Retards mentaux liés à l’X

Les retards mentaux liés au chromosome X (RMLX), qui touchent 1,8 garçons pour 1 000 naissances masculines, sont classiquement divisés en formes syndromiques et formes non spécifiques, selon la présence ou non de signes particuliers associés au retard mental. L’extrême hétérogénéité phénotypique et allélique, parfois visible au sein d’une même famille, complique toutefois cette classification. L’évaluation rétrospective appronfondie des familles atteintes, une fois la mutation identifiée dans un gène, devrait aider à clarifier la situation et faciliter la prise en charge du diagnostic moléculaire de ces retards mentaux. L’analyse des protéines produites par les 60 gènes de RMLX actuellement identifiés montre une grande diversité des fonctions biologiques affectées dans le retard mental. Dans cette revue, nous présenterons les données récentes concernant trois gènes, FMR1, ARX et le gène de l’oligophrénine 1, qui non seulement illustrent la complexité des RMLX, mais soulignent aussi l’importance des voies de signalisation impliquées dans la régulation de l’expression génique, ainsi que celles relayées pas les GTPases Rho dans la maturation et la plasticité neuronale.X-linked mental retardation (XLMR) affects 1.8 ‰ male births and is usually categorized as “syndromic” (MRXS) or “non-specific” (MRX) forms according to the presence or absence of specific signs in addition to the MR. Up to 60 genes have been implicated in XLMR and certain mutations can alternatively lead to MRXS or MRX. Indeed the extreme phenotypic and allelic heterogeneity of XLMR makes the classification of most genes difficult. Therefore, following identification of new genes, accurate retrospective clinical evaluation of patients and their families is necessary to aid the molecular diagnosis and the classification of this heterogeneous group of disorders. Analyses of the protein products corresponding to XLMR genes show a great diversity of cellular pathways involved in MR. Common mechanisms are beginning to emerge : a first group of proteins belongs to the Rho and Rab GTPase signaling pathways involved in neuronal differentiation and synaptic plasticity and a second group is related to the regulation of gene expression. In this review, we illustrate the complexity of XLMR conditions and present recent data about the FMR1, ARX and Oligophrenin 1 genes

Pharmacological rescue of adult hippocampal neurogenesis in a mouse model of X-linked intellectual disability

Oligophrenin-1 (OPHN1) is a Rho GTPase activating protein whose mutations cause X-linked intellectual disability (XLID). How loss of function of Ophnl affects neuronal development is only partly understood. Here we have exploited adult hippocampal neurogenesis to dissect the steps of neuronal differentiation that are affected by Ophn1 deletion. We found that mice lacking Ophnl display a reduction in the number of newborn neurons in the dentate gyrus. A significant fraction of the Ophn1-deficient newly generated neurons failed to extend an axon towards CM, and showed an altered density of dendritic protrusions. Since Ophnl-deficient mice display overactivation of Rho-associated protein kinase (ROCK) and protein kinase A (PICA) signaling, we administered a clinically approved ROCK/PICA inhibitor (fasudil) to correct the neurogenesis defects. While administration of fasudil was not effective in rescuing axon formation, the same treatment completely restored spine density to control levels, and enhanced the long-term survival of adult-born neurons in mice lacking Ophn1. These results identify specific neurodevelopmental steps that are impacted by Ophn1 deletion, and indicate that they may be at least partially corrected by pharmacological treatment. (C) 2017 The Authors. Published by Elsevier Inc

Conversion of total shoulder arthroplasty to reverse shoulder arthroplasty made possible by custom humeral adapter

AbstractReverse shoulder arthroplasty (RSA) is increasingly being used to revise anatomical total shoulder arthroplasty cases. This procedure's high complication rate has been reduced by the availability of modular shoulder systems, which allows the humeral component to be preserved during the conversion. This case report describes the revision of an anatomical shoulder implant inserted in 1998. Polyethylene wear and the resulting metal-on-metal contact had caused metallosis. Since the existing humeral implant was not compatible with standard conversion products, the manufacturer provided a custom humeral adapter that allowed the humeral stem to be preserved. This approach greatly simplified the surgical procedure and resulted in good anatomical and clinical outcomes after 9 months of follow-up

Characterization of the Rho GTPase-Activating Protein RhoGAP68F

Rho small GTPases control multiple aspects of neuronal morphogenesis by regulating the assembly and organization of the actin cytoskeleton. Although they are negatively regulated by GTPase activating proteins (GAPs), the roles of RhoGAPs in the nervous system have not been fully investigated. Here we describe a characterization of Drosophila RhoGAP68F that is mainly expressed in the embryonic central nervous system. RNA in situ hybridization analysis showed that expression of RhoGAP68F is highly restricted to the embryonic brain and ventral nerve cord. Database search revealed that RhoGAP68F contains an N-terminal Sec14 domain and a C-terminal RhoGAP domain. Rho-GTP pull-down assay demonstrated that the RhoGAP domain of RhoGAP68F inactivates RhoA but not Rac1 or Cdc42 in HEK293 cells. In addition, expression of RhoGAP68F in NIH3T3 cells suppressed LPA-induced stress fiber formation, which is mediated by RhoA. Finally, neuronal overexpression of RhoGAP68F causes synaptic overgrowth at the larval neuromuscular junction (NMJ). Taken together, these results suggest that RhoGAP68F may play a role in synaptic growth regulation by inactivating RhoA

Robustness and Reproducibility of a Glenoid-Centered Scapular Coordinate System Derived From Low-Dose Stereoradiography Analysis

A robust and reproducible scapular coordinate system is necessary to study scapulo-thoracic kinematics. The coordinate system recommended by the ISB (International Society of Biomechanics) is difficult to apply in studies using medical imaging, which mostly use a glenoid-centered coordinate system. The aim of this study was to assess the robustness of a glenoid-centered coordinate system compared to the ISB coordinate system, and to study the reproducibility of this coordinate system measure during abduction. A Monte-Carlo analysis was performed to test the robustness of the two coordinate systems. This method enabled the variability of the orientation of the coordinate system to be assessed in laboratory setting. A reproducibility study of the glenoid-centered coordinate system in the thorax reference frame was performed during abduction in the scapular plane using a low-dose stereoradiography system. We showed that the glenoid-centered coordinate system was slightly more robust than the ISB-recommended coordinate system. Most reproducible rotation was upward/downward rotation (x axis) and most reproducible translation was along the Y axis (superior-inferior translation). In conclusion, the glenoid-centered coordinate system can be used with confidence for scapular kinematics analysis. The uncertainty of the measures derived from our technique is acceptable compared to that reported in the literature. Functional quantitative analysis of the scapular-thoracic joint is possible with this method.We would like to thank Guillaume Simer and Benjamin Aubert for their technical support. Funding: IRSST, ParisTech BiomecAM Chair, Société Générale and Covea

3D scapular orientation on healthy and pathologic subjects using stereoradiographs during arm elevation.

Background Alterations of the scapular kinematics in different pathologic conditions have been widely studied. However, results have shown considerable discrepancies concerning the direction and the amplitude of scapular movement. The lack of consistency in the literature probably has several explanations. The purpose of this study was to analyze scapular orientation with the arm at rest and with 90° lateral elevation in healthy and pathologic subjects by use of stereoradiographs. Materials and methods All participants (n = 65) underwent a clinical examination and magnetic resonance imaging of the shoulder to assess rotator cuff status. Participants were separated into 3 groups: healthy, rotator cuff tear (RCT), and RCT and subacromial impingement syndrome (RCT+ SIS). A 3-dimensional model of the scapula was fitted to each low-dose stereoradiograph acquired with the arm at rest and 90° arm elevation. Results Orientation of the scapula with the arm at rest was not significantly different between groups. During lateral elevation, scapular orientation was not significantly different between the healthy group and the RCT group. However, upward rotation was significantly reduced in the RCT + SIS group. Conclusion Alterations of scapular kinematics in symptomatic subjects are multifactorial. We observed a link between clinically assessed subacromial impingement and scapular orientation during lateral elevation of the arm.Funding: IRSST, ParisTech BiomecAM Chair, Société Générale, and Covea

Three-Dimensional Rotations of the Scapula During Arm Abduction: Evaluation of the Acromion Marker Cluster Method in Comparison With a Model-Based Approach Using Biplanar Radiograph Images

Noninvasive methods enabling measurement of shoulder bone positions are paramount in clinical and ergonomics applications. In this study, the acromion marker cluster (AMC) method is assessed in comparison with a model-based approach allowing scapula tracking from low-dose biplanar radiograph images. Six healthy male subjects participated in this study. Data acquisition was performed for 6 arm abduction positions (0°, 45°, 90°, 120°, 150°, 180°). Scapula rotations were calculated using the coordinate systems and angle sequence was defined by the ISB. The comparison analysis was based on root mean square error (RMSE) calculation and nonparametric statistical tests. RMSE remained under 8° for 0° to 90° arm abduction and under 13.5° for 0° to 180° abduction; no significant differences were found between the 2 methods. Compared with previous works, an improved accuracy of the AMC approach at high arm abduction positions was obtained. This could be explained by the different sources of data used as the "gold standard.

IL-38 Ameliorates Skin Inflammation and Limits IL-17 Production from γδ T Cells

Summary: Interleukin-38 (IL-38) is a cytokine of the IL-1 family with a role in chronic inflammation. However, its main cellular targets and receptors remain obscure. IL-38 is highly expressed in the skin and downregulated in psoriasis patients. We report an investigation in cellular targets of IL-38 during the progression of imiquimod-induced psoriasis. In this model, IL-38 knockout (IL-38 KO) mice show delayed disease resolution with exacerbated IL-17-mediated inflammation, which is reversed by the administration of mature IL-38 or γδ T cell-receptor-blocking antibodies. Mechanistically, X-linked IL-1 receptor accessory protein-like 1 (IL1RAPL1) is upregulated upon γδ T cell activation to feedforward-amplify IL-17 production and is required for IL-38 to suppress γδ T cell IL-17 production. Accordingly, psoriatic IL1RAPL1 KO mice show reduced inflammation and IL-17 production by γδ T cells. Our findings indicate a role for IL-38 in the regulation of γδ T cell activation through IL1RAPL1, with consequences for auto-inflammatory disease. : Han et al. report that genetic depletion of IL-38 in mice delays the resolution of imiquimod-induced psoriasis by increasing the production of the inflammatory cytokine IL-17A by skin-infiltrating T cells. Depleting these T cells or the receptor that is targeted by IL-38 reduces psoriatic skin inflammation. Keywords: IL-38, IL1RAPL1, IL-17, γδ T cells, psoriasis, inflammatio

Investigation of 3D glenohumeral displacements from 3D reconstruction using biplane X-ray images: Accuracy and reproducibility of the technique and preliminary analysis in rotator cuff tear patients

Rotator cuff (RC) tears may be associated with increased glenohumeral instability; however, this instability is difficult to quantify using currently available diagnostic tools. Recently, the three-dimensional (3D) reconstruction and registration method of the scapula and humeral head, based on sequences of low-dose biplane X-ray images, has been proposed for glenohumeral displacement assessment. This research aimed to evaluate the accuracy and reproducibility of this technique and to investigate its potential with a preliminary application comparing RC tear patients and asymptomatic volunteers. Accuracy was assessed using CT scan model registration on biplane X-ray images for five cadaveric shoulder specimens and showed differences ranging from 0.6 to 1.4 mm depending on the direction of interest. Intra- and interobserver reproducibility was assessed through two operators who repeated the reconstruction of five subjects three times, allowing defining 95% confidence interval ranging from ±1.8 to ±3.6 mm. Intraclass correlation coefficient varied between 0.84 and 0.98. Comparison between RC tear patients and asymptomatic volunteers showed differences of glenohumeral displacements, especially in the superoinferior direction when shoulder was abducted at 20 and 45 . This study thus assessed the accuracy of the low-dose 3D biplane X-ray reconstruction technique for glenohumeral displacement assessment and showed potential in biomechanical and clinical research.Fondation Paris-Tech Programme BIOMECAM Chaire ParisTech Institut de Recherche Robert-Sauvé en Santé et Sécurité du Travail du Québec Natural Science and Engineering Research Council of Canada Fonds de Recherche sur la Nature et les Technologies du Québec Fonds de Recherche en Santé du Québec, EOS Imaging, and French pôle de compétitivité MEDICEN (STEREOS + program)

RhoE Deficiency Produces Postnatal Lethality, Profound Motor Deficits and Neurodevelopmental Delay in Mice

Rnd proteins are a subfamily of Rho GTPases involved in the control of actin cytoskeleton dynamics and other cell functions such as motility, proliferation and survival. Unlike other members of the Rho family, Rnd proteins lack GTPase activity and therefore remain constitutively active. We have recently described that RhoE/Rnd3 is expressed in the Central Nervous System and that it has a role in promoting neurite formation. Despite their possible relevance during development, the role of Rnd proteins in vivo is not known. To get insight into the in vivo function of RhoE we have generated mice lacking RhoE expression by an exon trapping cassette. RhoE null mice (RhoE gt/gt) are smaller at birth, display growth retardation and early postnatal death since only half of RhoE gt/gt mice survive beyond postnatal day (PD) 15 and 100% are dead by PD 29. RhoE gt/gt mice show an abnormal body position with profound motor impairment and impaired performance in most neurobehavioral tests. Null mutant mice are hypoactive, show an immature locomotor pattern and display a significant delay in the appearance of the hindlimb mature responses. Moreover, they perform worse than the control littermates in the wire suspension, vertical climbing and clinging, righting reflex and negative geotaxis tests. Also, RhoE ablation results in a delay of neuromuscular maturation and in a reduction in the number of spinal motor neurons. Finally, RhoE gt/gt mice lack the common peroneal nerve and, consequently, show a complete atrophy of the target muscles. This is the first model to study the in vivo functions of a member of the Rnd subfamily of proteins, revealing the important role of Rnd3/RhoE in the normal development and suggesting the possible involvement of this protein in neurological disorders