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.

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.

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.

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.

Acquired retinoschisis and vitreous hemorrhage as unusual findings in choroideremia: Case report.

PURPOSE: To report a case of choroideremia characterized by peripheral retinoschisis with vascular abnormalities and vitreous hemorrhage. OBSERVATIONS: A 58-year-old man affected by advanced-stage choroideremia was diagnosed with peripheral retinoschisis in both eyes. Vitreous hemorrhage was present in the right eye with a peculiar clot-like lesion at the periphery. At the 1-year follow-up, the vitreous hemorrhage had reabsorbed and the vascular clot-like lesion in the periphery had almost completely disappeared. CONCLUSION AND IMPORTANCE: We have reported fundoscopic and OCT features of peripheral-acquired retinoschisis with vascular abnormalities in a patient with choroideremia. OCT examination is extremely useful in clinical evaluation of the peripheral retinal alterations in these cases, where the absence of the retinal pigment epithelium and the choriocapillaris pose many diagnostic difficulties.

Near-infrared autofluorescence in young choroideremia patients.

Purpose: To study near-infrared autofluorescence (NIR-AF) and short- wave autofluorescence (SW-AF) imaging modalities in young patients affected with choroideremia (CHM).Methods: NIR-AF and SW-AF images, Optical coherence tomography (OCT) and color fundus images were acquired from 3 young CHM patients (6 eyes) enrolled at the Regional Reference Center for Hereditary Retinal Degenerations of the Eye Clinic in Florence.Results: We studied 3 young CHM patients (6 eyes). The mean age of the patients was 17,3 years. Using NIR-AF, patient P1 was characterized by speckled hypo-autofluorescent areas at the posterior pole with a preserved central hyper-autofluorescence while patient P2 and P3 were characterized by a preserved NIR-AF signal only at the fovea. Using SW-AF, patient P1 was characterized by a normal macular autofluorescence and by a speckled FAF pattern involved the vascular arcades while patient P2 and P3 showed well-demarcated hypo-autofluorescence areas involving the posterior pole with a preserved macular autofluorescence. The differences between NIR-AF and SW-AF were more pronounced in advanced stages. In correspondence of preserved NIR-AF, the OCT examination showed regular and continuous outer retinal hyperreflective bands. We observed abnormal RPE/Bruch's membrane complex and EZ band externally to the NIR-AF signal area.Conclusions: NIR-AF imaging confirms an early RPE involvement allowing us to identify and to quantify the RPE pigment loss in choroideremia. For this reason, NIR-AF imaging can be useful for monitoring the progression of the disease and to study the effect of future treatments.

Chronic Choroidal Neovascular Membrane in Choroideremia Treated With Intravitreal Bevacizumab.

Choroidal neovascular membrane (CNVM) is a rare complication of choroideremia. The authors report a case of a 13-year-old male presenting with metamorphopsia and decreased central vision of 1-year duration. Genetic testing was significant for a pathogenic c.1437dupA mutation in the CHM gene. Fundus biomicroscopy showed a subfoveal membrane; diagnosis of CNVM was substantiated with fluorescein angiography and swept-source optical coherence tomography angiography (SS-OCTA). The patient received six injections of intravitreal bevacizumab during a 13-month period with functional and anatomic improvement. Lesion area on SS-OCTA remained stable. CNVM should be suspected in young patients with choroideremia presenting with acute decrease in central vision. Treatment with anti-vascular endothelial growth factor should be considered even in chronic cases. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e188-e192.].

CHOROIDEREMIA: Retinal Degeneration With an Unmet Need.

PURPOSE: Choroideremia is an incurable, X-linked, recessive retinal dystrophy caused by loss of function mutations in the CHM gene. It is estimated to affect approximately 1 in 50,000 male patients. It is characterized by progressive degeneration of the retinal pigment epithelium, choroid, and photoreceptors, resulting in visual impairment and blindness. There is an unmet need in choroideremia, because currently, there are no approved treatments available for patients with the disease. METHODS: We review the patient journey, societal impact, and emerging treatments for patients with choroideremia. RESULTS: Its relative rarity and similarities with other retinal diseases in early years mean that diagnosis of choroideremia can often be delayed. Furthermore, its impact on affected individuals, and wider society, is also likely underestimated. AAV2-mediated gene therapy is an investigational treatment that aims to replace the faulty CHM gene. Early-phase studies reported potentially important visual acuity gains and maintenance of vision in some patients, and a large Phase 3 program is now underway. CONCLUSION: Choroideremia is a disease with a significant unmet need. Interventions that can treat progression of the disease and improve visual and functional outcomes have the potential to reduce health care costs and enhance patient quality of life.

Atypical choroideremia presenting with early-onset macular atrophy.

Choroideremia is an X-linked recessive retinal degeneration predominantly affecting hemizygous males. It is caused by mutations in the CHM gene that encodes the Rab escort protein-1. Characteristic features include early nyctalopia followed by progressive constriction of peripheral visual fields and sparing of the central vision until late in life with a distinct fundoscopic appearance. We present the case of a 17-year-old male with a c.282delT in exon 4 of CHM that has not previously been reported. Phenotypically this patient presented with an atypical choroideremia phenotype of early central macular degeneration in addition to the classic peripheral fundus characteristic findings.

Colour discrimination ellipses in choroideremia.

PURPOSE: The purpose of this study was to characterise alterations in colour discrimination in a cohort of patients with choroideremia prior to gene therapy, using a test previously validated for use in patients with retinal dystrophies. METHODS: We tested 20 eyes of 10 patients with a diagnosis of choroideremia and an age-matched cohort of 10 eyes of 10 normal controls using the "Cambridge Colour Test" (CCT), in which subjects are required to distinguish the gap in a C presented in one of 4 orientations in a Stilling-type array. Colour discrimination was probed along eight axes in the CIE L*u*v* colour space, and the resulting data were plotted in the CIE 1976 chromaticity diagram and fitted with least-squares ellipses. Subsequently, we estimated the achromatic area for each subject by calculating the area of the resultant discrimination ellipse and calculated sensitivity thresholds along relevant colour confusion axes. RESULTS: Colour discrimination-as quantified by log10 of the ellipse area expressed in square 1/1000th2 units in CIE 1976-was 2.26 (range 1.82 to 2.67) for normal subjects and 3.85 (range 2.35 to 5.41) for choroideremia patients. There was a statistically significant correlation between both achromatic area and red-green colour discrimination at the CCT and BCVA, and to a lesser degree between blue colour discrimination at the CCT and BCVA. The majority of ellipses in choroideremia were aligned close to the tritan axis, and loss of sensitivity was significantly larger in the tritan direction than in the red-green. CONCLUSIONS: The majority of our patients demonstrated greater loss in tritan discrimination than in red-green colour discrimination using the CCT. There was a significant correlation between achromatic area and BCVA. In keeping with our current understanding of the machinery of colour vision, there was a significant correlation between BCVA and colour discrimination thresholds, which was stronger for red-green colour discrimination, than for tritan colour discrimination. We propose that this and similar tests of colour discrimination may prove to be suitable tools for assessing functional outcomes in gene therapy trials for choroideremia.

Misdiagnosis of X-linked retinitis pigmentosa in a choroideremia patient with heavily pigmented fundi.

Inherited retinal diseases are thought to be the leading cause of sight loss in the working age population. Mutations found in the RPGR and CHM genes cause retinitis pigmentosa (RP) and choroideremia, respectively. In the first instance, an X-linked family history of visual field loss commonly raises the suspicion of one of these two genes. In choroideremia, the classic description of a white fundal reflex secondary to the widespread chorioretinal degeneration was made over a hundred years ago in Caucasians. But, it is not so obvious in heavily pigmented fundi. Hence, the clinical diagnosis of CHM in non-Caucasian patients may be challenging in the first stages of the disease. Here we report a case of a Southeast Asian gentleman who has a family history of X-linked retinal degeneration and was found to have a confirmed in-frame deletion of 12 DNA nucleotides in exon 15 of the RPGR gene. Later in life, however, his fundal appearance showed unusual areas of circular pigment hypertrophy and clumping. He was therefore tested for carrying a disease-causing mutation in the CHM gene and a null mutation was found. Since gene therapy trials are ongoing for both of these conditions, it has now become critically important to establish the correct genetic diagnosis in order to recruit suitable candidates. Moreover, this case demonstrates the necessity to remain vigilant in the interpretation of genetic results which are inconsistent with clinical features.

Retinal dystrophy and subretinal drusenoid deposits in female choroideremia carriers.

PURPOSE: To describe clinical and molecular characteristics in a group of Italian female choroideremia (CHM) carriers and report fundus patterns. METHODS: We retrospectively studied 11 female carriers belonging to six CHM families examined at the Regional Reference Center for Hereditary Retinal Degenerations at the Eye Clinic in Florence. We took into consideration patients with a comprehensive ophthalmological examination, fundus photography, optical coherence tomography (OCT), full field electro-retinography (ERG), and visual field (VF). All patients were screened for mutations of the CHM gene. RESULTS: Fundus examination revealed retinal abnormalities in all female carriers (11/11) in the study; in particular four fundus patterns were identified: pattern A (RPE dystrophy involving only the peripheral retina), pattern B (RPE dystrophy involving the peripheral retina and the posterior pole with small hypo-pigmented RPE areas), pattern C (RPE dystrophy involving the peripheral retina and the posterior pole with small yellowish well-defined dots), and pattern D (RPE dystrophy involving the peripheral retina and the posterior pole with large hypo-pigmented RPE areas and well-defined yellowish dots). Pattern D was characterized by widespread macular subretinal drusenoid deposits (SDD). Half of the observed mutations were novel mutations. A genotype-phenotype correlation was not identified. CONCLUSIONS: Retinal dystrophy and SDD were detected in our female CHM carriers, and fundus patterns have been described in this study. The recognition of specific fundoscopic patterns may permit a correct diagnosis, an appropriate molecular investigation and genetic counseling.

Single-base substitutions in the CHM promoter as a cause of choroideremia.

Although over 150 unique mutations affecting the coding sequence of CHM have been identified in patients with the X-linked chorioretinal disease choroideremia (CHM), no regulatory mutations have been reported, and indeed the promoter has not been defined. Here, we describe two independent families affected by CHM bearing a mutation outside the gene's coding region at position c.-98: C>A and C>T, which segregated with the disease. The male proband of family 1 was found to lack CHM mRNA and its gene product Rab escort protein 1, whereas whole-genome sequencing of an affected male in family 2 excluded the involvement of any other known retinal genes. Both mutations abrogated luciferase activity when inserted into a reporter construct, and by further employing the luciferase reporter system to assay sequences 5' to the gene, we identified the CHM promoter as the region encompassing nucleotides c.-119 to c.-76. These findings suggest that the CHM promoter region should be examined in patients with CHM who lack coding sequence mutations, and reveals, for the first time, features of the gene's regulation.

Choroidal neovascularization secondary to choroideremia.

CASE REPORT: The case is presented of a 30 year-old man, with night blindness and decreased visual acuity (VA) in both eyes, but more significant in the left eye (LE) of 20/100. Lesions consistent with choroideremia and LE macular hemorrhage was observed in the fundus. CNV was confirmed by OCT. A definitive diagnosis was obtained by genetic study. No treatment was given as the patient did not return. At 6 months there was a regression of CNV with VA 20/25 in the LE. CONCLUSIONS: CNV associated with choroideremia is uncommon. Treatment would antiangiogenic therapy, however spontaneous resolution is possible.

Treatment of cystic macular lesions in hereditary retinal dystrophies.

Cystic macular lesions frequently contribute to impaired visual acuity in hereditary retinal dystrophies. Their pathogenesis varies and is not entirely understood. Carbonic anhydrase inhibitors have proven to be potentially efficacious, although not in all cases. We discuss the various factors and mechanisms implicated in the etiology of cystic macular lesions (anatomical abnormalities, impairment of the blood-retinal barrier, tangential vitreous traction, and mutations in retinoschin, etc.) and the various treatments that have been proposed.