ABSTRACT
INTRODUCTION: Degeneration in choroideremia, unlike typical centripetal photoreceptor degenerations, is centred temporal to the fovea. Once the fovea is affected, the nasal visual field (temporal retina) is relatively spared, and the preferred retinal locus shifts temporally. Therefore, when reading left to right, only the right eye reads into a scotoma. We investigate how this unique property affects the ability to read an eye chart. METHODS: Standard- and low-luminance visual acuity (VA) for right and left eyes were measured with the Early Treatment of Diabetic Retinopathy Study (ETDRS) chart. Letters in each line were labelled by column position. The numbers of letter errors for each position across the whole chart were summed to produce total column error scores for each participant. Macular sensitivity was assessed using microperimetry. Central sensitivity asymmetry was determined by the temporal-versus-nasal central macular difference and subsequently correlated to a weighted ETDRS column error score. Healthy volunteers and participants with X-linked retinitis pigmentosa GTPase regulator associated retinitis pigmentosa (RPGR-RP) were used as controls. RESULTS: Thirty-nine choroideremia participants (median age 44.9 years [IQR 35.7-53.5]), 23 RPGR-RP participants (median age 30.8 years [IQR 26.5-40.5]) and 35 healthy controls (median age 23.8 years [IQR 20.3-29.0]) were examined. In choroideremia, standard VA in the right eye showed significantly greater ETDRS column errors on the temporal side compared with the nasal side (p = 0.002). This significantly correlated with greater asymmetry in temporal-versus-nasal central macular sensitivity (p = 0.04). No significant patterns in ETDRS column errors or central macular sensitivity were seen in the choroideremia left eyes, nor in RPGR-RP and control eyes. CONCLUSION: Difficulty in tracking across lines during ETDRS VA testing may cause excess errors independent of true VA. VA assessment with single-letter optotype systems may be more suitable, particularly for patients with choroideremia, and potentially other retinal diseases with asymmetric central macular sensitivity or large central scotomas including geographic atrophy.
Subject(s)
Choroideremia , Visual Acuity , Visual Fields , Humans , Choroideremia/physiopathology , Choroideremia/diagnosis , Visual Acuity/physiology , Male , Adult , Middle Aged , Female , Visual Fields/physiology , Macula Lutea/physiopathology , Macula Lutea/diagnostic imaging , Young Adult , Reading , Tomography, Optical Coherence/methods , Vision Tests/methods , Visual Field Tests/methodsABSTRACT
Choroideremia is an X-linked chorioretinal dystrophy caused by mutations in CHM, encoding Rab escort protein 1 (REP-1), leading to under-prenylation of Rab GTPases (Rabs). Despite ubiquitous expression of CHM, the phenotype is limited to degeneration of the retina, retinal pigment epithelium (RPE), and choroid, with evidence for primary pathology in RPE cells. However, the spectrum of under-prenylated Rabs in RPE cells and how they contribute to RPE dysfunction remain unknown. A CRISPR/Cas-9-edited CHM-/- iPSC-RPE model was generated with isogenic control cells. Unprenylated Rabs were biotinylated in vitro and identified by tandem mass tag (TMT) spectrometry. Rab12 was one of the least prenylated and has an established role in suppressing mTORC1 signaling and promoting autophagy. CHM-/- iPSC-RPE cells demonstrated increased mTORC1 signaling and reduced autophagic flux, consistent with Rab12 dysfunction. Autophagic flux was rescued in CHM-/- cells by transduction with gene replacement (ShH10-CMV-CHM) and was reduced in control cells by siRNA knockdown of Rab12. This study supports Rab12 under-prenylation as an important cause of RPE cell dysfunction in choroideremia and highlights increased mTORC1 and reduced autophagy as potential disease pathways for further investigation.
Subject(s)
Autophagy , Choroideremia , Induced Pluripotent Stem Cells , Retinal Pigment Epithelium , rab GTP-Binding Proteins , Humans , Adaptor Proteins, Signal Transducing , Choroideremia/pathology , Choroideremia/genetics , Choroideremia/metabolism , Induced Pluripotent Stem Cells/metabolism , Mechanistic Target of Rapamycin Complex 1/metabolism , Models, Biological , rab GTP-Binding Proteins/metabolism , rab GTP-Binding Proteins/genetics , Retinal Pigment Epithelium/metabolism , Retinal Pigment Epithelium/pathology , Signal TransductionABSTRACT
Choroideremia (CHM) is an X-linked retinal degeneration leading to loss of the photoreceptors, retinal pigment epithelium (RPE), and choroid. Adaptive optics optoretinography is an emerging technique for noninvasive, objective assessment of photoreceptor function. Here, we investigate parafoveal cone function in CHM using adaptive optics optoretinography and compare with cone structure and clinical assessments of vision. Parafoveal cone mosaics of 10 CHM and four normal-sighted participants were imaged with an adaptive optics scanning light ophthalmoscope. While acquiring video sequences, a 2 s 550Δ10 nm, 450 nW/deg2 stimulus was presented. Videos were registered and the intensity of each cone in each frame was extracted, normalized, standardized, and aggregated to generate the population optoretinogram (ORG) over time. A gamma-pdf was fit to the ORG and the peak was extracted as ORG amplitude. CHM ORG amplitudes were compared to normal and were correlated with bound cone density, ellipsoid zone to RPE/Bruch's membrane (EZ-to-RPE/BrM) distance, and foveal sensitivity using Pearson correlation analysis. ORG amplitude was significantly reduced in CHM compared to normal (0.22 ± 0.15 vs. 1.34 ± 0.31). In addition, CHM ORG amplitude was positively correlated with cone density, EZ-to-RPE/BrM distance, and foveal sensitivity. Our results demonstrate promise for using ORG as a biomarker of photoreceptor function.
Subject(s)
Choroideremia , Humans , Ophthalmoscopy/methods , Retinal Cone Photoreceptor Cells , Choroid , Retinal Pigment Epithelium/diagnostic imaging , Tomography, Optical Coherence/methodsABSTRACT
PURPOSE: Choroideremia is an X-linked inherited retinal degeneration involving the choriocapillaris, retinal pigment epithelium, and photoreceptors. Adaptive optics scanning light ophthalmoscopy allows visualization of retinal structure at the level of individual cells and is well poised to provide insight into the pathophysiologic mechanisms underpinning the retinal degeneration in choroideremia. METHODS: Foveal adaptive optics scanning light ophthalmoscopy images of 102 eyes of 54 individuals with choroideremia were analyzed. Measures were compared with those from standard clinical imaging. Visual acuity was also measured and compared with quantitative foveal metrics. RESULTS: The 3 distinct phenotypes observed were: relatively normal (5 eyes, 4 individuals), spiderweb (9 eyes, 7 individuals), and salt and pepper (87 eyes, 47 individuals). Peak cone density (86 eyes of 51 individuals) was significantly lower in choroideremia than in healthy retinas (P < 0.0001, range: 29,382-157,717 cones/mm2). Peak cone density was significantly related to extent of retained ellipsoid zone on en face optical coherence tomography (r2 = 0.47, P = 0.0009) and inversely related to visual acuity (r2 = 0.20, P = 0.001). CONCLUSION: Distinct phenotypes can be observed on adaptive optics scanning light ophthalmoscopy imaging in choroideremia that cannot always be discerned on standard clinical imaging. Quantitative measures on adaptive optics imaging are related to the structural and functional severity of disease.
Subject(s)
Choroideremia , Retinal Degeneration , Humans , Tomography, Optical Coherence/methods , Ophthalmoscopy/methods , Retinal Cone Photoreceptor CellsABSTRACT
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.
Subject(s)
Choroideremia , Disease Progression , Fluorescein Angiography , Tomography, Optical Coherence , Visual Acuity , Humans , Choroideremia/physiopathology , Choroideremia/diagnosis , Male , Prospective Studies , Visual Acuity/physiology , Adult , Middle Aged , Fluorescein Angiography/methods , Aged , Retina/physiopathology , Young Adult , Follow-Up Studies , AdolescentABSTRACT
INTRODUCTION: Molecular confirmation of pathogenic sequence variants in the CHM gene is required prior to enrolment in retinal gene therapy clinical trials for choroideremia. Individuals with mild choroideremia have been reported. The molecular basis of genotype-phenotype associations is of clinical relevance since it may impact on selection for retinal gene therapy. METHODS AND MATERIALS: Genetic testing and RNA analysis were undertaken in a patient with mild choroideremia to confirm the pathogenicity of a novel intronic variant in CHM and to explore the mechanism underlying the mild clinical phenotype. RESULTS: A 42-year-old male presented with visual field loss. Fundoscopy and autofluorescence imaging demonstrated mild choroideremia for his age. Genetic analysis revealed a variant at a splice acceptor site in the CHM gene (c.1350-3C > G). RNA analysis demonstrated two out-of-frame transcripts, suggesting pathogenicity, without any detectable wildtype transcripts. One of the two out-of-frame transcripts is present in very low levels in healthy controls. DISCUSSION: Mild choroideremia may result from +3 or -3 splice site variants in CHM. It is presumed that the resulting mRNA transcripts may be partly functional, thereby preventing the development of the null phenotype. Choroideremia patients with such variants may present challenges for gene therapy since there may be residual transcript activity which could result in long-lasting visual function which is atypical for this disease.
Subject(s)
Choroideremia , Male , Humans , Adult , Choroideremia/genetics , Choroideremia/pathology , Mutation , Exons/genetics , Retina , RNA Splice SitesSubject(s)
Choroideremia , Retinal Detachment , Retinal Perforations , Humans , Choroideremia/complications , Choroideremia/diagnosis , Retinal Detachment/diagnosis , Retinal Detachment/etiology , Retinal Detachment/surgery , Retinal Perforations/diagnosis , Retinal Perforations/etiology , Retinal Perforations/surgeryABSTRACT
Choroideremia (CHM) is a rare X-linked chorioretinal dystrophy affecting the photoreceptors, retinal pigment epithelium (RPE) and choroid, however, the involvement of the choroid in disease progression is not fully understood. CHM is caused by mutations in the CHM gene, encoding the ubiquitously expressed Rab escort protein 1 (REP1). REP1 plays an important role in intracellular trafficking of vesicles, including melanosomes. In this study, we examined the ultrastructure of the choroid in chmru848 fish and Chmnull/WT mouse models using transmission electron and confocal microscopy. Significant pigmentary disruptions were observed, with lack of melanosomes in the choroid of chmru848 fish from 4 days post fertilisation (4dpf), and a reduction in choroidal blood vessel diameter and interstitial pillars suggesting a defect in vasculogenesis. Total melanin and expression of melanogenesis genes tyr, tryp1a, mitf, dct and pmel were also reduced from 4dpf. In Chmnull/WT mice, choroidal melanosomes were significantly smaller at 1 month, with reduced eumelanin at 1 year. The choroid in CHM patients were also examined using spectral domain optical coherence tomography (SD-OCT) and OCT-angiography (OCT-A) and the area of preserved choriocapillaris (CC) was found to be smaller than that of overlying photoreceptors, suggesting that the choroid is degenerating at a faster rate. Histopathology of an enucleated eye from a 74-year-old CHM male patient revealed isolated areas of RPE but no associated underlying CC. Pigmentary disruptions in CHM animal models reveal an important role for REP1 in melanogenesis, and drugs that improve melanin production represent a potential novel therapeutic avenue.
Subject(s)
Choroideremia , Aged , Animals , Humans , Male , Mice , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Choroid/metabolism , Choroideremia/genetics , Choroideremia/pathology , Choroideremia/therapy , Melanins , Melanogenesis , Mice, KnockoutABSTRACT
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.
Subject(s)
Choroidal Neovascularization , Choroideremia , Male , Humans , Adolescent , Angiogenesis Inhibitors/therapeutic use , Choroideremia/complications , Choroideremia/diagnosis , Choroideremia/genetics , Intravitreal Injections , Bevacizumab/therapeutic use , Choroidal Neovascularization/diagnosis , Choroidal Neovascularization/drug therapy , Choroidal Neovascularization/etiology , Vision Disorders , Retinal Hemorrhage/diagnosis , Retinal Hemorrhage/etiology , Tomography, Optical Coherence , Atrophy/complications , Fluorescein AngiographyABSTRACT
The recent publication of Di Giosaffatte et al. [...].
Subject(s)
Choroideremia , Humans , Female , Choroideremia/genetics , Adaptor Proteins, Signal Transducing/genetics , PedigreeABSTRACT
We express our gratitude to Dr. Fry and Prof. McLaren [...].
Subject(s)
Choroideremia , Humans , Female , Choroideremia/genetics , Adaptor Proteins, Signal Transducing/geneticsABSTRACT
Choroideremia (CHM) is an X-linked chorioretinal dystrophy leading to progressive retinal degeneration that results in blindness by late adulthood. It is caused by mutations in the CHM gene encoding the Rab Escort Protein 1 (REP1), which plays a crucial role in the prenylation of Rab proteins ensuring correct intracellular trafficking. Gene augmentation is a promising therapeutic strategy, and there are several completed and ongoing clinical trials for treating CHM using adeno-associated virus (AAV) vectors. However, late-phase trials have failed to show significant functional improvements and have raised safety concerns about inflammatory events potentially caused by the use of viruses. Therefore, alternative non-viral therapies are desirable. Episomal scaffold/matrix attachment region (S/MAR)-based plasmid vectors were generated containing the human CHM coding sequence, a GFP reporter gene, and ubiquitous promoters (pS/MAR-CHM). The vectors were assessed in two choroideremia disease model systems: (1) CHM patient-derived fibroblasts and (2) chmru848 zebrafish, using Western blotting to detect REP1 protein expression and in vitro prenylation assays to assess the rescue of prenylation function. Retinal immunohistochemistry was used to investigate vector expression and photoreceptor morphology in injected zebrafish retinas. The pS/MAR-CHM vectors generated persistent REP1 expression in CHM patient fibroblasts and showed a significant rescue of prenylation function by 75%, indicating correction of the underlying biochemical defect associated with CHM. In addition, GFP and human REP1 expression were detected in zebrafish microinjected with the pS/MAR-CHM at the one-cell stage. Injected chmru848 zebrafish showed increased survival, prenylation function, and improved retinal photoreceptor morphology. Non-viral S/MAR vectors show promise as a potential gene-augmentation strategy without the use of immunogenic viral components, which could be applicable to many inherited retinal disease genes.
Subject(s)
Choroideremia , Retinal Dystrophies , Animals , Humans , Adult , Choroideremia/genetics , Choroideremia/therapy , Choroideremia/metabolism , Zebrafish/genetics , Zebrafish/metabolism , Retina/metabolism , Mutation , Retinal Dystrophies/metabolism , Plasmids , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolismABSTRACT
Choroideremia is a rare, X-linked retinal degeneration resulting in progressive vision loss. A randomized, masked, phase 3 clinical trial evaluated the safety and efficacy over 12 months of follow-up in adult males with choroideremia randomized to receive a high-dose (1.0 × 1011 vector genomes (vg); n = 69) or low-dose (1.0 × 1010 vg; n = 34) subretinal injection of the AAV2-vector-based gene therapy timrepigene emparvovec versus non-treated control (n = 66). Most treatment-emergent adverse events were mild or moderate. The trial did not meet its primary endpoint of best-corrected visual acuity (BCVA) improvement. In the primary endpoint analysis, three of 65 participants (5%) in the high-dose group, one of 34 (3%) participants in the low-dose group and zero of 62 (0%) participants in the control group had ≥15-letter Early Treatment Diabetic Retinopathy Study (ETDRS) improvement from baseline BCVA at 12 months (high dose, P = 0.245 versus control; low dose, P = 0.354 versus control). As the primary endpoint was not met, key secondary endpoints were not tested for significance. In a key secondary endpoint, nine of 65 (14%), six of 35 (18%) and one of 62 (2%) participants in the high-dose, low-dose and control groups, respectively, experienced ≥10-letter ETDRS improvement from baseline BCVA at 12 months. Potential opportunities to enhance future gene therapy studies for choroideremia include optimization of entry criteria (more preserved retinal area), surgical techniques and clinical endpoints. EudraCT registration: 2015-003958-41 .
Subject(s)
Choroideremia , Diabetic Retinopathy , Male , Humans , Adult , Choroideremia/genetics , Choroideremia/therapy , Visual Acuity , Genetic Therapy/adverse effects , Genetic Therapy/methods , RetinaABSTRACT
Choroideremia is an X-linked retinal degeneration resulting from the progressive, centripetal loss of photoreceptors and choriocapillaris, secondary to the degeneration of the retinal pigment epithelium. Affected individuals present in late childhood or early teenage years with nyctalopia and progressive peripheral visual loss. Typically, by the fourth decade, the macula and fovea also degenerate, resulting in advanced sight loss. Currently, there are no approved treatments for this condition. Gene therapy offers the most promising therapeutic modality for halting or regressing functional loss. The aims of the current review are to highlight the lessons learnt from clinical trials in choroideremia, review endpoints, and propose a future strategy for clinical trials.
Subject(s)
Choroideremia , Night Blindness , Child , Adolescent , Humans , Choroideremia/genetics , Choroideremia/therapy , Choroid , Fovea Centralis , Genetic TherapyABSTRACT
BACKGROUND: Variants in the patatin-like phospholipase domain containing 6 (PNPLA6) gene cause a broad spectrum of neurological disorders characterized by gait disturbance, visual impairment, anterior hypopituitarism, and hair anomalies. This review examines the clinical, cellular, and biochemical features found across the five PNPLA6-related diseases, with a focus on future questions to be addressed. MATERIALS AND METHODS: A literature review was performed on published clinical reports on patients with PNPLA6 variants. Additionally, in vitro and in vivo models used to study the encoded protein, Neuropathy Target Esterase (NTE), are summarized to lend mechanistic perspective to human diseases. RESULTS: Biallelic pathogenic PNPLA6 variants cause five systemic neurological disorders: spastic paraplegia type 39, Gordon-Holmes, Boucher-Neuhäuser, Laurence-Moon, and Oliver-McFarlane syndromes. PNPLA6 encodes NTE, an enzyme involved in maintaining phospholipid homeostasis and trafficking in the nervous system. Retinal disease presents with a unique chorioretinal dystrophy that is phenotypically similar to choroideremia and Leber congenital amaurosis. Animal and cellular models support a loss-of-function mechanism. CONCLUSIONS: Clinicians should be aware of choroideremia-like ocular presentation in patients who also experience growth defects, motor dysfunction, and/or hair anomalies. Although NTE biochemistry is well characterized, further research on the relationship between genotype and the presence or absence of retinopathy should be explored to improve diagnosis and prognosis.
Subject(s)
Blepharoptosis , Choroideremia , Nervous System Diseases , Retinal Diseases , Animals , Humans , Eye , Retinal Diseases/genetics , Acyltransferases , Phospholipases/geneticsABSTRACT
Purpose: In patients with choroideremia, it is not known how smooth and mottled patterns on short-wavelength fundus autofluorescence (AF) imaging relate to retinal function. Methods: A retrospective case-note review was undertaken on 190 patients with choroideremia at two specialist centers for retinal genetics. Twenty patients with both smooth and mottled zones on short-wavelength AF imaging and concurrent mesopic microperimetry assessments were included. Mean retinal sensitivities within the smooth and mottled zones were compared between choroideremia patients, and identical points on mesopic microperimetry collected from 12 age-matched controls. Longitudinal analyses were undertaken at 2 and 5 years in a subset of patients. Results: In patients with choroideremia, mean retinal sensitivities at baseline were significantly greater in the smooth zone (26.1 ± 2.0 dB) versus the mottled zone (20.5 ± 4.2 dB) (P < 0.0001). Mean retinal sensitivities at baseline were similar in the smooth zone between choroideremia patients and controls (P = 0.054) but significantly impaired in the mottled zone in choroideremia compared to controls (P < 0.0001). The rate of decline in total sensitivity over 5 years was not significant in either the smooth or mottled zone in a small subset of choroideremia patients (n = 7; P = 0.344). Conclusions: In choroideremia, retinal sensitivity as determined by microperimetry correlates with patterns on AF imaging: retinal function in the smooth zone, where the retinal pigment epithelium is anatomically preserved, is similar to controls, but retinal sensitivity in the mottled zone is impaired. Translational Relevance: Patterns on AF imaging may represent a novel, objective outcome measure for clinical trials in choroideremia as a surrogate for retinal function.
Subject(s)
Choroideremia , Humans , Choroideremia/genetics , Visual Field Tests , Retrospective Studies , Tomography, Optical Coherence/methods , Visual AcuityABSTRACT
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.
Subject(s)
Choroideremia , Retinal Cone Photoreceptor Cells , Humans , Choroideremia/diagnosis , Choroideremia/genetics , Ophthalmoscopy/methods , Retina/anatomy & histology , Retinal Pigment Epithelium , Tomography, Optical Coherence/methodsABSTRACT
Satellite avionics and electronic components are getting compact and have high power density. Thermal management systems are essential for their optimal operational performance and survival. Thermal management systems keep the electronic components within a safe temperature range. Phase change materials (PCMs) have high thermal capacity, so they are promising for thermal control applications. This work adopted a PCM-integrated thermal control device (TCD) to manage the small satellite subsystems under zero gravity conditions thermally. The TCD's outer dimensions were selected upon a typical small satellite subsystem. The PCM adopted was the organic PCM of RT 35. Pin fins with different geometries were adopted to boost the lower thermal conductivity of the PCM. Six-pin fins geometries were used. First, the conventional geometries were square, circular, and triangular. Second, the novel geometries were cross-shaped, I-shaped, and V-shaped fins. The fins were designed at two-volume fractions of 20% and 50%. The electronic subsystem was assumed to be "ON" for 10 min releasing 20 W of heat, and "OFF" for 80 min. The findings show a remarkable decrease in the TCD's base plate temperature by 5.7 â as the fins' number changed from 15 to 80 for square fins. The results also show that the novel cross-shaped, I-shaped, and V-shaped pin fins could significantly enhance thermal performance. The cross-shaped, I-shaped, and V-shaped reported a decrease in the temperature by about 1.6%, 2.6%, and 6.6%, respectively, relative to the circular fin geometry. V-shaped fins could also increase the PCM melt fraction by 32.3%.
Subject(s)
Animal Fins , Choroideremia , Animals , Bone Plates , Electronics , EstrusABSTRACT
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.
Subject(s)
Choroideremia , Retinal Diseases , Retinitis Pigmentosa , Humans , Female , Retina , Retinitis Pigmentosa/therapy , Choroideremia/diagnosis , Choroideremia/genetics , Choroideremia/therapy , Heterozygote , Retinal Diseases/diagnosis , Retinal Diseases/genetics , Retinal Diseases/therapy , Vision Disorders , MutationABSTRACT
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.