A rare case of pituitary dysfunction with Moyamoya disease.

Moyamoya disease is an idiopathic chronic and progressive vaso-occlusive disease ofthe bilateral intracranial branches of the internal carotid artery. Growth hormone failure, thyroid dysfunction, and low cortisol hormones are consequences of hypopituitarism. A 14-year-old girl with short stature presented with right-sided weakness associated with dysarthria. Ahormonal assay test showed abnormality ofthe anterior pituitary hormones. Magnetic resonance imaging of the brain and pituitary gland showed a reduction in the size of the adenohypophysis. A cerebral vessel angiogram showed multiple areas of stenosis in the right internal carotid artery. Magnetic resonance angiography demonstrated stenosis at the suprasellar region of the bilateral internal carotid artery. Pituitary dysfunction associated with moyamoya disease is rare but must be considered as adifferential diagnosis for any patient with hypopituitarism. Hypothalamopituitary dysfunction as result of carotid ischemia might be associated with moyamoya disease. Such patients require close follow-up and hormonal assay tests.

Clinico-radiological features, molecular spectrum, and identification of prognostic factors in developmental and epileptic encephalopathy due to inosine triphosphate pyrophosphatase (ITPase) deficiency.

Developmental and epileptic encephalopathy 35 (DEE 35) is a severe neurological condition caused by biallelic variants in ITPA, encoding inosine triphosphate pyrophosphatase, an essential enzyme in purine metabolism. We delineate the genotypic and phenotypic spectrum of DEE 35, analyzing possible predictors for adverse clinical outcomes. We investigated a cohort of 28 new patients and reviewed previously described cases, providing a comprehensive characterization of 40 subjects. Exome sequencing was performed to identify underlying ITPA pathogenic variants. Brain MRI (magnetic resonance imaging) scans were systematically analyzed to delineate the neuroradiological spectrum. Survival curves according to the Kaplan-Meier method and log-rank test were used to investigate outcome predictors in different subgroups of patients. We identified 18 distinct ITPA pathogenic variants, including 14 novel variants, and two deletions. All subjects showed profound developmental delay, microcephaly, and refractory epilepsy followed by neurodevelopmental regression. Brain MRI revision revealed a recurrent pattern of delayed myelination and restricted diffusion of early myelinating structures. Congenital microcephaly and cardiac involvement were statistically significant novel clinical predictors of adverse outcomes. We refined the molecular, clinical, and neuroradiological characterization of ITPase deficiency, and identified new clinical predictors which may have a potentially important impact on diagnosis, counseling, and follow-up of affected individuals.

Efficacy and safety of corpus callosotomy versus vagus nerve stimulation as long-term adjunctive therapies in children with Lennox-Gastaut syndrome: Experience of a tertiary care center.

OBJECTIVES: To compare the efficacy and safety of corpus callosotomy versus vagus nerve stimulation (VNS) as long-term adjunctive therapies in children with Lennox-Gastaut syndrome. METHODS: This retrospective study was conducted in King Fahad Medical City between 2010 and 2019. The authors identified and followed 9 patients with Lennox-Gastaut syndrome (LGS) who underwent corpus callosotomy or VNS implantation for at least 12 months; seizure frequency and major complications were monitored. Five patients with a mean age of 10.8±1.3 years had corpus callosotomy, and 4 patients with a mean age of 13.8±3.9 years were implanted with VNS stimulators. RESULTS: Reduction in seizure frequency was achieved in all 5 patients who underwent corpus callosotomy, with greater than 75% seizure reduction in more than 50% in one, and greater than 25% in 2 respectively. However, in those implanted with VNS, 2 (50%) patients achieved a reduction in seizure frequency of greater than 75% and 2 (50%) greater than 25%, respectively. No significant difference was observed between the 2 treatment groups. One patient who underwent corpus callosotomy suffered cerebrospinal fluid leakage, and swallowing difficulties in one patient who underwent VNS. CONCLUSION: Both corpus callosotomy and VNS are safe and effective as adjunctive treatments for LGS patients.

Clinical, molecular, and biochemical delineation of asparagine synthetase deficiency in Saudi cohort.

PURPOSE: Asparagine synthetase deficiency (ASNSD) is a rare neurometabolic disease. Patients may not demonstrate low asparagine levels, which highlights the advantage of molecular over biochemical testing in the initial work-up of ASNSD. We aimed to further delineate the ASNSD variant and phenotypic spectrum and determine the value of biochemical testing as a frontline investigation in ASNSD. METHODS: We retrospectively collected the clinical and molecular information on 13 families with ASNSD from the major metabolic clinics in Saudi Arabia. RESULTS: The major phenotypes included congenital microcephaly (100%), facial dysmorphism (100%), global developmental delay (100%), brain abnormalities (100%), spasticity (86%), and infantile-onset seizures (93%). Additional unreported phenotypes included umbilical hernia, osteopenia, eczema, lung hypoplasia, and hearing loss. Overall, seven homozygous variants accounted for ASNSD. The p.Tyr398Cys and p.Asn75Ile variants accounted for 54% of the cases. The clinical sensitivity and specificity of the proposed biochemical analysis of cerebrospinal fluid (CSF) for the detection of patients with ASNSD were 83% and 98%, respectively. CONCLUSION: Our study describes the largest reported ASNSD cohort with clinical, molecular, and biochemical characterization. Taking into consideration the suboptimal sensitivity of biochemical screening, the delineation of the phenotype variant spectrum is of diagnostic utility for accurate diagnosis, prognosis, counseling, and carrier screening.

Predicting future handedness and hemispheric dominance during infancy by analyzing sleep spindles.

OBJECTIVE: To investigate whether sleep spindles asynchrony (SSA) using scalp sleep electroencephalogram (EEG) among children below 2 years of age can predict future handedness. METHODS: This is a retrospective study conducted from October 2016 until June 2017 at the King Fahad Medical City (KFMC), Riyadh, Kingdom of Saudi Arabia. We retrospectively reviewed 300 EEGs recorded at our neurophysiology laboratory.We included EEGs performed during sleep for infants aged 2 months to 2 years who have already attained their handedness or those aged above 2 years. We excluded records of children younger than 2 months or above 2 years of age (at the time of the EEG) or those aged below 2 years (at the time of the interview), and severely abnormal tracings and those without sleep or enough SSA. RESULTS: The lateralization of Sleep Spindles (SS) was mostly right-hemispheric (52%) compared to left-hemispheric (36.4%). The overall SS laterality did not correlate with handedness (p=0.81). In the majority of right-handed (64%) and left-handed (60%) children, the SSA was contralateral to the side of hand preference; however, it did not correlate statistically (p=0.377). CONCLUSION: We were unable to prove a statistically significant correlation between SSA and future hand preference. Further research involving larger cohorts is still needed.

Genomic and phenotypic delineation of congenital microcephaly.

PURPOSE: Congenital microcephaly (CM) is an important birth defect with long term neurological sequelae. We aimed to perform detailed phenotypic and genomic analysis of patients with Mendelian forms of CM. METHODS: Clinical phenotyping, targeted or exome sequencing, and autozygome analysis. RESULTS: We describe 150 patients (104 families) with 56 Mendelian forms of CM. Our data show little overlap with the genetic causes of postnatal microcephaly. We also show that a broad definition of primary microcephaly -as an autosomal recessive form of nonsyndromic CM with severe postnatal deceleration of occipitofrontal circumference-is highly sensitive but has a limited specificity. In addition, we expand the overlap between primary microcephaly and microcephalic primordial dwarfism both clinically (short stature in >52% of patients with primary microcephaly) and molecularly (e.g., we report the first instance of CEP135-related microcephalic primordial dwarfism). We expand the allelic and locus heterogeneity of CM by reporting 37 novel likely disease-causing variants in 27 disease genes, confirming the candidacy of ANKLE2, YARS, FRMD4A, and THG1L, and proposing the candidacy of BPTF, MAP1B, CCNH, and PPFIBP1. CONCLUSION: Our study refines the phenotype of CM, expands its genetics heterogeneity, and informs the workup of children born with this developmental brain defect.

Seroprevalence of Human Cytomegalovirus in Pregnant Women in the Asir Region, Kingdom of Saudi Arabia.

BACKGROUND: Human cytomegalovirus (HCMV) infection spreads easily by interpersonal contact. OBJECTIVE: This study determined the prevalence of seropositivity of cytomegalovirus immunoglobulin G (IgG) in the Asir Region, Kingdom of Saudi Arabia. METHODS: The study evaluated the seropositivity for cytomegalovirus-specific IgG in 460 females. Collected samples were processed and tested using enzyme-linked immunosorbent assay and specific HCMV IgG. RESULTS: The study showed that all the respondents aged 15-20 years were seropositive for the HCMV. HCMV seropositive status was recorded in 99.2% of the older patients (>40 years of age). In the remaining age groups, the rate of seropositivity ranged from 95.7 (age range 20-25 years) to 98.9% (age range 30 years). CONCLUSIONS: In all age groups of females tested, the prevalence of seropositive for HCMV was high, i.e., in the range of 95.7-100%.

Pediatric intracranial hypertension. Experience from 2 Tertiary Centers.

OBJECTIVE: To review the experience of 2 tertiary centers in Saudi Arabia with intracranial hypertension (IH) in the pediatric population. METHODS: We retrospectively reviewed and analyzed pediatric patients diagnosed with IH from June 2002 to May 2017 in 2 institutes. RESULTS: We identified 53 patients (30 females and 23 males) with a mean age of 7 years at the time of presentation. Among them, 41 patients were younger than 12 years, and 12 were older. Obese and overweight patients constituted 27.00% (n = 14) of all cases, 8 (66.7%) of whom were older than 12 years. The most common presenting feature was papilledema followed by headache. Vitamin D deficiency, which constituted the most common associated condition, was identified in 12 (22.6%) patients. Acetazolamide was the treatment option in 98.11% of patients, and only 5.7% underwent surgical interventions. The length of follow-up ranged from 6 months to 8 years. CONCLUSION: Intracranial hypertension is rare in children and commonly seen in overweight females older than 12 years similar to adults. Patients younger than 12 years tend to develop secondary IH. More studies are needed to characterize the clinical presentation and guide the management plan.

FARS2 deficiency; new cases, review of clinical, biochemical, and molecular spectra, and variants interpretation based on structural, functional, and evolutionary significance.

An increasing number of mitochondrial diseases are found to be caused by pathogenic variants in nuclear encoded mitochondrial aminoacyl-tRNA synthetases. FARS2 encodes mitochondrial phenylalanyl-tRNA synthetase (mtPheRS) which transfers phenylalanine to its cognate tRNA in mitochondria. Since the first case was reported in 2012, a total of 21 subjects with FARS2 deficiency have been reported to date with a spectrum of disease severity that falls between two phenotypes; early onset epileptic encephalopathy and a less severe phenotype characterized by spastic paraplegia. In this report, we present an additional 15 individuals from 12 families who are mostly Arabs homozygous for the pathogenic variant Y144C, which is associated with the more severe early onset phenotype. The total number of unique pathogenic FARS2 variants known to date is 21 including three different partial gene deletions reported in four individuals. Except for the large deletions, all variants but two (one in-frame deletion of one amino acid and one splice-site variant) are missense. All large deletions and the single splice-site variant are in trans with a missense variant. This suggests that complete loss of function may be incompatible with life. In this report, we also review structural, functional, and evolutionary significance of select FARS2 pathogenic variants reported here.

Loss-of-function mutation in RUSC2 causes intellectual disability and secondary microcephaly.

Inherited aberrancies in intracellular vesicular transport are associated with a variety of neurological and non-neurological diseases. RUSC2 is a gene found on chromosome 9p13.3 that codes for iporin, a ubiquitous protein with high expression in the brain that interacts with Rab proteins (GTPases implicated in intracellular protein trafficking). Although mutations in Rab proteins have been described as causing brain abnormalities and intellectual disability, until now no disease-causing mutations in RUSC2 have ever been reported in humans. We describe, to our knowledge for the first time, three patients with inherited homozygous nonsense mutations identified in RUSC2 on whole-exome sequencing. All three patients had central hypotonia, microcephaly, and moderate to severe intellectual disability. Two patients had additional features of early-onset epilepsy and absence of the splenium. This report adds to the ever-expanding landscape of genetic causes of intellectual disability and increases our understanding of the cellular processes underlying this important neurological entity.

Case Report: A rare treatable metabolic syndrome (Brown-Vialetto-Van Laere syndrome) masquerading as chronic inflammatory demyelinating polyneuropathy from Saudi Arabia.

Background: Brown-Vialetto-Van Laere (BVVL) syndrome is an extremely rare autosomal recessive progressive motoneuron disease that is caused by a defect in the riboflavin transporter genes SLC52A2 and SLC52A3. BVVL syndrome has a variable age of presentation, and it is characterized by progressive auditory neuropathy, bulbar palsy, stridor, muscle weakness, and respiratory compromise secondary to diaphragmatic and vocal cord paralysis. BVVL syndrome has a poor prognosis in the absence of treatment, including morbidity with quadriparesis and sensorineural hearing loss, with mortality in the younger age group. Early administration of riboflavin is associated with prolonged survival, low morbidity, and reversal of some clinical manifestations. Case presentation: We describe an 18-month-old male infant with progressive pontobulbar palsy, loss of developmental milestones, and a clinical picture suggestive of chronic inflammatory demyelinating neuropathy. A nerve conduction study revealed axonal neuropathy, while molecular analysis revealed a homozygous mutation in one of the riboflavin transporter genes, SLC52A3, confirming BVVL syndrome. The patient needed long-term respiratory support and a gastrostomy tube to support feeding. With high-dose riboflavin supplementation, he experienced moderate recovery of motor function. Conclusion: This report highlights the importance of considering BVVL syndrome in any patient who presents with the clinical phenotype of pontobulbar palsy and peripheral axonal neuropathy, as early riboflavin treatment may improve or halt disease progression, thus reducing the associated mortality and morbidity.

Clinical and Molecular Characteristics of Neuronal Ceroid Lipofuscinosis in Saudi Arabia.

BACKGROUND: Neuronal ceroid lipofuscinoses (NCLs) represent a heterogeneous group of inherited metabolic lysosomal disorders characterized by neurodegeneration. This study sought to describe the clinical and molecular characteristics of NCLs in Saudi Arabia and determine the most common types in that population. METHODS: A retrospective review of electronic medical records was conducted for 63 patients with NCL (55 families) from six tertiary and referral centers in Saudi Arabia between 2008 and 2022. Clinical, radiological, and neurophysiological data as well as genetic diagnoses were reviewed. RESULTS: CLN6 was the predominant type, accounting for 45% of cases in 25 families. The most common initial symptoms were speech delay (53%), cognitive decline (50%) and/or gait abnormalities (48%), and seizure (40%). Behavioral symptomatology was observed in 20%, whereas visual impairment was less frequently (9.3%) encountered. Diffuse cerebral and cerebellar atrophy was the predominant finding on brain magnetic resonance imaging. Electroencephalography generally revealed background slowing in all patients with generalized epileptiform discharges in 60%. The most common genotype detected was the p.Ser265del variant found in 36% (20 of 55 families). The most rapidly progressive subtypes were CLN2 and CLN6. Two patients with each died at age five years. The earliest age at which a patient was nonambulatory was two years in a patient with CLN14. CONCLUSIONS: This is the largest molecularly confirmed NCL cohort study from Saudi Arabia. Characterizing the natural history of specific NLC types can increase understanding of the underlying pathophysiology and distinctive genotype-phenotype characteristics, facilitating early diagnosis and treatment initiation as well as genetic counseling for families.

SHQ1-associated neurodevelopmental disorder: Report of the first homozygous variant in unrelated patients and review of the literature.

Compound heterozygous mutations in SHQ1 have been associated with a rare and severe neurological disorder characterized by global developmental delay (GDD), cerebellar degeneration coupled with seizures, and early-onset dystonia. Currently, only five affected individuals have been documented in the literature. Here, we report three children from two unrelated families harboring a homozygous variant in the gene but with a milder phenotype than previously described. The patients had GDD and seizures. Magnetic resonance imaging analyses revealed diffuse white matter hypomyelination. Sanger sequencing confirmed the whole-exome sequencing results and revealed full segregation of the missense variant (SHQ1:c.833 T > C; p.I278T) in both families. We performed a comprehensive in silico analysis using different prediction classifiers and structural modeling of the variant. Our findings demonstrate that this novel homozygous variant in SHQ1 is likely to be pathogenic and leads to the clinical features observed in our patients.

Childhood absence epilepsy: Electro-clinical manifestations, treatment options, and outcome in a tertiary educational center.

Purpose and Background: To evaluate the electro-clinical manifestations and outcomes of children with absence epilepsy at a tertiary center in Saudi Arabia. Methods: This retrospective study reviewed the medical and EEG records of patients who were diagnosed to have CAE as per the International League Against Epilepsy (ILAE) definition for CAE. The study was conducted in the pediatric neurology clinic of King Khalid University Hospital, King Saud University Medical City, Riyadh, Saudi Arabia, between January 2000 and December 2019. Patients who did not meet (ILAE) criteria, lost follow-up, and those who did not receive treatment at KKUH were excluded. Data regarding the patient's disease, electro-clinical manifestations, anti-seizure medication response, and outcomes were collected. Results: A total of 35 patients, with an average age at diagnosis of 7 ± 2.1 y, were included in the study; among them, 51.4% were female and approximately 48.6% presented with a family history of epilepsy. Regarding clinical features, all patients experienced staring and altered awareness, 94.2% had less than 20 spells per day at the time of diagnosis, and 65.7% were provoked by the hyperventilation test. Regarding EEG findings, all patients had bilateral, symmetrical, and synchronous discharges in the form of regular 3 Hz spike-and-wave complexes, and 94.3% had a generalized initial ictal discharge. Also, 22.8% had eye fluttering with electrographic seizures. Ethosuximide (ESM) was used as the drug of choice in 45.7% of the patients. Regarding clinical outcomes, 94.3% had their disease clinically controlled, and 80% had a normalized EEG after few months of starting anti-seizure medication. Finally, 37.2% experienced complete remission of epilepsy after 3-5 y; however, one patient developed juvenile myoclonic epilepsy. Conclusion: This study described the electro-clinical manifestations of patients with childhood absence epilepsy and outcomes. Furthermore, early diagnosis and prompt treatment of childhood absence epilepsy improve treatment outcomes.

Impact of Rural vs. Urban Residence on Survival Rates of Patients with Glioblastoma: A Tertiary Care Center Experience.

Purpose: Although the association between residential location and survival in patients with different cancer types has been established, the conclusions are contentious, and the underlying mechanisms remain unknown. Here, we reviewed the impact of residence on the survival of patients with glioblastoma (GBM). Methods: We conducted a retrospective study to compare the impact of rural and urban residence on the survival rates of patients with GBM diagnosed in Riyadh City and outside Riyadh. All patients in this study were treated in a tertiary care hospital, and their survival rates were analyzed in relation to their residence and other related factors, namely radiotherapy timing. Results: Overall, 125 patients were included: 61 from Riyadh City and 64 from outside. The majority of patients in both groups were aged >50 years (p = 0.814). There was no statistically significant difference between the groups in the Eastern Cooperative Oncology Group Performance Status (p = 0.430), seizure (p = 0.858), or initiation timing of radiotherapy (p = 0.781). Furthermore, the median survival rate in the Riyadh group versus the other group was 14.4 months and 12.2 months, respectively, with no statistical significance (p = 0.187). Conclusions: Our study showed that residential location had no significant effect on GBM prognosis. However, further studies with a larger sample size are required to delineate the other factors of referral within the healthcare system to facilitate the management of these patients within a specific timeframe.

Hereditary Hyperekplexia in Saudi Arabia.

BACKGROUND: Hyperekplexia is a rare disorder characterized by exaggerated startle responses to unexpected sensory stimuli, recurrent apneas, and stiffness. Only few studies have been published on this disorder in populations with high rates of consanguinity. METHODS: We retrospectively reviewed Saudi patients with genetically confirmed hereditary hyperekplexia using a standard questionnaire that was sent to nine major referral hospitals in Saudi Arabia. RESULTS: A total of 22 Saudi patients (11 males, 11 females) from 20 unrelated families who had hereditary hyperekplexia were included. Based on molecular studies, they were classified into different subtypes: SLC6A5 variant (12 patients, 54.5%), GLRB variant (seven patients, 31.8%), and GLRA1 variant (three patients, 13.7%). All patients were homozygous for the respective causal variant. The combined carrier frequency of hereditary hyperekplexia for the encountered founder mutations in the Saudi population is 10.9 per 10,000, which translates to a minimum disease burden of 13 patients per 1,000,000. CONCLUSION: Our study provides comprehensive epidemiologic information, prevalence figures, and clinical characteristics of a large cohort of patients with hereditary hyperekplexia.

Management and Outcome of Post-Infectious Multiloculated Hydrocephalus: A Case Series.

BACKGROUND AND IMPORTANCE: Infection following ventriculoperitoneal shunt (VPS) placement is a recognized complication, with variable incidence rates worldwide. Development of post-infectious multiloculated hydrocephalus (MLH) is likely if VPS infection is improperly managed, in turn affecting the prognosis. There is a lack of studies from Saudi Arabia regarding patients' functional outcome in relation to different variables. OBJECTIVES: To study the causative organisms, related variables and patient outcomes in MLH after VPS infection. METHODS: This case series is a retrospective chart review of pediatric patients diagnosed with hydrocephalus from 2011 to 2019. Patients were included if they were aged <18 years, had confirmed cerebrospinal fluid/blood infection with radiological evidence of MLH, and were regularly followed-up. Functional status score was used to evaluate the outcomes. RESULTS: A total of 150 patients underwent VPS insertion during the study period, of which 12 (8%) had postinfection MLH. The mean age at diagnosis and follow-up was 9 and 19 months, respectively. Ten patients developed MLH after their first VPS infection and one each developed MLH following the second and third VPS infections. Cerebrospinal fluid cultures mostly grew only single organisms (6/12), with Staphylococcus species being the most common. All patients underwent navigated endoscopic fenestration; nine patients required VPS placement and three required redo endoscopic fenestration surgery. All patients were developmentally delayed, with the majority (75%) having a functional status score of 6-10. CONCLUSION: Development of MLH after VPS infection is debilitating and requires prompt treatment. Although the overall functional outcome is poor, evolving neuroendoscopic techniques with tailored preoperative planning may play a role in reducing the adverse effect of shunt multiplicity, shunt infections and the higher failure rate among patients with complex hydrocephalus.

Pattern of orthopedic injuries among Victims of Road Traffic Accidents in Aseer region, Saudi Arabia.

BACKGROUND: Road Traffic Accidents (RTA) are one of the most common causes of morbidity and mortality in Saudi Arabia despite preventive measures and programs. The major factors for the increase in the incidence of mortality and morbidity are due to human factors, such as over speeding, not obeying traffic laws, fatigue, and driving before the legal age. In this study, we aim to report the pattern of orthopedic injuries (OIs) from RTA in the south-western region of Saudi Arabia and to explore the healthcare outcomes of OIs. METHOD: This is a retrospective, record-based, case series study including RTA patients who were admitted to the Emergency Department (ED) at a tertiary hospital in the south-western region of Saudi Arabia. The data was collected for 531 admitted RTA patients with OIs over for five years from May 2011 to May 2016. Patients who were 15 years of age or above were included in this study. The data were analyzed using the statistical package for social science (SPSS) version 21. RESULTS: A total of 531 patients were included with an age range between 15 and 90 years with an average age of 29 ± 2 years. Most of the population was male constituting 91.3% of the sample while 91.9% of the sample were Saudis. About 75% of the OIs had simple fractures and complex fractures were recorded among 10.2% of the cases. About half of the cases (52%) had lower limb fractures and 32% had upper limb fractures. CONCLUSIONS: RTA and the resultant OIs, death, and permanent disabilities cause a tremendous burden on economic resources and should be of concern for local authorities. More attention and regularities should be paid to avoid life-threatening driving behaviors.

Reversible Cerebral Vasoconstriction Syndrome after Nifedipine Withdrawal.

Reversible cerebral vasoconstriction syndrome (RCVS) is an essential but often unrecognized cause of intracranial haemorrhage. While there are no specific causes of the syndrome, associations with many clinical conditions and drugs have been observed, and calcium channel blockers (CCBs) are often used to relieve the symptoms. This is a case of RCVS that was triggered by the sudden withdrawal of nifedipine, a CCB.