JAK Inhibitor Therapy in a Child with Inherited USP18 Deficiency.

Deficiency of ubiquitin-specific peptidase 18 (USP18) is a severe type I interferonopathy. USP18 down-regulates type I interferon signaling by blocking the access of Janus-associated kinase 1 (JAK1) to the type I interferon receptor. The absence of USP18 results in unmitigated interferon-mediated inflammation and is lethal during the perinatal period. We describe a neonate who presented with hydrocephalus, necrotizing cellulitis, systemic inflammation, and respiratory failure. Exome sequencing identified a homozygous mutation at an essential splice site on USP18. The encoded protein was expressed but devoid of negative regulatory ability. Treatment with ruxolitinib was followed by a prompt and sustained recovery. (Funded by King Saud University and others.).

Prevalence of DDC genotypes in patients with aromatic L-amino acid decarboxylase (AADC) deficiency and in silico prediction of structural protein changes.

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive genetic disorder affecting the biosynthesis of dopamine, a precursor of both norepinephrine and epinephrine, and serotonin. Diagnosis is based on the analysis of CSF or plasma metabolites, AADC activity in plasma and genetic testing for variants in the DDC gene. The exact prevalence of AADC deficiency, the number of patients, and the variant and genotype prevalence are not known. Here, we present the DDC variant (n = 143) and genotype (n = 151) prevalence of 348 patients with AADC deficiency, 121 of whom were previously not reported. In addition, we report 26 new DDC variants, classify them according to the ACMG/AMP/ACGS recommendations for pathogenicity and score them based on the predicted structural effect. The splice variant c.714+4A>T, with a founder effect in Taiwan and China, was the most common variant (allele frequency = 32.4%), and c.[714+4A>T];[714+4A>T] was the most common genotype (genotype frequency = 21.3%). Approximately 90% of genotypes had variants classified as pathogenic or likely pathogenic, while 7% had one VUS allele and 3% had two VUS alleles. Only one benign variant was reported. Homozygous and compound heterozygous genotypes were interpreted in terms of AADC protein and categorized as: i) devoid of full-length AADC, ii) bearing one type of AADC homodimeric variant or iii) producing an AADC protein population composed of two homodimeric and one heterodimeric variant. Based on structural features, a score was attributed for all homodimers, and a tentative prediction was advanced for the heterodimer. Almost all AADC protein variants were pathogenic or likely pathogenic.

Pattern and etiology of early childhood epilepsy: An Experience at a tertiary care University Center.

OBJECTIVES: To investigate seizure characteristics, types, and define the etiology of epilepsy in children aged ≤2 years using the 2017 ILAE classification. METHODS: A retrospective chart review was conducted at King Khalid University Hospital, King Saud University Medical City, Riyadh, Kingdom of Saudi Arabia for children below 2 years of age diagnosed with epilepsy, and on anti-seizure medications from January 2017 - December 2018. The collected data involved detailed information on the patients' seizure, electroclinical, neuroimaging, laboratory evaluations, and underlying etiology. RESULTS: One- hundred and fifty patients were included in the study and classified according to etiology into: genetic (43, 28.7%), structural (41, 27.3%), metabolic (10, 6.7%), infectious (8, 5.3%), immune-mediated (1, 0.7%) and unknown (47, 31.3%) groups. The most common seizure types were generalized epilepsy, among which generalized tonic-clonic seizures occurred in 56 (37%) patients, followed by tonic seizures in 31 (21%), infantile spasm in 19 (13%), myoclonic seizures in 4 (2.7%), atonic seizures in 6 (4%), and focal seizures in 33 (22%) patients. Global developmental delay and abnormalities in both neurologic exam and neuroimaging were more common in the structural and genetic groups. Electroencephalography was abnormal in 82 (55%) patients, including the majority of the structural group (26, 63.4%). CONCLUSION: The etiology of epilepsy in this cohort remains undetermined (unknown) in a large proportion of cases, followed by genetic and structural causes. This result added to the published international data about epilepsy in the first 2-years of life.

Phenotypic and molecular spectrum of pyridoxamine-5'-phosphate oxidase deficiency: A scoping review of 87 cases of pyridoxamine-5'-phosphate oxidase deficiency.

Pyridoxamine-5'-phosphate oxidase (PNPO) deficiency is an autosomal recessive pyridoxal 5'-phosphate (PLP)-vitamin-responsive epileptic encephalopathy. The emerging feature of PNPO deficiency is the occurrence of refractory seizures in the first year of life. Pre-maturity and fetal distress, combined with neonatal seizures, are other associated key characteristics. The phenotype results from a dependency of PLP which regulates several enzymes in the body. We present the phenotypic and genotypic spectrum of (PNPO) deficiency based on a literature review (2002-2020) of reports (n = 33) of patients with confirmed PNPO deficiency (n = 87). All patients who received PLP (n = 36) showed a clinical response, with a complete dramatic PLP response with seizure cessation observed in 61% of patients. In spite of effective seizure control with PLP, approximately 56% of patients affected with PLP-dependent epilepsy suffer developmental delay/intellectual disability. There is no diagnostic biomarker, and molecular testing required for diagnosis. However, we noted that cerebrospinal fluid (CSF) PLP was low in 81%, CSF glycine was high in 80% and urinary vanillactic acid was high in 91% of the cases. We observed only a weak correlation between the severity of PNPO protein disruption and disease outcomes, indicating the importance of other factors, including seizure onset and time of therapy initiation. We found that pre-maturity, the delay in initiation of PLP therapy and early onset of seizures correlate with a poor neurocognitive outcome. Given the amenability of PNPO to PLP therapy for seizure control, early diagnosis is essential.

Remote interviews for medical residency selection during the initial COVID-19 crisis: a national survey.

BACKGROUND: Medical training programs candidate's interview is an integral part of the residency matching process. During the coronavirus disease 2019 (COVID-19) pandemic, conducting these interviews was challenging due to infection prevention restrains (social distancing, namely) and travel restrictions. E-interviews were implemented by the Saudi Commission for Healthcare Specialties (SCFHS) since the matching cycle of March 2020 to hold the interviews in a safer virtual environment while maintaining the same matching quality and standards. AIM: This study was conducted to assess the medical training residency program applicants' satisfaction, stress, and other perspectives for the (SCFHS) March 2020 Matching-cycle conducted through an urgently implemented E-interviews process. METHOD: A cross-sectional, nationwide survey (Additional file 1) was sent to 4153 residency-nominated applicants to the (SCFHS) March 2020 cycle. RESULTS: Among the 510 candidates who responded, 62.2% applied for medical specialties, 20.2% applied for surgical specialties, and 17.6% applied for critical care and emergency specialties. Most respondents (61.2%) never had previous experience with web-based video conferences. Most respondents (80.2%) used the Zoom application to conduct the current E-interviews, whereas only 15.9% used the FaceTime application. 63.3% of the respondents preferred E-interviews over in-person interviews, and 60.6% rated their experience as very good or excellent. 75.7% of the respondents agreed that all their residency program queries were adequately addressed during the E-interviews. At the same time, 52.2% of them agreed that E-interviews allowed them to represent themselves accurately. 28.2% felt no stress at all with their E-interviews experience, while 41.2% felt little stressed and only 8.2% felt highly stressed. The factors that were independently and inversely associated with applicants' level of stress with E-interviews experience were their ability to represent themselves during the interviews (p = 0.001), cost-savings (p < 0.001), their overall rating of the E-interviews quality (p = 0.007) and the speed of the internet connection (p < 0.006). CONCLUSION: Videoconferencing was implemented on an urgent basis during the COVID-19 pandemic in the medical residency application process in Saudi Arabia. It was perceived as an adequate and promising tool to replace in-person interviews in the future. Applicants' satisfaction was mainly driven by good organization, cost-saving, and their ability to present themselves. Future studies to enhance this experience are warranted.

Neurodevelopmental and epilepsy outcomes of patients with infantile spasms treated in a tertiary care center.

OBJECTIVES: To assess the neurodevelopmental and epilepsy outcomes in children with infantile spasms (IS). METHODS: A retrospective chart review of all patients with infantile spasms admitted to King Khalid University Hospital (KKUH), Riyadh, Saudi Arabia between January 2000 and December 2017. Infants who were diagnosed to have IS as per the International League Against Epilepsy (ILAE) definition were included in this study. Patients who lost follow-up and those who did not receive treatment at KKUH were excluded. RESULTS: Total of 53 patients were included and categorized into unknown, cryptogenic and symptomatic type of IS. The majority had symptomatic etiology (71.7%). Type of etiology and delay in initiation of treatment were significant predictors of motor and cognitive outcomes, but not seizure control. Patients with unknown IS, who were diagnosed earlier (0.72-month), had better neurodevelopmental outcomes. Vigabatrin in combination with either Adrenocorticotropic hormone (ACTH) or Prednisolone showed better seizure control in comparison to monotherapy and other combination modalities. CONCLUSION: Neurodevelopmental outcomes of IS are strongly associated with the underlying etiology. Early initiation of treatments had a favorable cognitive and motor outcome. Early response to combination therapy with resolution of spasms and hypsarrhythmia had better seizure outcomes. However, motor and cognitive outcomes were not affected by the response to the combination therapy.

Mutations in NKX6-2 Cause Progressive Spastic Ataxia and Hypomyelination.

Progressive limb spasticity and cerebellar ataxia are frequently found together in clinical practice and form a heterogeneous group of degenerative disorders that are classified either as pure spastic ataxia or as complex spastic ataxia with additional neurological signs. Inheritance is either autosomal dominant or autosomal recessive. Hypomyelinating features on MRI are sometimes seen with spastic ataxia, but this is usually mild in adults and severe and life limiting in children. We report seven individuals with an early-onset spastic-ataxia phenotype. The individuals come from three families of different ethnic backgrounds. Affected members of two families had childhood onset disease with very slow progression. They are still alive in their 30s and 40s and show predominant ataxia and cerebellar atrophy features on imaging. Affected members of the third family had a similar but earlier-onset presentation associated with brain hypomyelination. Using a combination of homozygozity mapping and exome sequencing, we mapped this phenotype to deleterious nonsense or homeobox domain missense mutations in NKX6-2. NKX6-2 encodes a transcriptional repressor with early high general and late focused CNS expression. Deficiency of its mouse ortholog results in widespread hypomyelination in the brain and optic nerve, as well as in poor motor coordination in a pattern consistent with the observed human phenotype. In-silico analysis of human brain expression and network data provides evidence that NKX6-2 is involved in oligodendrocyte maturation and might act within the same pathways of genes already associated with central hypomyelination. Our results support a non-redundant developmental role of NKX6-2 in humans and imply that NKX6-2 mutations should be considered in the differential diagnosis of spastic ataxia and hypomyelination.

Clinical spectrum of neurofibromatosis type 1 among children in a tertiary care center.

OBJECTIVE: To identify the clinical and neuroradiological features of neurofibromatosis type 1 and the risk of malignancy in a pediatric age group. METHODS: This observational retrospective cohort study was conducted at King Saud University Medical City, Riyadh, Kingdom of Saudi Arabia, for the patients with neurofibromatosis type 1 who were seen and had follow up from January 2000 to January 2019. RESULTS: A total of 50 children were included. Approximately 90% of patients presented with cafe-au-lait macules, and 34% had skin-fold freckling. Moreover, 42% of the participants had a first-degree relative with neurofibromatosis type 1, and about a quarter presented with associated epilepsy. About 90% of the neuroradiological features were consistent with those of neurofibromatosis type 1. About 52% of the patients had one or multiple types of tumors, and 34% presented with optic pathway glioma. CONCLUSION: This study described clinical spectrum of neurofibromatosis type 1 among children. It showed also a higher percentage of tumors than previous studies.

Evaluation of adherence to pediatric status epilepticus management guidelines in Saudi Arabia.

OBJECTIVE: To assess compliance with the 2017 Saudi pediatric status epilepticus management guidelines and to printout the main obstacle for adherence to the guidelines. METHODS: A cross sectional study conducted in September 2019, using electronic survey. The survey sent to all the Pediatric Emergency physicians practicing in Kingdom of Saudi Arabia (KSA) through emails and WhatsApp and the questionnaire based on clinical scenario written in English language. RESULTS: One hundred and three (70%) of 147 physicians working in KSA and covering pediatric emergency departments responded to the survey. Only 20% of the physicians reported full compliance to all 4 guideline components; 57% reported that they were not aware of the published guidelines. CONCLUSION: Pediatric emergency physicians reported poor compliance to the 2017 published guidelines for the treatment of children with convulsive status epilepticus in KSA.

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.

Hypokalemic periodic paralysis due to CACNA1S gene mutation.

Hypokalemic periodic paralysis (HypoPP) is a relatively rare but treatable disorder caused by mutations in the CACNA1S gene. HypoPP patients may experience paralytic episodes associated with hypokalemia and, infrequently, may develop late-onset proximal myopathy. The paralytic attacks are characterized by reversible flaccid paralysis and, in most cases, spare the respiratory muscles and heart. We report a case of CACNA1S periodic paralysis precipitated by vigorous exercise in a 14-year-old boy who presented with sudden-onset paralysis of both his upper and lower extremities. Laboratory evaluation revealed a markedly low serum potassium level. The patients symptoms resolved after correction of the potassium abnormality, and he was discharged with no neurological deficits. Although rare, HypoPP must be differentiated from other causes of weakness and paralysis so that proper treatment can be promptly initiated to ensure good outcomes.

Effect of new modalities of treatment on physicians management plan for patients with spinal muscular atrophy.

OBJECTIVE: To determine physicians` attitudes and stated practice in the management of patients with spinal muscular atrophy (SMA). We also aimed to explore their knowledge about consensus statement for standard of care in SMA and the role of new treatment modalities in changing the method of practice in the management of these cases. METHODS: This is a quantitative observational cross-sectional study, conducted from February to May 2017 among physicians who manage SMA patients in Kingdom of Saudi Arabia. The study cohort included pediatric neurologists, adult neurologists, and physicians of other sub-specialties who manage SMA patients. We used online and paper-based questionnaires. RESULTS: Half of the 169 participants were aware of the consensus guidelines for the care of SMA patients. With regard to the newly released Nursinersen treatment protocol for SMA-diagnosed patients, half of the participants were uncertain, and the other half were hesitant about its outcomes. Junior physicians tended to be significantly more inclined to reverse the do-not-resuscitate (DNR) status of an SMA-diagnosed child than more senior physicians. CONCLUSION: Our results indicate the existence of wide differences in physician practice with children of SMA disease. Our data demonstrate a need for increased awareness of consensus guidelines and further awareness about the physician`s role in the variability of care for children with SMA.

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.

GWAS signals revisited using human knockouts.

PurposeGenome-wide association studies (GWAS) have been instrumental to our understanding of the genetic risk determinants of complex traits. A common challenge in GWAS is the interpretation of signals, which are usually attributed to the genes closest to the polymorphic markers that display the strongest statistical association. Naturally occurring complete loss of function (knockout) of these genes in humans can inform GWAS interpretation by unmasking their deficiency state in a clinical context.MethodsWe exploited the unique population structure of Saudi Arabia to identify novel knockout events in genes previously highlighted in GWAS using combined autozygome/exome analysis.ResultsWe report five families with homozygous truncating mutations in genes that had only been linked to human disease through GWAS. The phenotypes observed in the natural knockouts for these genes (TRAF3IP2, FRMD3, RSRC1, BTBD9, and PXDNL) range from consistent with, to unrelated to, the previously reported GWAS phenotype.ConclusionWe expand the role of human knockouts in the medical annotation of the human genome, and show their potential value in informing the interpretation of GWAS of complex traits.

Assessment of physicians knowledge and attitudes in the management of febrile seizures.

OBJECTIVE: To assess the knowledge and attitudes of physicians in different specialties who are involved in the care of children with FS. METHODS: We assessed knowledge and attitudes in the management of Febrile seizure (FS) among physicians working in different specialties in the Kingdom of Saudi Arabia using a questionnaire-based cross-sectional study conducted from September-December 2016. RESULTS: Of the 300 physicians who responded to the questionnaire, 178 (59.3%) were males, 119 (39.7%) were consultants, 92 (30.7%) were specialists, and 89 (29.7%) were residents. The majority were general pediatric consultants. Our study showed that the consultants were more aware of the definition of simple FS in comparison to other groups of physicians, and the difference was statistically significant. However, there was no difference between pediatric neurologists and general pediatricians. There was a statistically significant difference among various specialties in the perceived need to perform routine lumbar puncture, neuroimaging, and serum electrolyte determination in the evaluation of children with FS. On the other hand, there was no difference in the perceived need to perform an electroencephalogram among physicians in different specialties. CONCLUSION: The study highlighted the wide variation in knowledge and attitudes of physicians in different specialties with different levels of experience toward the management of FS. The use of clinical practice guidelines will help minimize this diversity.

Respiratory support attitudes among pediatric intensive care staff for spinal muscular atrophy patients in Saudi Arabia.

OBJECTIVE: To explore therapeutic attitude of healthcare providers practicing in pediatric critical care in Saudi Arabia toward patients with Spinal Muscular Atroph (SMA) Type I, and to explore their awareness about the International Consensus statement for SMA care. METHODS: A cross-sectional survey was conducted in April 2015 during 6th Saudi Critical Care Conference, targeting physicians and respiratory therapists practicing in Pediatric Critical Care. RESULTS: Sixty participants accepted to participate in this survey. Out of those who answered the questionnaire, 44 were included in the analysis. Majority (66%) of participants were unaware of the International Consensus guidelines for SMA. Endotracheal intubation was reported as an acceptable intervention in SMA patients with acute respiratory failure by 43% of participants. Similarly, chronic home ventilation was agreed by 41% of participants. CONCLUSION: A nationwide adaptation of the International SMA Consensus guidelines for children with SMA I is recommended, aiming to decrease variability and standardize their management across various healthcare facilities in Saudi Arabia.

Childhood epilepsies: What should a pediatrician know?

Seizures in children are among the most common neurological disorders. A pediatrician should know how to approach a child who presents with a seizure. This review will focus on points that are important in the evaluation of children who have experienced seizures. A comprehensive and neurologically focused framework for history taking and a thorough clinical examination are the cornerstones in diagnosing and managing seizures. This article reviews the clinical approach to the diagnosis, investigation, and management of epilepsy in children, excluding neonatal seizures. A pediatrician should also be aware of common epilepsy syndromes that occur in children such as Benign Childhood Epilepsy with Centro-Temporal Spikes, and childhood absence epilepsy.

ARL6IP6, a susceptibility locus for ischemic stroke, is mutated in a patient with syndromic Cutis Marmorata Telangiectatica Congenita.

Cutis Marmorata Telangiectatica Congenita (CMTC) is a congenital localized or generalized vascular anomaly, usually sporadic in occurrence. It can be associated with other cutaneous or systemic manifestations. About 300 cases have been reported. The molecular etiology remains largely unknown. The main purpose of this study is to delineate the molecular basis for a syndromic CMTC phenotype in a consanguineous Saudi family. Clinical phenotyping including detailed neurological imaging, followed by autozygosity mapping and trio whole exome sequencing (WES) are also studied. We have identified a homozygous truncating mutation in ARL6IP6 as the likely cause of a syndromic form of CMTC associated with major dysmorphism, developmental delay, transient ischemic attacks and cerebral vascular malformations. This gene was previously implicated by genome wide association study (GWAS) as a susceptibility locus to ischemic stroke in young adults. We identify ARL6IP6 as a novel candidate gene for a syndromic form of CMTC. This suggests that ischemic stroke or transient ischemic attacks (TIA) may represent, at least in some cases, the mild end of a phenotypic spectrum that has at its severe end autosomal recessive CMTC. This finding contributes to a growing appreciation of the continuum of Mendelian and common complex diseases.