Mary J. van Schooneveld

C-terminal truncations in human 3'-5' DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy

Autosomal dominant retinal vasculopathy with cerebral leukodystrophy is a microvascular endotheliopathy with middle-age onset. In nine families, we identified heterozygous C-terminal frameshift mutations in TREX1, which encodes a 3′-5′ exonuclease. These truncated proteins retain exonuclease activity but lose normal perinuclear localization. These data have implications for the maintenance of vascular integrity in the degenerative cerebral microangiopathies leading to stroke and dementias.

High-resolution homozygosity mapping is a powerful tool to detect novel mutations causative of autosomal recessive RP in the Dutch population

PURPOSEnTo determine the genetic defects underlying autosomal recessive retinitis pigmentosa (arRP) in the Dutch population and in a subset of patients originating from other countries. The hypothesis was that, because there has been little migration over the past centuries in certain areas of The Netherlands, a significant fraction of Dutch arRP patients carry their genetic defect in the homozygous state.nnnMETHODSnHigh-resolution genome-wide SNP genotyping on SNP arrays and subsequent homozygosity mapping were performed in a large cohort of 186 mainly nonconsanguineous arRP families living in The Netherlands. Candidate genes residing in homozygous regions were sequenced.nnnRESULTSnIn ~94% of the affected individuals, large homozygous sequences were identified in their genome. In 42 probands, at least one of these homozygous regions contained one of the 26 known arRP genes. Sequence analysis of the corresponding genes in each of these patients revealed 21 mutations and two possible pathogenic changes, 14 of which were novel. All mutations were identified in only a single family, illustrating the genetic diversity within the Dutch population.nnnCONCLUSIONSnThis report demonstrates that homozygosity mapping is a powerful tool for identifying the genetic defect underlying genetically heterogeneous recessive disorders like RP, even in populations with little consanguinity.

Original articleAutosomal Recessive Bestrophinopathy: Differential Diagnosis and Treatment Options

OBJECTIVEnTo describe the clinical and genetic characteristics of patients with autosomal recessive bestrophinopathy (ARB).nnnDESIGNnRetrospective case series.nnnPARTICIPANTSnTen patients with ARB from 7 different families.nnnMETHODSnAll patients underwent a complete ophthalmic examination, including dilated fundus examination, fundus photography, and fluorescein angiography (FA). In all probands, fundus autofluorescence (FAF) imaging, spectral-domain optical coherence tomography (OCT), full-field electroretinography (ERG), electro-oculography (EOG), and Goldmann perimetry were performed. In selected patients, multifocal ERG was performed. Blood samples were obtained to analyze the BEST1 gene for biallelic mutations that confirmed the diagnosis of ARB.nnnMAIN OUTCOME MEASURESnAge at onset; visual acuity; fundus appearance; characteristics on FA, FAF, OCT, full-field ERG, and EOG; BEST1 gene mutations; and genotype-phenotype correlation.nnnRESULTSnThe age at onset varied widely, from 2 to 54 years. A spectrum of fundus abnormalities was observed, such as multifocal yellowish subretinal deposits, subretinal fibrous scars, and cystoid intraretinal fluid collections in the macula. All ARB patients were hyperopic, and some had shallow anterior chamber angles that predisposed them to angle-closure glaucoma. The EOG results were abnormal in all patients. The full-field ERG results were abnormal in 8 ARB patients, whereas 2 patients demonstrated normal cone and rod responses on full-field ERG. Nine ARB patients carried biallelic mutations in the BEST1 gene, and in 1 patient with a characteristic ARB phenotype, only 1 mutation could be identified. Seven different mutations were detected, including 4 novel mutations.nnnCONCLUSIONSnAutosomal recessive bestrophinopathy is a recognizable phenotype caused by autosomal recessively inherited mutations in the BEST1 gene. A differential diagnosis with other conditions can be made on the basis of marked autofluorescence changes in combination with an absent light rise on the EOG that outweighs the full-field ERG abnormalities, which point to the BEST1-related hereditary nature of the disease. A number of currently available therapeutic options should be considered in ARB, a disease that seems to be a suitable candidate for future gene therapy.

Autosomal Recessive Retinitis Pigmentosa With Preserved Para-arteriolar Retinal Pigment Epithelium

Retinitis pigmentosa with preserved para-arteriolar retinal pigment epithelium is a rare form of retinitis pigmentosa that starts early in life with preservation of retinal pigment epithelium adjacent to and under the retinal arterioles and that has hitherto been described as an isolated form. We examined 22 patients from one large family, together with two isolated patients, and confirmed the presumed autosomal recessive mode of inheritance in this type of retinitis pigmentosa. New findings associated with retinitis pigmentosa with preserved para-arteriolar retinal pigment epithelium were asteroid hyalosis in four (17%) of 24 patients, tortuosity of retinal arterioles in 11 (46%) of 24 patients, peripheral regions of opacified vessels in eight (33%) of 24 patients, and preservation not only of the para-arteriolar pigment epithelium, but also of the peripheral retinal pigment epithelium in 13 (54%) of 24 patients. Previously reported signs present in these patients were nystagmus in six (25%) of 24 patients, hypermetropia in 23 (96%) of 24 patients, optic nerve head drusen in nine (38%) of 24 patients, vascular sheathing in 11 (46%) of 24 patients, maculopathy in all 24 patients (100%), yellow round deposits in the posterior pole in nine (38%) of 24 patients, exudates resembling those in Coats disease in two (8%) of 24 patients, visual field defects in all 24 patients (100%), and nondeductible electroretinograms in 21 (91%) of 23 patients. Linkage analysis carried out in the large family resulted in the assignment of a gene for retinitis pigmentosa with preserved para-arteriolar retinal pigment epithelium to chromosome 1q31-q32.1.

Retinal Vascular Lesions in Patients of Caucasian and Asian Origin With Type 2 Diabetes Baseline results from the ADVANCE Retinal Measurements (AdRem) study

OBJECTIVE—The objective of this study was to describe prevalent vascular retinal lesions among patients with type 2 diabetes enrolled in the ADVANCE Retinal Measurements (AdRem) study, a substudy of the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial. RESEARCH DESIGN AND METHODS—Seven-field stereoscopic photographs of both eyes were obtained at the baseline assessment of the ADVANCE trial. All photographs were graded in a central reading center. Gradable retinal images were received from 1,605 patients. RESULTS—The number of patients with any retinopathy (Early Treatment of Diabetic Retinopathy Study [ETDRS] score ≥20) was 645 (40.2% [95% CI 37.8–42.6]); of these, 35 (2.2% [1.6–3.0]) had severe diabetic retinopathy (ETDRS score ≥50). Focal arterial narrowing, venous beading, and arteriovenous nicking were present in 3.8, 5.1, and 9.8% of participants, respectively. Among participants included in this study, Chinese and South-Asian patients had more retinopathy than Caucasians, as defined both by ETDRS score (49.4, 46.0, and 31.3%, respectively; P < 0.001, adjusted for age, sex, A1C, systolic blood pressure, and duration of diabetes) and specific vascular lesions (e.g., arteriovenous nicking 12.3, 8.5, and 7.5%, respectively; adjusted P < 0.005). A1C, duration of diabetes, and systolic blood pressure were similarly associated with increased retinal lesions in Chinese, South-Asian, and Caucasian patients. CONCLUSIONS—Using a sensitive diagnostic procedure, more than one-third of patients with type 2 diabetes enrolled in the AdRem study had retinal lesions at baseline. Despite differences in prevalence and severity of retinopathy among Chinese, South-Asian, and Caucasian patients included in this study, the cross-sectional associations among established risk factors for retinopathy and retinal lesions were similar across ethnic groups.

A Homozygous Frameshift Mutation in LRAT Causes Retinitis Punctata Albescens

PURPOSEnTo determine the genetic defect and to describe the clinical characteristics in patients with retinitis punctata albescens (RPA) and fundus albipunctatus (FAP).nnnDESIGNnCase series/observational study.nnnPARTICIPANTSnWe included 13 patients affected by RPA or FAP.nnnMETHODSnThirteen patients were collected from 8 families with a retinal dystrophy characterized by tiny, yellow-white dots on funduscopy, typical for FAP or RPA. All patients underwent full ophthalmologic examinations, including visual field assessment. Fundus photography, and electroretinography were performed in 12 patients, and optical coherence tomography and fundus autofluorescence were performed in 4 patients. DNA samples of all patients were screened for mutations in RLBP1 and for mutations in RDH5 in patients who did not carry mutations in RLBP1. DNA samples of 2 sibling pairs of nonconsanguineous families who carried mutations neither in RLBP1 nor in RDH5 were analyzed by genome-wide homozygosity mapping. Sequence analysis was performed of LRAT, a candidate gene in a shared homozygous region.nnnMAIN OUTCOME MEASURESnWe assessed DNA sequence variants, best-corrected visual acuity, fundus appearance, visual field measurements, electroretinogram responses, optical coherence tomography, and fundus autofluorescence.nnnRESULTSnA homozygous frameshift mutation was identified in LRAT in 4 patients with RPA. Mutations in RLBP1 were identified in 7 patients with RPA and in 1 patient with FAP and cone dystrophy. One patient had compound heterozygous mutations in RDH5 and suffered from FAP with mild maculopathy.nnnCONCLUSIONSnA genetic defect was identified in LRAT as a novel cause of RPA. LRAT is therefore the fourth gene involved in the visual cycle that may cause a white-dot retinopathy. We also revealed that mutations in RLBP1 may lead to FAP with cone dystrophy.

Chronic Central Serous Chorioretinopathy Associated with Serous Retinal Detachment in a Series of Asian Patients

Purpose: To determine clinical features of patients with severe chronic central serous chorioretinopathy (diffuse retinal pigment epitheliopathy, DRPE) associated with bullous retinal detachment in Thailand. Methods: The authors reviewed clinical and imaging characteristics, visual outcomes, and complications of 7 patients with severe DRPE associated with bullous retinal detachment. Results: Included were 6 males and 1 female with average age at onset of 39 years (range 30–46 years) diagnosed with DRPE. Although 4 patients had unilateral complaints, retinal pigment epithelium (RPE) changes on fluorescein angiography (FA) were visible in both eyes in all patients and 10 out of 14 affected eyes exhibited large exudative bullous retinal detachments (RD) and evidence of multiple characteristic leakage points. The disease was induced by steroid medications in 3 patients and an additional 3 patients received steroid treatment after they were initially considered to have Harada disease. The administration of steroids caused worsening in all cases. Conclusion: Chronic central serous chorioretinopathy associated with bullous retinal detachment is a severe variant of DRPE, which might be mistaken for Harada disease. The early diagnosis of DRPE might prevent the complications from harmful medications as well as unnecessary surgery and visual loss.

Rieger's eye anomaly and persistent hyperplastic primary vitreous

The authors present a Turkish family (two generations, five affected persons) with symptoms of Riegers eye anomaly as well as Persistent Hyperplastic Primary Vitreous (PHPV). Although Riegers anomaly has been described in combination with other conditions, according to their knowledge a familial combination of Riegers anomaly and PHPV has never been described before. Only once an isolated case with the combination of an anterior chamber cleavage malformation and bilateral PHPV has been described. The authors suggest two possible explanations for the coexistence of PHPV and Riegers eye anomaly. It is feasible that we are dealing with symptoms until yet not diagnosed within the anomaly of Rieger. Another possibility is that there is a linkage between the genes for PHPV and Riegers anomaly and as a consequence they are inherited together in this family.

Development of Refractive Errors—What Can We Learn From Inherited Retinal Dystrophies?

PURPOSEnIt is unknown which retinal cells are involved in the retina-to-sclera signaling cascade causing myopia. As inherited retinal dystrophies (IRD) are characterized by dysfunction of a single retinal cell type and have a high risk of refractive errors, a study investigating the affected cell type, causal gene, and refractive error in IRDs may provide insight herein.nnnDESIGNnCase-control study.nnnMETHODSnStudy Population: Total of 302 patients with IRD from 2 ophthalmogenetic centers in the Netherlands. Reference Population: Population-based Rotterdam Study-III and Erasmus Rucphen Family Study (Nxa0= 5550). Distributions and mean spherical equivalent (SE) were calculated for main affected cell type and causal gene; and risks of myopia and hyperopia were evaluated using logistic regression.nnnRESULTSnBipolar cell-related dystrophies were associated with the highest risk of SE high myopia 239.7; odds ratio (OR) mild hyperopia 263.2, both P < .0001; SExa0-6.86 diopters (D) (standard deviation [SD] 6.38), followed by cone-dominated dystrophies (OR high myopia 19.5, P < .0001; OR high hyperopia 10.7, Pxa0= .033; SExa0-3.10 D [SD 4.49]); rod dominated dystrophies (OR high myopia 10.1, P < .0001; OR high hyperopia 9.7, Pxa0= .001; SExa0-2.27 D [SD 4.65]), and retinal pigment epithelium (RPE)-related dystrophies (OR low myopia 2.7; Pxa0= .001; OR high hyperopia 5.8; Pxa0= .025; SExa0-0.10 D [SD 3.09]). Mutations in RPGR (SExa0-7.63 D [SD 3.31]) and CACNA1F (SExa0-5.33 D [SD 3.10]) coincided with the highest degree of myopia and in CABP4 (SE 4.81 D [SD 0.35]) with the highest degree of hyperopia.nnnCONCLUSIONSnRefractive errors, in particular myopia, are common in IRD. The bipolar synapse and the inner and outer segments of the photoreceptor may serve as critical sites for myopia development.

Golden tapetal reflex in male patients with X-linked retinitis pigmentosa

The golden tapetal reflex in the ocular fundus is considered pathognomonic of the carrier state in some families with X-linked retinitis pigmentosa (XRP). Reports concerning affected males with this characteristic reflex are scarce. A six-year-old boy with XRP having a tapetal reflex is described. Recently the tapetal reflex has drawn attention in linkage studies. XRP is probably genetically heterogeneous and has at least two genetic forms. The finding of a tapetal reflex in one or more female carriers in a family with XRP may be helpful in differentiating between these two genetic forms.