LONGITUDINAL STUDY OF RPE65-ASSOCIATED INHERITED RETINAL DEGENERATIONS.

PURPOSE: To study the disease course of RPE65-associated inherited retinal degenerations (IRDs) as a function of the genotype, define a critical age for blindness, and identify potential modifiers. METHODS: Forty-five patients with IRD from 33 families with biallelic RPE65 mutations, 28 stemming from a genetic isolate. We collected retrospective data from medical charts. Coexisting variants in 108 IRD-associated genes were identified with Molecular Inversion Probe analysis. RESULTS: Most patients were diagnosed within the first years of life. Daytime visual function ranged from near-normal to blindness in the first four decades and met WHO criteria for blindness for visual acuity and visual field in the fifth decade. p.(Thr368His) was the most common variant (54%). Intrafamilial variability and interfamilial variability in disease severity and progression were observed. Molecular Inversion Probe analysis confirmed all RPE65 variants and identified one additional variant in LRAT and one in EYS in two separate patients. CONCLUSION: All patients with RPE65-associated IRDs developed symptoms within the first year of life. Visual function in childhood and adolescence varied but deteriorated inevitably toward blindness after age 40. In this study, genotype was not predictive of clinical course. The variance in severity of disease could not be explained by double hits in other IRD genes.

Whole-Exome Sequencing Identifies Biallelic IDH3A Variants as a Cause of Retinitis Pigmentosa Accompanied by Pseudocoloboma.

PURPOSE: To identify the genetic cause of and describe the phenotype in 4 families with autosomal recessive retinitis pigmentosa (arRP) that can be associated with pseudocoloboma. DESIGN: Case series. PARTICIPANTS: Seven patients from 4 unrelated families with arRP, among whom 3 patients had bilateral early-onset macular pseudocoloboma. METHODS: We performed homozygosity mapping and whole-exome sequencing in 5 probands and 2 unaffected family members from 4 unrelated families. Subsequently, Sanger sequencing and segregation analysis were performed in additional family members. We reviewed the medical history of individuals carrying IDH3A variants and performed additional ophthalmic examinations, including full-field electroretinography, fundus photography, fundus autofluorescence imaging, and optical coherence tomography. MAIN OUTCOME MEASURES: IDH3A variants, age at diagnosis, visual acuity, fundus appearance, visual field, and full-field electroretinography, fundus autofluorescence, and optical coherence tomography findings. RESULTS: We identified 7 different variants in IDH3A in 4 unrelated families, that is, 5 missense, 1 nonsense, and 1 frameshift variant. All participants showed symptoms early in life, ranging from night blindness to decreased visual acuity, and were diagnosed between the ages of 1 and 11 years. Four participants with biallelic IDH3A variants displayed a typical arRP phenotype and 3 participants were diagnosed with arRP and pseudocoloboma of the macula. CONCLUSIONS: IDH3A variants were identified as a novel cause of typical arRP in some individuals associated with macular pseudocoloboma. We observed both phenotypes in 2 siblings carrying the same compound heterozygous variants, which could be explained by variable disease expression and warrants caution when making assertions about genotype-phenotype correlations.

Changes in causes of low vision between 1988 and 2009 in a Dutch population of children.

PURPOSE: Causes of low vision in the Netherlands may have changed over time. The purpose of this study is to assess trends over the last two decades. METHODS: Socio-demographic and medical data, including ophthalmic diagnosis and inheritance patterns for 2843 children with low vision (0-21 years; 50% representation) referred to a Dutch institute for low vision (Bartiméus) over a 21-year period between 1988 and 2009, were included in the analysis. For the 19 most common diagnoses, inheritance and presence of mental impairment, trend analyses were performed with logistic regression models; odds ratios (OR) for a 10-year time span were reported. RESULTS: Cerebral visual impairment (CVI) was found in 27.2% (97% mental impairment), albinism in 8.0%. Over time, nystagmus (6.6%; OR = 1.42), retinitis pigmentosa (2.9%; OR = 1.61), cone-rod dystrophy (2.6%; OR = 1.98) and hyperopia (2.0%; OR = 3.66) increased significantly. Cataract (4.9%; OR = 0.64), aniridia (1.6%; OR = 0.42) and retinopathy of prematurity (ROP; 2.0%; OR = 0.45) decreased significantly. There was a significant increase in genetic disorders (41.0%; OR = 1.49) and in co-occurrence of mental impairment (52.2% OR = 1.16). CONCLUSION: In the last two decades, treatable or preventable disorders (such as cataract and ROP) have become a less common cause of low vision in children. However, the prevalence of complex (genetic) and untreatable disorders (CVI) has taken its place, as a result of increased survival of preterm and low birth weight children and improved diagnostic possibilities. Knowledge of the prevalence of low vision, its causes and trends over time may help policy makers to define effective intervention strategies and to monitor its impact.

Clinical and molecular evaluation of probands and family members with familial exudative vitreoretinopathy.

PURPOSE: To describe the ophthalmic characteristics and to identify the molecular cause of FEVR in a cohort of Dutch probands and their family members. METHODS: Twenty families with familial exudative vitreoretinopathy (FEVR) comprising 83 affected and nonaffected individuals were studied. Based on the presence of an avascular zone, the clinical diagnosis was made and biometric data of the posterior pole of 57 patients and family members were obtained by the analysis of fundus photographs and compared with the data of 40 controls. The FZD4, LRP5, and NDP genes were screened for mutations in one affected individual per family. The segregation of the gene variants was studied in the corresponding families. RESULTS: Forty of 83 individuals showed an avascular zone, the most evident clinical sign of FEVR, five showed major signs of FEVR, and 38 persons were not clinically affected. Compared with the control subjects the patients with FEVR had a significantly larger disc-to-macula distance and a significantly smaller optic disc. In 8 of 20 families, a FZD4 mutation was identified, in 2 a mutation in the LRP5 gene, and in 2 a mutation in the NDP gene. Three known and five novel mutations were identified. Nonpenetrance was observed in 26% of the mutation carriers. CONCLUSIONS: Significant anatomic differences were identified between the eyes of patients with FEVR with an avascular zone, when compared with those of the control subjects. In patients with an avascular zone, the optic disc was smaller and the disc-to-macula distance larger than in the control subjects. In 60% of the probands, mutations were identified in one of the three known FEVR genes.