PURA-Related Developmental and Epileptic Encephalopathy Phenotypic and Genotypic Spectrum

Background and Objectives Purine-rich element-binding protein A (PURA) gene encodes Pur-α, a conserved protein essential for normal postnatal brain development. Recently, a PURA syndrome characterized by intellectual disability, hypotonia, epilepsy, and dysmorphic features was suggested. The aim of this study was to define and expand the phenotypic spectrum of PURA syndrome by collecting data, including EEG, from a large cohort of affected patients. Methods Data on unpublished and published cases were collected through the PURA Syndrome Foundation and the literature. Data on clinical, genetic, neuroimaging, and neurophysiologic features were obtained. Results A cohort of 142 patients was included. Characteristics of the PURA syndrome included neonatal hypotonia, feeding difficulties, and respiratory distress. Sixty percent of the patients developed epilepsy with myoclonic, generalized tonic-clonic, focal seizures, and/or epileptic spasms. EEG showed generalized, multifocal, or focal epileptic abnormalities. Lennox-Gastaut was the most common epilepsy syndrome. Drug refractoriness was common: 33.3% achieved seizure freedom. We found 97 pathogenic variants in PURA without any clear genotype-phenotype associations. Discussion The PURA syndrome presents with a developmental and epileptic encephalopathy with characteristics recognizable from neonatal age, which should prompt genetic screening. Sixty percent have drug-resistant epilepsy with focal or generalized seizures. We collected more than 90 pathogenic variants without observing overt genotype-phenotype associations

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

Contribution aux bilans d’émissions de GES de la mobilité de troupeaux ovin sur parcours méditerranéen

International audienceAdaptation of farming activities and contribution to mitigation are at stake. In sheep livestock farming in the Mediterranean, increase in flock mobility and use of rangelands are adaptations of the last decades. We simulate three systems significant of these dynamics (sedentary S, single transhumance ST, double transhumance DT) while combining estimates concerning methane emissions, carbon sequestration on rangelands and whole farm model simulations. Mobility and rangeland food contribution, limiting inputs, contribute in defining efficient systems. GEG emissions are respectively estimated at 33.86; 39.45; 33.75 kg CO2 eq/ kg CW Coupling estimates of direct emissions and simulation of relationship between grazing and carbon cycle in rangelands allows an estimation of mitigation potential of the activity. On methodology, these results underline the interest in considering both emission and sequestrations and the necessity in coupling the analysis of farming systems functioning and ecological systems of grazed areas.L’adaptation des activités d’élevage et l’atténuation du changement climatique sont des enjeux. En élevage ovin méditerranéen, l’accroissement de la mobilité des troupeaux et de l’usage des parcours sont des adaptations des dernières décennies. Nous simulons trois systèmes archétypiques de ces dynamiques (sédentaire [S], simple transhumant [ST], double transhumant [DT]) en combinant estimations des émissions de méthane entérique, séquestration du carbone des parcours et fonctionnement de l’élevage. La mobilité et la contribution de ressources pâturées sur milieux naturels, en limitant les intrants, permet de développer des systèmes efficients. Les émissions de GES sont estimées respectivement à 33.86 ; 39.45 ; 33.75 eq. kg CO2/kg carcasse pour les systèmes Sed, ST, DT. Le couplage entre des simulations d’émissions directes et de l’incidence du pâturage sur le cycle du carbone permet d’évaluer le potentiel d’atténuation de l’activité. Sur un plan méthodologique, ces premiers résultats soulignent l’intérêt de considérer conjointement émission et séquestration, la nécessité de coupler plus étroitement l’analyse des fonctionnements des systèmes d’élevage et des systèmes écologiques des milieux pâturés

La mobilité des systèmes d’élevage ovins utilisateurs d’une grande variété de ressources pâturées en Provence : impacts sur le bilan énergétique et les émissions de méthane

La mobilité des systèmes d’élevage ovins utilisateurs d’une grande variété de ressources pâturées en Provence : impacts sur le bilan énergétique et les émissions de méthane. Réseau prairies – Symposium 201

Scoring People With Spinal Muscular Atrophy on the Motor Function Measure Using the Microsoft Kinect

International audiencePurpose: Assess the ability of the Kinect to capture movement and posture of people with spinal muscular atrophy (SMA) during completion of 14 items of the Motor Function Measure, a validated functional rating scale for people with neuromuscular diseases. Methods: Multicenter feasibility study in which Motor Function Measure items were scored as usual by the participant's therapist during the completion (Score-T) while another therapist scored items based only on the visualization of digital data collected using the Kinect (Score-D). Agreement and disagreement were investigated. Results: Twenty people with SMA type 2 or 3 were participants; 142 items were recorded and analyzed. There was 31.7% agreement between Score-T and ScoreD for participants with SMA type 2, and 76.2% for those with SMA type 3. Conclusions: The results prevent us from considering the use of Kinect capture to deduce an automated scoring, but this device may be of interest to highlight potential compensations

NR2F1 regulates regional progenitor dynamics in the mouse neocortex and cortical gyrification in BBSOAS patients

International audienceThe relationships between impaired cortical development and consequent malformations in neurodevelopmental disorders, as well as the genes implicated in these processes, are not fully elucidated to date. In this study, we report six novel cases of patients affected by BBSOAS (Boonstra-Bosch-Schaff optic atrophy syndrome), a newly emerging rare neurodevelopmental disorder, caused by loss-of-function mutations of the transcriptional regulator NR2F1. Young patients with NR2F1 haploinsufficiency display mild to moderate intellectual disability and show reproducible polymicrogyria-like brain malformations in the parietal and occipital cortex. Using a recently established BBSOAS mouse model, we found that Nr2f1 regionally controls long-term self-renewal of neural progenitor cells via modulation of cell cycle genes and key cortical development master genes, such as Pax6. In the human fetal cortex, distinct NR2F1 expression levels encompass gyri and sulci and correlate with local degrees of neurogenic activity. In addition, reduced NR2F1 levels in cerebral organoids affect neurogenesis and PAX6 expression. We propose NR2F1 as an area-specific regulator of mouse and human brain morphology and a novel causative gene of abnormal gyrification

Multiple molecular diagnoses in the field of intellectual disability and congenital anomalies: 3.5% of all positive cases

International audiencePurpose Wide access to clinical exome/genome sequencing (ES/GS) enables the identification of multiple molecular diagnoses (MMDs), being a long-standing but underestimated concept, defined by two or more causal loci implicated in the phenotype of an individual with a rare disease. Only few series report MMDs rates (1.8% to 7.1%). This study highlights the increasing role of MMDs in a large cohort of individuals addressed for congenital anomalies/intellectual disability (CA/ID). Methods From 2014 to 2021, our diagnostic laboratory rendered 880/2658 positive ES diagnoses for CA/ID aetiology. Exhaustive search on MMDs from ES data was performed prospectively (January 2019 to December 2021) and retrospectively (March 2014 to December 2018). Results MMDs were identified in 31/880 individuals (3.5%), responsible for distinct (9/31) or overlapping (22/31) phenotypes, and potential MMDs in 39/880 additional individuals (4.4%). Conclusion MMDs are frequent in CA/ID and remain a strong challenge. Reanalysis of positive ES data appears essential when phenotypes are partially explained by the initial diagnosis or atypically enriched overtime. Up-to-date clinical data, clinical expertise from the referring physician, strong interactions between clinicians and biologists, and increasing gene discoveries and improved ES bioinformatics tools appear all the more fundamental to enhance chances of identifying MMDs. It is essential to provide appropriate patient care and genetic counselling

Clinical and neuroimaging findings in 33 patients with MCAP syndrome: A survey to evaluate relevant endpoints for future clinical trials

Megalencephaly-CApillary malformation-Polymicrogyria (MCAP) syndrome results from somatic mosaic gain-of-function variants in PIK3CA. Main features are macrocephaly, somatic overgrowth, cutaneous vascular malformations, connective tissue dysplasia, neurodevelopmental delay, and brain anomalies. The objectives of this study were to describe the clinical and radiological features of MCAP, to suggest relevant clinical endpoints applicable in future trials of targeted drug therapy. Based on a French collaboration, we collected clinical features of 33 patients (21 females, 12 males, median age of 9.9 years) with MCAP carrying mosaic PIK3CA pathogenic variants. MRI images were reviewed for 21 patients. The main clinical features reported were macrocephaly at birth (20/31), postnatal macrocephaly (31/32), body/facial asymmetry (21/33), cutaneous capillary malformations (naevus flammeus 28/33, cutis marmorata 17/33). Intellectual disability was present in 15 patients. Among the MRI images reviewed, the neuroimaging findings were megalencephaly (20/21), thickening of corpus callosum (16/21), Chiari malformation (12/21), ventriculomegaly/hydrocephaly (10/21), cerebral asymmetry (6/21) and polymicrogyria (2/21). This study confirms the main known clinical features that defines MCAP syndrome. Taking into account the phenotypic heterogeneity in MCAP patients, in the context of emerging clinical trials, we suggest that patients should be evaluated based on the main neurocognitive expression on each patient