Choroideremia Carriers Research Articles

Longitudinal assessment of female carriers of choroideremia using multimodal retinal imaging

Background/aimsFemale choroideremia carriers present with a spectrum of disease severity. Unlike in men, the rate of disease progression has not been well characterised in carriers. This longitudinal study aimed to...

Retinal Characteristics of Female Choroideremia Carriers: Multimodal Imaging, Microperimetry, and Genetics

PurposeDescribe visual function and retinal features of female carriers of choroideremia (CHM), using multimodal imaging and microperimetry. DesignCross-sectional cohort study Participants and controlsCHM carriers seen in Australia (Melbourne or Perth) or United Kingdom (Oxford or Cambridge) between 2012 and 2023. Healthy age-matched controls seen in Melbourne, Australia, between 2022 and 2023. MethodsParticipants had visual acuity, fundus-tracked microperimetry, optical coherence tomography (OCT), and fundus autofluorescence (FAF) imaging performed. CHM carriers were either genetically and/or clinically confirmed (i.e., obligate carriers). CHM carriers were grouped according to their retinal phenotype and compared to healthy controls. Statistical analyses were performed on StataBE (v18.0). Main outcome measuresBest-corrected visual acuity (BCVA), low-luminance visual acuity (LLVA), average retinal sensitivity, volume of macular hill of vision (HoV), inner retinal thickness (IRT), and photoreceptor complex (PRC) thickness. ResultsEighty-six eyes of 43 CHM carriers and 60 eyes of 30 healthy controls were examined using multimodal imaging and microperimetry. Median age was 54 and 48.5 years for CHM carriers and controls, respectively (p=0.18). Most CHM carriers (86%) were genetically confirmed. CHM carriers and controls had strong inter-eye correlation between eyes for BCVA and average retinal sensitivity (p<0.001). LLVA and macular HoV tests were sensitive tests to detect changes in CHM carriers with mild phenotypes (i.e., fine and coarse). CHM carriers with geographic and/or male pattern phenotypes had reduced BCVA, LLVA, retinal sensitivity, and retinal thinning, compared to healthy controls. Retinal thickening of the inner retina was observed in the central 1 degree, despite generalised thinning of the PRC in the central 7 degrees, indicating retinal remodelling in CHM carriers, compared to controls. There were no genotype-phenotype correlations observed. ConclusionsFemale carriers of CHM with severe retinal phenotypes (i.e., geographic or male pattern) have significantly decreased visual function and retinal structural changes, when compared to age-matched controls and those carriers with milder phenotypes. LLVA and volumetric measures of the macular HoV were found to be the most sensitive functional tests to detect milder retinal disease (fine and coarse phenotypes) in CHM carriers.

A global survey of visual symptoms in female carriers of choroideremia and X-linked retinitis pigmentosa

PurposeTo investigate self-reported visual impairment in a large cohort of female carriers of X-linked retinal diseases around the world, using the validated Michigan Retinal Degeneration Questionnaire (MRDQ). DesignCross-sectional global survey study MethodsAn online survey collecting demographic and MRDQ data was distributed to self-reported female carriers of X-linked retinal diseases, and healthy controls (females with no eye disease). Respondents indicated their visual symptoms relating to everyday activities in seven visual domains: central vision, colour vision, contrast sensitivity, scotopic function, photopic peripheral vision, mesopic peripheral vision, and photosensitivity. Mann-Whitney test was used to compared visual disability scores between female carriers and healthy controls. ResultsTwo-hundred and thirty-seven female carriers of X-linked retinal diseases (74.3% choroideremia and 25.7% X-linked retinitis pigmentosa) and 100 age-matched healthy controls completed the questionnaire (median age: 51 vs. 47.5 years of age, respectively). Most female carriers resided in the USA (53.6%) and Australia (17.3%), whilst healthy controls were mostly from Australia (93%). Female carriers had significantly worse visual disability, compared to controls. Female carriers who were older than 50 years had significantly worse visual function impairment for all domains, except photosensitivity, when compared to carriers less than 50 years of age. ConclusionsThis study has shown that female carriers of choroideremia and X-linked RP report significantly worse visual symptoms, compared to healthy controls. Future studies are required to correlate MRDQ responses with clinical findings, to determine the degree of retinal changes required to impact female carriers’ quality of life.

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.

Multimodal Imaging of Retinochoroidopathy in Choroideremia Carrier

A 48-year-old woman was referred for ocular fundus abnormality by medical checkup. She had no subjective complaints. Fundus examination revealed diffuse moth-eaten appearance with chorioretinal atrophy in both eyes. Moreover, patchy areas of depigmentation were observed around the optic disc and in the peripheral retina. Fundus autofluorescence showed mosaic appearance in widespread retina, and patchy hypoautofluorescence areas corresponding to patchy areas of depigmentation. Although optical coherence tomography scan through the fovea of both eyes showed relatively preserved foveal contour and retinal layers, subtle irregularities at the level of the retinal pigment epithelium and ellipsoid zone observed. Based on these collective findings, we diagnosed our patient with retinochoroidopathy in choroideremia carrieir. Choroideremia is rare, occurring even less frequently as a symptomatic disease in female carriers. Our findings may contribute to a better understanding of this rare condition.

Choroideremia Carriers: Dark-Adapted Perimetry and Retinal Structures.

PurposeIn choroideremia (CHM) carriers, scotopic sensitivity was assessed by dark adapted chromatic perimetry (DACP) and outer retinal structure was evaluated by multimodal imaging.MethodsNine 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.ResultsDetection 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.ConclusionsRod 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.

Choroidal Vascularity Index in CHM Carriers

PurposeTo assess the choroidal structure using the Choroidal Vascularity Index (CVI) and analyse choroidal changes in choroideremia (CHM) carriers.Material and MethodsFemale CHM carriers, genetically characterized, and a control group were recruited at the Eye Clinic of Careggi Teaching Hospital, Florence. The patients underwent a complete ophthalmic evaluation and retinal imaging. In particular, the Stromal Area (SA), Luminal Area (LA), Total Choroidal Area (TCA), CVI, and Subfoveal Choroidal Thickness (SFCT) were calculated for each eye using Optical Coherence Tomography (OCT) examinations.ResultsTwelve eyes of 6 CHM carriers and 14 eyes of 7 age-matched controls were analysed. The mean SFCT was 270.9 ± 54.3μm in carriers and 281.4 ± 36.8μm in controls (p = 0.564); LA was 0.99 ± 0.25mm2 and 1.01 ± 0.13mm2 (p = 0.172); SA was 0.53 ± 0.09mm2 and 0.59 ± 0.07mm2 (p = 0.075), and TCA was 1.53 ± 0.34mm2 and 1.69 ± 0.19mm2 respectively (p = 0.146). Mean CVI measured 64.03 ± 3.98% in the CHM carriers and 65.25 ± 2.55% in the controls (p = 0.360).ConclusionsThe CVI and CVI-related parameters (SA, LA, and TCA) do not differ between CHM female carriers and controls. These findings reveal a preserved choroidal vasculature in eyes with RPE impairment and support the primary role of RPE in the pathogenesis of CHM disease.

Spectrum of Disease Severity and Phenotype in Choroideremia Carriers

To characterize and bring awareness to the disease spectrum of female choroideremia patients, as severity can vary from mild to severe disease, comparable to that observed in male patients. Retrospective cohort study. Twelve female carriers of disease-causing variants in the CHM gene confirmed by molecular genetic sequencing were characterized clinically and imaged with short-wave fundus autofluorescence (SW-FAF), spectral-domain optical coherence tomography (OCT), and color fundus imaging. Twelve unrelated female patients with a clinical and genetic diagnosis of choroideremia carriers were included in this study. Disease severity among these phenotypes ranged from mild to severe, resembling the typical presentation of choroideremia in male patients. Mild disease presented with retinal pigment epithelium mottling, a patchy pattern of hypoautofluorescent speckles on SW-FAF, and intact retinal layers on spectral-domain OCT. Severe disease presented with widespread chorioretinal atrophy as shown by SW-FAF and spectral-domain OCT. Each of the identified genetic variants in CHM was predicted to be disease-causing according to insilico prediction software. Disease progression analysis of 4 patients with follow-up showed a decline in visual acuity for 2 patients, with progression observed on spectral-domain OCT in 1 of the patients. No significant disease progression on SW-FAF was observed for any of the patients. Female carriers of choroideremia can present with a wide range of clinical phenotypes and disease severity, from mild to severe disease, similar to male subjects. Symptomatic female subjects should be considered for current and upcoming gene replacement therapy clinical trials.

High-Resolution Retinal Imaging Reveals Preserved Cone Photoreceptor Density and Choroidal Thickness in Female Carriers of Choroideremia.

To characterize the photoreceptors and choroidal morphology of heterozygous female carriers of choroideremia who typically do not have any visual defects but can have severe funduscopic changes. This was a clinical case series study. Detailed ophthalmic examinations were performed on six female carriers from four families with choroideremia. The subfoveal choroidal thickness (SFCT) was determined by spectral-domain optical coherence tomography (SD-OCT) and the cone photoreceptor density by adaptive optics (AO) retinal imaging. SFCT and cone densities of the carriers were compared to that of normal eyes of healthy subjects. The mean age of the carriers was 42.5 years. Fundus photographs showed diffuse, patchy depigmentation; however, the SFCT was within the normal limits. AO retinal imaging revealed preserved cone densities at temporal eccentricities from 2 to 8 angular degrees. The findings indicate that despite the presence of distinctive depigmentation of the retinal pigment epithelium in female carriers of choroideremia, their cone photoreceptor densities and SFCT are well-preserved. These observations may account for the good visual acuity and lack of an awareness of visual disturbances. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:76-85.].

Multimodal imaging of the carriers of choroideremia and X-linked retinitis pigmentosa.

Multimodal imaging of the carriers of choroideremia and X-linked retinitis pigmentosa.

MULTIMODAL IMAGING OF MOSAIC RETINOPATHY IN CARRIERS OF HEREDITARY X-LINKED RECESSIVE DISEASES.

To investigate the clinical features in carriers of X-linked retinitis pigmentosa, X-linked ocular albinism, and choroideremia (CHM) using multimodal imaging and to assess their diagnostic value in these three mosaic retinopathies. We prospectively examined 14 carriers of 3 X-linked recessive disorders (X-linked retinitis pigmentosa, X-linked ocular albinism, and CHM). Details of abnormalities of retinal morphology were evaluated using fundus photography, fundus autofluorescence (FAF) imaging, and spectral domain optical coherence tomography. In six X-linked retinitis pigmentosa carriers, fundus appearance varied from unremarkable to the presence of tapetal-like reflex and pigmentary changes. On FAF imaging, all carriers exhibited a bright radial reflex against a dark background. By spectral domain optical coherence tomography, loss of the ellipsoid zone in the macula was observed in 3 carriers (50%). Regarding the retinal laminar architecture, 4 carriers (66.7%) showed thinning of the outer nuclear layer and a dentate appearance of the outer plexiform layer. All five X-linked ocular albinism carriers showed a characteristic mud-splatter patterned fundus, dark radial streaks against a bright background on FAF imaging, and a normal-appearing retinal structure by spectral domain optical coherence tomography imaging. Two of the 3 CHM carriers (66.7%) showed a diffuse moth-eaten appearance of the fundus, and all 3 showed irregular hyper-FAF and hypo-FAF spots throughout the affected area. In the CHM carriers, the structural changes observed by spectral domain optical coherence tomography imaging were variable. Our findings in an Asian cohort suggest that FAF imaging is a practical diagnostic test for differentiating X-linked retinitis pigmentosa, X-linked ocular albinism, and CHM carriers. Wide-field FAF is an easy and helpful adjunct to testing for the correct diagnosis and identification of lyonization in carriers of these three mosaic retinopathies.

High resolution imaging analysis of female carriers and patients of Choroideremia with CHM gene mutation

PurposeTo report the high resolution imaging features of Japanese patient and female carriers of choroideremia using adaptive optics(AO) and other imaging modalities.MethodsThree carriers and one patient underwent comprehensive examinations including AO fundus camera (rtx1™ Imagine eyes, France), spectral domain optical coherence topography (SD‐OCT)and fundus autofluoresence (FAF). Cone density was measured by peak density method and compared with the data of 34 normal controls. The mutation analysis of the CHM gene was performed by Sanger sequencing. The protocol conformed to the tenets of the Declaration of Helsinki and was approved by the IRB of The Jikei University and Nippon Medical School.ResultsThree female carriers 1, 2, 3 (sister 9 y.o, mother 37 y.o and grandmother 65 y.o) and one patient (6 y.o, male). They had same CHM mutation, c.646delA, p.T216LfsX16. All carriers did not complain any symptoms, the BCVA of all were over 20/20. Fundus examination of carrier 2 showed mild generation in only periphery, the other carriers showed diffuse degeneration. AF showed mottled hypo‐autofluoresence in degeneration area. SD‐OCT of the carriers showed nearly normal,although peripheral SD‐OCT and patient showed diffuse disruptions of interdigitation and ellipsoid zones.Cone density was measured at 2 to 8 degree temporal from the fovea in every 1 degree, using 50 x 50 micron images. Cone counting was performed by AO detect (Imagine eyes) with manual correction. Patient showed lower cone density more than 2 SD of normal control. The carriers showed lower cone density only at 7 and 8 degrees.ConclusionsAO cone counting showed reduction of photoreceptors in carriers mainly at peripheral region. To elucidate the mechanism of peripheral degeneration and foveal sparing of female carriers may help preventing the disease progression of choroideremia patients.

Retinal dystrophy and subretinal drusenoid deposits in female choroideremia carriers.

To describe clinical and molecular characteristics in a group of Italian female choroideremia (CHM) carriers and report fundus patterns. 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. 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. 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.

Clinical features and gene mutations in a Chinese family with choroideremia

Objective To observe the clinical features, phenotypes and genotypes in a Chinese family with choroideremia (CHM). Methods A Chinese four-generation family (15 members) with CHM, including 5 patients (4 males/1 female), 2 female carriers and 8 healthy members, was enrolled in this study. Initially all family members underwent best corrected visual acuity (BCVA), indirect ophthalmoscopy, fundus fluorescein angiography, optical coherence tomography (OCT), visual field and full view electroretinogram (ERG). BCVA was followed up for 3 years. Venous blood samples were collected, and all of the 15 coding exons and flanking intron regions were amplified in the proband by polymerase chain reaction followed by direct sequencing. Protein structure was modeled based on the protein data bank and mutations in DeepView v4.0.1 to predict the effect of the mutations. A total of 180 healthy volunteers were enrolled as control group to matching CHM gene sequences. Results The visual acuity (VA) of 3/4 adult male patients began to decrease at less than 10, 10 and 30 years old, the average BCVA was 0.43. There were characteristic signs and symptoms of CHM including narrow visual field, extinguished rod and cone response in ERG, disappeared junction line and intermediate line of photoreceptor inner segment/outer segment on OCT. After 3 years, the mean BCVA decreased to 0.11. The BCVA of one young male patient was 1.0 in both eyes with minor changes fundus and visual field. The VA of the female patient began to decrease at 50 years old, her BCVA of two eyes were 0.5 and 0.25, respectively. The fundus changes were typical of CHM, with relative scotomas in the peripheral visual field of OD, and big scotomas in the OS. After 3 years, her mean BCVA decreased to 0.2. Of 2 female carriers, one had minor fundus changes (patches of pigmentary deposits, atrophy spots of retinal pigment epithelium cells), and the other was normal. A novel heterozygous c.1837G> A mutation in exon 15 of CHM was detected in the proband, which resulted in the substitution of serine by proline at codon 613 (p.D613N). Based on molecular modeling, the misfolded protein caused by the mutation might destabilize the structure of the helix that potentially could affect the global stability of the Rep-1 protein. Conclusions A novel c.1837G> A (p.D613N) mutation may be the causative mutation for CHM in this family. Female CHM carriers may have some signs and symptoms. Key words: Choroid diseases/diagnosis; Eye diseases, hereditary; DNA mutational analysis

Optical Coherence Tomography Angiography in Choroideremia: Correlating Choriocapillaris Loss With Overlying Degeneration.

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. 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 carriers, and 98.2% (1.3%) in controls. The mean (SD) CC density in affected eyes was higher in regions with preserved (92.6% [5.8%]) vs absent (75.9% [12.6%]) ellipsoid zone (mean difference, 16.7%; 95% CI, 12.1% to 21.3%; P < .001). Seventeen of 18 eyes of the patients and carriers had outer retinal tubulations forming pseudopod-like extensions from islands of preserved ellipsoid zone. Outer retinal tubulations were associated with absence of underlying retinal pigment epithelium and were longer (r = -0.62; 95% CI, -0.84 to -0.19; P < .001) and more numerous (r = -0.71; 95% CI, -0.91 to -0.27; P < .001) in more severely affected eyes. These findings suggest that regional changes in CC density correlate with photoreceptor structural alterations in choroideremia. Although closely coupled, the results suggest that retinal pigment epithelium loss is more extensive than photoreceptor loss.

Correlation of Retinal Structure and Function in Choroideremia Carriers

Correlation of Retinal Structure and Function in Choroideremia Carriers

High-Resolution Images of Retinal Structure in Patients with Choroideremia

To study retinal structure in choroideremia patients and carriers using high-resolution imaging techniques. Subjects from four families (six female carriers and five affected males) with choroideremia (CHM) were characterized with best-corrected visual acuity (BCVA), kinetic and static perimetry, full-field electroretinography, and fundus autofluorescence (FAF). High-resolution macular images were obtained with adaptive optics scanning laser ophthalmoscopy (AOSLO) and spectral domain optical coherence tomography (SD-OCT). Coding regions of the CHM gene were sequenced. Molecular analysis of the CHM gene identified a deletion of exons 9 to 15 in family A, a splice site mutation at position 79+1 of exon 1 in family B, deletion of exons 6 to 8 in family C, and a substitution at position 106 causing a premature stop in family D. BCVA ranged from 20/16 to 20/63 in carriers and from 20/25 to 5/63 in affected males. FAF showed abnormalities in all subjects. SD-OCT showed outer retinal layer loss, outer retinal tubulations at the margin of outer retinal loss, and inner retinal microcysts. Patchy cone loss was present in two symptomatic carriers. In two affected males, cone mosaics were disrupted with increased cone spacing near the fovea but more normal cone spacing near the edge of atrophy. High-resolution retinal images in CHM carriers and affected males demonstrated RPE and photoreceptor cell degeneration. As both RPE and photoreceptor cells were affected, these cell types may degenerate simultaneously in CHM. These findings provide insight into the effect of CHM mutations on macular retinal structure, with implications for the development of treatments for CHM. (ClinicalTrials.gov number, NCT00254605.).

Microperimetry and OCT findings in female carriers of choroideremia

Purpose: To evaluate structural retinal changes and macular function by a combined spectral domain optical coherence tomography/ scanning laser ophthalmoscope (OCT/ SLO) microperimetry device in choroideremia carriers.Methods and Materials: Ten choroideremia carriers were included in the study. All subjects had a complete ophthalmic examination in addition to Goldmann kinetic visual fields, OCT and microperimetry testing on a commercially available Spectral Domain (SD) OCT/SLO combination system.Results: Microperimetry results demonstrated focal areas of threshold abnormalities in 50% of the subjects. OCT findings show subtle retinal pigment epithelium (RPE) irregularities with attenuation more pronounced outside the macular region.Conclusions: Long term follow up with microperimetric testing could be useful in monitoring any progressive loss of retinal function in choroideremia carriers.

Progression of Retinal Pigment Epithelial Alterations During Long-term Follow-up in Female Carriers of Choroideremia and Report of a Novel CHM Mutation

To report clinical and functional findings in 2 female carriers of choroideremia who were followed up for 11 and 17 years and who showed progression of fundus alterations; and to report a novel CHM mutation. We performed follow-ups in 2 female carriers of choroideremia, including repeated clinical and electrophysiologic examinations and fundus autofluorescence. Molecular analysis of the CHM gene was done by direct sequencing of the coding exons. Follow-up of female carrier 327 took place during 17 years. A second female carrier (subject 869) with a novel gene mutation in CHM was followed up for 11 years. The 2 carriers showed marked pigmentary alterations in the periphery of the retina. At the initial visit, carrier 869 had multiple small, yellowish flecks in the macula. Both carriers developed subnormal 30-Hz flicker responses on full-field electroretinography during follow-up, whereas electrooculography responses were normal. In both carriers, progression of fundus alterations was noted. Fundus autofluorescence images showed multiple small flecks with reduced autofluorescence. Over time, fundus alterations in female carriers of choroideremia are visible, and mild cone dysfunction might develop. Multiple yellowish flecks can exist in the macula. The typical mottled irregularity in fundus autofluorescence is a valuable diagnostic criterion that facilitates specific genetic testing. Clinical Relevance Fundus alterations in female carriers of choroideremia can progress over time and a mild generalized cone dysfunction can develop. Characteristic irregularities are seen in fundus autofluorescence imaging, which is helpful in identifying female carriers of choroideremia.

Fundus Autofluorescence in Carriers of Choroideremia and Correlation with Electrophysiologic and Psychophysical Data

To describe fundus autofluorescence (FAF) in carriers of choroideremia (CHM), and to compare FAF findings with ophthalmoscopy and electrophysiologic and psychophysical data. Prospective, observational case series and systematic review. Six unrelated carriers of CHM. Clinical examination included a comprehensive ophthalmic examination, fundus photography, FAF, kinetic perimetry, 2-color threshold perimetry (2CTP), full-field electroretinography (ERG), and multifocal ERG (mfERG). All 6 carriers (33-60 years of age) were screened for mutations in the coding region of Rab Escort Protein 1 gene (REP1) including close flanking intronic sequence and deletions within 2160 bp of 5' untranslated sequence. Intensity and distribution of FAF, rod sensitivity loss, cone sensitivity loss in 2CTP, amplitude and latency in full-field ERG, amplitude in mfERG, and correlation of all 3 parameters. Mutations in the coding region of REP1 were identified in 3 of 6 carriers. All 6 carriers had good visual acuity. Three carriers complained of photophobia and 1 of impaired vision in dim light. Ophthalmoscopy revealed peripapillary atrophy and retinal pigment epithelium (RPE) mottling mainly in the macular region, and additional RPE clumping and flecks of atrophy in the periphery. A very irregular pattern of low- and high-density FAF speckles was seen. Low-density FAF surrounding the optic nerve head corresponded with the peripapillary atrophy. In areas of major FAF changes, mfERG was deteriorated. The 2CTP images revealed functional disturbances in rods and cones. No general pattern was observed. On MfERG, reduced amplitudes in areas with normal cone sensitivity in 2CTP were seen. All 6 carriers of CHM showed a characteristic FAF pattern that can guide mutation analysis. Even when other functional testing is inconspicuous, FAF is a rapid, noninvasive indicator. The authors have no proprietary or commercial interest in any of the materials discussed in this article.