Genetic Microcephaly in a Saudi Population: Unique Spectrum of Affected Genes Including a Novel One.

Background: Genetic microcephaly is linked to an increased risk of developmental disabilities, epilepsy, and motor impairment. The aim of this study is to describe the spectrum of identifiable genetic etiologies, clinical characteristics, and radiologic features of genetic microcephaly in patients referred to a tertiary center in Saudi Arabia. Method: This is a retrospective chart review study of all patients with identifiable genetic microcephaly presenting to a tertiary center in Saudi Arabia. The patients' demographics, clinical, laboratory, radiologic, and molecular findings were collected. Results: Of the total 128 cases referred, 52 cases (40%) had identifiable genetic causes. Monogenic disorders were found in 48 cases (92%), whereas chromosomal disorders were found in only 4 cases (8%). Developmental disability was observed in 40 cases (84%), whereas only 8 cases (16%) had borderline IQ or mild developmental delay. Epilepsy was seen in 29 cases (56%), and motor impairment was seen in 26 cases (50%). Brain magnetic resonance imaging (MRI) revealed abnormalities in 26 (50%) of the cohort. Hereditary neurometabolic disorders were seen in 7 (15%) of the 48 cases with monogenic disorders. The most common gene defect was ASPM, which is responsible for primary microcephaly type 5 and was seen in 10 cases (19%). A novel PLK1 gene pathogenic mutation was seen in 3 cases (6%). Conclusion: Single gene defect is common in this Saudi population, with the ASPM gene being the most common. Hereditary neurometabolic disorders are a common cause of genetic microcephaly. Furthermore, we propose the PKL1 gene mutation as a possible novel cause of genetic microcephaly.

Neonatal seizures: Etiologies, clinical characteristics, and radiological features: A cross-sectional study.

Seizures are a common clinical indication of central nervous system damage or abnormality in neonates. We aimed to identify the etiologies, clinical characteristics, and radiological features of neonatal seizures. This is a cross-sectional, retrospective, descriptive study using data obtained from the neonatal intensive care unit in King Abdulaziz Medical City (KAMC), a governmental, academic tertiary hospital in Riyadh, Saudi Arabia. The population of interest were neonates diagnosed with a neonatal seizure at KAMC between April 2015 and March 2019. A total of 61 patients with neonatal seizures were included in the study. The most common etiology was hypoxic-ischemic encephalopathy (43%). A total of 32 patients were full-term (52.5%). Around one-fifth of the study sample (21.3%) had a family history of neonatal seizures. Around 43.0% of the patients had epilepsy episodes. More than half of the patients (57.0%) were on one anti-seizure medication. Patients were followed up after 1 year, they had multiple comorbidities, including developmental delay, epilepsy, and cerebral palsy. Developmental delay was identified in 62.3% of the patients. A total of 19 patients have passed away (31%). Neonatal seizures are a common manifestation of neurologic disorders in neonates and are associated with high morbidity and mortality. Therefore, early identification of seizure etiology and proper management may help to improve the outcome.

Effectiveness of intra-thecal methotrexate in refractory Anti-N-methyl-d-aspartate receptor encephalitis.

BACKGROUND: Anti-N-methyl-d-aspartate "anti-NMDA" receptor encephalitis is one of the most common autoimmune encephalitis for which first- and second-line therapies have been recommended following international consensus. However, some refractory cases do not respond to the first- and second-line therapy and require further immune-modulatory therapies such as intra-thecal methotrexate. In this study, we reviewed six confirmed cases of refractory anti-NMDA receptor encephalitis from two tertiary centers in Saudi Arabia that required escalation of treatment and received a six-month course of intra-thecal methotrexate. The aim of this study was to evaluate the effectiveness of intra-thecal methotrexate as immunomodulatory therapy for refractory anti-NMDA receptor encephalitis. METHODS: We retrospectively evaluated six confirmed cases of refractory anti-NMDA receptor encephalitis who did not improve after first- and second-line therapy and received monthly intra-thecal methotrexate treatment course for six consecutive months. We reviewed patient demography, underlying etiologies, and compared their modified Rankin score prior to receiving intra-thecal methotrexate and six months after completing the treatment. RESULTS: Three of the six patients showed a marked response to intra-thecal methotrexate with a modified Rankin scale of 0-1 at 6-month follow-up. None of the patients experienced any side effects during or after intra-thecal methotrexate treatment, and no flareups were observed. CONCLUSION: Intra-thecal methotrexate may be a potentially effective and relatively safe escalation option for immunomodulatory therapy of refractory anti-NMDA receptor encephalitis. Future studies on intra-thecal methotrexate -specific treatment regimens may further support its utility, efficacy, and safety in treating refractory anti-NMDA receptor encephalitis.

Subclinical Neuropathy in Children With Type I Diabetes Mellitus: Tertiary Care Centre Experience.

INTRODUCTION: Diabetic peripheral neuropathy is a common complication of diabetes mellitus (DM) type 1. However, it can occur without evidence of symptoms or clinical signs of neuropathy labeled as subclinical neuropathy, which neurophysiological studies can best detect. PURPOSE: To evaluate the prevalence of subclinical neuropathy among children with DM type 1, determine the association with blood sugar control, and evaluate the pattern of nerve involvement in neurophysiological studies. METHODS: This cross-sectional study evaluated 100 children with DM type 1, aged five to 15 years, at least one year after the diagnosis. Subclinical neuropathy was evaluated using nerve conduction study. Glycemic control was assessed using hemoglobin A1c (HbA1c). RESULTS: The mean age of subjects was 11.5 ± 0.25 years. The average age at the onset of the disease was 5.95 ± 0.25 years. There were 64 patients who had electrophysiological evidence of peripheral neuropathy. The most observed electrophysiological changes were distal latency abnormalities in the left and right peroneal nerves in 39 and 33 patients, respectively. Sensory nerve amplitude, peak latency, and conduction velocity were normal in all patients (100%). HbA1c level did not show a statistically significant association with the incidence of subclinical neuropathy. CONCLUSION: Subclinical neuropathy was prevalent in children with DM type 1. Poor glucose control was only associated with an increased odds ratio of subclinical neuropathy.

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.

The comorbidity of headaches in pediatric epilepsy patients: How common and what types?

OBJECTIVE: To estimate the prevalence and characteristics of headache in pediatric epileptic patients. METHODS: This cross-sectional study was performed over 6 months period from January 2018 to June 2018 at King Abdullah Specialist Children Hospital, King Abdulaziz Medical City, Riyadh, Kingdom of Saudi Arabia using a structured questionnaire in pediatric patients with epilepsy. RESULTS: There were 142 patients enrolled (males, 57.7%; average age, 10.7+/-3.1 years) with idiopathic epilepsy (n=115, 81%) or symptomatic epilepsy (n=27, 19%). Additionally, patients had focal epilepsy (n=102, 72%) or generalized epilepsy (n=40, 28%), and among them, 11 had absence epilepsy. Overall, 65 (45.7%) patients had headaches compared with 3/153 (2%) in the control group (p<0.0001). Among the 65 patients with headaches, 29 (44.6%) had migraine-type, 12 (18.4%) had tension-type, and 24 (36.9%) had unclassified headache. There was no significant difference in age, gender, type of epilepsy syndrome, and antiepileptic used except in patients with or without headache. For migraine patients, there was a lower headache prevalence in the subgroup treated with valproic acid compared with other treatments. CONCLUSION: Headache, predominantly migraine, is a common problem in pediatric epileptic patients and choosing valproic acid when possible can be important in preventing migraine in these patients.

Clinical Presentation and outcome of acute disseminated encephalomyelitis in Saudi Arabia. Tertiary Center Experience.

OBJECTIVE: To evaluate the clinical presenation of acute disseminated Encephalomyelitis (ADEM) in pediatric age group, treatments, and to asses the outcome at King Abdulaziz Medical City, Riyadh, Kingdom of Saudia Arabia. METHODS: The medical records of all patients younger than 18 years of age with a diagnosis of ADEM and treated at King Abdulaziz Medical City from January 1996 to Decemeber 2016 were collected. A total of 20 patients were included. RESULTS: Of 20 patients enrolled in our study, 13 (65%) were female. Autumn and summer were the most common seasons in which ADEM presented (60%); 19 (95%) patients had a history of preceding viral illnesses. The most common neurological deficits on presentation were weakness (85%), ataxia (45%), and nystagmus (45%). Cortical and subcortical lesions (60%) were the most common finding on cranial magnetic resonance imaging. Seventeen patients (85%) received steroid only. Only 16 patients continued with follow-up, with a mean duration of 7 months. All 16 patients improved: 11 patients were recovered and 5 patients still had a neurological deficit at the clinic visits. No patient had relapsed. CONCLUSION: Most of the patients in this case series have an excellent outcome and attended follow-up visits and no disease relapses were identified. Further exploration of the disease is recommended.

Retrospective review of pediatric status epilepticus in 116 Saudi patients: predictors of outcome.

BACKGROUND: Status epilepticus (SE) is a common, life-threatening condition. Multiple factors are used to predict its outcome and evaluate its risks, and there have been only a few studies in Saudi Arabia. OBJECTIVES: Investigate predictors of SE outcome. DESIGN: Retrospective chart review study. SETTING: Tertiary center, Riyadh. PATIENTS AND METHODS: We reviewed all pediatric cases (age 14 years or younger) of SE admitted between January 2005 and December 2015, collecting data on age, sex, date of birth, developmental status, pre-existing neurological diseases, SE etiology, Glasgow Outcome Scale (GOS) scores, and electroencephalogram (EEG) findings. The outcome was categorized as poor based on any decrease in baseline GOS score or moderate-to-severe developmental delay in young children; otherwise outcome was considered good. MAIN OUTCOME MEASURE: Outcome of SE. RESULTS: One hundred and sixteen patients (54% boys) with ages from 1 month to 10 years were included in the analysis. Fifty-five (47.4%) had a poor outcome. The overall mortality rate related to SE was 2.6%. Four patients had an SE duration of more than 24 hours. Univariate and multivariate analysis revealed that poor outcome was related to symptomatic SE etiology and a history of epilepsy. Age, sex, SE duration, and EEG findings were not predictors of poor outcome. CONCLUSION: Pediatric status epilepticus is highly associated with neurological morbidity. The main pre.dictor of outcome is underlying symptomatic etiology of SE and to a lesser degree the presence of a history of epilepsy. Duration does not seem to play a major role. LIMITATIONS: The main limitation is the retrospective chart review nature of the study with possible bias.

Congenital disorders of glycosylation: The Saudi experience.

We retrospectively reviewed Saudi patients who had a congenital disorder of glycosylation (CDG). Twenty-seven Saudi patients (14 males, 13 females) from 13 unrelated families were identified. Based on molecular studies, the 27 CDG patients were classified into different subtypes: ALG9-CDG (8 patients, 29.5%), ALG3-CDG (7 patients, 26%), COG6-CDG (7 patients, 26%), MGAT2-CDG (3 patients, 11%), SLC35A2-CDG (1 patient), and PMM2-CDG (1 patient). All the patients had homozygous gene mutations. The combined carrier frequency of CDG for the encountered founder mutations in the Saudi population is 11.5 per 10,000, which translates to a minimum disease burden of 14 patients per 1,000,000. Our study provides comprehensive epidemiologic information and prevalence figures for each of these CDG in a large cohort of congenital disorder of glycosylation patients.