A Prospective, Observational, Non-interventional Clinical Study of Participants With Choroideremia: The NIGHT Study.

PURPOSE: The NIGHT study aimed to assess the natural history of choroideremia (CHM), an X-linked inherited chorioretinal degenerative disease leading to blindness, and determine which outcomes would be the most sensitive for monitoring disease progression. DESIGN: A prospective, observational, multicenter cohort study. METHODS: Males aged ≥18 years with genetically confirmed CHM, visible active disease within the macular region, and best-corrected visual acuity (BCVA) ≥34 Early Treatment Diabetic Retinopathy Study (ETDRS) letters at baseline were assessed for 20 months. The primary outcome was the change in BCVA over time at Months 4, 8, 12, 16, and 20. A range of functional and anatomical secondary outcome measures were assessed up to Month 12, including retinal sensitivity, central ellipsoid zone (EZ) area, and total area of fundus autofluorescence (FAF). Additional ocular assessments for safety were performed. RESULTS: A total of 220 participants completed the study. The mean BCVA was stable over 20 months. Most participants (81.4% in the worse eye and 77.8% in the better eye) had change from baseline > -5 ETDRS letters at Month 20. Interocular symmetry was low overall. Reductions from baseline to Month 12 were observed (worse eye, better eye) for retinal sensitivity (functional outcome; -0.68 dB, -0.48 dB), central EZ area (anatomical outcome; -0.276 mm2, -0.290 mm2), and total area of FAF (anatomical outcome; -0.605 mm2, -0.533 mm2). No assessment-related serious adverse events occurred. CONCLUSIONS: Retinal sensitivity, central EZ area, and total area of FAF are more sensitive than BCVA in measuring the natural progression of CHM.

Choroideremia presenting as vision loss secondary to choroidal neovascularization.

BACKGROUND: Choroidal neovascularization (CNV) is a rare complication of choroideremia that occurs secondary to relative atrophy of the retinal pigment epithelium and eventual rupture of Bruch's membrane. The ideal management of CNV in choroideremia is unclear. MATERIALS AND METHODS: Case report. OBSERVATIONS: A 14-year-old male with no known ocular history presented to the eye emergency department complaining of a central scotoma in the right eye for 4 days. He had no past medical history and family history was unremarkable for known ocular disease. Visual acuity was 20/70 in the right eye and 20/30 in the left eye. Posterior segment exam revealed chorioretinal atrophy extending from the outer macula to the midperiphery in both eyes. There was CNV with associated subretinal hemorrhage in the right eye. Optical coherence tomography demonstrated the presence of CNV with subretinal fluid in the right eye and parafoveal outer retinal atrophy in both eyes. Genetic testing revealed a hemizygous exon 2 deletion on the CHM gene, pathogenic for choroideremia. The patient received a total of 3 injections 4 weeks apart followed by 1 injection 6 weeks later with resolution of the subretinal hemorrhage and reduction in CNV size with improvement in visual acuity to 20/20 at last follow-up exam. CONCLUSIONS AND IMPORTANCE: Choroidal neovascularization is a rare cause of central vision loss in patients with choroideremia. In this report, we demonstrate a good functional and anatomic response to intravitreal bevacizumab in a 14-year-old patient with undiagnosed choroideremia who presented with CNV-induced central vision loss.

Female carriers of X-linked inherited retinal diseases - Genetics, diagnosis, and potential therapies.

Inherited retinal diseases (IRDs) are a group of heterogeneous conditions that cause progressive vision loss, typically due to monogenic mutations. Female carriers of X-linked IRDs have a single copy of the disease-causing gene, and therefore, may exhibit variable clinical signs that vary from near normal retina to severe disease and vision loss. The relationships between individual genetic mutations and disease severity in X-linked carriers requires further study. This review summarises the current literature surrounding the spectrum of disease seen in female carriers of choroideremia and X-linked retinitis pigmentosa. Various classification systems are contrasted to accurately grade retinal disease. Furthermore, genetic mechanisms at the early embryonic stage are explored to potentially explain the variability of disease seen in female carriers. Future research in this area will provide insight into the association between genotype and retinal phenotypes of female carriers, which will guide in the management of these patients. This review acknowledges the importance of identifying which patients may be at high risk of developing severe symptoms, and therefore should be considered for emerging treatments, such as retinal gene therapy.

Cone Photoreceptor Morphology in Choroideremia Assessed Using Non-Confocal Split-Detection Adaptive Optics Scanning Light Ophthalmoscopy.

Purpose: Choroideremia (CHM) is an X-linked inherited retinal degeneration causing loss of the photoreceptors, retinal pigment epithelium, and choriocapillaris, although patients typically retain a central island of relatively preserved, functioning retina until late-stage disease. Here, we investigate cone photoreceptor morphology within the retained retinal island by examining cone inner segment area, density, circularity, and intercone space. Methods: Using a custom-built, multimodal adaptive optics scanning light ophthalmoscope, nonconfocal split-detection images of the photoreceptor mosaic were collected at 1°, 2°, and 4° temporal to the fovea from 13 CHM and 12 control subjects. Cone centers were manually identified, and cone borders were segmented. A custom MATLAB script was used to extract area and circularity for each cone and calculate the percentage of intercone space in each region of interest. Bound cone density was also calculated. An unbalanced two-way ANOVA and Bonferroni post hoc tests were used to assess statistical differences between the CHM and control groups and along retinal eccentricity. Results: Cone density was lower in the CHM group than in the control group (P < 0.001) and decreased with eccentricity from the fovea (P < 0.001). CHM cone inner segments were larger in area (P < 0.001) and more circular (P = 0.042) than those of the controls. Intercone space in CHM was also higher than in the controls (P < 0.001). Conclusions: Cone morphology is altered in CHM compared to control, even within the centrally retained, functioning retinal area. Further studies are required to determine whether such morphology is a precursor to cone degeneration.

Clinical and Genetic Findings in Korean Patients with Choroideremia.

PURPOSE: We share and analyze the clinical presentations and genotypes of Korean male patients and female carriers who visited our clinic. METHODS: Six male patients and three female carriers with comprehensive ophthalmic examinations and next-generation sequencing were included. Detailed clinical features were identified using visual field (VF) test and multimodal imaging including color fundus photography, fundus autofluorescence (FAF), and optical coherence tomography (OCT). RESULTS: Six male patients were diagnosed with choroideremia at the median age of 25 years. Before genetic testing, three patients (50.0%) were clinically diagnosed with choroideremia, while the other three patients (50.0%) with retinitis pigmentosa. Patients showed different types of hemizygous CHM variants, including two nonsense variants, c.715C>T:p.(Arg239*) and c.799C>T:p.(Arg267*); two frameshift variants, c.1584_1587del:p.(Val529Hisfs*7) and c.403_404del:p.(Asp135Phefs*9); one splicing variant c.1511-28_1511-2del; and one exon 2-8 duplication. The latter three variants were novel. Two female carriers had heterozygous exon 2-8 duplication and the other one female carrier had heterozygous nonsense variant c.715C>T:p. (Arg239*). Fundus showed diffuse yellow-whitish scleral reflex and granular pigmented lesions. FAF showed multiple patchy hypofluorescence lesions, sparing macula. OCT showed thinning of outer nuclear layer, ellipsoid zone, retinal pigment epithelium layer, choroid thickness, interlaminar bridges, outer retinal tubulations, and microcysts in the inner nuclear layer. VF showed ring scotoma pattern with small amount of remaining central field. Asymptomatic female carriers showed variable fundus findings and mild changes in OCT. CONCLUSIONS: A detailed description of the genotypes with three novel mutations and phenotypes of six choroideremia patients and three CHM mutation female carriers are presented.

Outer retinal and choriocapillaris modifications in choroideremia: three differentially impaired retinal regions and the potential diagnostic role of the external limiting membrane.

BACKGROUND: The external limiting membrane (ELM) is formed by the apical processes of Müller cells attached to the inner segments of the photoreceptor cells. Both cells are implicated in the pathogenesis of choroideremia (CHM). The purpose of this study was to explore the diagnostic role of ELM in CHM. METHODS: The study was designed as observational case series. Sixteen CHM eyes were examined by multimodal imaging and were compared to healthy controls. The main outcome was the measurement of ELM thickness and reflectivity over the follow-up, and its relationship with other multimodal imaging quantitative parameters. RESULTS: Baseline ELM was characterized by 11 ± 1 µm of thickness and 0.68 ± 0.13 of reflectivity, resulting 8 ± 1 µm (p < 0.01) and 0.65 ± 0.14 (p > 0.05) at the last follow-up. Choriocapillaris (CC) analysis revealed 3 regions. The first was characterized by normal vessel density (VD). The second surrounding the partially preserved islet, showing significantly lower baseline VD and undergoing minor changes over the follow-up. The third was localized in the partially preserved islet, showing significantly lower VD at baseline, and resulted atrophic at the last follow-up. ELM reflectivity and ELM thickness correlated both with outer retinal atrophy progression and the CC status. CONCLUSIONS: ELM may be considered a useful imaging biomarker in CHM. Its assessment confirmed a primary role of Müller cells impairment in the pathogenesis of CHM.

AAV2-Mediated Gene Therapy for Choroideremia: 5-Year Results and Alternate Anti-sense Oligonucleotide Therapy.

PURPOSE: To assess the long-term safety and efficacy of AAV2-REP1 in choroideremia (CHM) patients, and to test a potential antisense oligonucleotide therapy for CHM. DESIGN: Extended, prospective phase 1/2 clinical trial and laboratory investigation. METHODS: Five patients who received a single subfoveal injection of AAV2-REP1 were studied. The long-term safety was evaluated by ophthalmic examination, spectral domain optical coherence tomography, and fundus autofluorescence (FAF) for up to 5 years. Functional and structural changes were determined by different test modalities. Four antisense oligonucleotides (ASOs) were designed to treat the CHM c.1245-521A>G mutation, which was present in 2 patients within this trial. RESULTS: Subject P3 experienced a localized intraretinal immune response that resulted in a significant loss of preserved retinal pigment epithelium (RPE). P4 experienced an exacerbation of peripheral retinoschisis. P2 had a constant ≥15-letter best-corrected visual acuity (BCVA) gain in the treated eye, whereas P5 had ≥15-letter BCVA improvement once in the untreated eye. The preserved FAF areas declined more rapidly in the treated eyes compared to the untreated eyes (P = .043). A customized 25-mer ASO recovered 83.2% to 95.0% of the normal RNA and 57.5% of the normal protein in fibroblasts from 2 trial patients. CONCLUSIONS: Intraretinal inflammation triggered by AAV2-REP1 subretinal injection stabilized after 2 years but resulted in permanent damage to the retinal structure. Long-term progression of the disease was seen in both treated and untreated eyes, casting doubt as to the effectiveness of this approach in late-stage CHM. Alternative approaches such as ASO may have a therapeutic effect in a subgroup of CHM patients.

DANON DISEASE: A MODEL OF PHOTORECEPTOR DEGENERATION SECONDARY TO PRIMARY RETINAL PIGMENT EPITHELIUM DISEASE.

PURPOSE: To describe in detail the retinal phenotype of LAMP2-associated Danon disease. METHODS: Three LAMP2-positive patients from two unrelated families were studied with spectral-domain optical coherence tomography and with short-wavelength and near-infrared fundus autofluorescence (FAF) imaging. Visual function was measured with full-field electroretinography and chromatic perimetry. A patient with choroideremia was also studied for comparison. RESULTS: A 45-year-old LAMP2-heterozygous woman, her 21-year-old hemizygous son, and an unrelated heterozygous 60-year-old woman had normal visual acuities. Central spectral-domain optical coherence tomographies were grossly normal in the younger two patients (mother and son). The oldest patient showed a tenuous interdigitation signal, interruptions of the inner segment ellipsoid zone band, and parafoveal outer nuclear layer thinning. Quantitatively, all patients had shorter than normal ellipsoid zone to retinal pigment epithelium distance in pericentral retina, normal at the foveola. A speckled hypoautofluorescence pattern on short-wavelength FAF contrasted with grossly abnormal near-infrared FAF in the heterozygous carriers. The oldest patient had reduced full-field electroretinography amplitudes (to ∼50% of normal) for rod- and cone-mediated responses and her perimetry showed severe rod dysfunction but substantial cone function. A disproportionate loss of the near-infrared FAF compared with the short-wavelength FAF, predominantly outer segment changes, and severe rod dysfunction with preserved cone function was similarly documented in a 9-year-old choroideremia hemizygous patient. CONCLUSION: A disproportionate loss of the near-infrared FAF signal compared with the short-wavelength FAF signal, outer segment abnormalities, and severe rod dysfunction but relatively preserved cone vision suggests a stereotypical pattern of primary retinal pigment epithelial or parallel retinal pigment epithelial + photoreceptor disease in Danon disease.

Choroideremia Carriers: Dark-Adapted Perimetry and Retinal Structures.

Purpose: In choroideremia (CHM) carriers, scotopic sensitivity was assessed by dark adapted chromatic perimetry (DACP) and outer retinal structure was evaluated by multimodal imaging. Methods: Nine carriers (18 eyes) and 13 healthy controls (13 eyes) underwent DACP testing with cyan and red stimuli. Analysis addressed peripapillary (4 test locations closest to the optic disc), macular (52 locations), and peripheral (60 locations outside the macula) regions. Responses were considered to be rod-mediated when cyan relative to red sensitivity was >5 dB. Fundus imaging included spectral domain optical coherence tomography (SD-OCT), short-wavelength (SW-AF), near-infrared (NIR-AF), ultrawide-field (200 degrees) pseudocolor fundus imaging, and quantitative (qAF) fundus autofluorescence. Results: Detection of the cyan stimulus was rod mediated in essentially all test locations (99.7%). In the macular and peripheral areas, DACP sensitivity values were not significantly different from healthy eyes. In the peripapillary area, sensitivities were significantly decreased (P < 0.05). SD-OCT imaging ranged from hyper-reflective lesions and discontinuities of the outer retinal bands to hypertransmission of signal. SW-AF and NIR-AF images presented with peripapillary atrophy in seven patients (14 eyes). Mosaicism was detectable in SW-AF images in seven patients and in NIR-AF images in five patients. Frank hypo-autofluorescence was visible in eight patients with distinct chorioretinopathy in seven patients. The qAF values were below the 95% confidence interval (CI) of healthy age-matched individuals in 12 eyes. Conclusions: Rod mediated scotopic sensitivity was comparable to that in control eyes in macular and peripheral areas but was decreased in the peripapillary area where changes in retinal structure were also most severe.

A Novel Hypothesis on Choroideremia-Manifesting Female Carriers: Could CHM In-Frame Variants Exert a Dominant Negative Effect? A Case Report.

Choroideremia is an X-linked recessive condition presenting in males, with progressive degeneration of retinal and choroidal tissues leading to progressive visual loss. Its pathological mechanism is due to alterations in the CHM gene that encodes for REP1, a protein required for prenylation of Rab by the Rab geranylgeranyl transferase (RGGT). Even though female carriers are predicted to be not affected by the disease, a wide phenotypic spectrum ranging from mild to severe cases has been reported in women. The reason why Choroideremia manifests in female carriers remains elusive. While X chromosome inactivation (XCI) skewing has been proposed as a leading putative mechanism, emerging evidence has shown that CHM could variably escape from XCI. We described a family with an initial clinical suspicion of Retinitis Pigmentosa in which a novel CHM pathogenic splicing variant was found by exome sequencing. The variant, initially found in the 63-year-old female presenting with impaired visual acuity and severe retinal degeneration, segregated in the 31-year-old daughter and the 37-year-old son, both presenting with fundus anomalies. mRNA studies revealed a shorter in-frame CHM isoform lacking exon 10. Molecular modeling of the ternary REP1/Rab/RGGT protein complex predicted significant impairing of REP1/Rab binding without alteration of REP1/RGGT interaction. We suggest that, in our female cases, the biallelic expression of CHM may have led to the production of both the mutant and wild type REP1. The mutant isoform, sequestrating RGGT, could reduce its available amount for Rab prenylation, thus exerting a dominant-negative effect. If confirmed with further studies and in large cohorts of female carriers, the here proposed molecular mechanism could help to explain the complexity of manifestation of Choroideremia in females.

Adeno-Associated Virus Serotype 2-hCHM Subretinal Delivery to the Macula in Choroideremia: Two-Year Interim Results of an Ongoing Phase I/II Gene Therapy Trial.

PURPOSE: To assess the safety of the subretinal delivery of a recombinant adeno-associated virus serotype 2 (AAV2) vector carrying a human choroideremia (CHM)-encoding cDNA in CHM. DESIGN: Prospective, open-label, nonrandomized, dose-escalation, phase I/II clinical trial. PARTICIPANTS: Fifteen CHM patients (ages 20-57 years at dosing). METHODS: Patients received uniocular subfoveal injections of low-dose (up to 5 × 1010 vector genome [vg] per eye, n = 5) or high-dose (up to 1 × 1011 vg per eye, n = 10) of a recombinant adeno-associated virus serotype 2 (AAV2) vector carrying a human CHM-encoding cDNA (AAV2-hCHM). Patients were evaluated preoperatively and postoperatively for 2 years with ophthalmic examinations, multimodal retinal imaging, and psychophysical testing. MAIN OUTCOME MEASURES: Visual acuity, perimetry (10-2 protocol), spectral-domain OCT (SD-OCT), and short-wavelength fundus autofluorescence (SW-FAF). RESULTS: We detected no vector-related or systemic toxicities. Visual acuity returned to within 15 letters of baseline in all but 2 patients (1 developed acute foveal thinning, and 1 developed a macular hole); the rest showed no gross changes in foveal structure at 2 years. There were no significant differences between intervention and control eyes in mean light-adapted sensitivity by perimetry or in the lateral extent of retinal pigment epithelium relative preservation by SD-OCT and SW-FAF. Microperimetry showed nonsignificant (< 3 standard deviations of the intervisit variability) gains in sensitivity in some locations and participants in the intervention eye. There were no obvious dose-dependent relationships. CONCLUSIONS: Visual acuity was within 15 letters of baseline after the subfoveal AAV2-hCHM injections in 13 of 15 patients. Acute foveal thinning with unchanged perifoveal function in 1 patient and macular hole in 1 patient suggest foveal vulnerability to the subretinal injections. Longer observation intervals will help establish the significance of the minor differences in sensitivities and rate of disease progression observed between intervention and control eyes.

Automated Assessment of Photoreceptor Visibility in Adaptive Optics Split-Detection Images Using Edge Detection.

Purpose: Adaptive optics scanning laser ophthalmoscopy (AOSLO) is a high-resolution imaging modality that allows measurements of cellular-level retinal changes in living patients. In retinal diseases, the visibility of photoreceptors in AOSLO images is affected by pathology, patient motion, and optics, which can lead to variability in analyses of the photoreceptor mosaic. Current best practice for AOSLO mosaic quantification requires manual assessment of photoreceptor visibility across overlapping images, a laborious and time-consuming task. Methods: We propose an automated measure for quantification of photoreceptor visibility in AOSLO. Our method detects salient edge features, which can represent visible photoreceptor boundaries in each image. We evaluate our measure against two human graders and two standard automated image quality assessment algorithms. Results: We evaluate the accuracy of pairwise ordering (PO) and the correlation of ordinal rankings (ORs) of photoreceptor visibility in 29 retinal regions, taken from five subjects with choroideremia. The proposed measure had high association with manual assessments (Grader 1: PO = 0.71, OR = 0.61; Grader 2: PO = 0.67, OR = 0.62), which is comparable with intergrader reliability (PO = 0.76, OR = 0.75) and outperforms the top standard approach (PO = 0.57; OR = 0.46). Conclusions: Our edge-based measure can automatically assess photoreceptor visibility and order overlapping images within AOSLO montages. This can significantly reduce the manual labor required to generate high-quality AOSLO montages and enables higher throughput for quantitative studies of photoreceptors. Translational Relevance: Automated assessment of photoreceptor visibility allows us to more rapidly quantify photoreceptor morphology in the living eye. This has applications to ophthalmic medicine by allowing detailed characterization of retinal degenerations, thus yielding potential biomarkers of treatment safety and efficacy.

[Genetic diagnosis of 3 families with choroideremia].

OBJECTIVE: To analyze the clinical manifestations and causative gene variants of the choroideremia patients, and to help the patients bedifferential diagnosed by whole exome sequencing and provide theoretical basis for their genetic counseling. METHODS: Clinical data of 3 families were collected and genomic DNA was extracted respectively from peripheral blood of patients and related subjects. Exome targeted sequencing was used to screen suspicious gene mutations. Sanger sequencing and quantitative PCR were used to verify the candidate mutations and investigate the mutation carrying status of other members of the family. The candidate mutations were searched through HGMD and PubMed databases for the pathogenicity reports, and the pathogenicity of candidate mutations was judged according to a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. RESULTS: The proband of family 1 is c.1584_1587del (p.Val529Hisfs*6) variant hemizygote, whose daughter carries c.1584_1587del (p.Val529Hisfs*6) heterozygous variation. The proband of family 2 is a hemizygote with deletion of exons 10 to 15 (E10-15del), and her mother and sister carry the E10-15del heterozygous variation. In family 3, the proband is c.544delT (p.Cys182Valfs*14) variant hemizygote, and his mother is c.544delT (p.Cys182Valfs*14) heterozygote, but the father do not detect this variant. All the 3 families were detected pathogenic gene variations of CHM, two of which were known pathogenic variation and one of which was novel CHM gene c.544delT (p.C182Vfs*14) in this study. The c.544delT frameshift mutation of CHM gene can lead to the premature termination of the product protein translation and nonfunctioning protein. It is a pathogenic mutation according to ACMG guidelines. CONCLUSION: The findings of this study expand the gene variation spectrum of choroideremia.

Repair of Rhegmatogenous Retinal Detachment in Choroideremia Secondary to Posterior Extramacular Retinal Hole.

Rhegmatogenous retinal detachment in choroideremia is a rare occurrence. The authors present a case of a 23-year-old man with choroideremia with a near-total rhegmatogenous retinal detachment. Fundus examination did not reveal any retinal breaks, but extensive preoperative optical coherence tomography detected a small posterior hole along the superior arcades. The retinal detachment was successfully managed with vitrectomy, perfluorooctane to confirm the absence of any peripheral breaks, endolaser, and 20% sulfur hexafluoride gas. Similar extramacular holes were found in the patient's other eye. Patients with choroideremia may develop posterior retinal breaks leading to retinal detachment.

Short-term Assessment of Subfoveal Injection of Adeno-Associated Virus-Mediated hCHM Gene Augmentation in Choroideremia Using Adaptive Optics Ophthalmoscopy.

Importance: Subretinal injection for gene augmentation in retinal degenerations forcefully detaches the neural retina from the retinal pigment epithelium, potentially damaging photoreceptors and/or retinal pigment epithelium cells. Objective: To use adaptive optics scanning light ophthalmoscopy (AOSLO) to assess the short-term integrity of the cone mosaic following subretinal injections of adeno-associated virus vector designed to deliver a functional version of the CHM gene (AAV2-hCHM) in patients with choroideremia. Design, Setting, and Participants: This longitudinal case series study enrolled adult patients with choroideremia from February 2015 to January 2016 in the US. To be included in the study, study participants must have received uniocular subfoveal injections of low-dose (5 × 1010 vector genome per eye) or high-dose (1 × 1011 vector genome per eye) AAV2-hCHM. Analysis began February 2015. Main Outcomes and Measures: The macular regions of both eyes were imaged before and 1 month after injection using a custom-built multimodal AOSLO. Postinjection cone inner segment mosaics were compared with preinjection mosaics at multiple regions of interest. Colocalized spectral-domain optical coherence tomography and dark-adapted cone sensitivity was also acquired at each time point. Results: Nine study participants ranged in age from 26 to 50 years at the time of enrollment, and all were White men. Postinjection AOSLO images showed preservation of the cone mosaic in all 9 AAV2-hCHM-injected eyes. Mosaics appeared intact and contiguous 1 month postinjection, with the exception of foveal disruption in 1 patient. Optical coherence tomography showed foveal cone outer segment shortening postinjection. Cone-mediated sensitivities were unchanged in 8 of 9 injected and 9 of 9 uninjected eyes. One participant showed acute loss of foveal optical coherence tomography cone outer segment-related signals along with cone sensitivity loss that colocalized with disruption of the mosaic on AOSLO. Conclusions and Relevance: Integrity of the cone mosaic is maintained following subretinal delivery of AAV2-hCHM, providing strong evidence in support of the safety of the injections. Minor foveal thinning observed following surgery corresponds with short-term cone outer segment shortening rather than cone cell loss. Foveal cone loss in 1 participant raises the possibility of individual vulnerability to the subretinal injection.

A UNILATERAL FOVEAL VITELLIFORM LESION IN A CHOROIDEREMIA CARRIER.

PURPOSE: To describe a unilateral foveal vitelliform lesion associated with subnormal visual acuity in a choroideremia carrier. METHODS: A retrospective case report, assessment of the best-corrected visual acuity, fundus photography, wide-angle scanning laser ophthalmoscopy, optical coherence tomography, and microperimetry. RESULTS: A 37-year-old woman with a pathogenic 907C>T mutation in the choroideremia gene encoding Rab escort protein-1 presented with blurred vision in her left eye.The Snellen best-corrected visual acuity was 20/20 in the right eye and 20/32 in the left eye, a unilateral decrease because it was 20/20 in both eyes at the most recent examination nine years earlier. In the left eye, a large vitelliform lesion with a diameter of 1,300 µ m had developed in the fovea, whereas in the right eye, a smaller similar lesion was seen close to the fovea. Both eyes showed classical radial patterns of multiple bright fundus patches with associated autofluorescence defects and focal drusenoid lesions of the outer retina. CONCLUSION: With its large size and foveal location the vitelliform lesion in this patient's left eye is an unusual manifestation in an otherwise common Rab escort protein-1 mutation carrier state, and its unilaterality fits the assumption of random X-chromosome inactivation.

Chronic untreated retinal detachment in a patient with choroideremia provides insight into the disease process and potential therapy.

AIM: We present the case of a 72-year-old male with advanced choroideremia and a left chronic rhegmatogenous retinal detachment, which to our knowledge is the first formal report of a retinal detachment in this disease. BACKGROUND: Choroideremia is a rare X-linked inherited retinal dystrophy, caused by mutations in the CHM gene which encodes Rab escort protein 1 (REP1), and affected males typically experience a progressive centripetal loss of vision. The disease pathology is caused by a primary retinal pigment epithelium degeneration, which leads to secondary loss of photoreceptors and choriocapillaris. This in turn leads to fusion of the degenerate outer retinal layers resulting in a retinopexy that is known to make subretinal gene therapy particularly challenging in these patients. CONCLUSION: Although retinal gene therapy is commonly targeted to the macular area in choroideremia, the observation of a rhegmatogenous retinal detachment indicates that the peripheral retina may not fuse with the residual choroid as occurs in the equatorial and macular regions. If this hypothesis is correct, targeting gene therapy to the retinal periphery even in advanced cases may be feasible and could potentially be used to preserve navigational vision.