PURA syndrome : clinical delineation and genotype-phenotype study in 32 individuals with review of published literature

Background De novo mutations in PURA have recently been described to cause PURA syndrome, a neurodevelopmental disorder characterised by severe intellectual disability (ID), epilepsy, feeding difficulties and neonatal hypotonia. Objectives T o delineate the clinical spectrum of PURA syndrome and study genotype-phenotype correlations. Methods Diagnostic or research-based exome or Sanger sequencing was performed in individuals with ID. We systematically collected clinical and mutation data on newly ascertained PURA syndrome individuals, evaluated data of previously reported individuals and performed a computational analysis of photographs. We classified mutations based on predicted effect using 3D in silico models of crystal structures of Drosophila-derived Pur-alpha homologues. Finally, we explored genotypephenotype correlations by analysis of both recurrent mutations as well as mutation classes. Results We report mutations in PURA (purine-rich element binding protein A) in 32 individuals, the largest cohort described so far. Evaluation of clinical data, including 22 previously published cases, revealed that all have moderate to severe ID and neonatal-onset symptoms, including hypotonia (96%), respiratory problems (57%), feeding difficulties (77%), exaggerated startle response (44%), hypersomnolence (66%) and hypothermia (35%). Epilepsy (54%) and gastrointestinal (69%), ophthalmological (51%) and endocrine problems (42%) were observed frequently. Computational analysis of facial photographs showed subtle facial dysmorphism. No strong genotype-phenotype correlation was identified by subgrouping mutations into functional classes. Conclusion We delineate the clinical spectrum of PURA syndrome with the identification of 32 additional individuals. The identification of one individual through targeted Sanger sequencing points towards the clinical recognisability of the syndrome. Genotype-phenotype analysis showed no significant correlation between mutation classes and disease severity.Peer reviewe

CERT1 mutations perturb human development by disrupting sphingolipid homeostasis

Neural differentiation, synaptic transmission, and action potential propagation depend on membrane sphingolipids, whose metabolism is tightly regulated. Mutations in the ceramide transporter CERT (CERT1), which is involved in sphingolipid biosynthesis, are associated with intellectual disability, but the pathogenic mechanism remains obscure. Here, we characterize 31 individuals with de novo missense variants in CERT1. Several variants fall into a previously uncharacterized dimeric helical domain that enables CERT homeostatic inactivation, without which sphingolipid production goes unchecked. The clinical severity reflects the degree to which CERT autoregulation is disrupted, and inhibiting CERT pharmacologically corrects morphological and motor abnormalities in a Drosophila model of the disease, which we call ceramide transporter (CerTra) syndrome. These findings uncover a central role for CERT autoregulation in the control of sphingolipid biosynthetic flux, provide unexpected insight into the structural organization of CERT, and suggest a possible therapeutic approach for patients with CerTra syndrome.This work was supported by the National Institute of Neurological Disorders and Stroke (NINDS), NIH (R01NS109858, to VAG); the Paul A. Marks Scholar Program at the Columbia University Vagelos College of Physicians and Surgeons (to VAG); a TIGER grant from the TAUB Institute at the Columbia Vagelos College of Physicians and Scientists (to VAG); the Swiss National Science Foundation (SNF 31003A-179371, to TH); the European Joint Program on Rare Diseases (EJP RD+SNF 32ER30-187505, to TH); the Swiss Cancer League (KFS-4999-02-2020, to GD); the EPFL institutional fund (to GD); the Kristian Gerhard Jebsen Foundation (to GD); the Swiss National Science Foundation (SNSF) (310030_184926, to GD); the Swiss Foundation for Research on Muscle Disease (FSRMM, to MAL); the Natural Science and Engineering Research Council of Canada (Discovery Grant 2020-04241, to JEB); the Italian Ministry of Health Young Investigator Grant (GR-2011-02347754, to EL); the Fondazione Istituto di Ricerca Pediatrica – Città della Speranza (18-04, to EL); the Wroclaw Medical University (SUB.E160.21.004, to RS); the National Science Centre, Poland (2017/27/B/NZ5/0222, to RS); Telethon Undiagnosed Diseases Program (TUDP) (GSP15001); the Temple Street Foundation/Children’s Health Foundation Ireland (RPAC 19-02, to IK); the Deutsche Forschungsgemeinschaft (DFG) (PO2366/2–1, to BP); the Instituto de Salud Carlos III, Spain (to ELM, EBS, and BMD); the National Natural Science Foundation of China (81871079 and 81730036, to HG and KX); and the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH (R01 DK115574, to SSC).The DEFIDIAG study is funded by grants from the French Ministry of Health in the framewok of the national French initiative for genomic medicine. The funders were not involved in the study design, data acquisition, analysis, or writing of the manuscript. Funding for the DECIPHER project was provided by Wellcome. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant number WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of Wellcome or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12, granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network.S

<i>GRIN2A</i>-related disorders:genotype and functional consequence predict phenotype

Alterations of the N-methyl-d-aspartate receptor (NMDAR) subunit GluN2A, encoded by GRIN2A, have been associated with a spectrum of neurodevelopmental disorders with prominent speech-related features, and epilepsy. We performed a comprehensive assessment of phenotypes with a standardized questionnaire in 92 previously unreported individuals with GRIN2A-related disorders. Applying the criteria of the American College of Medical Genetics and Genomics to all published variants yielded 156 additional cases with pathogenic or likely pathogenic variants in GRIN2A, resulting in a total of 248 individuals. The phenotypic spectrum ranged from normal or near-normal development with mild epilepsy and speech delay/apraxia to severe developmental and epileptic encephalopathy, often within the epilepsy-aphasia spectrum. We found that pathogenic missense variants in transmembrane and linker domains (misTMD+Linker) were associated with severe developmental phenotypes, whereas missense variants within amino terminal or ligand-binding domains (misATD+LBD) and null variants led to less severe developmental phenotypes, which we confirmed in a discovery (P = 10-6) as well as validation cohort (P = 0.0003). Other phenotypes such as MRI abnormalities and epilepsy types were also significantly different between the two groups. Notably, this was paralleled by electrophysiology data, where misTMD+Linker predominantly led to NMDAR gain-of-function, while misATD+LBD exclusively caused NMDAR loss-of-function. With respect to null variants, we show that Grin2a+/- cortical rat neurons also had reduced NMDAR function and there was no evidence of previously postulated compensatory overexpression of GluN2B. We demonstrate that null variants and misATD+LBD of GRIN2A do not only share the same clinical spectrum (i.e. milder phenotypes), but also result in similar electrophysiological consequences (loss-of-function) opposing those of misTMD+Linker (severe phenotypes; predominantly gain-of-function). This new pathomechanistic model may ultimately help in predicting phenotype severity as well as eligibility for potential precision medicine approaches in GRIN2A-related disorders

Social Competence in Newly Diagnosed Pediatric Brain Tumor Patients

Brain tumors (BTs) are a common pediatric malignancy. Improved treatment has resulted in higher survival rates. There is, however, increasing concern about adverse effects of the disease and its treatment, including effects on social competence (i.e. effective social functioning in everyday life). The aim of this study is to examine multiple levels of social competence (i.e. social skills and social adjustment) in newly diagnosed pediatric BT patients. Thirty newly diagnosed BT patients aged 5–12 years were assessed shortly after diagnosis with a neuropsychological test battery focusing on social competence, including tests for IQ, social skills (i.e. social-affective and executive functioning) and social adjustment (rated by parents and teachers). Their performance was compared to 95 healthy controls who completed the same assessment. Patients and healthy controls were largely comparable with regard to demographic and environmental factors and did not differ on measures of IQ, social skills and social adjustment. Furthermore, age was found to have a positive significant effect on social skills independent of group. Shortly after diagnosis, pediatric BT patients did not perform different from healthy controls on IQ and measures of social skills and social adjustment. This is an encouraging finding. However, because of potentially neurotoxic adjuvant therapy and the ongoing development of social skills, longitudinal follow-up studies are needed to investigate long-term outcome regarding social competence in BT survivors

Interprofessional simulation of acute care for nursing and medical students:interprofessional competencies and transfer to the workplace

BACKGROUND: Teamwork and communication are essential tools for doctors, nurses and other team members in the management of critically ill patients. Early interprofessional education during study, using acute care simulation, may improve teamwork and communication between interprofessional team members on the long run.METHODS: A comparative sequential quantitative-qualitative study was used to understand interprofessional learning outcomes in nursing and medical students after simulation of acute care. Students were assigned to a uni- or interprofessional training. Questionnaires were used to measure short and long term differences in interprofessional collaboration and communication between the intervention and control group for nursing and medical students respectively. Semi-structured focus groups were conducted to gain a better understanding of IPE in acute simulation.RESULTS: One hundred and ninety-one students participated in this study (131 medical, 60 nursing students). No differences were found between the intervention and control group in overall ICCAS scores for both medical and nursing students (p = 0.181 and p = 0.441). There were no differences in ICS scores between the intervention and control group. Focus groups revealed growing competence in interprofessional communication and collaboration for both medical and nursing students.CONCLUSIONS: Interprofessional simulation training did show measurable growth of interprofessional competencies, but so did uniprofessional training. Both medical and nursing students reported increased awareness of perspective and expertise of own and other profession. Furthermore, they reported growing competence in interprofessional communication and collaboration in transfer to their workplace.</p

Interprofessional simulation of acute care for nursing and medical students: interprofessional competencies and transfer to the workplace

BACKGROUND: Teamwork and communication are essential tools for doctors, nurses and other team members in the management of critically ill patients. Early interprofessional education during study, using acute care simulation, may improve teamwork and communication between interprofessional team members on the long run. METHODS: A comparative sequential quantitative-qualitative study was used to understand interprofessional learning outcomes in nursing and medical students after simulation of acute care. Students were assigned to a uni- or interprofessional training. Questionnaires were used to measure short and long term differences in interprofessional collaboration and communication between the intervention and control group for nursing and medical students respectively. Semi-structured focus groups were conducted to gain a better understanding of IPE in acute simulation. RESULTS: One hundred and ninety-one students participated in this study (131 medical, 60 nursing students). No differences were found between the intervention and control group in overall ICCAS scores for both medical and nursing students (p = 0.181 and p = 0.441). There were no differences in ICS scores between the intervention and control group. Focus groups revealed growing competence in interprofessional communication and collaboration for both medical and nursing students. CONCLUSIONS: Interprofessional simulation training did show measurable growth of interprofessional competencies, but so did uniprofessional training. Both medical and nursing students reported increased awareness of perspective and expertise of own and other profession. Furthermore, they reported growing competence in interprofessional communication and collaboration in transfer to their workplace

Acute toxicity profile of craniospinal irradiation with intensity-modulated radiation therapy in children with medulloblastoma : A prospective analysis

Background: To report on the acute toxicity in children with medulloblastoma undergoing intensity-modulated radiation therapy (IMRT) with daily intrafractionally modulated junctions. Methods: Newly diagnosed patients, aged 3-21, with standard-risk (SR) or high-risk (HR) medulloblastoma were eligible. A dose of 23.4 or 36.0Gy in daily fractions of 1.8Gy was prescribed to the craniospinal axis, followed by a boost to the primary tumor bed (54 or 55.8Gy) and metastases (39.6-55.8Gy), when indicated. Weekly, an intravenous bolus of vincristine was combined for patients with SR medulloblastoma and patients participating in the COG-ACNS-0332 study. Common toxicity criteria (CTC, version 2.0) focusing on skin, alopecia, voice changes, conjunctivitis, anorexia, dysphagia, gastro-intestinal symptoms, headache, fatigue and hematological changes were scored weekly during radiotherapy. Results: From 2010 to 2014, data from 15 consecutive patients (SR, n=7; HR, n=8) were collected. Within 72h from onset of treatment, vomiting (66%) and headache (46%) occurred. During week 3 of treatment, a peak incidence in constipation (33%) and abdominal pain/cramping (40%) was observed, but only in the subgroup of patients (n=9) receiving vincristine (constipation: 56 vs 0%, P=.04; pain/cramping: 67 vs 0%, P=.03). At week 6, 73% of the patients developed faint erythema of the cranial skin with dry desquamation (40%) or moist desquamation confined to the skin folds of the auricle (33%). No reaction of the skin overlying the spinal target volume was observed. Conclusions: Headache at onset and gastro-intestinal toxicity, especially in patients receiving weekly vincristine, were the major complaints of patients with medulloblastoma undergoing craniospinal irradiation with IMRT

Novel hypomyelinating leukoencephalopathy affecting early myelinating structures

To describe 4 children with a novel hypomyelinating leukoencephalopathy, defined by a distinct pattern of magnetic resonance imaging (MRI) abnormalities. In our ongoing study on leukoencephalopathies of unknown origin, MRIs of patients are rated in a standardized manner. Patients are grouped according to their MRI abnormalities. The clinical and laboratory data are retrospectively reviewed. The MRIs of approximately 3000 patients with a leukoencephalopathy of unknown origin were initially evaluated. Four unrelated patients (all male, aged 1.8-7.4 years) displayed similar MRI alterations. Patients displayed mild T2 hyperintensity of the medulla oblongata, caudal part of the pons, hilus of the dentate nucleus, peridentate white matter, subcortical cerebellar white matter, optic radiation, and frontoparietal periventricular white matter. The posterior limb of the internal capsule showed alternating T2 hyperintense-hypointense-hyperintense stripes in 3 patients. The T1-weighted images showed hyperintensity, isointensity, or mild hypointensity of T2 hyperintense structures. The thalamus had a neonatal appearance with a mildly hyperintense signal except for a darker lateral part. Clinically, patients presented with nystagmus between ages 6 and 20 months. Over time, cerebellar ataxia and mild spasticity developed. All achieved unsupported walking. Cognition and language were normal. Known causes of hypomyelination were excluded. The patients share a striking pattern of MRI abnormalities and have a similar clinical picture, suggesting that they have the same disorder. The hypomyelination in this disorder specifically occurs in structures that normally myelinate early. We hypothesize that the disease is caused by a defect in a gene involved in early myelinatio

Social competence in newly diagnosed pediatric brain tumor patients

Brain tumors (BTs) are a common pediatric malignancy. Improved treatment has resulted in higher survival rates. There is, however, increasing concern about adverse effects of the disease and its treatment, including effects on social competence (i.e. effective social functioning in everyday life). The aim of this study is to examine multiple levels of social competence (i.e. social skills and social adjustment) in newly diagnosed pediatric BT patients. Thirty newly diagnosed BT patients aged 5–12 years were assessed shortly after diagnosis with a neuropsychological test battery focusing on social competence, including tests for IQ, social skills (i.e. social-affective and executive functioning) and social adjustment (rated by parents and teachers). Their performance was compared to 95 healthy controls who completed the same assessment. Patients and healthy controls were largely comparable with regard to demographic and environmental factors and did not differ on measures of IQ, social skills and social adjustment. Furthermore, age was found to have a positive significant effect on social skills independent of group. Shortly after diagnosis, pediatric BT patients did not perform different from healthy controls on IQ and measures of social skills and social adjustment. This is an encouraging finding. However, because of potentially neurotoxic adjuvant therapy and the ongoing development of social skills, longitudinal follow-up studies are needed to investigate long-term outcome regarding social competence in BT survivors

A Dutch paediatric palliative care guideline:a systematic review and evidence-based recommendations for symptom treatment

Background: Children with life-threatening and life-limiting conditions can experience high levels of suffering due to multiple distressing symptoms that result in poor quality of life and increase risk of long-term distress in their family members. High quality symptom treatment is needed for all these children and their families, even more so at the end-of-life. In this paper, we provide evidence-based recommendations for symptom treatment in paediatric palliative patients to optimize care. Methods: A multidisciplinary panel of 56 experts in paediatric palliative care and nine (bereaved) parents was established to develop recommendations on symptom treatment in paediatric palliative care including anxiety and depression, delirium, dyspnoea, haematological symptoms, coughing, skin complaints, nausea and vomiting, neurological symptoms, pain, death rattle, fatigue, paediatric palliative sedation and forgoing hydration and nutrition. Recommendations were based on evidence from a systematic literature search, additional literature sources (such as guidelines), clinical expertise, and patient and family values. We used the GRADE methodology for appraisal of evidence. Parents were included in the guideline panel to ensure the representation of patient and family values. Results: We included a total of 18 studies that reported on the effects of specific (non) pharmacological interventions to treat symptoms in paediatric palliative care. A few of these interventions showed significant improvement in symptom relief. This evidence could only (partly) answer eight out of 27 clinical questions. We included 29 guidelines and two textbooks as additional literature to deal with lack of evidence. In total, we formulated 221 recommendations on symptom treatment in paediatric palliative care based on evidence, additional literature, clinical expertise, and patient and family values. Conclusion: Even though available evidence on symptom-related paediatric palliative care interventions has increased, there still is a paucity of evidence in paediatric palliative care. We urge for international multidisciplinary multi-institutional collaboration to perform high-quality research and contribute to the optimization of symptom relief in palliative care for all children worldwide.</p