35 research outputs found
A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement.
Mitochondrial DNA instability disorders are responsible for a large clinical spectrum, among which amyotrophic lateral sclerosis-like symptoms and frontotemporal dementia are extremely rare. We report a large family with a late-onset phenotype including motor neuron disease, cognitive decline resembling frontotemporal dementia, cerebellar ataxia and myopathy. In all patients, muscle biopsy showed ragged-red and cytochrome c oxidase-negative fibres with combined respiratory chain deficiency and abnormal assembly of complex V. The multiple mitochondrial DNA deletions found in skeletal muscle revealed a mitochondrial DNA instability disorder. Patient fibroblasts present with respiratory chain deficiency, mitochondrial ultrastructural alterations and fragmentation of the mitochondrial network. Interestingly, expression of matrix-targeted photoactivatable GFP showed that mitochondrial fusion was not inhibited in patient fibroblasts. Using whole-exome sequencing we identified a missense mutation (c.176C>T; p.Ser59Leu) in the CHCHD10 gene that encodes a coiled-coil helix coiled-coil helix protein, whose function is unknown. We show that CHCHD10 is a mitochondrial protein located in the intermembrane space and enriched at cristae junctions. Overexpression of a CHCHD10 mutant allele in HeLa cells led to fragmentation of the mitochondrial network and ultrastructural major abnormalities including loss, disorganization and dilatation of cristae. The observation of a frontotemporal dementia-amyotrophic lateral sclerosis phenotype in a mitochondrial disease led us to analyse CHCHD10 in a cohort of 21 families with pathologically proven frontotemporal dementia-amyotrophic lateral sclerosis. We identified the same missense p.Ser59Leu mutation in one of these families. This work opens a novel field to explore the pathogenesis of the frontotemporal dementia-amyotrophic lateral sclerosis clinical spectrum by showing that mitochondrial disease may be at the origin of some of these phenotypes
Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly.
International audienceThe genetic causes of malformations of cortical development (MCD) remain largely unknown. Here we report the discovery of multiple pathogenic missense mutations in TUBG1, DYNC1H1 and KIF2A, as well as a single germline mosaic mutation in KIF5C, in subjects with MCD. We found a frequent recurrence of mutations in DYNC1H1, implying that this gene is a major locus for unexplained MCD. We further show that the mutations in KIF5C, KIF2A and DYNC1H1 affect ATP hydrolysis, productive protein folding and microtubule binding, respectively. In addition, we show that suppression of mouse Tubg1 expression in vivo interferes with proper neuronal migration, whereas expression of altered Îł-tubulin proteins in Saccharomyces cerevisiae disrupts normal microtubule behavior. Our data reinforce the importance of centrosomal and microtubule-related proteins in cortical development and strongly suggest that microtubule-dependent mitotic and postmitotic processes are major contributors to the pathogenesis of MCD
Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease
BACKGROUND: Acute graft-versus-host disease (GVHD) remains a major limitation of allogeneic stem-cell transplantation; not all patients have a response to standard glucocorticoid treatment. In a phase 2 trial, ruxolitinib, a selective Janus kinase (JAK1 and JAK2) inhibitor, showed potential efficacy in patients with glucocorticoid-refractory acute GVHD. METHODS: We conducted a multicenter, randomized, open-label, phase 3 trial comparing the efficacy and safety of oral ruxolitinib (10 mg twice daily) with the investigator's choice of therapy from a list of nine commonly used options (control) in patients 12 years of age or older who had glucocorticoid-refractory acute GVHD after allogeneic stem-cell transplantation. The primary end point was overall response (complete response or partial response) at day 28. The key secondary end point was durable overall response at day 56. RESULTS: A total of 309 patients underwent randomization; 154 patients were assigned to the ruxolitinib group and 155 to the control group. Overall response at day 28 was higher in the ruxolitinib group than in the control group (62% [96 patients] vs. 39% [61]; odds ratio, 2.64; 95% confidence interval [CI], 1.65 to 4.22; P<0.001). Durable overall response at day 56 was higher in the ruxolitinib group than in the control group (40% [61 patients] vs. 22% [34]; odds ratio, 2.38; 95% CI, 1.43 to 3.94; P<0.001). The estimated cumulative incidence of loss of response at 6 months was 10% in the ruxolitinib group and 39% in the control group. The median failure-free survival was considerably longer with ruxolitinib than with control (5.0 months vs. 1.0 month; hazard ratio for relapse or progression of hematologic disease, non-relapse-related death, or addition of new systemic therapy for acute GVHD, 0.46; 95% CI, 0.35 to 0.60). The median overall survival was 11.1 months in the ruxolitinib group and 6.5 months in the control group (hazard ratio for death, 0.83; 95% CI, 0.60 to 1.15). The most common adverse events up to day 28 were thrombocytopenia (in 50 of 152 patients [33%] in the ruxolitinib group and 27 of 150 [18%] in the control group), anemia (in 46 [30%] and 42 [28%], respectively), and cytomegalovirus infection (in 39 [26%] and 31 [21%]). CONCLUSIONS: Ruxolitinib therapy led to significant improvements in efficacy outcomes, with a higher incidence of thrombocytopenia, the most frequent toxic effect, than that observed with control therapy
Ăvaluation neurodĂ©veloppementale Ă 2 ans chez les nouveau-nĂ©s prĂ©maturĂ©s (valeur prĂ©dictive de l'Ă©lectroencĂ©phalogramme et de l'Ă©chographie transfontanellaire)
ANGERS-BU MĂ©decine-Pharmacie (490072105) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF
LĂ©sions intracrĂąniennes aprĂšs un traumatisme crĂąnien accidentel chez l'enfant de moins de trois ans
Objectif : Etude descriptive clinique et radiologique des traumatismes crĂąniens graves de l enfant de moins de trois ans afin de dĂ©terminer s il existe des concordances entre les circonstances de survenue, les signes cliniques et les signes tomodensitomĂ©triques. MĂ©thodologie : Etude rĂ©trospective portant sur les donnĂ©es cliniques, cutanĂ©es, et radiologiques des enfants de moins de trois ans, hospitalisĂ©s pour un traumatisme crĂąnien accidentel et ayant bĂ©nĂ©ficiĂ© d un TDM cĂ©rĂ©bral entre janvier 2002 Ă fĂ©vrier 2010. Les conditions de survenue ont Ă©tĂ© classĂ©es en fonction du mĂ©canisme (haute ou basse Ă©nergie). Les signes d alerte et les signes de gravitĂ© ainsi que les signes cutanĂ©s ont Ă©tĂ© recherchĂ©s. Les scanners cĂ©rĂ©braux ont Ă©tĂ© revus. Les atteintes des parties molles, des structures osseuses et cĂ©rĂ©brales ont Ă©tĂ© notĂ©es. La lĂ©sion cĂ©rĂ©brale la plus sĂ©vĂšre a Ă©tĂ© retenue. Conclusion : Il existe un lien fort entre mĂ©canisme du traumatisme, lĂ©sions osseuses et lĂ©sions intracrĂąniennes. Les hĂ©matomes sous-duraux surviennent lors d accident Ă haute Ă©nergie . Les hĂ©matomes extraduraux sont possibles pour des chutes de petite hauteur. La recherche d un maximum de tĂ©moignages fiables de l accident ainsi que de lĂ©sions cutanĂ©es associĂ©es est nĂ©cessaire. En cas de doute sur la concordance des lĂ©sions intracrĂąniennes et du mĂ©canisme de l accident, une Ă©quipe pluridisciplinaire doit ĂȘtre systĂ©matiquement rĂ©unie afin de statuer sur le cas prĂ©sentĂ©.ANGERS-BU MĂ©decine-Pharmacie (490072105) / SudocSudocFranceF
EnquĂȘte de pratique sur les examens complĂ©mentaires neurologiques en nĂ©onatologie de niveau III en France en 2009
Cette Ă©tude a pour but de dĂ©crire l utilisation des examens complĂ©mentaires d Ă©valuation neurologique en rĂ©animation nĂ©onatale.MĂ©thodes : Il s agissait d une Ă©tude effectuĂ©e par l intermĂ©diaire d un questionnaire envoyĂ© Ă tous les services de nĂ©onatalogie de niveau III en France mĂ©tropolitaine et DOM-TOM soit 70 centres. Celui-ci portait sur la pratique des examens complĂ©mentaires (EEG conventionnel et simplifiĂ©, ETF, TDM et IRM).RĂ©sultats : Nous avons obtenu une rĂ©ponse de 26 centres dont la moitiĂ© de CHU. L ETF reste l examen le plus utilisĂ© et le plus accessible. Il Ă©tait utilisĂ© systĂ©matiquement dans la surveillance des prĂ©maturĂ©s et trĂšs frĂ©quemment pour les enfants Ă terme (84,6%). Pour les deux populations, il permettait une Ă©valuation prĂ©coce. Cependant, il existait une grande diversitĂ© en termes de frĂ©quence. L IRM Ă©tait prĂ©sent dans 88,5% pour les prĂ©maturĂ©s et 80,8% pour les enfants Ă terme. Le moment de sa rĂ©alisation Ă©tait extrĂȘmement variable. L EEG n Ă©tait effectuĂ© que dans 25% des centres, en pĂ©riode de garde, pour surveillance d un nouveau-nĂ© en souffrance neurologique. On le retrouvait dans 73,1% des centres, pour la surveillance systĂ©matique des prĂ©maturĂ©s. Les techniques simplifiĂ©es d EEG n ont pas encore investis les services de nĂ©onatologie (42,3%).Conclusion : Il existait une grande variabilitĂ© en termes de frĂ©quence d utilisation de chaque examen. L ETF reste l examen privilĂ©giĂ© notamment pour l Ă©valuation neurologique prĂ©coce. L IRM pose encore des problĂšmes d accessibilitĂ© et surtout du moment de rĂ©alisation pour obtenir le maximum d informations. L aEEG n a pas rĂ©solu le problĂšme d accessibilitĂ© de l EEG.ANGERS-BU MĂ©decine-Pharmacie (490072105) / SudocSudocFranceF
Le syndrome de Guillain Barré chez l'enfant (revue de la littérature à propos de cinq observations)
Le syndrome de Guillain BarrĂ© est une polyradiculonĂ©vrite aiguĂ« de pathogĂ©nie auto-immune complexe, atteignant la myĂ©line et/ou l'axone, dĂ©fini par une triade clinico-biologique (paralysie ascendante, arĂ©flexie et dissociation albuminocytologique dans le liquide cĂ©phalo-rachidien), d'Ă©volution triphasique plutĂŽt favorable chez l'enfant. Les formes cliniques sont nombreuses, plus ou moins Ă©vocatrices mais doivent toujours faire rĂ©aliser un Ă©lectromyogramme en cas de doute car les complications neurovĂ©gĂ©tatives sont imprĂ©visibles et potentiellement fatales. Elles doivent ĂȘtre attentivement recherchĂ©es imposant toujours une hospitalisation en rĂ©animation ou a proximitĂ© immĂ©diate. Des traitement spĂ©cifiques incomplĂštement Ă©valuĂ©s chez l'enfant sont utilisables en cas de perte de la marche ou de dĂ©faillance respiratoire.NANTES-BU MĂ©decine pharmacie (441092101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF
Hemispheric Asymmetry of Supplementary Motor Area Proper: A Functional Connectivity Study of the Motor Network
International audienc