Bi-allelic genetic variants in the translational GTPases GTPBP1 and GTPBP2 cause a distinct identical neurodevelopmental syndrome.

The homologous genes GTPBP1 and GTPBP2 encode GTP-binding proteins 1 and 2, which are involved in ribosomal homeostasis. Pathogenic variants in GTPBP2 were recently shown to be an ultra-rare cause of neurodegenerative or neurodevelopmental disorders (NDDs). Until now, no human phenotype has been linked to GTPBP1. Here, we describe individuals carrying bi-allelic GTPBP1 variants that display an identical phenotype with GTPBP2 and characterize the overall spectrum of GTP-binding protein (1/2)-related disorders. In this study, 20 individuals from 16 families with distinct NDDs and syndromic facial features were investigated by whole-exome (WES) or whole-genome (WGS) sequencing. To assess the functional impact of the identified genetic variants, semi-quantitative PCR, western blot, and ribosome profiling assays were performed in fibroblasts from affected individuals. We also investigated the effect of reducing expression of CG2017, an ortholog of human GTPBP1/2, in the fruit fly Drosophila melanogaster. Individuals with bi-allelic GTPBP1 or GTPBP2 variants presented with microcephaly, profound neurodevelopmental impairment, pathognomonic craniofacial features, and ectodermal defects. Abnormal vision and/or hearing, progressive spasticity, choreoathetoid movements, refractory epilepsy, and brain atrophy were part of the core phenotype of this syndrome. Cell line studies identified a loss-of-function (LoF) impact of the disease-associated variants but no significant abnormalities on ribosome profiling. Reduced expression of CG2017 isoforms was associated with locomotor impairment in Drosophila. In conclusion, bi-allelic GTPBP1 and GTPBP2 LoF variants cause an identical, distinct neurodevelopmental syndrome. Mutant CG2017 knockout flies display motor impairment, highlighting the conserved role for GTP-binding proteins in CNS development across species.

Lactoferrin versus iron hydroxide polymaltose complex for the treatment of iron deficiency anemia in children with cerebral palsy: a randomized controlled trial.

Iron deficiency anemia (IDA) is common among children with cerebral palsy (CP), and studies on the efficacy of lactoferrin (Lf) in the treatment of IDA are limited. This study aimed to compare the efficacy of Lf with that of iron hydroxide polymaltose complex (IPC) in the treatment of IDA in children with CP. This randomized controlled study, conducted at Alexandria University Children's Hospital, enrolled 70 children aged 1-10 years with CP and IDA; 35 children randomly received IPC, whereas the other 35 received Lf. Four children withdrew from the study; thus, only 66 children were analyzed (32 in the IPC group and 34 in the Lf group). At baseline, the hemoglobin level and other blood parameters were similar between the two intervention groups. After four weeks of treatment, both the IPC and Lf groups showed significant improvements in hemoglobin (Hb), serum ferritin (SF), serum iron, total iron-binding capacity, mean corpuscular volume, and mean corpuscular hemoglobin from baseline. Upon comparing the two treatment groups, adjusted mean Hb and SF changes in the Lf group were significantly higher than that of the IPC group (p =0.001and p= 0.033, respectively), and constipation was less likely to occur in the Lf group than the IPC group (p = 0.049 ).Conclusion: Lactoferrin is effective and superior to IPC as an oral iron replacement therapy in children with CP and IDA, as it has fewer side effects. What is Known: • Lactoferrin (LF) is a natural glycoprotein capable of treating iron deficiency anemia (IDA). • Studies on the efficacy of Lf in the treatment of IDA in children with cerebral palsy (CP) are limited. What is New? • This trial compared the efficacy of Lf and iron hydroxide polymaltose complex (IPC) as treatments of IDA in children with CP. • Lf is effective and even better than IPC as a treatment of IDA in children with CP, as it has fewer side effects.

Clinical Characteristics and Appropriateness of Investigations in Children With Headaches at the Emergency Department.

BACKGROUND: Identifying the cause of headaches in pediatric emergency departments (PEDs) can be challenging due to the lack of comprehensive research. This study aims to identify the frequency, characteristics, and unnecessary diagnostic procedures of patients with headaches in the PED setting. METHODS: A six-month cross-sectional study was conducted at the PED of Alexandria University Children's Hospital, including all children with headaches. Children were classified as having primary headache (PH), secondary benign headache (SBH), and secondary serious headache (SSH) according to predetermined criteria. Logistic regression was employed to analyze the risk factors associated with SSH. RESULTS: A total of 164 visits to the PED were recorded, out of a total of 22,662 visits, accounting for approximately 0.72% of all visits and 1.17% of the total number of children admitted. PH was the most common cause, accounting for 61.0% of cases, followed by SSH with 24.4%, whereas SBH was the least common with 13.4%. Abnormal neurological examination (odds ratio, 53.752 [1.628 to 1774.442], P = 0.026∗) was found to have a strong and statistically significant association with SSH in the multivariate analysis. Regarding the appropriateness of the investigations conducted, it was found that over half (66.5%) of the cases had unnecessary neuroimaging, with 52% of these cases being children with PH. CONCLUSIONS: Headaches in children are commonly reported during visits to the PED. PH was the most prevalent, followed by SSH, whereas SBH was the least common. Many of the children received inaccurate first diagnoses and performed unnecessary laboratory tests, neuroimaging, and other tests, mostly electroencephalography.

Adapting Evidence-Based Practice Guidelines for Emergency Management of Seizures in Children Beyond the Neonatal Period.

BACKGROUND: The presented evidence-based clinical practice guideline (CPG) is proposed as a National CPG where we adapted the international recommendations for the emergency management of seizures in children beyond the neonatal period to suit the health care in Egypt. The quality of evidence and the strength of recommendations are indicated. This study aimed to standardize the treatment of acute epileptic seizures and to provide an easy-to-apply acute treatment protocol that will allow immediate and appropriate seizure control. METHODS: This is part of a larger program by the Egyptian Pediatric Clinical Practice Guidelines Committee (EPG) in collaboration with the staff of pediatric departments of 15 Egyptian universities and the National Research Centre. EPG was affiliated later to the Supreme Council of the Egyptian University Hospitals aiming to define the topics of, assign authors to, and assist in the adaptation of pediatric evidence-based CPGs according to a national strategic plan (http://epg.edu.eg). The committee is guided by a formal CPG adaptation methodology: the "Adapted ADAPTE." RESULTS: The Egyptian Childhood Seizure Group (ECSG) reviewed the results of the Appraisal of Guidelines for Research and Evaluation II assessment and decided to adapt the recommendations of three source CPGs: American Epilepsy Society, Italian League Against Epilepsy, Neurocritical Care Society, and Neurologic & Psychiatric Society of Zambia. Eight implementation tools were included. A comprehensive set of multifaceted CPG implementation strategies was provided for the clinicians, patients, nurses, and other relevant stakeholders contextualized to the national settings. CONCLUSIONS: Our experience with this adaptation methodology provides useful insight into its national utilization in Egypt.

Unravelling undiagnosed rare disease cases by HiFi long-read genome sequencing.

Solve-RD is a pan-European rare disease (RD) research program that aims to identify disease-causing genetic variants in previously undiagnosed RD families. We utilised 10-fold coverage HiFi long-read sequencing (LRS) for detecting causative structural variants (SVs), single nucleotide variants (SNVs), insertion-deletions (InDels), and short tandem repeat (STR) expansions in extensively studied RD families without clear molecular diagnoses. Our cohort includes 293 individuals from 114 genetically undiagnosed RD families selected by European Rare Disease Network (ERN) experts. Of these, 21 families were affected by so-called 'unsolvable' syndromes for which genetic causes remain unknown, and 93 families with at least one individual affected by a rare neurological, neuromuscular, or epilepsy disorder without genetic diagnosis despite extensive prior testing. Clinical interpretation and orthogonal validation of variants in known disease genes yielded thirteen novel genetic diagnoses due to de novo and rare inherited SNVs, InDels, SVs, and STR expansions. In an additional four families, we identified a candidate disease-causing SV affecting several genes including an MCF2 / FGF13 fusion and PSMA3 deletion. However, no common genetic cause was identified in any of the 'unsolvable' syndromes. Taken together, we found (likely) disease-causing genetic variants in 13.0% of previously unsolved families and additional candidate disease-causing SVs in another 4.3% of these families. In conclusion, our results demonstrate the added value of HiFi long-read genome sequencing in undiagnosed rare diseases.

Knowledge, Skills, and Attitudes Towards Children with Epilepsy Among Egyptian Parents: A Comparative Cross-Sectional Study.

INTRODUCTION: Epilepsy is one of the most common neurological disorders affecting children. As a chronic disease, it affects not only the child but also the entire family. The attitudes towards the children suffering from epilepsy and the skills required to deal with acute seizures are influenced by the level of knowledge the parents have about that disease. AIM: To evaluate the knowledge, attitudes, and skills toward epilepsy among parents of children diagnosed with epilepsy in comparison to parents of children without epilepsy. METHOD: Data collected through a structured questionnaire that was designed, translated into Arabic, and analyzed statistically in a cross-sectional study for a total of 534 Egyptian parents as two groups, group I (n = 223) consist of parents with children with epilepsy and group II (n = 311) of parents with children without epilepsy. Parents with children with epilepsy were recruited from the Paediatric Neurology Outpatient Clinic of Alexandria University Children's Hospital (AUCH). Parents with children without epilepsy were recruited from other outpatient clinics or wards of AUCH. RESULTS: This study showed a poor knowledge score percentage of (89.7 %) among parents with children with epilepsy and (83.3 %) among parents with children without epilepsy. The difference between both groups was statistically significant with fewer knowledge scores among parents of children with epilepsy. Parents of both groups showed a negative attitude score percentage; (69.5 %) of group I and (62.7 %) of group II. The difference between both groups was statistically significant with a more negative attitude score percentage among parents with children without epilepsy. Parents of both groups had poor practice score percentage of (66.8 %) of group I and (74.3 %) of group II having poor practice skills needed for emergency management of acute seizures. A high level of education was significantly associated with fair knowledge score percentage and positive attitude score percentage. CONCLUSIONS: Poor knowledge, negative attitudes, and poor skills required for the management of acute seizures were found among both parents of children with epilepsy and those with children without epilepsy. Educational programs are needed to eliminate all the misconceptions and myths and to change attitudes of the Egyptian parents towards epilepsy.