The Prevalence of Active Epilepsy in the Kingdom of Saudi Arabia: A Cross-Sectional Study.

INTRODUCTION: The global prevalence of active epilepsy is around 6.38/1,000 persons. In the Arabian region, the median prevalence of active epilepsy is 4.4/1,000 persons. In the Kingdom of Saudi Arabia (KSA), the last prevalence study for active epilepsy cases was conducted in 2001 and showed an estimate of 6.5/1,000 persons. OBJECTIVES: The aim of the study was to investigate the prevalence of active epilepsy and etiological factors among Saudi individuals of all ages resident in the Riyadh area, the central province, and the capital of KSA. METHOD: This is a door-to-door cross-sectional epidemiological study that was conducted between 2012 and 2016. Patients were initially screened at their homes using a questionnaire, and then suspected individuals were interviewed in the clinic by neurologists and epileptologists. Data related to age, age at seizure onset, gender, probable etiology, treatment, family history, duration of epilepsy, and seizure control, as well as images for electroencephalogram and magnetic resonant imaging, were collected and analyzed. RESULTS: Among the 13,873 participants, active epilepsy was evidenced in 55 patients (3.96; 95% CI: [2.99-5.16]/1,000 persons). No significant variation in the prevalence rate was detected between male and female patients (3.99 vs. 3.94/1,000 persons). The age-specific prevalence was the highest among the infants (1-12 months) (14.78/1,000 persons). Of the various seizure types, complex partial seizures were the most common (33%), followed by generalized seizures (29.1%). Concerning etiology, epilepsies with idiopathic and cryptogenic etiologies were the most common in 18 (36.3%) cases. Structural, vascular, and focal abnormalities were the most commonly diagnosed abnormalities (18.2%, 14.5%, and 39.2%, respectively). CONCLUSION: The prevalence of active epilepsy in KSA has dramatically decreased during the last decades to a rate lower than those reported in most developing countries.

Correction to: Expanding the genetic heterogeneity of intellectual disability.

Variant nomenclature discrepancy was identified in the article.

Expanding the genetic heterogeneity of intellectual disability.

Intellectual disability (ID) is a common morbid condition with a wide range of etiologies. The list of monogenic forms of ID has increased rapidly in recent years thanks to the implementation of genomic sequencing techniques. In this study, we describe the phenotypic and genetic findings of 68 families (105 patients) all with novel ID-related variants. In addition to established ID genes, including ones for which we describe unusual mutational mechanism, some of these variants represent the first confirmatory disease-gene links following previous reports (TRAK1, GTF3C3, SPTBN4 and NKX6-2), some of which were based on single families. Furthermore, we describe novel variants in 14 genes that we propose as novel candidates (ANKHD1, ASTN2, ATP13A1, FMO4, MADD, MFSD11, NCKAP1, NFASC, PCDHGA10, PPP1R21, SLC12A2, SLK, STK32C and ZFAT). We highlight MADD and PCDHGA10 as particularly compelling candidates in which we identified biallelic likely deleterious variants in two independent ID families each. We also highlight NCKAP1 as another compelling candidate in a large family with autosomal dominant mild intellectual disability that fully segregates with a heterozygous truncating variant. The candidacy of NCKAP1 is further supported by its biological function, and our demonstration of relevant expression in human brain. Our study expands the locus and allelic heterogeneity of ID and demonstrates the power of positional mapping to reveal unusual mutational mechanisms.

High school versus graduate entry in a Saudi medical school - is there any difference in academic performance and professionalism lapses?

BACKGROUND: King Saud bin Abdulaziz University for Health Sciences (KSAU-HS) was the first university in the Kingdom of Saudi Arabia offering both high school entry and graduate entry (GE) students into medical school. We compared the academic performance and professionalism lapses of high school entry and GE students who undertook the same curriculum and examinations in the College of Medicine, Riyadh, KSAU-HS. METHODS: Examination scores of 196 high school graduates and 54 GE students over a 4-year period (2010-2014) were used as a measure of academic achievement. For assessment of professionalism lapses, we compared the number of warning letters in both streams of students. RESULTS: In some pre-clinical courses, high school entry students performed significantly better than GE students. There was no significant difference in academic performance of high school entry and GE students in clinical rotations. GE students had a significantly greater number of warning letters per student as compared to high school entry students. DISCUSSION: This is the first Saudi study to compare the performance of high school entry and GE students in a medical school. Overall, both streams of students performed equally well with high school entry students performing better than GE students in a few pre-clinical courses. We compared professionalism lapses and found an increase in number of warning letters for GE students. More studies are needed to evaluate if there are differences in other assessments of professionalism between these two streams of students.

Cerebral sinus venous thrombosis in a child with nephrotic syndrome.

Cerebral venous thrombosis (CVT) as a complication in children with nephrotic syndrome is rarely reported. Although clinical characteristics are increasingly recognized, therapeutic management and clinical outcomes are not well documented. This case report presents a 10-year-old female who presented with dehydration associated with headache and decreased level of consciousness, which required intubation. Brain imaging revealed CVT. Thrombolytic therapy was started, and she showed a good clinical, as well as radiological recovery. The literature was reviewed to highlight the benefit of such therapy in cases with life threatening complications.

Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome.

Joubert syndrome is a congenital brain malformation of the cerebellar vermis and brainstem with abnormalities of axonal decussation (crossing in the brain) affecting the corticospinal tract and superior cerebellar peduncles. Individuals with Joubert syndrome have motor and behavioral abnormalities, including an inability to walk due to severe clumsiness and 'mirror' movements, and cognitive and behavioral disturbances. Here we identified a locus associated with Joubert syndrome, JBTS3, on chromosome 6q23.2-q23.3 and found three deleterious mutations in AHI1, the first gene to be associated with Joubert syndrome. AHI1 is most highly expressed in brain, particularly in neurons that give rise to the crossing axons of the corticospinal tract and superior cerebellar peduncles. Comparative genetic analysis of AHI1 indicates that it has undergone positive evolutionary selection along the human lineage. Therefore, changes in AHI1 may have been important in the evolution of human-specific motor behaviors.

The Response of Synthetic Adrenocorticotropic Hormone (ACTH) Treatment in Pediatric Drug-Resistant Epilepsy Other Than Infantile Epileptic Spasms Syndrome: A Retrospective Observational Study.

INTRODUCTION:  Adrenocorticotropic hormone (ACTH) is a tropic hormone naturally secreted by the anterior pituitary gland to stimulate the secretion of cortisol and androgens. ACTH is used in non-tuberous sclerosis infantile epileptic spasms syndrome (IESS), and it has shown significant, promising results in epilepsy syndromes with possible inflammatory processes. However, many studies have also demonstrated a promising potential even in other types of drug-resistant epilepsy.  Material and method: This study is a retrospective observational study that follows the clinical characteristics and outcomes of nine pediatric patients with drug-resistant epilepsy treated with short-term synthetic ACTH in Saudi Arabia. The response was assessed during the ACTH infusion and after three months. RESULTS: During infusion, six of the nine (66%) patients had a short-term (within two weeks) favorable response, with a more than 50% reduction in seizure frequency. Four of the nine (44%) patients had complete responses with seizure freedom. After three months, four patients (44%) had a three-month seizure frequency reduction of more than 30% attributed to ACTH, including one patient with an IESS history who had a 70% reduction in seizure frequency. Of the four patients who had a complete response, three (75%) had a seizure relapse after tapering in the following three months.  Conclusion: This case series adds to the literature to suggest ACTH treatment of drug-resistant epilepsies other than IESS might benefit some patients in the acute setting but they are less likely to maintain a sustained treatment response. Randomized and large sample size studies are necessary to assess treatment response and accurately aid in appropriate patient selection.

Prevalence and prediction of abnormal CT scan in pediatric patients presenting with a first seizure.

OBJECTIVE: To estimate the prevalence of abnormal neuroimaging in children presenting to the emergency department (ED) with a new-onset seizure, and to identify the significant clinical predictors for an abnormal CT scan. METHODS: In this cross-sectional study, all children age 12 or younger, admitted to the ED at King Abdulaziz Medical City (KAMC) in Riyadh, Kingdom of Saudi Arabia, between January 2005 and December 2010, with a first seizure clinically suspected of neurological condition, and a CT scan before discharge from the ED (N=124), were identified through a chart review. The charts for all patients with abnormal neuroimaging were reviewed for patient characteristics, seizure characteristics, and neuroimaging results. A logistic regression analysis was used to identify the independent predictors of an abnormal CT scan. Statistical significance was calculated at a p-value of ≤ = 0.05. RESULTS: Abnormal CT results were found in 53/124 patients (42.7%). These were significantly associated with the presence of a lesional CNS disorder (x² =16.1, p<0.01), developmental delays (Fisher exact test, p<0.01), generalized seizure (x² =4.17, p=0.04), and the presence of new focal neurological findings (x² = 21.70, p<0.01). However, after applying a logistic regression analysis to adjust for different confounders, only developmental delay (odds ratio [OR]=4.79, p=0.01) and focal neurological findings (OR=7.85, p=0.006) significantly predicted an abnormal CT scan. CONCLUSION: This study demonstrates a high prevalence of abnormalities identified on the CT scans of children who presented with their first apparent seizure. An emergency CT may be considered in children presenting with their first seizure.

Moyamoya Disease in a 13-Month-Old Middle Eastern Boy.

Moyamoya disease (MMD) is a rare, chronic cerebrovascular disease affecting the cerebral arteries, leading to the development of unique collateral vessels. Few cases were reported from Saudi Arabia; however, the incidence rate is not well-defined. Hence, we present a case of a 13-month-old child who presented to the emergency room with first onset focal seizures with relatively unremarkable past medical and family history. Investigations were ordered accordingly including head computed tomography (CT) scan, brain magnetic resonance imaging (MRI), and cerebral angiogram, and he was diagnosed with MMD and considering a broader variety of differential diagnoses for seizures in children is highlighted in our case. Furthermore, considering their predominance in east Asian countries, it highlights a rare presentation in the middle eastern race.

Mutated VWA8 Is Associated With Developmental Delay, Microcephaly, and Scoliosis and Plays a Novel Role in Early Development and Skeletal Morphogenesis in Zebrafish.

Von Willebrand A domain-containing protein 8 (VWA8), also named KIAA0564, is a poorly characterized, mitochondrial matrix-targeted protein having a putative ATPase activity. VWA8 is comprising of ATPase-associated domains and a VWFA domain associated with ATPase activity inside the cell. In the present study, we describe a large consanguineous family of Saudi origin segregating a complex developmental syndrome in an autosomal recessive fashion. All the affected individuals exhibited severe developmental disorders. DNA from three patients was subjected to whole-exome sequencing followed by Sanger sequencing. VWA8 knock-down zebrafish morpholinos were used to study the phenotypic effect of this gene on zebrafish development. A homozygous missense variant [c.947A > G; p.(Asp316Gly)] was identified in exon 8 of the VWA8 gene, which perfectly segregated with the disease phenotype. Using zebrafish morpholino, we observed delayed development at an early stage, lack of movement, light sensitivity, severe skeletal deformity such as scoliosis, and facial dysmorphism. This is the first homozygous variant identified in the VWA8 gene underlying global developmental delay, microcephaly, scoliosis, limbs, and cardiovascular malformations in humans. We provide genetic and molecular evidence using zebrafish morpholino for a homozygous variant in the VWA8 gene, associated with such a complex developmental syndrome in humans.

The Leukodystrophy Spectrum in Saudi Arabia: Epidemiological, Clinical, Radiological, and Genetic Data.

Background: Leukodystrophies (LDs) are inherited heterogeneous conditions that affect the central nervous system with or without peripheral nerve involvement. They are individually rare, but collectively, they are common. Thirty disorders were included by the Global Leukodystrophy Initiative Consortium (GLIA) as LDs. Methods: We conducted a retrospective chart review of a consecutive series of patients diagnosed with different types of LD from four large tertiary referral centers in Riyadh, Saudi Arabia. Only those 30 disorders defined by GLIA as LDs were included. Results: In total, 83 children from 61 families were identified and recruited for this study. The male-to-female ratio was 1.5:1, and a consanguinity rate of 58.5% was observed. An estimated prevalence of 1:48,780 or 2.05/100,000 was observed based on the clinical cohort, whereas a minimum of 1:32,857 or 3.04/100,000 was observed based on the local genetic database. The central region of the country exhibited the highest prevalence of LDs (48.5%). The most common LD was metachromatic leukodystrophy (MLD), and it accounted for 25.3%. The most common disorder based on carrier frequency was AGS. Novel variants were discovered in 51% of the cases, but 49% possessed previously reported variants. Missense variants were high in number and accounted for 73% of all cases. Compared with other disorders, MLD due to saposin b deficiency was more common than expected, Pelizaeus-Merzbacher-like disease was more prevalent than Pelizaeus-Merzbacher disease, and X-linked adrenoleukodystrophy was less common than expected. The mortality rate among our patients with LD was 24%. Conclusion: To the best of our knowledge, this is the largest cohort of patients with LD from Saudi Arabia. We present epidemiological, clinical, radiological, and genetic data. Furthermore, we report 18 variants that have not been reported previously. These findings are of great clinical and molecular utility for diagnosing and managing patients with LD.

Utilization of Complementary Medicine by Pediatric Neurology Patients and Their Families in Saudi Arabia.

Introduction Complementary medicine (CM) consumption is a common practice worldwide. The objective of this study is to find the prevalence of parents visiting the neurology clinic who utilize CM to treat their children. Methods This is a cross-sectional study that was done at King Abdullah Specialized Children Hospital (KASCH), Riyadh, Saudi Arabia between 2018 and 2019. By using a self-administered questionnaire, data were collected to recognize the prevalence of using CM and to identify the commonest type or method. Results A total of 352 parents were given the questionnaire. The prevalence of CM usage among participant was 42%, the most common type of CM was Quran recitation at 66%, followed by herbal medicine at 30% and cautery at 26%. Conclusion Almost half of the parents who visited the neurology clinic at KASCH have used complementary medicine for their children, and nearly three-quarters of the parents who never used CM have thought about using it. Therefore, CM is common in the Saudi Arabian culture.

Prevalence and outcomes of Guillain-Barré syndrome among pediatrics in Saudi Arabia: a 10-year retrospective study.

BACKGROUND: Guillain-Barré syndrome (GBS) is a progressive acute form of paralysis most probably secondary to an immune-mediated process. GBS among Saudis has been seldom investigated, which leaves both clinicians and researchers with scarcity in knowledge. Therefore, this study aims to assess the prevalence and clinical prognosis of GBS among pediatrics admitted with acute paralysis at a large healthcare facility in Riyadh, Saudi Arabia. METHODS: This retrospective study reviewed patients' medical records between 2005 and 2015. Eligible cases were children (<14 years old) admitted to the hospital complaining of acute paralysis and later diagnosed with one form or variant of GBS. Pearson's chi-square, Fisher's exact test, and binary logistic regression were employed to analyze the collected data. RESULTS: The prevalence of GBS was 49%. The male-to-female ratio was 1.45:1. The mean ± standard deviation age was 7±3.7 years. There were 34 (69.4%) cases with progression to maximum paralysis in ≤2 weeks, while 15 (30.6%) cases occurred beyond 2 weeks. Males (n=24, 82.8%) were more likely to endure progression to maximum paralysis in ≤2 weeks after the disease onset, compared to females (n=10, 50%), P=0.014. All cases complaining of respiratory problems exhibited a progression to maximum paralysis in ≤2 weeks, compared to those with no respiratory problems, P=0.027. Residual paralysis at 60 days post disease onset was highly associated with GBS patients of age 8-14 years (n=15, 65.2%), compared to younger patients (n=8, 30.8%), P=0.016. Patients admitted in colder seasons (n=14, 63.6%) were more likely to suffer residual paralysis too, compared to those in warmer seasons (n=9, 33.3%), P=0.035. GBS cases who complained of facial weakness (n=9, 75%) and ocular abnormalities (n=10, 71.4%) were also more likely to endure residual paralysis at 60 days post disease onset, P=0.025 and P=0.03, respectively. CONCLUSION: Male gender could be a determinant of rapid progression to maximum paralysis, while the older age group in pediatrics is expected to endure residual paralysis at 60 days post disease onset. GBS can be accounted as a rare disease, especially in pediatrics, so confirmed cases should be investigated comprehensively for research purposes.

Current management of Duchenne muscular dystrophy in the Middle East: expert report.

Aim: Duchenne muscular dystrophy (DMD) is a severe and rare X-linked neuromuscular childhood disorder that results in functional decline, loss of ambulation and early death due to cardiac or respiratory failure. The objective of this paper is to address different aspects of the current management of DMD in the Middle East, north Africa (MENA) region, and to gather experts' recommendations on how to optimally diagnose and treat patients suffering from this disease. Methods: A group of experts (neuromuscular medicine, neuropediatricians and geneticists) convened to discuss the diagnosis and management of DMD in the MENA region. A list of practical statements was prepared by the chair of the meeting to guide the discussions around critical aspects relating to the current and future management of DMD. Results & conclusion: Ideally, DMD management should be a multidisciplinary approach. Nevertheless, few tertiary care hospitals in the region are currently able to provide the full spectrum of medical expertise and services needed by DMD patients. Clinical practice in the region remains heterogeneous. Specific guidelines for diagnosis and treatment are needed in the MENA region to improve outcomes. Disease awareness among the general public and the medical community is lacking. Now that mutation-specific therapies are being developed and more widely studied, general education programs regarding early signs and symptoms, a standardized referral and diagnosis pathway, patient registries and support groups will significantly improve the management of the disease.

Targeted SLC19A3 gene sequencing of 3000 Saudi newborn: a pilot study toward newborn screening.

BACKGROUND: Biotin-thiamine-responsive basal ganglia disease (BTBGD) is an autosomal recessive neurometabolic disorder mostly presented in children. The disorder is described as having subacute encephalopathy with confusion, dystonia, and dysarthria triggered by febrile illness that leads to neuroregression and death if untreated. Using biotin and thiamine at an early stage of the disease can lead to significant improvement. METHODS: BTBGD is a treatable disease if diagnosed at an early age and has been frequently reported in Saudi population. Keeping this in mind, the current study screened 3000 Saudi newborns for the SLC19A3 gene mutations using target sequencing, aiming to determine the carrier frequency in Saudi Population and whether BTBGD is a good candidate to be included in the newborn-screened disorders. RESULTS: Using targeted gene sequencing, DNA from 3000 newborns Saudi was screened for the SLC19A3 gene mutations using standard methods. Screening of the SLC19A3 gene revealed a previously reported heterozygous missense mutation (c.1264A>G (p.Thr422Ala) in six unrelated newborns. No probands having homozygous pathogenic mutations were found in the studied cohort. The variant has been frequently reported previously in homozygous state in Saudi population, making it a hot spot mutation. The current study showed that the carrier frequency of SLC19A3 gene mutation is 1 of 500 in Saudi newborns. CONCLUSION: For the first time in the literature, we determined the carrier frequency of SLC19A3 gene mutation in Saudi population. The estimated prevalence is too rare in Saudi population (at least one in million); therefore, the data are not in favor of including such very rare disorders in newborn screening program at population level. However, a larger cohort is needed for a more accurate estimate.

Teaching clinical reasoning through hypothetico-deduction is (slightly) better than self-explanation in tutorial groups: An experimental study.

BACKGROUND: Self-explanation while individually diagnosing clinical cases has proved to be an effective instructional approach for teaching clinical reasoning. The present study compared the effects on diagnostic performance of self-explanation in small groups with the more commonly used hypothetico-deductive approach. METHODS: Second-year students from a six-year medical school in Saudi Arabia (39 males; 49 females) worked in small groups on seven clinical vignettes (four criterion cases representing cardiovascular diseases and three 'fillers', i.e. cases of other unrelated diagnoses). The students followed different approaches to work on each case depending on the experimental condition to which they had been randomly assigned. Under the self-explanation condition, students provided a diagnosis and a suitable pathophysiological explanation for the clinical findings whereas in the hypothetico-deduction condition students hypothesized about plausible diagnoses for signs and symptoms that were presented sequentially. One week later, all students diagnosed eight vignettes, four of which represented cardiovascular diseases. A mean diagnostic accuracy score (range: 0-1) was computed for the criterion cases. One-way ANOVA with experimental condition as between-subjects factor was performed on the mean diagnostic accuracy scores. RESULTS: Students in the hypothetico-deduction condition outperformed those in the self-explanation condition (mean = 0.22, standard deviation = 0.14, mean = 0.17; standard deviation = 0.12; F(1, 88) = 4.90, p = 0.03, partial η2 = 0.06, respectively). CONCLUSIONS: Students in the hypothetico-deduction condition performed slightly better on a follow-up test involving similar cases, possibly because they were allowed to formulate more than one hypothesis per case during the learning phase.

Further delineation of the phenotypic spectrum of ISCA2 defect: A report of ten new cases.

Iron-Sulfur Cluster (ISC) biogenesis is a vital cellular process required to produce various ISC-containing proteins. These ISC proteins are responsible for essential functions such as glycine cleavage and the formation of lipoic acid, an essential cofactor of respiratory chain complexes. Defects in ISC biogenesis lead to multiple mitochondrial dysfunction syndromes including: ISCA2 with infantile onset leukodystrophy. Recently, a founder mutation, c.229G > A, p.Gly77Ser in ISCA2 was reported to cause Multiple Mitochondrial Dysfunction Syndrome type 4. In a retrospective review of children diagnosed with the ISCA2 defect, we were able to identify ten new patients who were not reported previously with the identical founder mutation. High CSF glycine levels and elevated glycine peaks on MR spectroscopy were demonstrated in all tested probands. All patients were between 3 and 7 months of age with a triad of neurodevelopmental regression, nystagmus and optic atrophy and leukodystrophy. MRI findings were typical in the patients with diffuse, abnormal white matter signal in the cerebrum, cerebellum, brain stem and spinal cord. The patients ended up in a vegetative state, and often premature death due to respiratory infections. We alert clinicians to consider the ISCA2 defect as a differential diagnosis of infantile onset leukodystrophies affecting the brain as well as the spinal cord, especially in the presence of elevated CSF glycine or elevated glycine peaks in MR spectroscopy.

Early-Onset Parkinsonism: Case Report and Review of the Literature.

BACKGROUND: Early-onset parkinsonism can be caused by PTEN-induced putative kinase 1 (PINK1) gene defects and is usually characterized by an age of onset in the fourth decade of life, slow disease progression, resting tremor, rigidity, bradykinesia, postural instability, and levodopa-induced dyskinesia. METHODS: We evaluated a child with early-onset symptoms and performed a literature review for previously reported examples of children aged 18 years or less with PINK1 gene defects. RESULTS: We describe a five-year-old boy with autosomal recessive early-onset parkinsonism caused by a homozygous missense mutation in the PINK1 gene. This is the youngest individual yet reported with early-onset parkinsonism. CONCLUSION: PINK1-type of early-onset parkinsonism can occur in very young patients, and phenotypic expression of PINK1 mutations may depend on age of onset and ethnicity.

Clinical exome sequencing: results from 2819 samples reflecting 1000 families.

We report our results of 1000 diagnostic WES cases based on 2819 sequenced samples from 54 countries with a wide phenotypic spectrum. Clinical information given by the requesting physicians was translated to HPO terms. WES processes were performed according to standardized settings. We identified the underlying pathogenic or likely pathogenic variants in 307 families (30.7%). In further 253 families (25.3%) a variant of unknown significance, possibly explaining the clinical symptoms of the index patient was identified. WES enabled timely diagnosing of genetic diseases, validation of causality of specific genetic disorders of PTPN23, KCTD3, SCN3A, PPOX, FRMPD4, and SCN1B, and setting dual diagnoses by detecting two causative variants in distinct genes in the same patient. We observed a better diagnostic yield in consanguineous families, in severe and in syndromic phenotypes. Our results suggest that WES has a better yield in patients that present with several symptoms, rather than an isolated abnormality. We also validate the clinical benefit of WES as an effective diagnostic tool, particularly in nonspecific or heterogeneous phenotypes. We recommend WES as a first-line diagnostic in all cases without a clear differential diagnosis, to facilitate personal medical care.