Pathogenic <i>NR2F1</i> variants cause a developmental ocular phenotype recapitulated in a mutant mouse model.

Funder: National Institute of Health Research Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of OphthalmologyPathogenic NR2F1 variants cause a rare autosomal dominant neurodevelopmental disorder referred to as the Bosch-Boonstra-Schaaf Optic Atrophy Syndrome. Although visual loss is a prominent feature seen in affected individuals, the molecular and cellular mechanisms contributing to visual impairment are still poorly characterized. We conducted a deep phenotyping study on a cohort of 22 individuals carrying pathogenic NR2F1 variants to document the neurodevelopmental and ophthalmological manifestations, in particular the structural and functional changes within the retina and the optic nerve, which have not been detailed previously. The visual impairment became apparent in early childhood with small and/or tilted hypoplastic optic nerves observed in 10 cases. High-resolution optical coherence tomography imaging confirmed significant loss of retinal ganglion cells with thinning of the ganglion cell layer, consistent with electrophysiological evidence of retinal ganglion cells dysfunction. Interestingly, for those individuals with available longitudinal ophthalmological data, there was no significant deterioration in visual function during the period of follow-up. Diffusion tensor imaging tractography studies showed defective connections and disorganization of the extracortical visual pathways. To further investigate how pathogenic NR2F1 variants impact on retinal and optic nerve development, we took advantage of an Nr2f1 mutant mouse disease model. Abnormal retinogenesis in early stages of development was observed in Nr2f1 mutant mice with decreased retinal ganglion cell density and disruption of retinal ganglion cell axonal guidance from the neural retina into the optic stalk, accounting for the development of optic nerve hypoplasia. The mutant mice showed significantly reduced visual acuity based on electrophysiological parameters with marked conduction delay and decreased amplitude of the recordings in the superficial layers of the visual cortex. The clinical observations in our study cohort, supported by the mouse data, suggest an early neurodevelopmental origin for the retinal and optic nerve head defects caused by NR2F1 pathogenic variants, resulting in congenital vision loss that seems to be non-progressive. We propose NR2F1 as a major gene that orchestrates early retinal and optic nerve head development, playing a key role in the maturation of the visual system

Pathogenic NR2F1 variants cause a developmental ocular phenotype recapitulated in a mutant mouse model.

Pathogenic NR2F1 variants cause a rare autosomal dominant neurodevelopmental disorder referred to as the Bosch-Boonstra-Schaaf Optic Atrophy Syndrome. Although visual loss is a prominent feature seen in affected individuals, the molecular and cellular mechanisms contributing to visual impairment are still poorly characterized. We conducted a deep phenotyping study on a cohort of 22 individuals carrying pathogenic NR2F1 variants to document the neurodevelopmental and ophthalmological manifestations, in particular the structural and functional changes within the retina and the optic nerve, which have not been detailed previously. The visual impairment became apparent in early childhood with small and/or tilted hypoplastic optic nerves observed in 10 cases. High-resolution optical coherence tomography imaging confirmed significant loss of retinal ganglion cells with thinning of the ganglion cell layer, consistent with electrophysiological evidence of retinal ganglion cells dysfunction. Interestingly, for those individuals with available longitudinal ophthalmological data, there was no significant deterioration in visual function during the period of follow-up. Diffusion tensor imaging tractography studies showed defective connections and disorganization of the extracortical visual pathways. To further investigate how pathogenic NR2F1 variants impact on retinal and optic nerve development, we took advantage of an Nr2f1 mutant mouse disease model. Abnormal retinogenesis in early stages of development was observed in Nr2f1 mutant mice with decreased retinal ganglion cell density and disruption of retinal ganglion cell axonal guidance from the neural retina into the optic stalk, accounting for the development of optic nerve hypoplasia. The mutant mice showed significantly reduced visual acuity based on electrophysiological parameters with marked conduction delay and decreased amplitude of the recordings in the superficial layers of the visual cortex. The clinical observations in our study cohort, supported by the mouse data, suggest an early neurodevelopmental origin for the retinal and optic nerve head defects caused by NR2F1 pathogenic variants, resulting in congenital vision loss that seems to be non-progressive. We propose NR2F1 as a major gene that orchestrates early retinal and optic nerve head development, playing a key role in the maturation of the visual system

Warmer Weather Linked to Tick Attack and Emergence of Severe Rickettsioses

The impact of climate on the vector behaviour of the worldwide dog tick Rhipicephalus sanguineus is a cause of concern. This tick is a vector for life-threatening organisms including Rickettsia rickettsii, the agent of Rocky Mountain spotted fever, R. conorii, the agent of Mediterranean spotted fever, and the ubiquitous emerging pathogen R. massiliae. A focus of spotted fever was investigated in France in May 2007. Blood and tissue samples from two patients were tested. An entomological survey was organised with the study of climatic conditions. An experimental model was designed to test the affinity of Rh. sanguineus for biting humans in variable temperature conditions. Serological and/or molecular tools confirmed that one patient was infected by R. conorii, whereas the other was infected by R. massiliae. Dense populations of Rh. sanguineus were found. They were infected with new genotypes of clonal populations of either R. conorii (24/133; 18%) or R. massiliae (13/133; 10%). April 2007 was the warmest since 1950, with summer-like temperatures. We show herein that the human affinity of Rh. sanguineus was increased in warmer temperatures. In addition to the originality of theses cases (ophthalmic involvements, the second reported case of R. massiliae infection), we provide evidence that this cluster of cases was related to a warming-mediated increase in the aggressiveness of Rh. sanguineus, leading to increased human attacks. From a global perspective, we predict that as a result of globalisation and warming, more pathogens transmitted by the brown dog tick may emerge in the future

Intérêt de l'étude de l'épaisseur de la couche des fibres nerveuses de la rétine en OCT (Optical Coherence Tomography) chez des patients atteints de sclérose en plaques

MONTPELLIER-BU Médecine UPM (341722108) / SudocPARIS-BIUM (751062103) / SudocMONTPELLIER-BU Médecine (341722104) / SudocSudocFranceF

Progressive ataxia related to PRRT2 gene mutation

International audienc

[Validation of the 13–30 ARAMAV assessment, a new quality of life and autonomy questionnaire adapted to visually impaired patients]

International audiencePurpose: To evaluate the ARAMAV 13-30 questionnaire, a new autonomy and quality of life questionnaire developed for visually impaired patients.Methods: We carried out a single-center prospective study at the ARAMAV institute in collaboration with the University Hospital of Nîmes. The patients included were admitted for low vision rehabilitation. Each patient received an occupational therapy assessment, the Short Forms 36 (SF36) quality of life questionnaire and the ARAMAV 13-30 questionnaire at the start and at the end of rehabilitation. We verified the reproducibility, the sensitivity to change, and internal and external consistency of the questionnaire.Results: We included 231 patients over a period of 4 years. All the patients were blind or visually impaired. We observed excellent intra- and interuser reproducibility of the questionnaire, with a Lin coefficient>0.9 (0.99 and 0.91, respectively). By comparing the variations of the different scores between before and after low vision rehabilitation, we observed excellent sensitivity to change for both the autonomy and quality of life portions of the questionnaire. Finally, we observed excellent internal and external consistency.Conclusion: We therefore propose the ARAMAV 13-30 questionnaire as a new tool in evaluating autonomy and quality of life specifically in visually impaired patients, which may also be used to assess the effect of low vision rehabilitation.Objectif : Évaluer le bilan 13–30 ARAMAV, un nouveau questionnaire d’autonomie et de qualité de vie développé pour les patients en situation de handicap visuel.Méthodes :Nous avons réalisé une étude prospective monocentrique à l’institut ARAMAV en collaboration avec le CHU de Nîmes. Les patients inclus étaient hospitalisés pour une rééducation basse vision. Chaque patient a bénéficié d’un bilan d’ergothérapie, du questionnaire de qualité de vie Short Forms 36 (SF36) et du bilan 13–30 ARAMAV au début et en fin de rééducation. Nous avons vérifié la reproductibilité, la sensibilité au changement ainsi que la cohérence interne et externe du questionnaire.Résultats : Nous avons inclus 231 patients sur une durée de 4 ans. Les patients présentaient tous un état de cécité ou de malvoyance. Nous avons retrouvé une excellente reproductibilité intra- et interutilisateur du questionnaire avec un coefficient de Lin > 0,9 (respectivement 0,99 et 0,91). En comparant les variations des différents scores entre avant et après rééducation, nous avons retrouvé une excellente sensibilité au changement pour la partie autonomie et pour la partie qualité de vie du questionnaire. Enfin, nous avons retrouvé une très bonne cohérence interne et externe.Conclusion :Nous proposons donc le bilan 13–30 ARAMAV comme un nouvel outil d’évaluation de l’autonomie et de la qualité de vie spécifiquement destiné au sujet déficient visuel et pouvant être utilisé pour évaluer l’impact d’une rééducation basse vision