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PurposeTo report the retinal phenotype in two patients simulating type 2 macular telangiectasis with new variants inCYP2U1implicated in Hereditary Spastic Paraplegia type 56 (HSP 56).MethodsFive members of a non-consanguineous family (parents and three male children) were investigated. All family members underwent a full ophthalmological evaluation and multimodal retinal imaging. Two family members demonstrating retinal anomalies underwent additional OCT angiography, dual wavelength autofluorescence and fluorescence lifetime imaging ophthalmoscopy, kinetic perimetry, fundus-correlated microperimetry, electroretinography and electro-oculography. Whole exome sequencing was performed in all five family members.ResultsThe two siblings with compound heterozygous novel variants c.452C>T; p.(Pro151Leu), c.943C>T; p.(Gln315Ter) inCYP2U1demonstrated parafoveal loss of retinal transparency and hyperreflectivity to blue light, redistribution of luteal pigment to the parafoveal edge, photoreceptor loss, FLIO anomalies: a pattern compatible with that seen in macular telangiectasia type 2 (MacTel). One had manifest neurological abnormalities since early childhood, the second had no neurological abnormalities. Each parent and the third sibling were heterozygous for one variant and were neurologically and ophthalmologically normal.ConclusionTheseCYP2U1variants are associated with a retinal phenotype very similar to that otherwise specific for MacTel, suggestive of possible links in the aetiology/pathogenesis of these diseases.

North Carolina macular dystrophy (NCMD) is a rare autosomal dominant disease affecting macular development. The disease is caused by non-coding single nucleotide variants (SNVs) in two hotspot regions near PRDM13 and by duplications in two distinct chromosomal loci, overlapping DNase I hypersensitive sites near either PRDM13 or IRX1.To unravel the mechanisms by which these variants cause disease, we first established a genome-wide multi-omics retinal database, RegRet. Integration of UMI-4C profiles we generated on adult human retina then allowed fine-mapping of the interactions of the PRDM13 and IRX1 gene promoters, and the identification of eighteen candidate cis-regulatory elements (cCREs), the activity of which was investigated by luciferase and Xenopus enhancer assays.Next, luciferase assays showed that the non-coding SNVs located in the two hotspot regions of PRDM13 affect cCRE activity, including two novel NCMD-associated non-coding SNVs that we identified. Interestingly, the cCRE containing one of these SNVs was shown to interact with the PRDM13 promoter, demonstrated in vivo activity in Xenopus, and is active at the developmental stage when progenitor cells of the central retina exit mitosis, putting forward this region as a PRDM13 enhancer.Finally, mining of single-cell transcriptional data of embryonic and adult retina revealed the highest expression of PRDM13 and IRX1 when amacrine cells start to synapse with retinal ganglion cells, supporting the hypothesis that altered PRDM13 or IRX1 expression impairs interactions between these cells during retinogenesis.Overall, this study gained insight into the cis-regulatory mechanisms of NCMD and supports that this condition is a retinal enhanceropathy.Graphical abstract

Biallelic gene defects in

Purpose: To assess the long-term anatomical and functional findings in patients with symptomatic vitreomacular traction (VMT), with or without full thickness macular hole (FTMH), after eye treatment with intravitreal ocriplasmin injection (IOI). Methods: This longitudinal case series includes 51 eyes from 51 symptomatic patients with VMT (

Background: We present a longitudinal clinical characterization of PYGM-linked pattern dystrophy in an adult male patient.Materials and Methods: A patient affected by McArdle disease (glycogen storage disease type V) and homozygous for the nonsense variant PYGM c.148C>T p.(Arg50*) underwent ophthalmic examinations over a 9-year-interval, including fundus photography, fundus autofluorescence, optical coherence tomography (OCT), OCT-angiography and electroretinography (ERG).Results: At age 52, the patient was asymptomatic but yellow flecks were first observed in the macula of both eyes. This yellow flecks at the posterior pole progressed towards a pattern-like dystrophy over a 5-year-period. By fundus autofluorescence imaging the appearance of new hyperautofluorescent flecks and the extension of existing ones was observed over time. Concomitantly, a slow progression of the size of atrophic areas was seen at the posterior pole. Scotopic ERGs were within normal limits, but photopic Flicker responses were decreased, indicating reduced cone function.Conclusions: This additional case of PYGM-linked pattern dystrophy further confirms retinopathy as a clinical phenotype associated with McArdle disease. PYGM expression pattern suggests a disease mechanism involving impaired glycogen metabolism both in the retinal pigment epithelium and in cone photoreceptors.

Background Whereas crystals deposit in the retina, the cornea and limbus in Bietty corneo-retinal dystrophy (BCD) is now well established and documented, only two published cases report their findings in the lens and no cases deep in the lens cortex. Material and methods Four consecutive adult patients from three different unrelated families presenting lens crystals associated with advanced genetically confirmed BCD were enrolled with advanced disease and long follow up (>12 years). Demographics, visual acuity, slit lamp biomicroscopy, lens and posterior pole photography, optical coherence tomography (OCT), autofluorescence, and screening for CYP4V2 type of mutation were performed. The setting was Jules Gonin Eye Hospital, Switzerland, between 1.1 2013 and 1.11. 2019. Results All patients were European women. The ages ranged from 40 to 81 years. Best Snellen visual acuity ranged from light perception to 1.0. All patients presented with limbus and retinal crystals deposit that disappeared over time and the development of severe chorioretinal atrophy. With long-term follow up, multiple crystal-like deposits appeared in the anterior, posterior lens capsule and cortex. All patients, but one, had homozygous or compound heterozygous mutations in CYP4V2 gene. Conclusions To the best of our knowledge, there are no published cases of crystal deposits in the cortex of the lens of patients diagnosed with BCD associated with CYP4V2 gene mutation. This could be a feature of advanced BCD, and their presence in the lens cortex questions the hypothesis of floating deposits from posterior pole although their exact etiology remains to be determined.

The authors wish to make a correction to the published version of their paper [...]

ABCA4-associated autosomal recessive Stargardt disease (STGD1; MIM 248200), also known as Stargardt macular dystrophy, is the most common monogenic macular dystrophy in adults and children (Allikmets et al. 1997; Stone et al. 2017). There is an estimated prevalence of 1 in 8000 to 1 in 10,000 (Blacharski 1988). Most common onset of disease symptoms is during childhood or teenage years and is characterized by impairment of central vision that usually progresses to legal blindness (Fishman et al. 1987; Rotenstreich et al. 2003). The peripheral vision is preserved most of the time (Aaberg 1986). Some late and adult onset Stargardt phenotypes are associated with milder missense mutations (Fujinami et al. 2013b; Genead et al. 2009).

PURPOSE To expand the genotype/phenotype correlations in patients with autosomal dominant retinitis pigmentosa (adRP) harboring PRPF8 variants. MATERIALS AND METHODS Two patients, a father and his daughter, harboring a novel p.PRPF8-Glu2331* variant, underwent ophthalmic examination at 3-year-interval, including fundus photography, fundus autofluorescence, optical coherence tomography, and ISCEV standard full field ERGs. All reported disease-causing PRPF8 variants were collected and localized in the PRPF8 and PRPF8/SNRNP200 protein structures. RESULTS The p.PRPF8-Glu2331* variant results in a truncated PRPF8 protein lacking the last five C-terminal amino acids and caused in the two patients a severe clinical phenotype, with the macula being affected from the second decade on. All but two adRP-linked variants are located in the last exon 43 encoding the C-terminal tail of the C-terminal PRPF8 Jab1 domain. The p.PRPF8-Ser2118Phe and -Asn2280Lys variants encoded by exons 39 and 42, respectively, are located at the basis of the C-terminal tail. CONCLUSIONS Frame-shift mutations and nonconservative amino acid changes in PRPF8 typically cause severe clinical phenotypes. The conservative missense variant p.PRPF8-Arg2310Lys that is not altering the global charge of the C-terminal tail, and variants located at the basis of the C-terminal tail show milder clinical phenotypes, in accordance with functional data on PRPF8/SNRNP200 interactions in yeast.

To describe the multimodal imaging findings, including optical coherence tomography angiography analysis, and spectrum of etiologies associated with Amalric triangular choroidal infarction. This study is a multicenter, retrospective, observational case series review of the clinical and multimodal imaging findings for six patients with Amalric triangular choroidal infarction. Six patients (10 eyes) with Amalric triangular choroidal infarction were enrolled. Patients' ages ranged from 7 years to 90 years (mean 54 years, median 60 years). Wedge-shaped or triangular areas of choroidal ischemia were evident with fluorescein angiography in all patients and with indocyanine green angiography in one patient. Optical coherence tomography angiography demonstrated choriocapillaris flow reduction that colocalized with outer retinal structural abnormalities with en face optical coherence tomography and corresponded with the triangular zones of choroidal infarction identified with fluorescein angiography in one patient. Etiologies included giant cell arteritis in three cases: traumatic carotid dissection, traumatic retrobulbar hemorrhage, and malignant hypertension secondary to lupus-associated nephropathy. The Amalric triangular syndrome of choroidal infarction can occur as a result of a spectrum of etiologies, especially giant cell arteritis. Infarction is evident on traditional angiography in all cases. Optical coherence tomography angiography may provide a simple noninvasive tool to evaluate choroidal ischemia.

Mutations in BEST1 cause several phenotypes including autosomal dominant (AD) Best vitelliform macular dystrophy type 2 (BVMD), AD vitreo-retino-choroidopathy (ADVIRC), and retinitis pigmentosa-50 (RP50). A rare subtype of Bestrophinopathy exists with biallelic mutations in BEST1. Its frequency is estimated to be 1/1,000,000 individuals. Here we report 6 families and searched for a genotype-phenotype correlation. All patients were referred due to reduced best-corrected visual acuity (BCVA), ranging from 0.1/10 to 3/10. They all showed vitelliform lesions located at the macula, sometimes extending into the midperiphery, along the vessels and the optic disc. Onset of the disease varied from the age of 3 to 25 years. Electrooculogram (EOG) revealed reduction in the EOG light rise in all patients. Molecular analysis revealed previously reported mutations p.(E35K), (E35K), p.(L31M), (L31M), p.(R141H), (A195V), p.(R202W), (R202W), and p.(Q220*), (Q220*) in five families. One family showed a novel mutation: p.(E167G), (E167G). All mutations were heterozygous in the parents. In one family, heterozygous children showed various reductions in the EOG light rise and autofluorescent deposits. Autosomal recessive Bestrophinopathy (ARB), although rare, can be recognized by its phenotype and should be validated by molecular analysis. Genotype-phenotype correlations are difficult to establish and will require the analysis of additional cases.

Background: We present a macular dystrophy of differing severity in a single kindred caused by a heterozygous nonsense mutation in CRX.Case report: A 21-year-old Caucasian male from a Swiss family was investigated for decreasing central visual acuity associated with dischromatopsia. Clinical examination revealed posterior pole atrophy, including the maculopapillary bundle. Multimodal imaging, including autofluorescence, showed a hyperautofluorescent paramacular ring in both eyes. Genetic analysis identified a c.313C>T, p.Q105* nonsense mutation in CRX. The same mutation was identified in his father and uncle. Both of them showed signs of the disease, however with different severity.Conclusion: We describe an intrafamilial variable expressivity of a CRX mutation causing an isolated macular dystrophy.

Reference EPFL-ARTICLE-219311doi:10.1055/s-0042-102585View record in Web of Science Record created on 2016-07-19, modified on 2017-05-12

Hereditary retinal degenerations encompass a group of genetic diseases characterized by extreme clinical variability. Following next-generation sequencing and autozygome-based screening of patients presenting with a peculiar, recessive form of cone-dominated retinopathy, we identified five homozygous variants [p.(Asp594fs), p.(Gln117*), p.(Met712fs), p.(Ile756Phe), and p.(Glu543Lys)] in the polyglutamylase-encoding gene TTLL5, in eight patients from six families. The two male patients carrying truncating TTLL5 variants also suffered from a substantial reduction in sperm motility and infertility, whereas those carrying missense changes were fertile. Defects in this polyglutamylase in humans have recently been associated with cone photoreceptor dystrophy, while mouse models carrying truncating mutations in the same gene also display reduced fertility in male animals. We examined the expression levels of TTLL5 in various human tissues and determined that this gene has multiple viable isoforms, being highly expressed in testis and retina. In addition, antibodies against TTLL5 stained the basal body of photoreceptor cells in rat and the centrosome of the spermatozoon flagellum in humans, suggesting a common mechanism of action in these two cell types. Taken together, our data indicate that mutations in TTLL5 delineate a novel, allele-specific syndrome causing defects in two as yet pathogenically unrelated functions, reproduction and vision.

Malattia Leventinese, also known as dominant radial drusen or Doyne honeycomb retinal dystrophy, was first described in patients living in the Leventine Valley in canton Ticino of southern Switzerland in 1925. A missense mutation (Arg345Trp) in the gene EFEMP1 was discovered to be causative for both conditions. Malattia Leventinese is reported to be autosomal dominant with variable expressivity phenotype. Characteristic clinical findings consist of radial macular drusen, large confluent drusen, and juxtapapillary drusen, which can be an isolated finding. Early visual symptoms, typically starting at age of 30–50 years, include reduced central vision, photophobia, and metamorphopsia. The vision gradually deteriorates over many years. No curative treatment is available for ML; however, some prophylactic argon laser treatment has been promising in improving visual acuity and reducing the drusen volume. Anti-vascular endothelial growth (VEGF) treatment is efficient in stabilizing a choroidal neovascular membrane.

PURPOSE To report on the clinical and electrophysiological findings in a patient with oculo auricular syndrome due to HMX1 mutation with a follow up of 12 years. BACKGROUND Oculo auricular syndrome (MIM: 612109) is a rare developmental recessive condition affecting the eye and external ear that results from a mutation in the HMX1 gene. Previously described ocular abnormalities include bilateral microcornea posterior synechiae cataract chorioretinal colobomas and rod cone dystrophy. METHODS Retrospective chart review of an affected boy followed over a period of 12 years who had serial complete ophthalmologic examinations fundus photographs Goldmann perimetry and full field electroretinograms (ERG). RESULTS Initial ERG tracings revealed generalized rod more than cone dysfunction. Thereafter a rapid deterioration in rod and cone function was detected on follow up ERGs. CONCLUSION The retinal degeneration in the recessively inherited oculo auricular syndrome is a progressive rod cone dystrophy. Visual prognosis is guarded considering the progressive nature of the retinal dystrophy in early infancy.

PRPF8-retinitis pigmentosa is said to be severe but there has been no overview of phenotype across different mutations. We screened RP patients for PRPF8 mutations and identified three new missense mutations, including the first documented mutation outside exon 42 and the first de novo mutation. This brings the known RP-causing mutations in PRPF8 to nineteen. We then collated clinical data from new and published cases to determine an accurate prognosis for PRPF8-RP. Clinical data for 75 PRPF8-RP patients were compared, revealing that while the effect on peripheral retinal function is severe, patients generally retain good visual acuity in at least one eye until the fifth or sixth decade. We also noted that prognosis for PRPF8-RP differs with different mutations, with p.H2309P or p.H2309R having a worse prognosis than p.R2310K. This correlates with the observed difference in growth defect severity in yeast lines carrying the equivalent mutations, though such correlation remains tentative given the limited number of mutations for which information is available. The yeast phenotype is caused by lack of mature spliceosomes in the nucleus, leading to reduced RNA splicing function. Correlation between yeast and human phenotypes suggests that splicing factor RP may also result from an underlying splicing deficit. (C) 2010 Wiley-Liss, Inc.

Purpose The aim of this study was to report detailed genotype/phenotype correlation in two British autosomal dominant retinitis pigmentosa (adRP) families with recently described mutations in PRPF8. Methods Ten affected members from the two families (excluded for PRPF31 mutations) were assessed clinically. Seven subjects had fundus photography; some had electrophysiology, autofluorescence imaging, and visual field testing. Linkage analysis was performed from genomic DNA in one family. RNA was extracted from lymphocytes of the proband from both families, reverse transcribed into cDNA and subsequently screened for mutations in PRPF8. Segregation of mutations in each family was tested by direct genomic sequencing of the specific exons carrying the mutation. Results All affected members complained of nyctalopia with variable age of onset. In the first family, there was marked variation in the clinical phenotype among affected individuals ranging from severe rod-cone dystrophy to a 67-year-old patient with a normal retinal appearance and mild rod dysfunction on scotopic electroretinography (ERG). The second family demonstrated similar variability and a history of a nonpenetrant individual. Linkage analysis in the first family showed strong evidence for linkage to markers on chromosome 17p implicating PRPF8 as a candidate gene. A c.6353 C>T change causing a nonconservative missense mutation p.S2118F was found in exon 38 of PRPF8 by direct sequencing of the cDNA. The mutation c.6930G>C (p.R2310S) was found in the second family. Conclusions This is the first report of marked intrafamilial variability associated with mutations in the PRPF8 gene, including incomplete penetrance. PRPF8 mutations should be suspected in patients with adRP and variable expressivity.

PURPOSE: To characterize the clinical, psychophysical, and electrophysiological phenotypes in a five-generation Swiss family with dominantly inherited retinitis pigmentosa caused by a T494M mutation in the Precursor mRNA-Processing factor 3 (PRPF3) gene, and to relate the phenotype to the underlying genetic mutation. METHODS: Eleven affected patients were ascertained for phenotypic and genotypic characterization. Ophthalmologic evaluations included color vision testing, Goldmann perimetry, and digital fundus photography. Some patients had autofluorescence imaging, Optical Coherence Tomography, and ISCEV-standard full-field electroretinography. All affected patients had genetic testing. RESULTS: The age of onset of night blindness and the severity of the progression of the disease varied between members of the family. Some patients reported early onset of night blindness at age three, with subsequent severe deterioration of visual acuity, which was 0.4 in the best eye after their fifties. The second group of patients had a later onset of night blindness, in the mid-twenties, with a milder disease progression and a visual acuity of 0.8 at age 70. Fundus autofluorescence imaging and electrophysiological and visual field abnormalities also showed some degree of varying phenotypes. The autofluorescence imaging showed a large high-density ring bilaterally. Myopia (range: -0.75 to -8) was found in 10/11 affected subjects. Fundus findings showed areas of atrophy along the arcades. A T494M change was found in exon 11 of the PRPF3 gene. The change segregates with the disease in the family. CONCLUSIONS: A mutation in the PRPF3 gene is rare compared to other genes causing autosomal dominant retinitis pigmentosa (ADRP). Although a T494M change has been reported, the family in our study is the first with variable expressivity. Mutations in the PRPF3 gene can cause a variable ADRP phenotype, unlike in the previously described Danish, English, and Japanese families. Our report, based on one of the largest affected pedigree, provides a better understanding as to the phenotype/genotype description of ADRP caused by a PRPF3 mutation.

Purpose To characterize the clinical, psychophysical, and electrophysiological phenotype of 19 patients with enhanced S-cone syndrome (ESCS) and relate the phenotype to the underlying genetic mutation. Methods Patients underwent ophthalmic examination and functional testing including pattern ERG, full-field ERG, and long-duration and short-wavelength stimulation. Further tests were performed in some patients, including color contrast sensitivity (CCS), multifocal ERG, fundus autofluorescence imaging (FAI), optical coherence tomography (OCT), and fundus fluorescein angiography (FFA). Mutational screening of NR2E3 was undertaken in 13 patients. Results The fundus appearance was variable, from normal to typical nummular pigment clumping at the level of the retinal pigment epithelium in older patients. Nine patients had foveal schisis, and one had peripheral schisis. Pattern ERG was abnormal in all patients. In all patients, ISCEV Standard photopic and scotopic responses had a similar waveform, the rod-specific-ERG was undetectable and the 30-Hz flicker ERG was markedly delayed with an amplitude lower than the photopic a-wave. Most ERG responses arose from short-wavelength-sensitive mechanisms, and a majority of patients showed possible OFF-related activity. Multifocal ERG showed relative preservation of central function, but reduced responses with increased eccentricity. Mutations were identified in NR2E3 in 12 of 13 patients including four novel variants. Conclusions The phenotype in ESCS is variable, both in fundus appearance and in the severity of the electrophysiological abnormalities. The ERGs are dominated by short-wavelength-sensitive mechanisms. The presence, in most of the patients, of possible OFF-related ERG activity is a finding not usually associated with S-cones.

Enhanced S-cone syndrome (ESCS) is a rare autosomal recessive disorder related to mutations in NR2E3. There is early nyctalopia with peripheral field loss and possible macular involvement with loss of central vision. 1 Signs include nummular pigmentary deposition at the level of the retinal pigment epithelium (RPE) around the vascular arcades and foveal schisis. There are no rods; most of an increased number of cones are short-wavelength sensitive. 2 ¿ 4 There are pathognomonic electroretinography (ERG) changes. NR2E3 encodes a transcription factor which promotes differentiation and survival ¿

Purpose Missense mutations in the splicing factor gene PRPF31 cause a dominant form of retinitis pigmentosa (RP11) with reduced penetrance. Missense mutations in PRPF31 have previously been shown to cause reduced protein solubility, suggesting insufficiency of functional protein as the disease mechanism. Here we examine in further detail the effect of the A216P mutation on splicing function. Methods Splicing activity was assayed using an in vivo assay in transfected mammalian cells with rhodopsin (RHO) and transducin (GNAT1) splicing templates. Pull-down assays were used to study the interaction between PRPF31 and one of its cognate partners in the spliceosome, PRPF6. Results Splicing of RHO intron 3 and GNAT1 introns 3–5 mini-gene templates was inefficient with both spliced and unspliced products clearly detected. Assays using the RHO minigene template revealed a direct negative effect on splicing efficiency of the mutant. However, no effect of the mutation on splicing efficiency could be detected using the longer GNAT1 minigene template or using a full-length RHO transcript, splicing of which had an efficiency of 100%. No unspliced RHO transcripts could be detected in RNA from human retina. Pull-down assays between PRPF31 and PRPF6 proteins showed a stronger interaction for the mutant than wild type, suggesting a mechanism for the negative effect. Conclusions Splicing of full-length RHO is more efficient than splicing of the minigene, and assays using a full-length template more accurately mimic splicing in photoreceptors. The RP11 missense mutations exert their pathology mainly via a mechanism based on protein insufficiency due to protein insolubility, but there is also a minor direct negative effect on function.

To determine if integrity of the retinal pigment epithelium (RPE)/photoreceptor complex as assessed by autofluorescence imaging can be predicted on the basis of visual acuity (VA), size, or fluorescein angiographic characteristics of the lesion in the early stage of choroidal neovascularization in age-related macular degeneration (AMD).Prospective, observational, consecutive case series.Seventy-nine eyes of 78 patients with untreated early-stage subfoveal neovascular AMD.Digital color fundus photography and fluorescein angiography were carried out by certified photographers using the same camera throughout the study. Confocal scanning laser ophthalmoscopy images were obtained using a retinal angiograph. Autofluorescence images were compared with digital fluorescein angiography and fundus color photographs using IMAGEnet.Autofluorescence at the macula was correlated with VA, angiographic lesion characteristics, lesion size, and length of symptoms.Of the 79 eyes studied, 40 had classic and predominantly classic choroidal neovascularization, 10 had minimally classic, 29 had occult, 75 were subfoveal, and 4 were juxtafoveal. In 54 eyes, autofluorescence was continuous at the central macula, and this correlated significantly with VA, lesion size, and symptom length but not choroidal neovascularization type. However, there was considerable overlap between the 2 groups such that the integrity of RPE autofluorescence could not be predicted on the basis of these criteria.Intact autofluorescence at the macula in early choroidal neovascularization correlates with VA, lesion size, and symptom length but not lesion type. None predict with any certainty the integrity of the outer retina. Our data suggest that the RPE/photoreceptor complex may be intact at the macula for several months in the presence of choroidal neovascularization, suggesting that VA might be rescued if treatment were effective in suppressing neovascular growth without damaging the RPE/retina complex, although this remains to be tested. It would be sensible to assess autofluorescence in treatment protocols to test this concept because it may be a marker for earlier disease and predict outcomes of treatment.

PURPOSE. Retinitis pigmentosa is a clinically and genetically heterogeneous disorder. It is characterized by progressive degeneration of the peripheral retina, leading to night blindness and loss of the peripheral visual field. PRPF31 is one of four pre-mRNA splicing factors identified as causing autosomal dominant retinitis pigmentosa, with incomplete penetrance being the unique feature associated with mutations in this gene. The purpose of this study was to identify PRPF31 mutations in a cohort of 118 cases of autosomal dominant retinitis pigmentosa and determine the genotype-phenotype correlation emerging from the spectrum of mutations in this gene.METHODS. Probands with autosomal dominant retinitis pigmentosa underwent. ophthalmic evaluation. Blood samples were obtained, genomic DNA was isolated, and PRPF31 exons along with adjacent splice junctions were amplified by PCR and screened by direct sequencing.RESULTS. In the 118 individuals with autosomal dominant retinitis pigmentosa, six mutations were identified, of which four were novel. One previously known splice site mutation was identified in two other apparently unrelated families.CONCLUSIONS. Mutations in PRPF31 causing adRP were present in nearly 5% of a mixed U.K. population. The age of onset and the severity of the disease varied with different mutations. In addition, individuals carrying the same mutation showed a range of phenotypic variation, suggesting the involvement of other modifying genes.

X-linked retinoschisis (XLRS) is a common cause of macular dysfunction in young men,1,2 with an incidence of 1 in 5000 to 1 in 25 000.3 Individuals with XLRS are typically first identified as school-aged boys who fail vision screening examinations (60%), have strabismus (30%), or have vitreous hemorrhage.1,2,4 Initially, the characteristic “spoke-wheel” appearance may be seen at the fovea, caused by cystic changes,3 but this is commonly replaced with nonspecific macular atrophy in middle age.5 There is allelic heterogeneity at the retinoschisis (X-linked, juvenile) 1 locus (RS1), with different mutations causing a wide spectrum of phenotypes. The gene mutated in XLRS, RS1, has 6 exons that encode the 224–amino acid protein retinoschisin, which is processed by means of N-terminal cleavage of a 23–amino acid hydrophobic leader sequence into a mature protein of 201 amino acid residues (23 kDa) and is assembled into a disulfide-linked octamer.6 In many cases, this mutant protein cannot fold properly and is retained intracellularly.4 The predicted protein sequence contains a highly conserved discoidin domain, which is implicated in cell-cell adhesion and phospholipid binding. This function is consistent with the observed splitting of the fiber layer of Henle in the retina of patients with XLRS,7,8 suggesting that retinoschisin is essential during retinal development.9 The electronegative electroretinographic (ERG) configuration that is typically seen in patients with XLRS describes a waveform with a b-wave smaller than the a-wave and suggests that the primary functional defect occurs after phototransduction or is inner retinal. This study describes 7 patients with genetically confirmed mutations in RS1 that manifest atypical signs in the form of multiple white spots at the macula. The genotype and functional (ERG) phenotype are described.

Biallelic gene defects in MFSD8 are not only a cause of the late-infantile form of neuronal ceroid lipofuscinosis, but also of rare isolated retinal degeneration. We report clinical and genetic data of seven patients compound heterozygous or homozygous for variants in MFSD8, issued from a French cohort with inherited retinal degeneration, and two additional patients retrieved from a Swiss cohort. Next-generation sequencing of large panels combined with whole-genome sequencing allowed for the identification of twelve variants from which seven were novel. Among them were one deep intronic variant c.998+1669A>G, one large deletion encompassing exon 9 and 10, and a silent change c.750A>G. Transcript analysis performed on patients’ lymphoblastoid cell lines revealed the creation of a donor splice site by c.998+1669A>G, resulting in a 140 bp pseudoexon insertion in intron 10. Variant c.750A>G produced exon 8 skipping. In silico and in cellulo studies of these variants allowed us to assign the pathogenic effect, and showed that the combination of at least one severe variant with a moderate one leads to isolated retinal dystrophy, whereas the combination in trans of two severe variants is responsible for early onset severe retinal dystrophy in the context of late-infantile neuronal ceroid lipofuscinosis.

Objective: To identify disease causing mutation in three generations of a Swiss family with pattern dystrophy and high intrafamilial variability of phenotype. To assess the effect of intravitreal ranibizumab injections in the treatment of subfoveal choroidal neovascularization associated with pattern dystrophy in one patient. Methods: Affected family members were ascertained for phenotypic and genotypic characterization. Ophthalmic evaluations included fundus photography, autofluorescence imaging, optical coherence tomography, and International Society for Clinical Electrophysiology of Vision standard full-field electroretinography. When possible family members had genetic testing. The proband presented with choroidal neovascularization and had intravitreal injections as needed according to visual acuity and optical coherence tomography. Results: Proband had a multifocal type pattern dystrophy, and his choroidal neovascularization regressed after four intravitreal injections. The vision improved from 0.8 to 1.0, and optical coherence tomography showed complete anatomical restoration. A butterfly-shaped pattern was observed in her cousin, whereas a fundus pulverulentus pattern was seen in a second cousin. Aunt had a multifocal atrophic appearance, simulating geographic atrophy in age-related macular degeneration. The Y141C mutation was identified in the peripherin/RDS gene and segregated with disease in the family. Conclusion: This is the first report of marked intrafamilial variation of pattern dystrophy because of peripherin/RDS Y141C mutation. Intravitreal ranibizumab injections might be a valuable treatment for associated subfoveal choroidal neovascularization. RETINA 32:1942-1949, 2012