Bi-allelic loss-of-function variants in PPFIBP1 cause a neurodevelopmental disorder with microcephaly, epilepsy, and periventricular calcifications.

PPFIBP1 encodes for the liprin-ß1 protein, which has been shown to play a role in neuronal outgrowth and synapse formation in Drosophila melanogaster. By exome and genome sequencing, we detected nine ultra-rare homozygous loss-of-function variants in 16 individuals from 12 unrelated families. The individuals presented with moderate to profound developmental delay, often refractory early-onset epilepsy, and progressive microcephaly. Further common clinical findings included muscular hyper- and hypotonia, spasticity, failure to thrive and short stature, feeding difficulties, impaired vision, and congenital heart defects. Neuroimaging revealed abnormalities of brain morphology with leukoencephalopathy, ventriculomegaly, cortical abnormalities, and intracranial periventricular calcifications as major features. In a fetus with intracranial calcifications, we identified a rare homozygous missense variant that by structural analysis was predicted to disturb the topology of the SAM domain region that is essential for protein-protein interaction. For further insight into the effects of PPFIBP1 loss of function, we performed automated behavioral phenotyping of a Caenorhabditis elegans PPFIBP1/hlb-1 knockout model, which revealed defects in spontaneous and light-induced behavior and confirmed resistance to the acetylcholinesterase inhibitor aldicarb, suggesting a defect in the neuronal presynaptic zone. In conclusion, we establish bi-allelic loss-of-function variants in PPFIBP1 as a cause of an autosomal recessive severe neurodevelopmental disorder with early-onset epilepsy, microcephaly, and periventricular calcifications.

NAIP Gene Deletion and SMN2 Copy Number as Molecular Tools in Predicting the Severity of Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) is one of the most prevalent autosomal recessive illnesses with type I being the most severe type. Genomic alterations including survival motor neuron (SMN) copy number as well as deletions in SMN and Neuronal Apoptosis Inhibitory Protein (NAIP) are greatly implicated in the emergence of SMA. However, the association of such alterations with the severity of the disease is yet to be investigated. This study was directed to elucidate the molecular assessment of NAIP and SMN genomic alterations as a useful tool in predicting the severity of SMA among patients. This study included 65 SMA pediatric patients (30 type I and 35 type II) and 65 healthy controls. RFLP-PCR was employed to determine the genetic polymorphisms of the SMN1, SMN2, and NAIP genes. In addition, qRT-PCR was used to identify the expression of the SMN1 and SMN2 genes, and serum levels of creatine kinase were measured using a colorimetric method. DNA sequencing was performed on some samples to detect any single nucleotide polymorphisms in SMN1, SMN2, and NAIP genes. All SMA patients had a homozygous deficiency of SMN1 exon 7. The homozygous deficiency of SMN1 exons 7 and 8, with the deletion of NAIP exon 5 was found among the majority of Type I patients. In contrast, patients with the less severe condition (type II) had SMN1 exons 7 and 8 deleted but did not have any deletions in NAIP, additionally; 65.7% of patients had multiple copies of SMN2. Analysis of NAIP deletion alongside assessing SMN2 copy number might enhance the effectiveness of the diagnosis that can predict severity among Spinal Muscular Atrophy patients.

Psychometric properties of an Arabic translation of the quality of life in childhood epilepsy questionnaire (QOLCE-55).

OBJECTIVE: To develop an Arabic translation of the Quality of Life in Children with Epilepsy-55 questionnaire (QOLCE-55), and to assess its validity and reliability to be readily used in Arabic and Egyptian cultures. SUBJECTS AND METHODS: The original English version of the QOLCE-55 was translated into Arabic using a forward-backward translation method, and then a cross-sectional survey was conducted including 100 children with epilepsy aged 4-18 years. Caregivers of children completed the Arabic version of the QOLCE-55. Assessment of psychometric properties of the translated questionnaire was conducted using test-retest reliability, internal consistency, and convergent and divergent validity. RESULTS: The translated questionnaire showed excellent test-retest reliability with the intra-class correlation coefficient for all questionnaire domains, as well as the overall questionnaire ranging from 0.91 to 0.98. Cronbach alpha exceeded 0.7 denoting good internal consistency except for the emotional functioning scale. Convergent and divergent validity assessment showed that items of all domains significantly correlated with their scale scores with r > 0.4 and these correlations were much higher than correlations with other scales' scores, consistent with good convergent and divergent validity. The mean total HRQOL score was 65.63 ±â€¯8.79 with the highest score for social functioning domain and lowest score for physical functioning domain. CONCLUSION: The Arabic version of the QOLCE-55 can be considered a suitable, reliable, and valid tool to assess the HRQOL of children with epilepsy through their caregivers' reports.

Evaluation of salivary parameters and Streptococcus' Mutans count in children with cerebral palsy in Egypt: a case control study.

BACKGROUND: Children with cerebral palsy (CP) are at high risk for dental caries. Alteration of some salivary properties encountered among them compared to healthy children, could play a role in this elevated risk. OBJECTIVES: The aim of the present study was to assess salivary physicochemical properties; including total antioxidant (TAC), flow rate, viscosity, pH and buffering capacity, as well as Streptococcus mutans level among children with CP, also to correlate these variables to their caries experience. MATERIALS AND METHODS: This case control study included 80 children with CP, study group (SG) and matched number of healthy children for control group (CG). Interview-based questionnaire, clinical examination, salivary biochemical and microbiological investigations using MALDI-TOF were done. RESULTS: In SG, the caries experience in primary teeth dmft and S. mutans log value were significantly higher than CG (P = 0.039, P = 0.002) while unstimulated salivary flow rate, buffering capacity and salivary TAC were significantly lower (P < 0.0001). Multivariate linear regression showed that the presence of CP was significantly associated with the greatest variation in caries experience in the primary teeth and permanent teeth. Higher unstimulated salivary flow rate, or an increase in buffering capacity by 1 ml of acid/ml of saliva were associated with lower number of the affected primary and permanent teeth. On the other hand, One-unit increase in S. mutans log count and higher salivary TAC were associated with higher caries experience. CONCLUSION: Children with CP have higher caries experience (dmf) due to lower salivary protective factors and higher S. mutans counts.

Egyptian Pediatric Guidelines for the Management of Children with Isolated Thrombocytopenia Using the Adapted ADAPTE Methodology-A Limited-Resource Country Perspective.

BACKGROUND: Thrombocytopenia is a prevalent presentation in childhood with a broad spectrum of etiologies, associated findings, and clinical outcomes. Establishing the cause of thrombocytopenia and its proper management have obvious clinical repercussions but may be challenging. This article provides an adaptation of the high-quality Clinical Practice Guidelines (CPGs) of pediatric thrombocytopenia management to suit Egypt's health care context. METHODS: The Adapted ADAPTE methodology was used to identify the high-quality CPGs published between 2010 and 2020. An expert panel screened, assessed and reviewed the CPGs and formulated the adapted consensus recommendations based on the best available evidence. DISCUSSION: The final CPG document provides consensus recommendations and implementation tools on the management of isolated thrombocytopenia in children and adolescents in Egypt. There is a scarcity of evidence to support recommendations for various management protocols. In general, complete clinical assessment, full blood count, and expert analysis of the peripheral blood smear are indicated at initial diagnosis to confirm a bleeding disorder, exclude secondary causes of thrombocytopenia and choose the type of work up required. The International Society of Hemostasis and thrombosis-Bleeding assessment tool (ISTH-SCC BAT) could be used for initial screening of bleeding manifestations. The diagnosis of immune thrombocytopenic purpura (ITP) is based principally on the exclusion of other causes of isolated thrombocytopenia. Future research should report the outcome of this adapted guideline and include cost-analysis evaluations.

Adapting global evidence-based practice guidelines to the Egyptian healthcare context: the Egyptian Pediatric Clinical Practice Guidelines Committee (EPG) initiative.

Background: In Egypt, academic organizations, professional societies, and research groups develop clinical practice guidelines (CPGs) in order to improve patient quality care and safety. Although important improvements have been made over the past years, many of these consensus-based guideline documents still lack the transparency and methodological rigor of international standards and methodologies recommended by reference evidence-based healthcare and guideline organizations like the Guidelines International Network. Main body of the abstract: In the Egyptian Pediatric Clinical Practice Guidelines Committee (EPG), we have adopted one of the CPG formal adaptation methodological frameworks named the 'Adapted ADAPTE', relevant CPG resources (e.g., the Appraisal of Guidelines for Research and Evaluation or AGREE II Instrument), and involved key stakeholders including clinical and healthcare topic experts and guideline methodologists in producing 32 trustworthy national evidence-based CPGs and one protocol customized to the healthcare context and services provided for Egyptian children. An EPG online website was launched to make these CPGs available and accessible as CPG summaries for pediatricians and relevant healthcare providers. Short conclusion: The lessons learned, enablers, challenges, and solutions relevant to Egyptian National Pediatric CPGs identified in this paper could be used to address and enrich the debate on pediatric high-quality CPGs, especially for countries of similar contexts and systems. Supplementary Information: The online version contains supplementary material available at 10.1186/s42269-023-01059-0.

Adapted Evidence-Based Clinical Practice Guidelines for Diagnosis and Treatment of Epilepsies in Children: A Tertiary Children's Hospital Update.

HYPOTHESIS AND/OR BACKGROUND: We recently updated and merged the adapted clinical practice guidelines (CPGs) for the diagnosis and treatment of children with epilepsy of a tertiary-level hospital. Medical knowledge is always evolving. As a result, it is critical to revisit the clinical standards on a frequent basis to ensure that the best services are offered to the target receivers. The purpose of this article was to update and merge the CPGs at Alexandria University Children Hospital (AUCH) for the diagnosis (2014) and treatment (2016) of children with epilepsy to unify and standardize the practice for better care and outcome. METHODS: This review and update CPG project was initiated by assembling a Guideline Review Group (GRG). The GRG conducted focus group discussions and decided to search any published updates of the recommendations of the previously identified high-quality and evidence-based CPG developed by the SIGN (Scottish Intercollegiate Guidelines Network) and to merge the two previous local CPGs under one comprehensive CPG for full management of epilepsy in children. The high quality of the selected source CPG from SIGN was based on quality assessment of CPGs undertaken previously using the Appraisal of Guidelines for Research and Evaluation II Instrument. The GRG followed the Checklist for the Reporting of Updated Guidelines (CheckUp), which is the CPG tool recommended by the Enhancing the Quality and Transparency of health Research Network for reporting of updated CPGs in addition to the RIGHT-Ad@pt Checklist for Adapted CPGs. The finalized updated CPG draft was sent to the external reviewer group topic experts. RESULTS: The group updated 10 main categories of recommendations from one source CPG (SIGN). The recommendations included (1) epilepsy diagnosis; (2) recognition, identification, and referral; (3) pharmacological treatment of epilepsy and epilepsy syndromes; (4) nonpharmacological treatment of epilepsy and epilepsy syndromes; (5) managing pharmacoresistant epilepsy; (6) management of epilepsy in special groups; (7) medications; (8) children and caregiver education and support; (9) comorbidities and mortality; and (10) transitional care from pediatric to adult care services. CONCLUSIONS: The finalized CPG provides evidence-based guidance to health care providers in AUCH for the diagnosis and management of epilepsy in children. The study also established the significance of a collaborative clinical and methodological expert group for the update of CPGs, as well as the usability of the "CheckUp" and "RIGHT-Ad@pt" CPG Tools.

Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy.

Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. To date, biallelic mutations in 31 ARS genes are known to cause recessive, early-onset severe multi-organ diseases. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. Here, we report seven patients from five unrelated families with five different biallelic missense variants in VARS. Subjects present with a range of global developmental delay, epileptic encephalopathy and primary or progressive microcephaly. Longitudinal assessment demonstrates progressive cortical atrophy and white matter volume loss. Variants map to the VARS tRNA binding domain and adjacent to the anticodon domain, and disrupt highly conserved residues. Patient primary cells show intact VARS protein but reduced enzymatic activity, suggesting partial loss of function. The implication of VARS in pediatric neurodegeneration broadens the spectrum of human diseases due to mutations in tRNA synthetase genes.