Les neuropathies optiques héréditaires : du signe clinique au diagnostic

Inherited optic atrophy must be considered when working up any optic nerve involvement and any systemic disease with signs of optic atrophy, even with a negative family history. There are two classical forms: dominant optic atrophy, characterized by insidious, bilateral, slowly progressive visual loss and temporal disc pallor, and Leber\u27s optic atrophy, characterized by acute loss of central vision followed by the same event in the fellow eye within a few weeks to months, with disc hyperemia in the acute phase. Family history is critical for diagnosis. In the absence of family history, the clinician must rule out an identifiable acquired cause, i.e. toxic, inflammatory, perinatal injury, traumatic or tumoral, with orbital and brain imaging (MRI). Recessive optic atrophies are more rare and more severe and occur as part of multisystemic disorders, particularly Wolfram syndrome (diabetes mellitus, diabetes insipidus, and hearing loss). Effective treatments are limited; alcohol and smoking should be avoided. A cyclosporine trial (taken immediately upon visual loss in the first eye) is in progress in Leber\u27s optic atrophy to prevent involvement of the fellow eye

Evidence for the role of normal-state electrons in nanoelectromechanical damping mechanisms at very low temperatures

We report on experiments performed at low temperatures on aluminum covered silicon nanoelectromechanical resonators. The substantial difference observed between the mechanical dissipation in the normal and superconducting states measured within the same device unambiguously demonstrates the importance of normal-state electrons in the damping mechanism. The dissipative component becomes vanishingly small at very low temperatures in the superconducting state, leading to exceptional values for the quality factor of such small silicon structures. A critical discussion is given within the framework of the standard tunneling model

Molecular screening of 980 cases of suspected hereditary optic neuropathy with a report on 77 novel OPA1 mutations

We report the results of molecular screening in 980 patients carried out as part of their work-up for suspected hereditary optic neuropathies. All the patients were investigated for Leber\u27s hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (ADOA), by searching for the ten primary LHON-causing mtDNA mutations and examining the entire coding sequences of the OPA1 and OPA3 genes, the two genes currently identified in ADOA. Molecular defects were identified in 440 patients (45% of screened patients). Among these, 295 patients (67%) had an OPA1 mutation, 131 patients (30%) had an mtDNA mutation, and 14 patients (3%), belonging to three unrelated families, had an OPA3 mutation. Interestingly, OPA1 mutations were found in 157 (40%) of the 392 apparently sporadic cases of optic atrophy. The eOPA1 locus-specific database now contains a total of 204 OPA1 mutations, including 77 novel OPA1 mutations reported here. The statistical analysis of this large set of mutations has led us to propose a diagnostic strategy that should help with the molecular work-up of optic neuropathies. Our results highlight the importance of investigating LHON-causing mtDNA mutations as well as OPA1 and OPA3 mutations in cases of suspected hereditary optic neuropathy, even in absence of a family history of the disease. © 2009 Wiley-Liss, Inc

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

Standardization of the Fully Stapled Laparoscopic Roux-en-Y Gastric Bypass for Obesity Reduces Early Immediate Postoperative Morbidity and Mortality: A Single Center Study on 2606 Patients

Various techniques of laparoscopic Roux-en-Y gastric bypass have been described. We completely standardized this procedure to minimize its sometimes substantial morbidity and mortality. This study describes our experience with the standardized fully stapled laparoscopic Roux-en-Y gastric bypass (FS-LRYGB) and its influence on the 30-day morbidity and mortality.status: publishe

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