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.

Transfusion of blood components in pediatric age groups: an evidence-based clinical practice guideline adapted for the use in Egypt using 'Adapted ADAPTE'.

Pediatric transfusion is a complex area of medicine covering a wide age range, from neonates to young adults. Compared to adult practice, there is a relative lack of high-quality research to inform evidence-based guidelines. We aimed to adapt the pre-existing high-quality practice guidelines for the transfusion of blood components in different pediatric age groups to be available for national use by general practitioners, pediatricians, and other health care professionals. The guideline panel included 17 key leaders from different Egyptian institutions. The panel used the Adapted ADAPTE methodology. The panel prioritized the health questions and recommendations according to their importance for clinicians and patients. The procedure included searching for existing guidelines, quality appraisal, and adaptation of the recommendations to the target context of use. The guideline covered all important aspects of the indications, dosing, and administration of packed red cells, platelets, and fresh frozen plasma. It also included transfusion in special situations, e.g., chronic hemolytic anemia and aplastic anemia, management of massive blood loss, malignancies, surgery, recommendations for safe transfusion practices, and recommendations for modifications of cellular blood components. The final version of the adapted clinical practice guideline (CPG) has been made after a thorough review by an external review panel and was guided by their official recommendations and modifications. A set of implementation tools included algorithms, tables, and flow charts to aid decision-making in practice. This adapted guideline serves as a tool for safe transfusion practices in different pediatric age groups.

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.

Effectiveness of virtual reality glasses versus white noise on dental anxiety in children with attention-deficit hyperactivity disorder: A randomised controlled clinical trial.

BACKGROUND: Management of children with attention-deficit hyperactivity disorder (ADHD) can be challenging due to their disruptive behaviour. Basic behaviour management techniques (BMTs) may not be sufficient, and adjunctive strategies such as virtual reality (VR) glasses or white noise can be employed. AIM: To assess and compare the effectiveness of VR, white noise and basic BMTs on dental anxiety and behaviour of children with ADHD. DESIGN: Forty-eight children with ADHD were recruited for this parallel, three-armed randomised controlled clinical trial, which involved three visits at one-week intervals, including examination, preventive measures and restorations. Children were randomly divided into three groups: VR, white noise and basic BMTs. Outcome measures were Faces Image Scale (FIS), Heart Rate (HR) and Venham's Behaviour Rating Scale (VBRS). RESULTS: No significant difference was found between the groups in FIS scores. White noise group had a significantly lower mean HR than control group in all visits. Scores of VBRS in VR and white noise groups were significantly lower than those in the control group during the restorative visit. CONCLUSIONS: VR and white noise could be beneficial in managing dental anxiety and improving behaviour in children with ADHD and could be used as adjunctive strategies to basic BMTs.

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.

Bi-allelic GAD1 variants cause a neonatal onset syndromic developmental and epileptic encephalopathy.

Developmental and epileptic encephalopathies are a heterogeneous group of early-onset epilepsy syndromes dramatically impairing neurodevelopment. Modern genomic technologies have revealed a number of monogenic origins and opened the door to therapeutic hopes. Here we describe a new syndromic developmental and epileptic encephalopathy caused by bi-allelic loss-of-function variants in GAD1, as presented by 11 patients from six independent consanguineous families. Seizure onset occurred in the first 2 months of life in all patients. All 10 patients, from whom early disease history was available, presented with seizure onset in the first month of life, mainly consisting of epileptic spasms or myoclonic seizures. Early EEG showed suppression-burst or pattern of burst attenuation or hypsarrhythmia if only recorded in the post-neonatal period. Eight patients had joint contractures and/or pes equinovarus. Seven patients presented a cleft palate and two also had an omphalocele, reproducing the phenotype of the knockout Gad1-/- mouse model. Four patients died before 4 years of age. GAD1 encodes the glutamate decarboxylase enzyme GAD67, a critical actor of the γ-aminobutyric acid (GABA) metabolism as it catalyses the decarboxylation of glutamic acid to form GABA. Our findings evoke a novel syndrome related to GAD67 deficiency, characterized by the unique association of developmental and epileptic encephalopathies, cleft palate, joint contractures and/or omphalocele.

Quality of care provided to children with cerebral palsy, Alexandria, Egypt.

BACKGROUND: Assessing the quality of care has become increasingly important to health care providers, regulators and purchasers of care. AIMS: This study assessed the quality of care provided to children with cerebral palsy attending Alexandria University Children's Hospital, Egypt. METHODS: Paediatric neurology residents (n = 15) who provided care to children with cerebral palsy at the hospital completed a structured checklist assessing their compliance with generic care standards. The medical records of 84 children with cerebral palsy who received care at the hospital were reviewed using the same checklist. Another checklist was completed by the head of the paediatric neurology unit, medical director of the hospital, head of physical medicine and head nurse to assess adherence to process and service improvement standards. Face-to-face interviews were conducted with the caregivers/parents of the children using a client satisfaction questionnaire. RESULTS: Based on what was reported by health care providers, most did not adhere to the recommended practices in the care of children with cerebral palsy. Review of the medical records also showed a lack of compliance with standards. The mean total satisfaction percentage score of parents/caregivers was 55.43% (SD 18.16). Satisfaction was particularly low for waiting time, waiting area and availability of required facilities for their child's care. CONCLUSIONS: There is a wide gap between the actual care provided to children with cerebral palsy and the recommended standards. Moreover, the documentation system in the hospital is poor. A quality improvement plan is needed for the provision of care to children with cerebral palsy.

Bisphenol A exposure assessment from olive oil consumption.

The use of bisphenol A (BPA) in packaging has grown over the past 50 years despite concerns of its migration into packaged food and beverages, resulting in human exposure. Many studies have reported tumorigenic effects and endocrine alterations associated with BPA in animal models. This study aims at assessing human exposure to BPA from olive oil. A total of 27 olive oil samples were collected from mills and local villagers in the Hasbaya District, a major olive oil harvesting region in Lebanon. Information on storage conditions was also collected. BPA was extracted and quantified by HPLC. Results showed significantly higher BPA levels in olive oil samples stored in plastic vs. non-plastic packaging (mean = 333 vs. 150 µg/kg, p value = 0.006), samples with a plastic storage duration of >1 year compared to those with a storage duration of <1 year (mean = 452 vs. 288 µg/kg, p value = 0.008), and oil samples sourced from locals compared to oil mills (mean = 376 vs. 228 µg/kg, p value = 0.022). Statistically significant higher BPA levels remained for samples stored in plastic vs. non-plastic packaging in the bootstrap multivariable linear regression (B = 121.56, 95% CI 53.44-194.39, p value = 0.009). This is the first report on BPA levels in Mediterranean olive oil. The estimated exposure was 1.38% of the EFSA tolerable daily intake, hence there are no concerns about potential health risks from olive oil consumption.

Mutations in LAMB1 cause cobblestone brain malformation without muscular or ocular abnormalities.

Cobblestone brain malformation (COB) is a neuronal migration disorder characterized by protrusions of neurons beyond the first cortical layer at the pial surface of the brain. It is usually seen in association with dystroglycanopathy types of congenital muscular dystrophies (CMDs) and ocular abnormalities termed muscle-eye-brain disease. Here we report homozygous deleterious mutations in LAMB1, encoding laminin subunit beta-1, in two families with autosomal-recessive COB. Affected individuals displayed a constellation of brain malformations including cortical gyral and white-matter signal abnormalities, severe cerebellar dysplasia, brainstem hypoplasia, and occipital encephalocele, but they had less apparent ocular or muscular abnormalities than are typically observed in COB. LAMB1 is localized to the pial basement membrane, suggesting that defective connection between radial glial cells and the pial surface mediated by LAMB1 leads to this malformation.

Megalencephalic leukoencephalopathy with cysts in twelve Egyptian patients: novel mutations in MLC1 and HEPACAM and a founder effect.

Two genes causing megalencephalic leukoencephalopathy with subcortical cysts (MLC) have been discovered so far. Here, we identified MLC1 and HEPACAM mutations in ten and two patients, respectively. The molecular results included an unreported inframe duplication mutation (c.929_930dupCTGCTG; p.L309dup) of MLC1 and a novel missense mutation c.293G>A (p.R98H) of HEPACAM. Further, the previously reported missense (c.278C>T; p.S93L) and the deletion/insertion (c.908_918delinsGCA; p.V303Gfs*96) were found in one and 8 patients (75 %), respectively. The 8 patients carrying the p.V303Gfs*96 shared a similar haplotype suggesting a founder effect. All mutations were in the homozygous state proving the autosomal recessive mode of inheritance. The core phenotype of macrocephaly, subcortical cysts and white matter appeared homogeneous although the patients differed in the onset, clinical course, disease severity and brain imaging findings. Our study expands the spectrum of mutations in MLC1 and HEPACAM and supports the genetic and clinical heterogeneity. Further, It confirms c.908_918delinsGCA (p.V303Gfs*96) as a founder mutation among Egyptian patients. This finding will contribute to provide targeted testing for this mutation in MLC patients in our population.

Oral health status and behaviours of children with Autism Spectrum Disorder: a case-control study.

BACKGROUND: Autism Spectrum Disorder (ASD) is a lifelong neuro-developmental disorder characterized by abnormalities in social interactions and communication and by stereotyped, repetitive activities. PURPOSE: Assess the oral health status and behaviours of children with ASD. METHODS: The study included 100 children with ASD and 100 healthy children from Alexandria, Egypt. Data were collected using a questionnaire and clinical examination. Questionnaire assessed socio-demographics, medical history, dental history, oral hygiene, dietary habits, and presence of self-injurious behaviours. Clinical examination assessed behaviour during examination, gingival condition, plaque accumulation, caries, and other oral conditions. RESULTS: Children with ASD had significantly poorer oral hygiene and gingival condition than healthy children (P < 0.001 for both). No significant differences were found in caries prevalence or experience in primary or permanent dentition. More children with ASD behaved 'negatively' or 'definitely negatively' (37% and 11%) than did healthy controls (11% and 2%) (P < 0.0001). Self-injurious behaviour and bruxism were more practised by children with ASD (32% of children with ASD and 2% of healthy children, P < 0.001). More children with ASD had difficulty in accessing dental care (P = 0.002). CONCLUSIONS: The oral condition of children with ASD might increase the risk of developing dental diseases. Their behaviour and life factors may complicate provision of services and limit access to dental care. Therefore, individualized oral health education programmes should be implemented for those children.

Assessing the Relationship between Physical Health, Mental Health and Students' Success among Universities in Lebanon: A Cross-Sectional Study.

BACKGROUND: Achieving high academic success is known to be influenced by many factors including, but not limiting to, physical and mental health. The present study aimed to assess the relationship between physical health, mental health, and university students' success, and to explore the associations between these factors and their academic achievement. METHODS: A cross-sectional, self-administered online survey was used to collect data from college students in three different universities in Lebanon during the Fall 2023 semester. Mental health was evaluated using validated screening tools for depression, anxiety, and stress, specifically the Patient Health Questionnaire (PHQ-9), the General Anxiety Disorder (GAD-7), and Cohen's Perceived Stress Scale (PSS), respectively. Additionally, general questions regarding physical health and lifestyle factors were incorporated into the questionnaire. Academic achievement was measured using students' grade point average (GPA). RESULTS: A total of 261 students completed the self-administered online survey. The results revealed that approximately 42% and 36% of students were experiencing moderate to severe symptoms of depression and anxiety, respectively, and 75.1% of students exhibited symptoms of moderate stress. The majority of participants (99.2%) did not report any physical disability. Chi-square analysis revealed a significant association between mental health status (depression, anxiety, and stress) and GPA level (p = 0.03, p = 0.044, p = 0.015, respectively). Multiple logistic regression models identified eight correlates of GPA and highlighted the relationship between physical health and student success. For instance, students who considered themselves moderately active had lower odds of achieving a higher GPA than those who considered themselves active (OR = 0.41, p = 0.045). CONCLUSIONS: This is the first investigation into Lebanese university students' academic success in relation to lifestyle and mental health profiles. The findings indicate that implementing public health programs and interventions targeting mental health and lifestyle behaviors is essential for enhancing student success.

Unraveling the relative abundance of psychobiotic bacteria in children with Autism Spectrum Disorder.

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder characterized by social deficits. Accumulated evidence has shown a link between alterations in the composition of gut microbiota and both neurobehavioural and gastrointestinal symptoms in children with ASD which are related to the genera Lactobacillus and Bifidobacterium. These genera have been recently categorized as "psychobiotics". Moreover, this study aimed to compare the relative abundance of psychobiotics (L. plantarum, L. reuteri, and B. longum) to the total gut microbiome in typically developing (TD) children and those with ASD in order to correlate the distribution of psychobiotic with the severity and sensory impairments in autism. The ASD children were assessed using the Childhood Autism Rating Scale (CARS), while sensory impairments were evaluated using the Short Sensory Profile (SSP). Furthermore, the gut microbiome was analyzed using the quantitative real-time PCR. The study revealed a statistically significant increase in the relative abundance of L. reuteri and L. plantarum in the TD group in comparison to ASD children. Regarding the SSP total score of ASD children, a statistically significant negative correlation was found between both Lactobacillus and L. plantarum with the under-responsive subscale. For the Autism Treatment Evaluation Checklist (ATEC) score, B. longum and Lactobacillus showed a significant positive correlation with Health/Physical/Behaviour.

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.

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.

Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome-1 in two new patients with the same homozygous TMCO1 variant and review of the literature.

Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome-1 (CFSMR1; OMIM#213980) is a rare autosomal recessive disorder characterized by the clinical triad of developmental delay and/or intellectual disability, a typical facial gestalt with brachycephaly, highly-arched bushy eyebrows, synophrys, hypertelorism, wide nasal bridge, and short nose, as well as multiple vertebrae and rib malformations, such as bifid and fused ribs and abnormal vertebral segmentation and fusion. Biallelic loss-of-function variants in TMCO1 cause CFSMR1. We report on two unrelated Egyptian patients with a phenotype suggestive of CFSMR. Single whole-exome sequencing in patient 1 and Sanger sequencing of TMCO1 in patient 2 revealed the same homozygous TMCO1 nonsense variant c.187C > T/p.(Arg63*) in both affected individuals; patients' healthy parents were heterozygous carriers of the variant. Congenital hearing loss in patients 1 and 2 is an occasional finding in individuals affected by CFSMR. Camptodactyly and syndactyly, which were noted in patient 2, have not or rarely been reported in CFSMR. Review of the literature revealed a total of 30 individuals with the clinically recognizable and unique phenotype of CFSMR1, including the patients reported here, who all carried biallelic TMCO1 variants. Six different TMCO1 variants have been reported in the 30 patients from 14 families, comprising three nonsense, two 2-bp deletions, and a splice donor site variant. All disease-associated TMCO1 variants likely represent null alleles resulting in absence of the encoded protein. TMCO1 has been proposed to act as a Ca2+ channel, while other data revealed TMCO1 as a mitochondrial protein and a component of the translocon at the endoplasmic reticulum, a cellular machinery important for the biogenesis of multi-pass membrane proteins. RAB5IF/C20orf24 has recently been identified as causative gene for craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome-2 (CFSMR2; OMIM#616994). Heterodimerization of RAB5IF/C20orf24 and TMCO1 and their interdependence may suggest a pathophysiological role of ER-mitochondria interaction underlying CFSMR.

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.

Clinical Outcome After Replacement of Distal Femur/Proximal Tibia in a Heterogeneous Patient Cohort: Function Following Tumour, Trauma, and Loosening.

BACKGROUND: Distal femur and proximal tibia replacements as limb-salvage procedures with good outcome parameters for patients with tumours have been broadly described. However, the overall midterm outcome in a mixed, heterogeneous patient collective is still unclear. PATIENTS AND METHODS: We retrospectively analysed 59 consecutive patients (33 for primary and 26 for revision surgery) between 1998 and 2017. Indication for implantation was tumour (n=16), periprosthetic fracture (n=14), traumatic fracture (n=14), infection (n=10), aseptic loosening (n=3), and pathological fracture (n=2). The mean follow-up duration was 3 years. Clinical functions were evaluated by Toronto Extremity Salvage Score and Knee Society Score. Knee extension and flexion force were measured. RESULTS: The overall survival rate of arthroplasties was 59% (n=35). Major complications were observed in 36 (61%) patients. During the follow-up period, 14 (24%) patients died. We recorded periprosthetic joint infection in 21 (36%) patients, recurrence of tumour in two (3%), and aseptic implant failure in three (5%). The mean Toronto Extremity Salvage Score was 66±33, and the mean Knee Society Score was 49±30. The mean extension force on the operated side was significantly reduced at 60° and 180° compared to the healthy side (p=0.0151 and p=0.0411, respectively). CONCLUSION: Distal femur and proximal tibia replacements showed limited clinical function in a heterogeneous patient collective. Indication for implantation should be considered carefully.