Clinical and molecular findings in a cohort of 152 Brazilian severe early onset inherited retinal dystrophy patients

Leber congenital amaurosis (LCA) and early‐onset retinal dystrophy (EORD) are severe inherited retinal dystrophy that can cause deep blindness childhood. They represent 5% of all retinal dystrophies in the world population and about 10% in Brazil. Clinical findings and molecular basis of syndromic and nonsyndromic LCA/EORD in a Brazilian sample (152 patients/137 families) were studied. In this population, 15 genes were found to be related to the phenotype, 38 new variants were detected and four new complex alleles were discovered. Among 123 variants found, the most common were CEP290: c.2991+1655A>G, CRB1: p.Cys948Tyr, and RPGRIP1: exon10‐18 deletion

Expanding the clinical phenotype in patients with disease causing variants associated with atypical Usher syndrome

Atypical Usher syndrome (USH) is poorly defined with a broad clinical spectrum. Here, we characterize the clinical phenotype of disease caused by variants in CEP78, CEP250, ARSG, and ABHD12. Chart review evaluating demographic, clinical, imaging, and genetic findings of 19 patients from 18 families with a clinical diagnosis of retinal disease and confirmed disease-causing variants in CEP78, CEP250, ARSG, or ABHD12. CEP78-related disease included sensorineural hearing loss (SNHL) in 6/7 patients and demonstrated a broad phenotypic spectrum including: vascular attenuation, pallor of the optic disc, intraretinal pigment, retinal pigment epithelium mottling, areas of mid-peripheral hypo-autofluorescence, outer retinal atrophy, mild pigmentary changes in the macula, foveal hypo-autofluorescence, and granularity of the ellipsoid zone. Nonsense and frameshift variants in CEP250 showed mild retinal disease with progressive, non-congenital SNHL. ARSG variants resulted in a characteristic pericentral pattern of hypo-autofluorescence with one patient reporting non-congenital SNHL. ABHD12-related disease showed rod-cone dystrophy with macular involvement, early and severe decreased best corrected visual acuity, and non-congenital SNHL ranging from unreported to severe. This study serves to expand the clinical phenotypes of atypical USH. Given the variable findings, atypical USH should be considered in patients with peripheral and macular retinal disease even without the typical RP phenotype especially when SNHL is noted. Additionally, genetic screening may be useful in patients who have clinical symptoms and retinal findings even in the absence of known SNHL given the variability of atypical USH

Novel codon 15 RHO gene mutation associated with retinitis pigmentosa

 Manuel AP Vilela,1 Roberta K Menna Barreto,2 Pedro K Menna Barreto,1 Juliana MF Sallum,3 Vanessa S Mattevi1 1Department of Ophthalmology, Federal Health Sciences University of Porto Alegre, Porto Alegre, Brazil; 2Medical School, Federal University of Rio Grande do Sul, Rio Grande do Sul, Brazil; 3Department of Ophthalmology, Federal University of São Paulo, São Paulo, Brazil Objective: To describe, in a multimodal way, a new RHO gene mutation with lysine-for-asparagine substitution in autosomal dominant retinitis pigmentosa.Methods: Case report. Retrospective data analysis.Results: The mutation is located within codon 15 of exon 1 of the RHO gene. A single base-pair transversion lead to a specific lysine-for-asparagine substitution (Asn15Lys). Hypoacusis, myopia, dyschromatopsis and diffuse retinitis pigmentosa were detected. Detailed multimodal images for the posterior segment are presented.Conclusion: We present a new mutation with a specific substitution that may cause eye disease and which has not been described previously. There is no description of this variant in the genetic databases. Keywords: tapetoretinal degeneration, rod-cone dystrophy, pigmentary retinopathy, opsins, retinal pigment

Clinical, ophthalmological, imaging and genetic features in Brazilian patients with ARSACS

BACKGROUND: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an important form of inherited ataxia with a varied clinical spectrum. Detailed studies of phenotype and genotype are necessary to improve diagnosis and elucidate this disorder pathogenesis. OBJECTIVE AND METHODS: To investigate the clinical phenotype, retinal architecture, neuroimaging features and genetic profile of Brazilian patients with ARSACS, we performed neurological and ophthalmological evaluation in thirteen Brazilian patients with molecularly confirmed ARSACS, and examined their mutation profiles. Optical coherence tomography protocol (OCT) consisted in peripapillary retinal nerve fiber layer (RNFL) measurement and qualitative analysis of perifoveal scans. Neuroimaging protocol accessed the frequency of atrophy in cerebellum, corpus callosum and parietal lobe, brainstem signal abnormalities, and posterior fossa arachnoid cysts. We reviewed the literature to delineate the ARSACS phenotype in the largest series worldwide. RESULTS: All patients had ataxia and spasticity, and 11/13 had peripheral neuropathy. Macular microcysts were present in two patients. Peripapillary striations, dentate appearance of inner retina and papillomacular fold were found in eleven cases. All individuals exhibited thickening of RNFL in OCT. The most frequent radiological signs were cerebellar atrophy (13/13), biparietal atrophy (12/13), and linear pontine hypointensities (13/13). Genetic analysis revealed 14 different SACS variants, of which two are novel. CONCLUSION: Macular microcysts, inner retina dentate appearance and papillomacular fold are novel retinal imaging signs of ARSACS. Ophthalmological and neuroimaging changes are common findings in Brazilian patients. The core clinical features of ARSACS are ataxia, spasticity and peripheral neuropathy with onset predominantly in the first decade of life

Retinal Architecture in Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS): Insights into Disease Pathogenesis and Biomarkers

Background Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) causes unique retinal abnormalities, which have not been systematically investigated. Objective To deeply phenotype the retina in ARSACS in order to better understand its pathogenesis and identify potential biomarkers. Methods We evaluated 29 patients with ARSACS, 66 with spinocerebellar ataxia (SCA), 38 with autosomal recessive cerebellar ataxia (ATX), 22 with hereditary spastic paraplegia (SPG), 21 cases of papilledema, and 20 healthy controls (total n = 196 subjects). Participants underwent visual acuity assessment, intraocular pressure measurement, fundoscopy, and macular and peripapillary optical coherence tomography (OCT). Macular layers thicknesses in ARSACS were compared with those of age-matched healthy controls. Ophthalmologists analyzed the scans for abnormal signs in the different patient groups. Linear regression analysis was conducted to look for associations between retinal changes and age, age at onset, disease duration, and Scale for the Assessment and Rating of Ataxia (SARA) scores in ARSACS. Results Only patients with ARSACS exhibited peripapillary retinal striations (82%) on fundoscopy, and their OCT scans revealed foveal hypoplasia (100%), sawtooth appearance (89%), papillomacular fold (86%), and macular microcysts (18%). Average peripapillary retinal nerve fiber layer (pRNFL) was thicker in ARSACS than in SCA, ATX, SPG, and controls; a cut-off of 121 μm was 100% accurate in diagnosing ARSACS. All macular layers were thicker in ARSACS when compared to healthy controls. RNFL thickness in the inferior sector of the macula positively correlated with SARA scores. Conclusions Retinal abnormalities are highly specific for ARSACS, and suggest retinal hyperplasia due to abnormal retinal development. OCT may provide potential biomarkers for future clinical trials