case and a novel finding on MRI Brain, consisting of a normal symmetrical signal intensity in the dorsal brainstem and pons, and it substantiates the significance of genetic testing in the evaluation of children with developmental delays, which influences clinical decisions to enhance patient outcomes.

Childhood-related neural genotype-phenotype in ATP1A3 mutations: comprehensive analysis.

BACKGROUND: ATP1A3 is a gene that encodes the ATPase Na + /K + transporting subunit alpha-3 isoenzyme that is widely expressed in GABAergic neurons. It maintains metabolic balance and neurotransmitter movement. These pathways are essential for the proper functioning of the nervous system. A mutation in the ATP1A3 gene demonstrates remarkable genotype-phenotype heterogeneity. OBJECTIVES: To provide insight into patients with ATP1A3 mutation. MATERIAL AND METHODS: These cases were identified using next generation sequencing. The patients' clinical and genetic data were retrieved. Detailed revision of the literature was conducted to illustrate and compare findings. The clinical, genetical, neuroimaging, and electrophysiological data of all pediatric patients were extracted. RESULTS: The study included 14 females and 12 males in addition to two novel females cases. Their mean current age is 6.3 ± 4.24 years. There were 11.54% preterm pregnancies with 5 cases reporting pregnancy complications. Mean age of seizure onset was 1.07 ± 1.06 years. Seizure semiology included generalized tonic-clonic, staring spells, tonic-clonic, and others. Levetiracetam was the most frequently used Anti-seizure medication. The three most frequently reported classical symptoms included alternating hemiplegia of childhood (50%), cerebellar ataxia (50%), and optic atrophy (23.08%). Non-classical symptoms included dystonia (73.08%), paroxysmal dyskinesias (34.62%), and encephalopathy (26.92%). Developmental delay was reported among 84.62% in cognitive, 92.31% in sensorimotor, 80.77% in speech, and 76.92% in socioemotional. EEG and MRI were non-specific. CONCLUSION: Our study demonstrated high heterogeneity among patients with pathogenic variants in the ATP1A3 gene. Such variation is multifactorial and can be a predisposition of wide genetic and clinical variables. Many patients shared few similarities in their genetic map including repeatedly reported de novo, heterozygous, mutations in the gene. Clinically, higher females prevalence of atypical presentation was noted. These findings are validated with prior evidence and the comprehensive analysis in this study.

A novel homozygous splice donor variant in the LRPPRC gene causing Leigh syndrome with epilepsy, a French-Canadian disorder in a Saudi family: case report.

Background: The mitochondria are a cellular power house. Tissues are involved in frequent energy consumption, and any failure or irregularity in the continuous energy production could lead to abnormalities. The leucine-rich pentatricopeptide repeat (LRPPRC) gene is one of the mitochondrial-related functions genes; variations in these genes are responsible for complex phenotypes that affect many organs such as the brain, liver, and muscles. Materials and methods: This study enrolled a family with Leigh syndrome-like phenotype. The molecular diagnosis was conducted by first performing whole exome sequencing (WES), followed by Sanger sequencing. Results: A novel splice-site variant (c.469 + 2T > A) at the exon-intron boundary in the LRPPRC gene was identified using the WES data analysis. Sanger validation confirmed the autosomal recessive inheritance of the identified variant. Based on the ACMG criteria for variant classification, PVS1 and PM2 suggest that the identified variant in the LRPPRC gene is likely to be pathogenic. Conclusion: To the best of our knowledge, there have been no previous reports of this variant in the LRPPRC gene. Our research not only identifies a novel variant in the LRPPRC gene, but also confirms the unresolved molecular diagnosis of the family. WES can be used as a first-line diagnostic tool in familial cases, particularly in those cases when detailed clinical phenotyping is not possible. Once the molecular diagnosis is confirmed in a family, it is necessary to conduct a thorough re-evaluation of the patients' specific clinical phenotypes in order to establish a clear genotype-phenotype correlation.

GAMT Deficiency Among Pediatric Population: Clinical and Molecular Characteristics and Management.

Objective: Analyze the treatment modalities used in real practice by synthesizing available literature. Methods: We reviewed and evaluated 52 cases of GAMT deficiency including 4 novel cases from Saudi Arabia diagnosed using whole-exome sequencing. All data utilized graphical presentation in the form of line charts and illustrated graphs. Results: The mean current age of was 117 months (±29.03) (range 12-372 months). The mean age of disease onset was 28.32 months (±13.68) (range 8 days - 252 months). The most prevalent symptom was developmental delays, mainly speech and motor, seizures, and intellectual disability. The male-to-female ratio was 3:1. Multiple treatments were used, with 54 pharmacological interventions, valproic acid being the most common. Creatinine monohydrate was the prevalent dietary intervention, with 25 patients reporting an improvement. Conclusion: The study suggests that efficient treatment with appropriate dietary intervention can improve patients' health, stressing that personalized treatment programs are essential in managing this disorder.

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.

Evaluation of Health Science Students' Health Fatalism and Perception Towards Patients With Epilepsy: A Cross-Sectional Global Study.

Introduction The social acceptance of patients with epilepsy is largely determined by society's opinion of epilepsy; therefore, individuals with epilepsy could face prejudice and stigma as a result of negative impressions. Religious beliefs and mystical notions have been shown to influence attitudes toward epilepsy. Health fatalism could also be detrimental to society's and caregivers' approach toward such patients. In extreme settings, this could hinder them from obtaining an adequate treatment process. Methods A cross-sectional exploratory study was conducted from February 2022 to May 2022 in Saudi Arabia, Spain, Scotland, and Italy using an online questionnaire consisting of 33 questions concerning the Health Fatalism Scale (HFS), the Epilepsy Knowledge Scale (EKS), and the Epilepsy Attitude Scale (EAS). Results A total of 735 health science students (HSS) participated in the present study. The majority of participants were females (64.1%) while male participants represented 34.6% of the study. Health science students currently studying in Saudi Arabia represented the majority of participants with a percentage of 58.5%. Among the four countries, students in Saudi Arabia presented with the highest knowledge mean score. Students in Spain had the highest mean attitude score. Muslim students had the highest mean fatalism scores followed by Christian students. Conclusion In general, a high level of knowledge was observed among the participants, most notably, among Saudis who presented with the highest level of knowledge across the four countries. Regarding attitude, Spanish students presented the best attitude towards patients with epilepsy. Low fatalism scores were commonly observed across all countries regardless of their different demographic characteristics. Fatalism perception should be further detailed to ensure optimal services are delivered without prejudgment by future healthcare workers.

Clinical whole exome sequencing revealed de novo heterozygous stop-gain and missense variants in the STXBP1 gene associated with epilepsy in Saudi families.

Intellectual disability and developmental encephalopathies are mostly linked with infant epilepsy. Epileptic encephalopathy is a term that is used to define association between developmental delay and epilepsy. Mutations in the STXBP1 (Syntaxin-binding protein 1) gene have been previously reported in association with multiple severe early epileptic encephalopathies along with many neurodevelopmental disorders. Among the disorders produced due to any mutations in the STXBP1 gene is developmental and epileptic encephalopathy 4 (OMIM: 612164), is an autosomal dominant neurologic disorder categorized by the onset of tonic seizures in early infancy (usually in the first months of life). In this article, we report two Saudi families one with de novo heterozygous stop-gain mutation c.364C > T and a novel missense c. 305C > A p.Ala102Glu in exon 5 of the STXBP1 gene (OMIM: 602926) lead to development of epileptic encephalopathy 4. The variants identified in the current study broadened the genetic spectrum of STXBP1 gene related with diseases, which will help to add in the literature and benefit to the studies addressing this disease in the future.

Next-Generation Sequencing Reveals Novel Homozygous Missense Variant c.934T > C in POLR1C Gene Causing Leukodystrophy and Hypomyelinating Disease.

Leukodystrophies are a diverse group of genetically established disorders categorized by unusual white matter changes on brain imaging. Hypomyelinating leukodystrophies (HLDs) are a group of neurodevelopmental disorders that affect myelin sheath development in the brain. These disorders are categorized as developmental delay, spasticity, hypotonia, and intellectual disabilities. We describe a patient with developmental delay, cerebellar ataxia, spasticity, hypotonia, and intellectual disability from a healthy family member. Whole exome sequencing (WES) was performed to identify causative variants, which were further analyzed by bioinformatic analysis. WES was performed, and Sanger sequencing-based segregation analysis confirmed the presence of the homozygous missense variants of NM_203290.3 c.934T > C p.Ser312Pro of RNA polymerase I and III subunit C (POLR1C) gene in this patient and heterozygous variant in the unaffected carrier father and mother, supporting the pathogenicity and inheritance pattern of this variant. Furthermore, the variant identified by WES was validated in healthy controls (n = 100) using Sanger sequencing analysis. Finally, our study explained the important use of WES in disease diagnosis and provided further evidence that the variant in the POLR1C gene may play an important role in the development of hypomyelinating leukodystrophy in Saudi families.

Brain Magnetic Resonance Imaging Findings in Infantile Spasms.

BACKGROUND: Infantile spasms are an age-specific epileptic disorder. They occur in infancy and early childhood. They can be caused by multiple etiologies. Structural abnormalities represent an important cause of infantile spasms. Brain magnetic resonance imaging (MRI) is one of the integral modalities in the evaluation of this condition. PURPOSE: The aim of this study is to review and analyze the clinical characteristics and brain MRI findings in a cohort of children diagnosed with infantile spasms. MATERIAL AND METHODS: A cohort of fifty-six children diagnosed with infantile spasms in infancy and early childhood was included. All of them underwent brain MRI for evaluation. The study was conducted in the period from January 2016 to January 2020. RESULTS: Females comprised 57% of the cohort. The mean age for seizure onset was 5.9 months (SD 2.7). Forty-one patients (73%) had active epilepsy, and 51% were diagnosed with global developmental delay. Consanguinity was present in 59% of the cohort. Most of the follow-up MRIs showed structural abnormalities (84%). Hypoxia was reported in 17% of MRIs. Malformations of cortical development were seen in five patients. Brain MRI findings were normal in 16% of patients, and delayed myelination was seen in nineteen patients. Most of the children with active epilepsy (64%) and developmental delay (82%) had an abnormal brain MRI. It was noticed that abnormal second brain MRIs were more likely to be associated with active epilepsy and developmental delay (p = 0.05). CONCLUSIONS: Brain MRI is an integral part of infantile spasms' clinical evaluation. Infantile spasms and abnormal brain MRI can be associated with active epilepsy and global developmental delay.

Valproic acid for children below 2 years of age with epilepsy.

OBJECTIVES: To evaluate the efficacy of valproic acid (VPA) in a cohort of children below 2 years of age. We also aim to review the characteristics of such patients and the role and safety of VPA for this age group. METHODS: A retrospective chart review conducted at King Abdulaziz University Hospital, Jeddah, Kingdome of Saudi Arabia, for children below 2 years of age diagnosed with epilepsy and treated with valproic acid from January 2016 to January 2020. RESULTS: The cohort for this study includes 50 children below the age of 2 years (25 males, 25 females). Aged 3 months to 23 months at commencing valproic acid. The mean age of seizure onset was 9 months and the mean age of starting valproic acid was 16 months. Thirty-two patients (64%) had more than 50% seizure improvement after valproic acid. Eleven patients (22%) were seizure-free. No statistical significance abnormalities in blood count indices and ammonia were seen during the treatment period. Two patients had dose-related lethargy that improved after decreasing their dosage. Asymptomatic mild elevation in glutamate dehydrogenase was noticed in 18% of patients. CONCLUSION: Using valproic acid in infants and children below the age of 2 years can be considered as a safe and effective treatment option for epilepsy in this age group.

Consensus Statement on the Management of Duchenne Muscular Dystrophy in Saudi Arabia During the Coronavirus Disease 2019 Pandemic.

Background: The coronavirus disease 2019 (COVID-19) pandemic has caused overwhelming challenges in healthcare worldwide. During such an outbreak, some needs of high-risk groups who require regular follow-ups and long-term management are not met. The vulnerable populations include patients with Duchenne muscular dystrophy (DMD). Duchenne muscular dystrophy is characterized by respiratory complications caused by muscle weakness. Hence, patients with this condition are at high risk of severe diseases including COVID-19. Methods: To standardize care and provide optimal treatment to DMD patients in Saudi Arabia during the COVID-19 pandemic, a panel of experts including neurologists and pediatricians consolidated recommendations for healthcare professionals and caregivers. Results: During this pandemic, substituting unnecessary clinic visits with virtual clinic services was highly recommended, if possible, without compromising clinical outcomes. Duchenne muscular dystrophy patients with respiratory complications should be closely monitored, and those with cardiovascular complications must continue taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Moreover, individualized home-based rehabilitation management was preferred. Glucocorticoid and new gene correction therapies should be continued. However, new gene correction therapy must be post-poned in newly diagnosed patients. A multidisciplinary decision was required before the initiation of hydroxychloroquine based on the COVID-19 treatment protocol. Conclusion: COVID-19 has caused challenges and transformed access to health care. However, these limitations have provided opportunities for the health care system to adapt. Further, telemedicine has become a reliable platform for follow-up appointments that should be conducted by a multidisciplinary team including physicians, dieticians, and physical therapists.

Whole-Exome Sequencing Reveals a Missense Variant c.1612C>T (p.Arg538Cys) in the BTD Gene Leading to Neuromyelitis Optica Spectrum Disorder in Saudi Families.

Biotinidase deficiency is an autosomal recessive, multiple carboxylase deficiency usually associated with seizures, eczema, hypotonia, visual disturbances, hearing loss, and developmental delays. Only a handful of cases of biotinidase deficiency that had clinical features of neuromyelitis optica spectrum disorder have been reported in the literature. The case report study is about the clinical and genetic features of two pediatric patients from different families with biotinidase deficiency whose brain and spine MRI scans were suggestive of neuromyelitis optica. Neither child improved with immunotherapy. They come from a first-degree blood-related family. In both cases, a deficiency of the enzyme biotinidase was detected. The missense variant NM_001370658.1 (BTD):c.1612C>T (p.Arg538Cys) NM_000060.4 in exon 4 was identified by whole-exome sequencing. The identified sequence variation was validated using Sanger sequencing analysis. The intake of biotin resulted in clinical improvement. After a follow-up period of 12 months, the patient was gradually weaned from tracheostomy. His vision had improved significantly. He was able to walk and run independently. In conclusion, biotinidase deficiency is a rare and treatable cause of neuromyelitis optica. Early diagnosis can prevent poor clinical outcomes. Biotinidase enzyme levels should be considered as part of the examination algorithm for neuromyelitis optica spectrum disorder.

Treating epilepsy with options other than antiepileptic medications.

Epilepsy is a common health burden worldwide. Epilepsy is linked to variety of factors, including infectious, vascular, immune, structural, genetic, and metabolic etiologies. Despite the existence of multiple antiepileptic drugs (AEDs), many patients are diagnosed with intractable epilepsy. Many nonpharmacological options are available for epilepsy. Some types of epilepsy respond to cofactors. Other patients may be candidates for a ketogenic diet. Inflammatory mediators, such as intravenous immunoglobulins (IVIgs) and steroids, are other options for epilepsy. Recently, cannabinoids have been approved for epilepsy treatment. Refractory epilepsy can be treated with surgical interventions. Focal resections, hemispherectomies, and corpus callosotomies are some common epilepsy surgery approaches. Neuromodulation techniques are another option. Thermal ablation is a minimally invasive approach for epilepsy treatment. Epilepsy outcomes are improving, and treatment modalities are expanding. Trials of nonpharmacological options for epilepsy patients are recommended. This article summarizes available nonpharmacological options other than AEDs for the treatment of epilepsy.

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.