Short-term effectiveness and side effects of ketogenic diet for drug-resistant epilepsy in children with genetic epilepsy syndromes.

Background: Drug-resistant epilepsy (DRE) impacts a significant portion, one-third, of individuals diagnosed with epilepsy. In such cases, exploring non-pharmacological interventions are crucial, with the ketogenic diet (KD) standing out as a valuable option. KD, a high-fat and low-carb dietary approach with roots dating back to the 1920s for managing DRE, triggers the formation of ketone bodies and modifies biochemistry to aid in seizure control. Recent studies have increasingly supported the efficacy of KD in addressing DRE, showcasing positive outcomes. Furthermore, while more research is needed, limited data suggests that KD May also be beneficial for specific genetic epilepsy syndromes (GESs). Objective: This study aimed to assess the short-term efficacy of KD among pediatric patients diagnosed with GESs. Materials and methods: This is a multi-center retrospective analysis of pediatric patients with GESs diagnosed using next-generation sequencing. The enrolled patients followed the keto-clinic protocol, and the KD efficacy was evaluated at 3, 6, and 12-month intervals based on seizure control and compliance. The collection instrument included demographic, baseline, and prognostic data. The collected data was coded and analyzed promptly. Results: We enrolled a cohort of 77 patients with a mean current age of 7.94 ± 3.83 years. The mean age of seizure onset was 15.5 months. Notably, patients experienced seizures at a younger age tended to have less positive response to diet. Overall, 55 patients responded favorably to the diet (71.4%) while 22 patients (28.6%) showed no improvement. Patients with genetic etiology showed a significantly more favorable responses to the dietary intervention. Patients with Lennox-Gastaut syndrome showed the most significant improvement (14/15) followed by patients with Dravet syndrome (6/8), and West syndrome (3/4). The number of used anti-seizure medications also played a significant role in determining their response to the diet. While some patients experienced mild adverse events, the most common being constipation, these occurrences were not serious enough to necessitate discontinuation of the diet. Conclusion: The study revealed a high improvement rate in seizure control, especially among younger patients and those with later seizure onset. The success of dietary treatment hinges greatly on early intervention and the patient's age. Certain genetic mutations responded favorably to the KD, while efficacy varied among various genetic profiles.

Effectiveness of phototherapy with and without probiotics for the treatment of indirect hyperbilirubinaemia in preterm neonates: a randomised controlled trial.

INTRODUCTION: Raised serum bilirubin levels can cause kernicterus, and premature infants are at increased risk owing to metabolic immaturity. The standard treatment for neonatal jaundice is phototherapy, but probiotics alone can reduce the duration of phototherapy and hospitalisation. OBJECTIVES: To determine the effectiveness of phototherapy with and without probiotics for the treatment of indirect hyperbilirubinaemia in preterm neonates. PATIENTS AND METHODS: The open-labelled randomised controlled trial was conducted from January 2022 to January 2023 in the neonatal unit of the University of Lahore Teaching Hospital, Pakistan. A total of 76 preterm neonates who fulfilled the selection criteria were included and divided into two groups. Both groups received standard phototherapy. In Group B, a probiotic (Saccharomyces boulardii) 125 mg, twice daily, orally (in 5 cc of whichever milk the infant was receiving) was given until discharge from hospital. The primary outcome measurements were the duration of phototherapy and the length of hospitalisation. RESULTS: The mean (SD) duration of phototherapy was 36.55 (14.25) hours in Group A and 24.61 (9.25) hours in Group B (p <0.05). The mean (SD) duration of hospital stay was 47.36 (16.51) hours in Group A and 33.13 (8.93) hours in Group B (p <0.05). CONCLUSION: Oral probiotics (Saccharomyces boulardii) have a significant effect on the duration of phototherapy for neonatal hyperbilirubinaemia, and they decrease the chances of nosocomial infection. Exploration of clinical outcomes by investigating faecal flora and undertaking large randomised controlled trials of various probiotics are needed. ABBREVIATIONS: ABE: acute bilirubin encephalopathy; CNS: central nervous system; GA: gestational age; IVIG: intravenous immunoglobulin; KSD: kernicterus; NNU: neonatal unit; RCT: randomised controlled trial; S. boulardii: Saccharomyces boulardii.

Prevalence of Esophageal Eosinophilia, Eosinophilic Esophagitis, and Lymphocytic Gastritis in Children with Celiac Disease: A Saudi Tertiary Center Experience.

Background: Celiac disease (CD) is an immune-mediated enteropathy that has been associated with other immune-related gastrointestinal disorders, such as eosinophilic esophagitis (EoE) and lymphocytic gastritis (LG). To our knowledge, this is the first study in Saudi Arabia that has described such an association. Aim: To evaluate the prevalence of EoE and LG in children and adolescents with CD. Methods: This was a retrospective cross-sectional study of all pediatric patients (aged 0-18 years) with CD following up at King Abdulaziz University Hospital, between January, 2014, and December, 2021. The study examined clinical, demographic, endoscopic, and histopathological data. Results: Seventy-five patients with CD were included in the analysis. The median age was 12 years (range, 2-18 years). Male constituted 54.7% of the overall cohort (n = 41). The most common clinical symptoms were short stature (54.7%), weight loss (34.7%), abdominal pain (33.3%), abdominal distension (29.3%), anorexia (29.3%), diarrhea (24%), and vomiting (21.3%). The esophageal biopsy results reported were basal cell hyperplasia in 24 patients (32.9%), esophageal eosinophilia in 23 patients (31.5%), and EoE in 3 patients (4.1%). The gastric biopsy results were normal in 40 patients (53.3%). The most common abnormality was chronic inactive gastritis with no Helicobacter pylori (HP) infection (16%). LG was found in 3 patients (4%). Conclusions: The prevalence of EoE in this cohort of patients with CD was lower than the prevalence recorded in a number of other studies. Further studies are needed to determine the effects of a gluten-free diet (GFD) on EOE and LG.

Rare variant burden analysis from exomes of three consanguineous families reveals LILRB1 and PRSS3 as potential key proteins in inflammatory bowel disease pathogenesis.

Background: Inflammatory bowel disease (IBD) is a chronic autoimmune disorder characterized by severe inflammation and mucosal destruction of the intestine. The specific, complex molecular processes underlying IBD pathogenesis are not well understood. Therefore, this study is aimed at identifying and uncovering the role of key genetic factors in IBD. Method: The whole exome sequences (WESs) of three consanguineous Saudi families having many siblings with IBD were analyzed to discover the causal genetic defect. Then, we used a combination of artificial intelligence approaches, such as functional enrichment analysis using immune pathways and a set of computational functional validation tools for gene expression, immune cell expression analyses, phenotype aggregation, and the system biology of innate immunity, to highlight potential IBD genes that play an important role in its pathobiology. Results: Our findings have shown a causal group of extremely rare variants in the LILRB1 (Q53L, Y99N, W351G, D365A, and Q376H) and PRSS3 (F4L and V25I) genes in IBD-affected siblings. Findings from amino acids in conserved domains, tertiary-level structural deviations, and stability analysis have confirmed that these variants have a negative impact on structural features in the corresponding proteins. Intensive computational structural analysis shows that both genes have very high expression in the gastrointestinal tract and immune organs and are involved in a variety of innate immune system pathways. Since the innate immune system detects microbial infections, any defect in this system could lead to immune functional impairment contributing to IBD. Conclusion: The present study proposes a novel strategy for unraveling the complex genetic architecture of IBD by integrating WES data of familial cases, with computational analysis.

Outcomes of Biliary Atresia in a Single Center in Jeddah, Saudi Arabia.

Background Biliary atresia (BA) is a rare but severe cause of obliterative cholangiopathy in neonates. Its incidence differs worldwide varying from 5/100,000 to 32/100,000 live births. The highest incidence is seen in Asia and the Pacific region. Diagnosing this disease is difficult in its early stages; thus, screening is necessary to avoid serious complications that can be minimized with early intervention during the first few months of life. Currently, although there are no medical treatments for BA, once the diagnosis is confirmed, the Kasai procedure may be a treatment option. The earlier the Kasai surgery is performed, the higher the success rate. Liver transplantation may be needed if the operation fails. This study aimed to determine the incidence of BA and the factors influencing the outcomes of the Kasai procedure at King Abdulaziz University Hospital, Jeddah, Saudi Arabia. Methodology This retrospective cohort study was conducted in the Pediatric Department at King Abdulaziz University Hospital, Jeddah from January 2019 to July 2019 and included consecutive patients with BA from 2010 to 2018. Results In total, 14 patients (57.1% female) were included in the study. The median age at the time of presentation was 90 (19-720) days, and the median age at the time of implementing the Kasai procedure was 90 (60-150) days. Eight patients underwent the Kasai procedure, and only one patient had a liver transplant. Conclusions Antenatal screening for BA tended to ensure early diagnosis and better outcomes. Delay in diagnosis and intervention is associated with increased morbidity and mortality.

Granulomatous hepatitis in a Saudi child with IL2RA defect: a case report and literature review.

Interleukin-2 receptor alpha (IL2RA) defect (OMIM- # 606367) is an immune disease where affected patients are vulnerable to developing recurrent microbial infections in addition to lymphadenopathy and dermatological manifestations. This condition is known to be caused by pathogenic variants in the IL2RA gene, which are inherited in an autosomal recessive fashion. In this case report, we present a patient with IL2RA defect from Saudi Arabia who presented with chronic diarrhea, poor weight gain, mild villous atrophy, malnutrition, hepatomegaly, nonspecific inflammation, and an eczematous skin rash. His genetic analysis revealed a novel, homozygous, and likely pathogenic variant, that is, c.504 C>A (Cys168Ter), located in the exon 4of the IL2RA gene, which was inherited from his parents in an autosomal recessive mode of inheritance. This variant produces a 272-amino-acid shorter IL2RA protein chain, which most likely becomes degraded in the cytosol. Thus, we assume that the c.504 C>A is a null allele that abolishes the synthesis of IL2RA, malforms the IL-2 receptor complex, and eventually causes immunodeficiency manifestations. To our knowledge, this is the first time a person with IL2RA defect has shown signs of granulomatous hepatitis on a liver biopsy.

Complex Inheritance of Rare Missense Variants in PAK2, TAP2, and PLCL1 Genes in a Consanguineous Arab Family With Multiple Autoimmune Diseases Including Celiac Disease.

Background: Autoimmune diseases (AIDs) share a common molecular etiology and often present overlapping clinical presentations. Thus, this study aims to explore the complex molecular basis of AID by whole exome sequencing and computational biology analysis. Methods: Molecular screening of the consanguineous AID family and the computational biology characterization of the potential variants were performed. The potential variants were searched against the exome data of 100 healthy individuals and 30 celiac disease patients. Result: A complex inheritance pattern of PAK2 (V43A), TAP2 (F468Y), and PLCL1 (V473I) genetic variants was observed in the three probands of the AID family. The PAK2 variant (V43A) is a novel one, but TAP2 (F468Y) and PLCL1 (V473I) variants are extremely rare in local Arab (SGHP and GME) and global (gnomAD) databases. All these variants were localized in functional domains, except for the PAK2 variant (V43A) and were predicted to alter the structural (secondary structure elements, folding, active site confirmation, stability, and solvent accessibility) and functional (gene expression) features. Therefore, it is reasonable to postulate that the dysregulation of PAK2, TAP2, and PLCL1 genes is likely to elicit autoimmune reactions by altering antigen processing and presentation, T cell receptor signaling, and immunodeficiency pathways. Conclusion: Our findings highlight the importance of exploring the alternate inheritance patterns in families presenting complex autoimmune diseases, where classical genetic models often fail to explain their molecular basis. These findings may have potential implications for developing personalized therapies for complex disease patients.

Colonoscopy Quality Assurance and Maintenance of Competency Among Pediatric Gastroenterology Staff Members: A Canadian Center Experience.

Introduction Colonoscopy quality indicators and maintenance of competency skills are relatively well established in the adult literature as compared to the pediatric gastroenterology. One of the suggested quality assurance measures is cecal intubation rate, which is suggested to be >90% in all colonoscopies as per American Society of Gastrointestinal Endoscopy (ASGE) guidelines. Terminal ileum (TI) intubations are essentially required for diagnostic reasons in pediatric colonoscopies as compared to the screening reasons in adults. Maintenance of competency in pediatric colonoscopies has been described in the literature but in smaller studies contrary to the adult ones. The aims of this study are to compare our center's individual and group cecal intubation rates and compare it with the published literature, assess the group's terminal ileal intubation rates in comparison with the published literature, assess the most common reasons for failure to intubate the cecum and/or terminal ileum, and to assess whether the presence of a trainee affects the intubation rates and the duration of the procedure. Methods A retrospective chart review was performed on all pediatric patients (0-18 years). Colonoscopies performed over a two-year period at our single center were included in the study. Patients scheduled for sigmoidoscopy and with altered anatomy of their colon were excluded from the study. The endoscopy and pathology reports were reviewed to ascertain whether the cecum and TI were reached. Quality of bowel preparation and any other stated reasons for incompletion were obtained. Clinical charts were reviewed to obtain indication for colonoscopy. Skin-to-skin time, which is the time from starting to the finishing of the procedure, was recorded for each procedure. Results A total of 391 colonoscopies were performed during the two-year study period by six gastroenterologists. The number of colonoscopies per staff ranged from 57 to 89 procedures. The overall cecal intubation rate was observed to be 98.5% (range: 95.9%-98.9%). TI intubation rate was lower at a rate of 83.1% (range: 63.3%-92.1%). The main stated reason for the inability to attain cecum/TI was technical difficulty and poor bowel prep. Daytime colonoscopies were shorter (39.5 minutes vs 50.3 minutes) compared to after-hours ones and had a higher TI intubation rate (84.5% vs 62.5%). No complications were encountered in the procedures. Conclusion Despite relatively low volumes, cecal intubation rates are very high, exceeding suggested standards. TI intubation rates were low, and there was noted to be a high degree of variability. However, multicentric collaborative evaluations are required over a longer period of time to establish relevant parameters for quality assurance and competency in pediatric endoscopy.

Comprehensive Analysis of Genes Associated With Sudden Infant Death Syndrome.

Background: Sudden infant death syndrome (SIDS) is a tragic incident which remains a mystery even after post-mortem investigation and thorough researches. Methods: This comprehensive review is based on the genes reported in the molecular autopsy studies conducted on SIDS so far. A total of 20 original studies and 7 case reports were identified and included in this analysis. The genes identified in children or adults were not included. Most of the genes reported in these studies belonged to cardiac channel and cardiomyopathy. Cardiac channel genes in SIDS were scrutinized for further analysis. Results: After screening and removing the duplicates, 42 unique genes were extracted. When the location of these genes was assessed, it was observed that most of these belonged to Chromosomes 11, 1 and 3 in sequential manner. The pathway analysis shows that these genes are involved in the regulation of heart rate, action potential, cardiac muscle cell contraction and heart contraction. The protein-protein interaction network was also very big and highly interactive. SCN5A, CAV3, ALG10B, AKAP9 and many more were mainly found in these cases and were regulated by many transcription factors such as MYOG C2C1 and CBX3 HCT11. Micro RNA, "hsa-miR-133a-3p" was found to be prevalent in the targeted genes. Conclusions: Molecular and computational approaches are a step forward toward exploration of these sad demises. It is so far a new arena but seems promising to dig out the genetic cause of SIDS in the years to come.

TagSNP approach for HLA risk allele genotyping of Saudi celiac disease patients: effectiveness and pitfalls.

BACKGROUND: Celiac disease (CD) is a genetically complex autoimmune disease which is triggered by dietary gluten. Human leukocyte antigen (HLA) class II genes are known to act as high-risk markers for CD, where >95% of CD patients carry (HLA), DQ2 and/or DQ8 alleles. Therefore, the present study was conducted to investigate the distribution of HLA haplotypes among Saudi CD patients and healthy controls by using the tag single nucleotide polymorphisms (SNP). METHODS: HLA-tag SNPs showing strong linkage value (r2>0.99) were used to predict the HLA DQ2 and DQ8 genotypes in 101 Saudi CD patients and in 103 healthy controls by using real-time polymerase chain reaction technique. Genotype calls were further validated by Sanger sequencing method. RESULTS: A total of 63.7% of CD cases and of 60.2% of controls were predicted to carry HLA-DQ2 and DQ8 heterodimers, either in the homozygous or heterozygous states. The prevalence of DQ8 in our CD patients was predicted to be higher than the patients from other ethnic populations (35.6%). More than 32% of the CD patients were found to be non-carriers of HLA risk haplotypes as predicted by the tag SNPs. CONCLUSION: The present study highlights that the Caucasian specific HLA-tag SNPs would be of limited value to accurately predict CD specific HLA haplotypes in Saudi population, when compared with the Caucasian groups. Prediction of risk haplotypes by tag SNPs in ethnic groups is a good alternate approach as long as the tag SNPs were identified from the local population genetic variant databases.

Liver function changes following the introduction of a gluten-free diet in patients with celiac disease.

Aim of the study: Disturbance in liver enzymes is a well-described observation in patients with celiac disease (CD). We aim to describe the prevalence of all liver function abnormalities in CD and assess their response to a gluten-free diet (GFD). Material and methods: This is a retrospective cross-sectional study of all CD patients diagnosed from 2007 to 2020 in King Abdulaziz University Hospital, Jeddah. Demographic, biochemical, and histologic patient data were collected. Results: The study included 132 patients with CD. The median age was 9.5 years (range, 1-18 years). Males constituted 56.1% (n = 74) of the whole cohort. The most common associated morbidities were type 1 diabetes (33%), thyroid disease (15.7%), and Down syndrome (7.6%). Ninety-seven percent of patients were determined to have a severe form of CD (Marsh score 3). Aspartate aminotransferase (AST) was high in 38 patients (28.8%), while alanine aminotransferase (ALT) was high in 10 (7.6%). Two patients (1.5%) had elevated γ-glutamyl transferase (GGT) levels, and 2 patients (1.5%) had elevated AST, ALT, and GGT levels. Albumin levels were low in 29 patients (22%), while bilirubin levels were elevated in 1 patient. Introduction of a GFD resulted in improvement in ALT levels at 6 months, and improvement in albumin levels both after 6 months and 12 months. Conclusions: Transaminase and albumin disturbances are frequently found in CD, with the most common abnormality being elevated AST. A decreased ALT level is the most pronounced response to a GFD.

Unusual Case of an Infant with Urinary Tract Infection Presenting as Cholestatic Jaundice.

Neonatal jaundice is considered one of the most common reasons for admission to the pediatric medical ward. We report a case of a 1-month-old infant who presented with jaundice but no fever or any other signs of systemic illnesses. Laboratory test results revealed high direct hyperbilirubinemia, and urine culture showed a urinary tract infection with Enterobacter cloacae as the causative agent. He was admitted to the pediatric medical ward where he was treated with a course of antibiotics for 14 days, and cholestasis resolved completely following a course of antibiotics. We conclude that direct hyperbilirubinemia can be related to urinary tract infection in neonates. It is unusual for urinary tract infection to present clinically and biochemically as cholestatic jaundice.