Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies.

Pre-mRNA splicing factors play a fundamental role in regulating transcript diversity both temporally and spatially. Genetic defects in several spliceosome components have been linked to a set of non-overlapping spliceosomopathy phenotypes in humans, among which skeletal developmental defects and non-syndromic retinitis pigmentosa (RP) are frequent findings. Here we report that defects in spliceosome-associated protein CWC27 are associated with a spectrum of disease phenotypes ranging from isolated RP to severe syndromic forms. By whole-exome sequencing, recessive protein-truncating mutations in CWC27 were found in seven unrelated families that show a range of clinical phenotypes, including retinal degeneration, brachydactyly, craniofacial abnormalities, short stature, and neurological defects. Remarkably, variable expressivity of the human phenotype can be recapitulated in Cwc27 mutant mouse models, with significant embryonic lethality and severe phenotypes in the complete knockout mice while mice with a partial loss-of-function allele mimic the isolated retinal degeneration phenotype. Our study describes a retinal dystrophy-related phenotype spectrum as well as its genetic etiology and highlights the complexity of the spliceosomal gene network.

Mutation update: TGFBI pathogenic and likely pathogenic variants in corneal dystrophies.

Human transforming growth factor ß-induced (TGFBI), is a gene responsible for various corneal dystrophies. TGFBI produces a protein called TGFBI, which is involved in cell adhesion and serves as a recognition sequence for integrins. An alteration in cell surface interactions could be the underlying cause for the progressive accumulation of extracellular deposits in different layers of the cornea with the resulting changes of refractive index and transparency. To this date, 69 different pathogenic or likely pathogenic variants in TGFBI have been identified in a heterozygous or homozygous state in various corneal dystrophies, including a novel variant reported here. All disease-associated variants were inherited as autosomal-dominant traits but one; this latter was inherited as an autosomal recessive trait. Most corneal dystrophy-associated variants are located at amino acids Arg124 and Arg555. To keep the list of corneal dystrophy-associated variant current, we generated a locus-specific database for TGFBI (http://databases.lovd.nl/shared/variants/TGFBI) containing all pathogenic and likely pathogenic variants reported so far. Non-disease-associated variants are described in specific databases, like gnomAD and ExAC but are not listed here. This article presents the most recent up-to-date list of disease-associated variants.

Visual Outcomes of Fractionated Radiotherapy in Optic Nerve Sheath Meningioma: A Retrospective Study.

BACKGROUND: Optic nerve sheath meningioma (ONSM) is a rare benign tumour of the optic nerve sheath that can lead to blindness if untreated. Radiotherapy is commonly accepted as being the treatment of choice. We conducted a retrospective monocentric study to assess the effect of radiotherapy on visual outcomes and tumour control in patients with ONSM. PATIENTS AND METHODS: The charts of all patients affected by ONSM between 1994 and 2016 were reviewed retrospectively. Inclusion criteria were: having been followed by our department, initial visual acuity (VA) better than no light perception, and stereotactic fractionated radiotherapy. VA (Snellen), colour vision (Ishihara), and visual field mean defect (in dB), as well as ONSM size (on MRI) were compared before and after radiotherapy. Visual function was considered improved if two or more criteria improved, stabilised if none or only one criterion changed, and worsened if two or more criteria worsened. The Wilcoxon signed-rank test was used to assess the effect of radiotherapy (significant if p value < 0.05). RESULTS: VA improved or stabilised in 13/16 patients (81.25%), with median VA improving from 0.1 logMAR (8/10) to 0 logMAR (10/10) (p value = 0.0134). Colour vision improved or stabilised in 11/15 patients (73.33%), with median results improving from 5/13 to 12/13 (p value = 0.3212). The visual field mean defect improved in 13/15 patients (86.66%), and the median mean defect (MD) improved from 10 dB to 4 dB (p value = 0.0106). The size of the ONSM diminished or stabilised in 100% of our patients. No adverse events of radiotherapy were either reported or detected. CONCLUSION: Fractionated radiotherapy is a safe procedure and may improve visual function in patients with ONSM.

Multimodal imaging of retinal pigment epithelial detachments in patients with C3 glomerulopathy: case report and review of the literature.

BACKGROUND: To describe the optical coherence tomography angiograhy (OCTA) of drusenoid pigment epithelial detachments (PEDs) in a woman affected by Complement 3 (C3) glomerulopathy, which represents a spectrum of glomerular diseases characterized on fluorescent microscopy by C3 accumulation with absent, or scanty, immunoglobulin deposits. It is due to acquired or genetically defective alternative pathway control and is generally associated with drusen-like deposits in Bruch's membrane, as well as choriocapillaris. These retinal lesions can be associated with choroidal neovascularization and central serous chorioretinopathy (CSCR). OCTA is useful to detect neovascularization without injecting a contrast product, particularly in these patients who may have renal insufficiency. CASE PRESENTATION: A 28-year-old woman affected by C3 glomerulpathy was diagnosed with asymptomatic multiple bilateral PEDs during a routine ophthalmologic consultation. To better characterize the lesions, multimodal imaging was performed and included: optic coherence tomography (OCT), en-face OCT, OCTA, fluorescence and indocyanine angiography. The OCTA clearly identified vascular network rarefaction with decreased choriocapillary vascularization. It confirmed that PEDs associated with C3 glomerulonephritis are not vascularized, but rather of serous type. CONCLUSIONS: Patients affected by C3 glomerulopathy can develop neovascular membranes as retinal complications of pigment epithelial detachments. Optical coherence angiography may be indicated to identify this complication, without injecting any contrast product that could produce further kidney damage.

MULTIPLE SEROUS PIGMENT EPITHELIAL DETACHMENTS IN ASSOCIATION WITH MAJOR WEIGHT LOSS: CASE REPORT AND REVIEW OF THE LITERATURE.

PURPOSE: To report about two cases with bilateral multiple serous pigment epithelial detachments (sPED) following major acute weight loss. METHODS: Retrospective chart review of patients who presented with bilateral multiple sPED following acute major weight loss. The files were reviewed for their general and ophthalmic history, medication, ophthalmic status, optical coherence tomography (OCT) and enhanced depth imaging, fluorescein and indocyanine green angiography, arterial pressure, and laboratory workup. RESULTS: Two patients, both women, aged 45 and 50 years were identified. The sPED counted 50 and 5, respectively. They were located in the mid-periphery and the macula. Multimodal imaging including optical coherence tomography, fundus autofluorescence, fluorescein angiography, and indocyanine green angiography did not reveal an underlying ocular pathology. However, both patients had a thick choroid (455 µm and 542 µm). They both had gone through intentional major weight loss induced by protein-rich Dukan's diet (-20 kg in 3 months) and gastric bypass with protein-enriched diet (-35 kg in less than 1 year), respectively. They were substituted with vitamins (vitamin B, C, D). CONCLUSION: Bilateral multiple serous PEDs may occur in the context of acute major weight loss and protein-rich diet. The precise pathogenesis remains to be elucidated. However, potential candidates include the protein-, mineral- and/or vitamin-related metabolism disturbing the pigment epithelium function. A predisposition for a central serous chorioretinopathy like response might have contributed.