Choroideremia (CHM) is a rare inherited disorder that causes progressive loss. of vision due to degeneration of the choroid and retina. It affects about 1 in 50,000. males and the first symptom of these individuals is usually difficulty seeing at night or in. dim environments. These individuals gradually and progressively lose their side vision. and often become legally blind in young adulthood. The condition is passed through. families by an X-linked pattern of inheritance. This means that females (who have two. X chromosomes) can carry one bad choroideremia gene but usually do not have the. full-blown condition since they also carry a good gene. Since males only have one X. chromosome, they are more vulnerable: if they receive the chromosome with the bad. gene, they will develop the condition.. The mutation in the choroideremia gene causes a lack of RAB Escort Protein-1 (REP-1).. Our group, teamed with that of Dr. M. Seabra, was involved in some of the first attempts. to correct the ...
Choroideremia is an outer retinal degeneration with a characteristic clinical appearance that was first described in the nineteenth century. The disorder begins with reduction of night vision and gradually progresses to blindness by middle age. The appearance of the fundus in sufferers is recognizable by the characteristic pale color caused by the loss of the outer retina, retinal-pigmented epithelium, and choroidal vessels, leading to exposure of the underlying sclera. Choroideremia shows X-linked recessive inheritance and the choroideremia gene (CHM) was one of the first to be identified by positional cloning in 1990. Subsequent identification and characterization of the CHM gene, which encodes Rab escort protein 1 (REP1), has led to better comprehension of the disease and enabled advances in genetic diagnosis. Despite several decades of work to understand the exact pathogenesis, no established treatments currently exist to stop or even slow the progression of retinal degeneration in choroideremia.
Purpose: : To test for copy number variants in the CHM gene. Choroideremia (CHM) is an X-linked progressive chorioretinal degenerative disease that affects 1 in 50,000 males. CHM results from relative deficiency or absence of Rab escort protein-1 which is encoded by the CHM gene; however, the exact pathogenesis remains to be determined. Through genetic studies, we have determined that CHM can arise from partial and complete deletions, insertions, frameshifts, point mutations (missense and nonsense) and splice site mutations in the CHM gene. Methods: : Case control, non-randomized, study design. One female and eight male subjects were identified with fundus features consistent with a clinical diagnosis of CHM. In all cases, previous sequencing of the coding region and adjacent intronic splice sites had not found a mutation. We designed a multiplex ligation-dependent probe amplification (MLPA) assay kit for the detection of copy number variants in the CHM gene. Using this MLPA assay, we tested the ...
Abstract Importance Novel therapies for choroideremia, an X-linked recessive chorioretinal degeneration, demand a better understanding of the primary site(s) of cellular degeneration. Optical coherence tomography angiography allows for choriocapillaris (CC) imaging. We compared the extent of structural alterations of the CC, retinal pigment epithelium, and photoreceptors with multimodal imaging. Observations In a clinical case series conducted from September 15, 2014, through February 5, 2015, 14 eyes of 7 male patients with choroideremia (median age, 34 years [interquartile range, 15-46 years]; age range, 13-48 years), 4 eyes of 2 women with choroideremia carrier state (both in mid-50s), and 6 eyes of 6 controls (median age, 42.5 years [interquartile range, 33-55 years]; age range, 24-55 years) underwent multimodal imaging with optical coherence tomography angiography and electroretinography. The mean (SD) macular CC density was 82.9% (13.4%) in patients with choroideremia, 93.0% (3.8%) in female
Following on from a successful worlds first Phase I gene therapy trial for choroideremia, Professor Robert MacLaren and his team have started a Phase II trial enrolling 30 patients. The project has been funded by the Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council (MRC) and NIHR partnership. In this trial, Professor MacLaren is using an operating microscope with integrated optical coherence tomography (OCT) that will refine the surgery that is integral to the gene replacement therapy. The purchase of this vital piece of equipment called OPMI Lumera 700 Rescan is thanks to a number of funders including: Fight for Sight, Tommy Salisbury Choroideremia Fund at Fight for Sight, National Eye Research Centre, Choroideremia Research Foundation USA, Saturday Hospital Fund and benefactors of the MacLaren Group. Choroideremia, is an incurable genetic condition affecting approximately 50,000 men worldwide. It is caused by a genetic fault in the REP-1 gene and gene therapy is ...
Background Choroideremia is an X-linked recessive disease that leads to blindness due to mutations in the CHM gene, which encodes the Rab escort protein 1 (REP1). We assessed the eff ects of retinal gene therapy with an adenoassociated viral (AAV) vector encoding REP1 (AAV.REP1) in patients with this disease. Methods In a multicentre clinical trial, six male patients (aged 35-63 years) with choroideremia were administered AAV.REP1 (0.6-1.0 × 10 10 genome particles, subfoveal injection). Visual function tests included best corrected visual acuity, microperimetry, and retinal sensitivity tests for comparison of baseline values with 6 months after surgery. This study is registered with ClinicalTrials.gov, number NCT01461213. Findings Despite undergoing retinal detachment, which normally reduces vision, two patients with advanced choroideremia who had low baseline best corrected visual acuity gained 21 letters and 11 letters (more than two and four lines of vision). Four other patients with near normal
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.
PURPOSE: Choroideremia is a rare degenerative retinal disease that causes incurable blindness. It occurs as a result of the deficiency of the X-linked CHM gene, which encodes the Rab escort protein 1 (REP1). Gene therapy has been developed to treat CHM using adeno-associated viral vectors and is currently undergoing clinical trials. Expression of the CHM gene is ubiquitous throughout the retina, and it is therefore important to identify which retinal layers are affected in the disease process. The purpose of this study was to assess in particular the choriocapillaris using optical coherence tomography angiography because this layer is difficult to see with conventional imaging techniques. METHODS: Six men with choroideremia were identified and underwent standardized optical coherence tomography angiography as part of an ethics-approved clinical study and were compared with age-matched control subjects. RESULTS: The choriocapillaris appeared normal in regions where the retinal pigment epithelium remained
Nightstar Therapeutics has announced the initiation of the companys STAR Phase 3 registrational trial to study the safety and efficacy of NSR-REP1 in patients with choroideremia. In data from 32 patients treated with NSR-REP1 across four open-label Phase 1/2 clinical trials, over 90% of treated patients maintained or improved their visual acuity over a one-year follow-up period.. The STAR trial is expected to enroll approximately 140 patients across 18 clinical sites in the United States, Europe, Canada and South America, of which six sites will be surgical centers. Eligible patients will be randomized into one of three study arms: 56 patients receiving a high-dose of NSR-REP1 in one-eye (1.0 × 10^11 genome particles, or gp); 28 patients receiving a low-dose of NSR-REP1 in one-eye (1.0 × 10^10 gp); and 56 patients receiving no treatment (no-sham, parallel control arm). Patients in the STAR trial are expected to be recruited primarily from the existing Nightstar-sponsored natural history ...
26-year-old man has choroideremia. He has noticed some swirling lights in the peripheral vision, more in the left eye than the right eye. VISUAL ACUITY: Vision OU is 20/60. IOP: 17 OD, 13 OS. There is 1+ nuclear sclerosis OU. EXTENDED OPHTHALMOSCOPY: OU: Vertical C/D ratio is 0.2. The macula has a small area that is not atrophic and there is severe peripheral atrophy. Photos confirm clinical findings. IMPRESSION: 1. CHOROIDEREMIA - BOTH EYES DISCUSSION: I explained to the patient that his choroideremia does look stable. I asked him to return for check in 6-12 months, sooner should he notice any problem. ...
Choroideremia occurs almost exclusively in males. In childhood, night blindness is the most common first symptom. As the disease progresses there is loss of peripheral vision leading to tunnel vision, and later a loss of central vision. Progression of the disease continues throughout the individuals life, although both the rate and the degree of vision loss vary among those affected, even within the same family.. Vision loss due to choroideremia is caused by degeneration of several layers of cells that are essential to sight. These layers, which line the inside of the back of eyes, are called the choroid, the retinal pigment epithelium and the photoreceptors. The choroid consists of several blood vessel layers that are located between the retina and the sclera (the white of the eye). Choroidal vessels provide the retinal pigment epithelium and photoreceptors with oxygen and nutrients necessary for normal function. The retinal pigment epithelium and the photoreceptors are part of the retina. ...
In CHM, centripetal loss of AF typically progresses steadily over a patients lifetime. By analyzing a cohort comprising a range of ages, it is possible to predict the average rate and extent of AF area loss over time (Fig. 3). The worse and better eyes follow a very similar pattern and are not significantly different (P = 0.21, Mann-Whitney U test). An extra sum of squares F-test showed that nonlinear regression models for the better and worse eyes were not significantly different (P = 0.269); hence the preferred model was one curve for all data sets (see Fig. 4). The gradient of the line is the rate of residual retinal loss, which we have defined as the Choroideremia Index. Taking into account the log axes, the Choroideremia Index for the remaining retina can be defined as log y = (−0.04 * x) + 2.53, where y represents the area of residual retina and x is age in years. More simply, average log area (mm2) for a given age is 2.53 − age/25. Hence the average 25-year-old patient would have 34 ...
73 year old female with choroideremia (carrier). She has her father with choroideremia. She has noticed distortion in the right eye for 4 months. She had never been told her retinas were abnormal. VA 20/80 OD, 20/32 OS. ...
TY - JOUR. T1 - L1 retrotransposition can occur early in human embryonic development. AU - van den Hurk, José A.J.M.. AU - Meij, Iwan C.. AU - del Carmen Seleme, Maria. AU - Kano, Hiroki. AU - Nikopoulos, Konstantinos. AU - Hoefsloot, Lies H.. AU - Sistermans, Erik A.. AU - de Wijs, Ilse J.. AU - Mukhopadhyay, Arijit. AU - Plomp, Astrid S.. AU - de Jong, Paulus T.V.M.. AU - Kazazian, Haig H.. AU - Cremers, Frans P.M.. PY - 2007/7/1. Y1 - 2007/7/1. N2 - L1 elements are autonomous retrotransposons that can cause hereditary diseases. We have previously identified a full-length L1 insertion in the CHM (choroideremia) gene of a patient with choroideremia, an X-linked progressive eye disease. Because this L1 element, designated L1CHM, contains two 3′-transductions, we were able to delineate a retrotransposition path in which a precursor L1 on chromosome 10p15 or 18p11 retrotransposed to chromosome 6p21 and subsequently to the CHM gene on chromosome Xq21. A cell culture retrotransposition assay ...
Since the CHM gene is located on the X chromosome, symptoms are seen almost exclusively in men. While there are a few exceptions, female carriers have a noticeable lack of pigmentation in the RPE but do not experience any symptoms.[5] Female carriers have a 50% chance of having either an affected son or a carrier daughter, while a male with choroideremia will have all carrier daughters and unaffected sons. Even though the disease progression can vary significantly,[1][6] there are general trends. The first symptom many individuals with choroideremia notice is a significant loss of night vision, which begins in youth.[7] Peripheral vision loss occurs gradually, starting as a ring of vision loss, and continuing on to tunnel vision in adulthood.[8] Individuals with choroideremia tend to maintain good visual acuity into their 40s, but eventually lose all sight at some point in the 50-70 age range.[8] A study of 115 individuals with choroideremia found that 84% of patients under the age of 60 had a ...
Choroideremia (CHM) is an X-linked recessive eye disease causing degeneration of the choriocapillaris, retinal pigment epithelium, and photoreceptors, leading to severe visual impairment by adulthood. The pathogenetic mechanisms are unknown. The first clinical manifestation in CHM is night blindness during early adulthood followed by reduction of central vision and constriction of visual fields. The choroid and retina undergo complete atrophy. Heterozygous female carriers have no visual defect but often show striking funduscopic changes such as irregular pigmentation and atrophy around the optic disc.
Choroideremia is a rare inherited disorder that causes severe sight loss progressively throughout ones life, primarily within men.
Tod Purvis and his brother Justin were diagnosed with choroideremia and took a road trip chronicled in the movie Driving Blind.
Importance: The early decline and recovery of retinal structure and function following iatrogenic macular detachment for retinal gene therapy is not well characterized in those with relatively preserved central visual function. Here, the recovery of retinal structure and function over the first month following iatrogenic retinal detachment for the delivery of adeno-associated viral vector encoding Rab Escort Protein 1 is described as a part of gene therapy for choroideremia. Objective: To study changes in both retinal structure and function during the first month following iatrogenic macular detachment surgery. Design, Setting, and Participants: This prospective interocularly controlled study was conducted between February 1 and December 31, 2015. Treatment consisted of a subretinal injection of 0.1 mL of a gene therapy solution containing 1 × 1011 viral particles performed unilaterally. The participants were 5 males, aged 23 to 71 years, with a clinical and genetic diagnosis of choroideremia. Main
About Nightstar. Nightstar is a leading clinical-stage gene therapy company focused on developing and commercializing novel one-time treatments for patients suffering from rare inherited retinal diseases that would otherwise progress to blindness. Nightstars lead product candidate, NSR-REP1, is being developed as a treatment for patients with choroideremia, a rare, degenerative, genetic retinal disorder that has no current treatments and affects approximately one in every 50,000 people. Positive results from a Phase 1/2 trial of NSR-REP1 were published in The Lancet in 2014 and in The New England Journal of Medicine in 2016. Nightstar plans to commence a Phase 3 registrational trial of NSR-REP1 for choroideremia at sites in the United States, Europe and Canada in the first half of 2018. Nightstars second product candidate, NSR-RPGR, is currently being evaluated in a Phase 1/2 clinical trial for the treatment of patients with X-linked retinitis pigmentosa, an inherited X-linked recessive ...
The Choroideremia Research Foundation gave me hope and a sense of community.- Brent Rische, CRF member The Choroideremia Research Foundations Provides Education. ...
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In this report, we show that in normal melanocytes Rab27a colocalizes with melanosomes and myosin-V. In melanocytes from a GS patient, we observed a lack of Rab27a expression that coincides with the absence of melanosome accumulation at the dendrite tips. Sequencing of Rab27a cDNA from this patient revealed a deletion of five nucleotides in the terminal exon. This deletion leads to a frameshift, a conversion Q172N, and the appearance of a premature termination codon in 173 (Menasché et al. 2000). At the protein level, the termination codon in 173 implies that 49 COOH-terminal amino acids are deleted in the mutant form of Rab27a. This deletion involves the hypervariable domain of Rab GTPases that contains a geranylgeranylation motif (CXC) and structural elements that determine the association of Rab proteins with their specific target vesicles. In choroideremia, impairment of Rab27a geranylgeranylation results in a decreased expression of the protein (Seabra et al. 1993). Thus, the mistargeting ...
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Authors: Ian C. Han, MD1; S. Scott Whitmore, PhD1; D. Brice Critser, BS, CRA1; Edwin M. Stone, MD, PhD1. Author Affiliations: 1Institute for Vision Research, Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA 52242. Purpose: Choroideremia is an X-linked condition characterized by profound choroidal thinning and outer retinal loss which typically begin peripherally and spare the central macula until later in the disease course. The depth of imaging and wide field of view enabled by swept-source optical coherence tomography (SS-OCT) and angiography (SS-OCTA) may be advantageous for characterizing the extent of pathology deep to the choroid and beyond the macula. We aim to describe SS-OCT and SS-OCTA findings in a cohort of patients with choroideremia. Methods: This is a retrospective, cross-sectional study of consecutive patients with molecularly-confirmed choroideremia seen at a tertiary referral center from September 12, 2017 to September 11, 2018. All patients ...
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2M.D., Sisli Etfal Training and Research Hospital, Eye Clinic, Istanbul/TURKEY Twenty-three years old male patient applied because of night blindness and decreased vision. Corrected visual acuity was 10/10 bilaterally. Anterior segment examination was normal. Fundus examination revealed bilateral equatorial and peripheral widespread choroidal and retinal pigment epithelial atrophy with preserved central macular area. Diagnosis was compatible with choroideremia clinically. Imaging properties of the disease was evaluated using fundus fluorescein angiography and spectral domain optical coherence tomography. Keywords : Choroideremia, fluorescein angiography, optical coherence tomography ...
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PURPOSE: To identify valid and reproducible methods for quantifying anatomic outcome measures for eyes with choroideremia (CHM) in clinical trials.. DESIGN: Reliability analysis study.. METHODS: In this multicenter study, patients with confirmed genetic diagnosis of CHM were enrolled. All cases underwent spectral-domain optical coherence tomography (SDOCT) and fundus autofluorescence (FAF) imaging. Two graders independently delineated boundaries of preserved autofluorescence (PAF) and preserved ellipsoid zone (EZ) on FAF and OCT images, respectively. The results of the 2 independent gradings of both FAF and OCT images were compared to assess the reproducibility of the grading methods.. RESULTS: A total of 148 eyes from 75 cases were included. In 21% of eyes PAF and in 43% of eyes preserved EZ had extended beyond the image capture area. After exclusion of these eyes and low-quality images, 114 FAF and 77 OCT images were graded. The mean PAF areas from 2 independent gradings were 3.720 ± 3.340 ...
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While getting an accurate diagnosis can be challenging, trying to do so is important because it may enable an affected person to: 1) determine which clinical trials and emerging treatments may be appropriate; 2) better understand how vision may change over time; and 3) figure out if family members may be at risk for the disease.. So why can diagnoses be tough to come by? First and foremost, most eye doctors dont see many patients affected by inherited retinal diseases, because the conditions are rare. They simply dont have familiarity with them, even if they learned about them in medical school and during their residency training.. Another major reason diagnoses are tough is that some conditions can look the same to even a well-trained retinal specialist. For example, cone-rod dystrophy affects the macula, the central region of the retina, much in the same way that Stargardt disease does. X-linked retinitis pigmentosa (XLRP) and choroideremia can look similar in appearance. Sometimes it isnt ...
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When hiring an escort, you should note that prostitution industry is illegal in the UK. And since youll likely engage in sex with the escort, its necessary to know if she is of the legal age. This is 18 years old, and since sex for prostitution is illegal, it also applies to escorts. Escort agencies should, therefore, ensure their escorts are above 18 years old, licensed to work in the UK since if thats not the case, then they could be charged for child trafficking ...
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