Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients with Dopa-responsive dystonia

Dopa-responsive dystonia is a childhood-onset dystonic disorder, characterized by a dramatic response to low dose of l-Dopa. Dopa-responsive dystonia is mostly caused by autosomal dominant mutations in the GCH1 gene (GTP cyclohydrolase1) and more rarely by autosomal recessive mutations in the TH (tyrosine hydroxylase) or SPR (sepiapterin reductase) genes. In addition, mutations in the PARK2 gene (parkin) which causes autosomal recessive juvenile parkinsonism may present as Dopa-responsive dystonia. In order to evaluate the relative frequency of the mutations in these genes, but also in the genes involved in the biosynthesis and recycling of BH4, and to evaluate the associated clinical spectrum, we have studied a large series of index patients (n = 64) with Dopa-responsive dystonia, in whom dystonia improved by at least 50% after l-Dopa treatment. Fifty seven of these patients were classified as pure Dopa-responsive dystonia and seven as Dopa-responsive dystonia-plus syndromes. All patients were screened for point mutations and large rearrangements in the GCH1 gene, followed by sequencing of the TH and SPR genes, then PTS (pyruvoyl tetrahydropterin synthase), PCBD (pterin-4a-carbinolamine dehydratase), QDPR (dihydropteridin reductase) and PARK2 (parkin) genes. We identified 34 different heterozygous point mutations in 40 patients, and six different large deletions in seven patients in the GCH1 gene. Except for one patient with mental retardation and a large deletion of 2.3 Mb encompassing 10 genes, all patients had stereotyped clinical features, characterized by pure Dopa-responsive dystonia with onset in the lower limbs and an excellent response to low doses of l-Dopa. Dystonia started in the first decade of life in 40 patients (85%) and before the age of 1 year in one patient (2.2%). Three of the 17 negative GCH1 patients had mutations in the TH gene, two in the SPR gene and one in the PARK2 gene. No mutations in the three genes involved in the biosynthesis and recycling of BH4 were identified. The clinical presentations of patients with mutations in TH and SPR genes were strikingly more complex, characterized by mental retardation, oculogyric crises and parkinsonism and they were all classified as Dopa-responsive dystonia-plus syndromes. Patient with mutation in the PARK2 gene had Dopa-responsive dystonia with a good improvement with l-Dopa, similar to Dopa-responsive dystonia secondary to GCH1 mutations. Although the yield of mutations exceeds 80% in pure Dopa-responsive dystonia and Dopa-responsive dystonia-plus syndromes groups, the genes involved are clearly different: GCH1 in the former and TH and SPR in the late

Finger creases lend a hand in Kabuki syndrome.

International audienceKabuki syndrome (KS) is a rare syndrome associating malformations with intellectual deficiency and numerous visceral, orthopedic, endocrinological, immune and autoimmune complications. The early establishment of a diagnostic of KS leads to better care of the patients and therefore prevents complications such as perception deafness, severe complications of auto-immune diseases or obesity. However, the diagnosis of KS remains difficult because based on the appreciation of facial features combined with other highly variable features. We describe a novel sign, namely the attenuation and/or congenital absence of the IPD crease of the third and fourth fingers associated with limitation of flexion of the corresponding joints, which seems to be specific of KS and could help the clinician to diagnose KS

A targeted next-generation sequencing assay for the molecular diagnosis of genetic disorders with orodental involvement.

BACKGROUND: Orodental diseases include several clinically and genetically heterogeneous disorders that can present in isolation or as part of a genetic syndrome. Due to the vast number of genes implicated in these disorders, establishing a molecular diagnosis can be challenging. We aimed to develop a targeted next-generation sequencing (NGS) assay to diagnose mutations and potentially identify novel genes mutated in this group of disorders. METHODS: We designed an NGS gene panel that targets 585 known and candidate genes in orodental disease. We screened a cohort of 101 unrelated patients without a molecular diagnosis referred to the Reference Centre for Oro-Dental Manifestations of Rare Diseases, Strasbourg, France, for a variety of orodental disorders including isolated and syndromic amelogenesis imperfecta (AI), isolated and syndromic selective tooth agenesis (STHAG), isolated and syndromic dentinogenesis imperfecta, isolated dentin dysplasia, otodental dysplasia and primary failure of tooth eruption. RESULTS: We discovered 21 novel pathogenic variants and identified the causative mutation in 39 unrelated patients in known genes (overall diagnostic rate: 39%). Among the largest subcohorts of patients with isolated AI (50 unrelated patients) and isolated STHAG (21 unrelated patients), we had a definitive diagnosis in 14 (27%) and 15 cases (71%), respectively. Surprisingly, COL17A1 mutations accounted for the majority of autosomal-dominant AI cases. CONCLUSIONS: We have developed a novel targeted NGS assay for the efficient molecular diagnosis of a wide variety of orodental diseases. Furthermore, our panel will contribute to better understanding the contribution of these genes to orodental disease. TRIAL REGISTRATION NUMBERS: NCT01746121 and NCT02397824.journal articleresearch support, non-u.s. gov't2016 Feb2015 10 26importe

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

Place de l'hydroxyurée dans la prise en charge de la drépanocytose (au sujet de la revue de la littérature et d'une enquête chez les patients drépanocytaires du CHU de Rennes)

La drépanocytose est la maladie génétique la plus répandue en France et dans le monde. Cette hémoglobinopathie entraîne une vaso-occlusion atteignant de multiples organes et provoquant des crises douloureuses, nécessitant des hospitalisations à répétition. Lors des premiers essais cliniques, l'hydroxyurée était utilisée comme inducteur de l'hémoglobine fœtale afin de réduire la polymérisation de l'hémoglobine S. Des travaux récents nous ont depuis démontré que son mécanisme d'action est bien plus complexe et qu'elle agit sur l'ensemble de la physiopathologie de la drépanocytose. La revue de la littérature nous révèle que son efficacité est maintenant bien établie ainsi que son utilisation même chez les jeunes enfants. L'étude réalisée au CHU de Rennes montre que l'hydroxyurée a globalement amélioré la qualité de vie des patients drépanocytaires. Pourtant, elle reste sous-utilisée notamment en raison de craintes sur sa potentielle toxicité à long terme.Sickle cell disease is the most common genetic disease in France and worldwide. This hemoglobinopathy leads to a vaso-occlusion attaining multiple organs and causing painful crisis requiring hospitalization repeatedly. In the first clinical trial, hydroxyurea was used as an inducer of fetal hemoglobin to reduce the polymerization of hemoglobin S. Recent works have since demonstrated that its mechanism of action is much more complex and it acts for the most part of the physiopathology of sickle cell disease. The literature review reveals that its efficiency is now well established and it is safe even for young children. The study done at the University Hospital Center of Rennes shows that hydroxyurea has globally improved the life quality of patients with sickle cell disease. Yet it remains underutilized especially due to fears about its potential long term toxicity.RENNES1-BU Santé (352382103) / SudocLYON1-BU Santé (693882101) / SudocSudocFranceF

Le rôle de l’enseignant-médiateur dans un écosystème éducatif entrepreneurial

Notre recherche vise à comprendre le rôle des enseignants-médiateurs au sein des écosystèmes éducatifs entrepreneuriaux (EEE) dans l’école primaire et secondaire. Les résultats de nos neuf études de cas européens montrent que les enseignants-médiateurs occupent une place centrale qui leur permet d’exercer une médiation active influencée par leur perception de l’éducation entrepreneuriale, en relation avec les parties prenantes et un contexte institutionnel plus ou moins porteur. Ils contribuent à assurer une cohérence dans l’EEE, qui reste cependant fragile.Our research aims to understand the role of teacher-mediators within Entrepreneurial Educational Ecosystems (EEE) in primary and secondary schools. The results of our 9 European case studies show that teacher-mediators occupy a central place that allows them to actively mediate, influenced by their perception of entrepreneurship education, in relation to stakeholders and a more or less supportive institutional context. They help to ensure coherence in the EEE, which remains fragile.Nuestra investigación pretende entender el papel de los profesores-mediadores dentro de los Ecosistemas Educativos Empresariales (EEE) en las escuelas primarias y secundarias. Los resultados de nuestros 9 estudios de caso europeos muestran que los profesores-mediadores ocupan un lugar central que les permite ejercer una mediación activa influenciada por su percepción de la educación empresarial, en relación con las partes interesadas y un contexto institucional más o menos favorable. Contribuyen a garantizar la coherencia en la EEE, que sigue siendo frágil

Néphrotoxicité après chimiothérapie par ifosfamide chez l'enfant (à propos de 6 cas et de la revue de la littérature)

CAEN-BU Médecine pharmacie (141182102) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Decoding Entrepreneurship Education Ecosystems (EEE): A Cross-European Study in Primary, Secondary Schools and Vocational Training

This article studies entrepreneurship education as a living ecosystem, on the basis of the ecological metaphor. It contributes to a multidimensional model to analyse Entrepreneurship Education Ecosystems (EEE). This model contains six key dimensions, extracted from the literature review: a/the learning framework; b/networks, connections and relational proximity; c/entrepreneurial culture; d/pedagogical solutions; e/learning spaces and materials; and f/the motivation of its actors. Based on these dimensions, we analyse nine case studies (53 interviews) of best practice programmes across schools in Spain, Germany and Finland to understand how the single actors experience their ecosystem at individual and collective levels.Cet article étudie l’éducation à l’entrepreneuriat en tant qu’écosystème dynamique. Nous modélisons l’écosystème éducatif entrepreneurial à partir de six dimensions issues de la revue de littérature : a/le cadre d’apprentissage; b/ les réseaux, les liens et la proximité relationnelle; c/ la culture entrepreneuriale; d/ les solutions pédagogiques; e/ les espaces et le matériel d’apprentissage; et f/ la motivation des acteurs. Ces dimensions sont utilisées pour analyser neuf études de cas provenant des écoles d’Espagne, d’Allemagne et de Finlande pour comprendre comment les différents acteurs forment leur écosystème aux niveaux individuel et collectif.Este artículo examina la educación empresarial como un ecosistema dinámico. Modelamos el ecosistema educativo empresarial basado en seis dimensiones de la revisión de la literatura: a/marco de aprendizaje; b/ redes, vínculos y proximidad relacional; c/ cultura empresarial; d/ soluciones pedagógicas; e/ espacios y materiales de aprendizaje; y f/ motivación de las partes interesadas. Estas dimensiones se utilizan para analizar nueve estudios de caso de escuelas de España, Alemania y Finlandia para entender cómo los diferentes actores forman sus ecosistemas a nivel individual y colectivo

L’approche critique au cœur du positionnement de la revue Entreprendre & Innover

EDITORIAL Ce numéro sur les approches critiques a été longtemps désiré dans la revue. Après 13 ans d’existence, il voit enfin le jour. C’est l’occasion pour le comité de rédaction d’Entreprendre & Innover de repenser collectivement ce qui l’anime et de s’interroger sur la dimension critique du positionnement de la revue. Le comité de rédaction est composé de 22 chercheurs et 11 experts professionnels de l’entrepreneuriat et de l’innovation et se réunit 4 fois par an. Tous les membres du comité ont participé à la rédaction collective de cette tribune-manifeste, à travers une procédure d’écriture collaborative

Pediatric Acute B-Cell Lymphoblastic Leukemia Developing Following Recent SARS-CoV-2 Infection

Coronavirus disease-2019 in children has been linked to various clinical presentation, from paucisymptomatic cutaneous eruptions, to multisystemic inflammatory syndrome. We report the case of an 8-year-old boy who presented with persistent fever and pancytopenia, associated to a skin rash. An extensive etiological workup showed a positive serology for severe acute respiratory syndrome coronavirus 2 and Epstein-Barr virus. A few weeks later, type B acute lymphocytic leukemia was diagnosed. This case underlines the polymorphic appearance of coronavirus disease-2019 and the need for critical appraisal