Evolution of structural neuroimaging biomarkers in a series of adult patients with Niemann-Pick type C under treatment

International audienceBackground: Niemann-Pick type C (NPC) disease is a lysosomal storage disorder characterized by a wide clinical spectrum and non-specific conventional magnetic resonance imaging (MRI) signs. As substrate reduction therapy with miglustat is now used in almost all patients, its efficacy and the course of the disease are sometimes difficult to evaluate. Neuroimaging biomarkers could prove useful in this matter. We first performed a retrospective analysis of volumetric and diffusion tensor imaging (DTI) data on 13 adult NPC patients compared to 13 controls of similar age and sex. Eleven NPC patients were then studied using the same neuroimaging modalities over a mean of 5 years. The NPC composite score was used to evaluate disease severity.ResultsNPC patients showed atrophy in basal ganglia – pallidum (p = 0.029), caudate nucleus (p = 0.022), putamen (p = 0.002) and thalamus (p < 0.001) – cerebral peduncles (p = 0.003) and corpus callosum (p = 0.006), compared to controls. NPC patients also displayed decreased fractional anisotropy (FA) in several regions of interest – corona radiata (p = 0.015), internal capsule (p = 0.007), corpus callosum (p = 0.032) and cingulate gyrus (p = 0.002) – as well as a broad increase in radial diffusivity (p < 0.001), compared to controls. Over time, 3 patients worsened clinically, including 2 patients who interrupted treatment, while 8 patients remained stable. With miglustat, no significant volumetric change was observed but FA improved after 2 years in the corpus callosum and the corona radiata of NPC patients (n = 4; p = 0.029) – although that was no longer observed at further time points.ConclusionThis is the first study conducted on a series of adult NPC patients using two neuroimaging modalities and followed under treatment. It confirmed that NPC patients displayed cerebral atrophy in several regions of interest compared to controls. Furthermore, miglustat showed an early effect on diffusion metrics in treated patients. DTI can detect brain microstructure alterations caused by neurometabolic dysfunction. Its potential as a biomarker in NPC shall be further evaluated in upcoming therapeutic trials

Mutations in the J domain of DNAJB6 cause dominant distal myopathy

Eight patients from five families with undiagnosed dominant distal myopathy underwent clinical, neurophysiological and muscle biopsy examinations. Molecular genetic studies were performed using targeted sequencing of all known myopathy genes followed by segregation of the identified mutations in the affected families using Sanger sequencing. Two novel mutations in DNAJB6 J domain, c.149C>T (p.A50V) and c.161A>C (p.E54A), were identified as the cause of disease. The muscle involvement with p.A50V was distal calf-predominant, and the p.E54A was more proximo-distal. Histological findings were similar to those previously reported in DNAJB6 myopathy. In line with reported pathogenic mutations in the glycine/phenylalanine (G/F) domain of DNAJB6, both the novel mutations showed reduced anti-aggregation capacity by filter trap assay and TDP-43 disaggregation assays. Modeling of the protein showed close proximity of the mutated residues with the G/F domain. Myopathy-causing mutations in DNAJB6 are not only located in the G/F domain, but also in the J domain. The identified mutations in the J domain cause dominant distal and proximo-distal myopathy, confirming that mutations in DNAJB6 should be considered in distal myopathy cases.Peer reviewe

Phenotype Presentation and Molecular Diagnostic Yield in Non-5q Spinal Muscular Atrophy

BACKGROUND AND OBJECTIVES: Spinal muscular atrophy (SMA) is mainly caused by homozygous SMN1 gene deletions on 5q13. Non-5q SMA patients' series are lacking, and the diagnostic yield of next-generation sequencing (NGS) is largely unknown. The aim of this study was to describe the clinical and genetic landscape of non-5q SMA and evaluate the performance of neuropathy gene panels in these disorders. METHODS: Description of patients with non-5q SMA followed in the different neuromuscular reference centers in France as well as in London, United Kingdom. Patients without a genetic diagnosis had undergone at least a neuropathy or large neuromuscular gene panel. RESULTS: Seventy-one patients from 65 different families were included, mostly sporadic cases (60.6%). At presentation, 21 patients (29.6%) showed exclusive proximal weakness (P-SMA), 35 (49.3%) showed associated distal weakness (PD-SMA), and 15 (21.1%) a scapuloperoneal phenotype (SP-SMA). Thirty-two patients (45.1%) had a genetic diagnosis: BICD2 (n = 9), DYNC1H1 (n = 7), TRPV4 (n = 4), VCP, HSBP1, AR (n = 2), VRK1, DNAJB2, MORC2, ASAH1, HEXB, and unexpectedly, COL6A3 (n = 1). The genetic diagnostic yield was lowest in P-SMA (6/21, 28.6%) compared with PD-SMA (16/35, 45.7%) and SP-SMA (10/15, 66.7%). An earlier disease onset and a family history of the disease or consanguinity were independent predictors of a positive genetic diagnosis. Neuropathy gene panels were performed in 59 patients with a 32.2% diagnostic yield (19/59). In 13 additional patients, a genetic diagnosis was achieved through individual gene sequencing or an alternative neuromuscular NGS. DISCUSSION: Non-5q SMA is genetically heterogeneous, and neuropathy gene panels achieve a molecular diagnosis in one-third of the patients. The diagnostic yield can be increased by sequencing of other neuromuscular and neurometabolic genes. Nevertheless, there is an unmet need to cluster these patients to aid in the identification of new genes

7. Quand les citoyens québécois font la science

Dans différents champs de recherche, les sociétés d’amateurs participent à l’avancement des connaissances et à la compréhension du monde. Avec le concours des technologies de l’information et de la communication se sont formés de véritables réseaux citoyens qui alimentent la recherche scientifique. En 2005, le Québécois Gilbert Saint-Onge a fait une importante découverte en astrophysique. Cet amateur d’astronomie, concierge de son état, a commencé ses observations avec son télescope personnel..

Proximité et actionnabilité des dispositifs de formation continue dans les petites entreprises

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Contribution to the management of vocational training policies in organizations

Cette thèse s’inscrit dans une ambition de Validation des Acquis de l’Expérience. À ce titre sa première partie décrit un itinéraire professionnel à travers l’exercice de différentes responsabilités dans une carrière essentiellement dédiée à la formation professionnelle. Elle cherche à démontrer que le professionnalisme acquis peut s’assimiler à des compétences d’expertise. La deuxième partie explique comment un praticien de la formation a pu et voulu, pour l’exercice opérationnel de son propre métier, bénéficier des apports de la recherche et des chercheurs. Au point d’instituer une certaine porosité entre leurs activités respectives, facteur objectif de progrès réciproques. La troisième partie témoigne d’une recherche approfondie sur les conditions de pilotage des politiques de formation dans les institutions de travail. À partir du récit des pratiques issues de la Loi française de 1971, elle démontre le caractère unilatéral de la seule logique d’investissement en matière de formation, négligeant, de ce fait la réalité des pratiques effectives. Forte de ce constat, elle propose un nouveau postulat, postulat d’une double logique de pilotage de la formation dans les organisations : celle liée aux risques de dysfonctionnements dans la production du travail et celle d’investissements pour faire face aux risques d’inemployabilité liés aux évolutions des organisations et des technologies... Les modalités de mise en œuvre de la formation qui en résultent y sont présentées dans leur détail. Enfin, ce chapitre se termine sur les conditions actuelles et prospectives pour une mise en œuvre positive de ce pilotage.This thesis is part of an ambition to Validation des Acquis de l’Expérience (Validation of Acquired Experience). As such, its first part describes a career path through the exercise of different responsibilities in a career mainly dedicated to vocational training. It seeks to demonstrate that the professionalism acquired can be assimilated to expertise skills. The second part explains how a training practitioner was able and willing, for the operational exercise of his own profession, to benefit from the contributions of research and researchers. To the point of instituting a certain porosity between their respective activities, objective factor of reciprocal progress. The third part shows an in-depth research on the management conditions of training policies in work institutions. From the narrative of the practices resulting from the French Law of 1971, it demonstrates the unilateral character of the sole logic of investment in training, neglecting, therefore, the reality of the actual practices. On the strength of this observation, it proposes a new postulate: a postulate of a dual logic of training management in organizations, one related to the risks of dysfunctions in the production of work and one related to the investments to cope with the risks of unemployability due to the evolution of organizations and technologies ... The resulting methods of implementing the training are presented in detail. Finally, this chapter ends with the current and prospective conditions for a positive implementation of this pilotage

Les caractéristiques du leader transformationnel : voyage au cœur d’une organisation bureaucratique

International audienc

La perception du management public par les DRH du secteur marchand: résultats d’une étude exploratoire

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Manager, est-ce instrumentaliser des hommes ?

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