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Purpose : Mutations in RPE65 have been primarily associated with Leber Congenital Amaurosis (LCA) and Early Onset Retinitis Pigmentosa (EORP). To extend the phenotypic spectrum associated with genetic defects in this gene, we report two cases of Fundus albipunctatus, a type of Congenital Stationary Night Blindness (CSNB), that harbor biallelic pathogenic variants in RPE65. Methods : Two unrelated Caucasian pediatric patients, born to non-consanguineous parents, underwent a complete ophthalmological assessment. Detailed physical examinations were performed to exclude systemic disease. Genetic analysis was performed by targeted Next Generation Sequencing (clinical exome). Results : An 11-year-old girl presented with night blindness from early childhood and a 15-year-old girl reported night blindness and narrowing of visual field from childhood. Both patients displayed the same clinical findings. Best corrected visual acuity was 20/20 in both eyes. Fundus examination revealed numerous white-yellow dots scattered in the mid periphery of the retina. OCT examination showed normal retinal structure, thickness and photoreceptor layer. Fundus autofluorescence displayed normal autofluorescence at the posterior pole with focal areas of hypoautofluorescence at the middle retinal periphery. Goldmann visual field showed mild reduction of visual field. Full field electroretinography (ERG) showed scotopic responses below the noise level and normal photopic responses with electronegative ERG findings. Genetic analysis identified, in the first patient, the younger one, two missense likely pathogenic variants (p.Arg347His, p.Tyr368His) in RPE65. Segregation analysis in the unaffected parents confirmed their presence in trans. While, in the other patient biallelic pathogenic variants (p.Glu254Asp, p.Leu328Phe) were identified in RPE65. Conclusions : Our study extends the phenotypic spectrum of the retinal dystrophies associated with biallelic variants in RPE65 ranging from LCA to CNSB. The findings indicate that patients harboring mutations in RPE65 gene can present different phenotypes and a careful clinical evaluation is indispensable for the selection/prioritisation of patients that can benefit from available therapeutic options.

Purpose : Pericentral Retinitis Pigmentosa (pericentral RP) is an atypical form of RP characterized by bone-spicule pigmentation and/or atrophy confined in the near mid-periphery of the retina. In contrast to classic RP, the far periphery is better preserved. We performed a detailed clinical and molecular analysis of a cohort of Italian subjects with pericentral RP to determine the phenotypic features and genetic bases of the disease. Methods : Fifty-four subjects (from 48 unrelated families) with pericentral RP underwent a complete ophthalmological examination and genetic analysis by clinical exome or retinopathy gene panel sequencing. The cohort included both cases with isolated RP (n = 42) as well as patients presenting syndromic forms (n = 12). Results : The patients had a mean Best Corrected Visual Acuity (BCVA) of 0.7 ± 0.3 decimals, ranging from light perception to 20/20 in both eyes, and the majority (85%) achieved a BCVA of 20/40 or better in at least one eye. Fundus examination revealed a normal-appearing disk and macula, mid-peripheral bone spicule pigmentation and a normal far periphery in all patients. Almost 50% of patients showed a pericentral field loss at Goldman visual field test. Dark-adapted ERG responses were reduced in 39 patients (72%) and were below noise level in 15 subjects (28%). Light-adapted 3.0 and 30Hz responses were subnormal in all patients but one, who showed normal amplitudes. Disease-causative variants were identified in 63% of cases. Fourteen of the 34 likely pathogenic variants were novel. We found a significant enrichment of pathogenic variants in USH2A (41% of cases) and in other genes causing syndromic RP. Following molecular analysis (identification of variants in PEX1), one patient who presented amelogenesis imperfecta and nail abnormalities, in addition to RP and hearing loss, was retrospectively diagnosed with Heimler Syndrome. Conclusions : We conclude that pericentral RP is a rather uncommon, mild RP subtype. A significant percentage of the cases reported herein were identified in the context of syndromic forms, namely Usher Syndrome type 2. In agreement, mutations in USH2A were the most recurrent cause of pericentral RP in the analyzed cohort. The current study extends the spectrum of genes associated with this atypical RP form and provides insights on its clinical presentation.

Purpose : Natural history data of Usher Syndrome (USH) due to MYO7A mutations are scarce. In view of future gene therapy studies, we assessed the natural course and investigated potential clinical endpoints in patients with USH due to MYO7A mutations. Methods : a multicenter prospective longitudinal (two-year) natural history study was designed within Ushther project (www.ushther.eu/). Patients aged 8 years or older with USH due to MYO7A mutations and a visual acuity ≥ 20/640 in at least one eye were recruited. We assessed: best-corrected visual acuity (BCVA, ETDRS), kinetic Visual field (VF, Octopus 900), spectral domain optical coherence tomography (OCT), microperimetry (MP, MAIA), and full-field electroretinogram (ERG). Regression analysis on baseline data was performed to estimate progression with age. Results : Forty-four patients aged 9-72 years (34.7 ± 16.1 years) were enrolled at the 3 centers. At baseline, patients showed a reduced BCVA (0.47 ± 0.30 logMAR in RE; 0.43 ± 0.32 logMAR in LE) and a constricted visual field (using V4e stimulus size: 5,436°2 ± 878°2 in RE; 5,722°2 ± 903°2 in LE). Moreover, MP showed a reduced macular sensitivity (8.2 ± 1.7 dB in RE; 8.2 ± 1.7 in LE). From preliminary analysis of OCT scans, we observed a disrupted Ellipsoid Zone (EZ) band with a mean width of 1,880 ± 329 µm in RE and of 1,842 ± 307 µm in LE. ERG responses were below noise level in all patients but five who showed markedly reduced responses in a rod-cone pattern. Cross-sectional analysis showed a decline with age of the BCVA (at a mean annual rate of 0.015 logMAR/year equivalent to about 1 EDTRS letter / year; P

Purpose: To assess the contribution of Italian radiation oncologists in the current management of recurrent high-grade gliomas (HGG), focusing on a reirradiation (reRT) approach. Methods: In 2015, the Reirradiation and the Central Nervous System Study Groups on behalf of the Italian Association of Radiation Oncology (AIRO) proposed a survey. All Italian radiation oncologists were individually invited to complete an online questionnaire regarding their clinical management of recurrent HGG, focusing on a reRT approach. Results: A total of 37 of 210 questionnaires were returned (18% of all centers): 16 (43%) from nonacademic hospitals, 14 (38%) from academic hospitals, 5 (13%) from private institutions, and 2 (6%) from hadron therapy centers. The majority of responding centers (59%) treated ≤5 cases per year. Performance status at the time of recurrence, along with a target diameter Conclusions: Although there were wide variations in the clinical practice of reRT across the 37 centers, the core activities were reasonably consistent. These findings provide a basis for encouraging a national collaborative study to develop, implement, and monitor the use of reRT in this challenging clinical setting.