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Introduction: Caused by mutation or deletion of the CHM gene, choroideremia is a rare X-linked recessive chorioretinal dystrophy characterized by progressive degeneration of the retinal pigment epithelium, photoreceptors, and the choriocapillaris. There are few published reports of choroideremia associated with complex syndromic phenotypes due to large or contiguous gene deletions., Methods: Case report and review of literature., Results: We present a case of a 46-year-old male with a prior clinical diagnosis of syndromic retinitis pigmentosa, who was found to have syndromic choroideremia associated with a novel multi-gene deletion of 13.5 megabase pairs. This deletion encompassing 18 genes is one of the largest deletions reported in the literature. A total of 18 male cases of choroideremia associated with confirmed large or contiguous gene deletions have been published to date. Previously reported deletions range in size from 4 to 15 megabase pairs, and observed phenotypes include cleft lip and palate, ptosis, obesity, metabolic diseases, developmental delay, and hearing loss., Discussion: The contribution of our case aims to expand our understanding of Xq21 deletions and prompts further investigation of genes found in this locus. Furthermore, it highlights the importance of including syndromic choroideremia on the differential diagnosis in the workup of other syndromic retinopathies, particularly those that feature obesity, hearing loss, or intellectual disability.

Introduction: Choroideremia (CHM) is an X-linked inherited retinal disease mostly affecting males. However, women with phenotypic and/or genotypic evidence of CHM may develop degenerative visual disability with advancing age. Our objective was to determine the visual impacts of phenotypic and/or genotypic evidence of CHM in women and its associated psychosocial burden and influence on activities of daily living (ADLs)., Methods: We conducted an international cross-sectional survey from April to December 2022 using an e-questionnaire distributed through not-for-profit stakeholder organizations and social media plat-forms., Results: With a total of 55 respondents ( n = 55), most women with phenotypic and/or genotypic evidence of CHM (76%) reported a change in their visual acuity. When assessing its impact on ADLs, Pearson's correlation coefficient showed a negative correlation between driving ( p = 0.046) and mobility capabil-ities (0.046) with the respondent's age. More than half of women reported being afraid, anxious, and stressed, with women below the age of 50 years old reporting a significantly higher level of distress and hopelessness ( p = 0.003), anxiety ( p = 0.00007), issues with relaxing ( p = 0.025), and negative personal thoughts ( p = 0.042)., Conclusion: Overall, this survey outlines both physical and psychological burden of being a woman with phenotypic and/or genotypic evidence of CHM. Given the limited clinical research in females affected by CHM, this patient-centered survey is a crucial advocacy tool for these individuals.

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.

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.

Background: Choroideremia is an X-linked chorioretinal dystrophy caused by mutations in the CHM gene. The main differential diagnosis is X-linked retinitis pigmentosa. Clinically, male patients that are affected by these two diseases have similar symptoms. This work aims to report a familial case of choroideremia initially diagnosed as X-linked retinitis pigmentosa with a novel mutation in the CHM gene, and the relevance of fundus autofluorescence (FAF) in female carriers., Materials and Methods: A complete ophthalmological evaluation was done in a 37-year-old woman and her 53-year-old maternal uncle; the uncle had been diagnosed previously with X-linked retinitis pigmentosa. A visual field test, FAF imaging, full-field electroretinography, and a genetic test were performed., Results: In the proband, the fundoscopy revealed diffuse changes in the retinal pigment epithelium in both eyes, and the FAF showed a speckled pattern of low- and high-density. The maternal uncle's ophthalmological evaluation showed choroidal and retinal atrophy consistent with choroideremia. The molecular analysis revealed a pathogenic variant in the CHM gene, c.190-1 G > T., Conclusions: In female carriers of choroideremia and X-linked retinitis pigmentosa, differential diagnosis may be challenging. A speckled pattern of low- and high-density in autofluorescence is commonly found in female carriers of choroideremia. FAF is a powerful tool for making a correct clinical diagnosis because the pattern in FAF is much more apparent than the visible retinal changes obtained by fundoscopy. Although it is crucial to perform molecular analysis to confirm the diagnosis, FAF is useful when genetic testing may not be readily available.

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.

Background : To learn from the experiences of potential clinical trial participants, participants in a Phase 1 ocular gene therapy trial, and their partners to improve communications and trial conduct. Materials and methods : Primary and secondary qualitative analysis of semi-structured interviews of potential participants (n = 20), clinical trial participants (n = 2) and their partners (n = 2) in a gene therapy clinical trial for choroideremia (NCT02077361). Analysis included: 1) thematic analysis of transcribed entrance and exit semi-structured interviews with trial participants and their partners; and 2) secondary qualitative analysis of interviews with potential trial participants, conducted prior to the initiation of the clinical trial. Results : Participants and partners who had received information during the consent process had a better understanding of the risks and benefits of participation in a Phase 1 gene therapy clinical trial than potential trial participants. However, participants and partners reported deficiencies in communication throughout the trial. Results highlight additional opportunities for trial staff to reinforce initial information about the trial, communicate logistical information and individual outcome data, and express appreciation for participation. Conclusions : Our study enabled clinical trial participants to describe their experiences in a clinical trial for a novel gene therapy. We provide practical recommendations to future clinical trial staff on communications and conduct participant perspectives. Communications strategies should address changing information needs over the course of the trial, express appreciation for participation and enable feedback from participants and their supporting family members, friends, or caregivers.

Purpose : To confirm the pathogenic role of a novel mutation in PNPLA6 and detail the phenotype of a patient presenting with choroideremia-like chorioretinal degeneration. Methods : A 40-year-old man with presumed choroideremia underwent a complete ophthalmic examination, full-field electroretinography (ERG), kinetic fields and two-color automated static perimetry and retinal imaging with spectral domain optical coherence tomography (SD-OCT) and near-infrared (NIR) and short wavelength (SW) fundus autofluorescence (FAF). Results : Visual acuity was 20/200 and 20/40 for the right and left eye, respectively, with a ~ 5D myopic correction. Small cone-mediated ERG responses were detectable. The visual field by kinetic perimetry (V-4e stimulus) was limited to small (<5°) central islands separated from large peripheral islands of vision by an absolute midperipheral scotoma. There were minute islands of apparently spared retina near the foveal center separated from large peripheral islands of better appearing retina by severe pericentral and midperipheral chorioretinal atrophy. SD-OCT confirmed detectable photoreceptors near the center and in nasal midperipheral retina despite severe outer segment loss. Central photoreceptor loss was associated with disproportionately severe retinal pigment epithelium (RPE) depigmentation and choroidal atrophy. NIR- and SW-autofluorescence was widely hypoautofluorescent with the exception of residual autofluorescence along peripheral regions of relative RPE preservation. Gene screening revealed biallelic mutations (p.Arg1031GlnfsTer38/p.Arg1183Gln) in PNPLA6 . Hypogonadotropic hypogonadism and cerebellar vermis hypoplasia by MRI confirmed a diagnosis of Boucher-Neuhäuser syndrome. Conclusions : PNPLA6 -associated retinal degenerations can present with predominantly retinal findings and subtle systemic abnormalities and should be considered in the differential diagnosis of diffuse chorioretinal atrophies.

Background: The RPE65 gene was recently described to cause autosomal dominant retinitis pigmentosa (adRP), presenting with a phenotype resembling choroideremia. This study presents the 2-year progression of RPE65 adRP in a patient., Methods: This is an observational case report of one patient. The patient received a full ophthalmic examination during both visits, including diagnostic imaging such as spectral domain optical coherence tomography (SD-OCT), OCT-angiography (OCT-A), short-wave fundus autofluorescence (FAF), and fundus photography. Genetic characterization was obtained by DNA sequencing from peripheral blood lymphocytes obtained during the first visit., Results: RPE65 adRP phenocopied choroideremia at the initial fundoscopy. Upon the patient's return to our clinic 2 years later, DNA sequencing revealed a heterozygous mutation in the RPE65 gene. Diagnostic imaging by SD-OCT and FAF suggested disease progression. In conjunction with clinical examination and imaging, the diagnosis was revised to adRP caused by RPE65., Conclusion: adRP due to a mutation in the gene encoding RPE65 phenocopied choroideremia. Based on our analysis of the 2-year disease progression in this patient, RPE65 adRP is mild and has a slow rate of disease progression.

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.

Purpose: To investigate the possibility of duplications or deletions within the CHM gene as a cause of choroideremia (CHM)., Materials and Methods: Eight males and one female subject were identified in whom clinical features were consistent with a clinical diagnosis of CHM. In all cases, sequencing of the coding region and adjacent intronic splice sites did not identify a mutation. In some cases, supplemental immunoblot analysis of protein from peripheral blood leukocytes with anti-REP-1 antibody confirmed absence of Rab escort protein-1, REP-1. A multiplex ligation-dependent probe amplification assay (MLPA) for the CHM gene was developed to test for deletions and duplications within the CHM gene., Results: A duplication of exons 3-8 of the CHM gene (NM&#95;000390.2) was identified in one case., Discussion: While likely an uncommon event, duplication within the CHM gene could be considered as an explanation for CHM cases in which no mutation is found by sequence analysis.

Choroideremia (CHM) is an X-linked retinal dystrophy belonging to the family of blinding disorders. It is characterized by progressive degeneration of the choriocapillaris, retinal pigment epithelium and photoreceptors. CHM is caused by mutations in the Rab Escort Protein 1 (REP-1) gene, which encodes a protein involved in vesicular trafficking. This paper gives an overview of the clinical features, visual function, biochemistry, histology, molecular genetics, pathogenesis, diagnosis and treatment of CHM.

Background/aims: The extent and time course of vision loss in Choroideremia (CHM) is still unclear. We undertook this study to quantitate the change in visual acuity (VA) over time in order to gain a better understanding of the natural course of this retinal disorder., Methods: Corrected VA of 120 males with CHM and 53 female carriers were collected from 24 studies and/or case reports published between 1981 and 2010, as well as from data on 15 patients examined at the Cole Eye Institute (Cleveland Clinic). Cross-sectional and longitudinal analyses were used to investigate the relationship between VA and age, as well as the progression rate of VA with age, respectively. Age grouping effects were investigated using ANOVA., Results: The mean age of affected males was 36.6 ± 17.7 years. The mean logMAR VA was 0.35 ± 0.53. There was a significant 0.0072 decrease in logMAR VA per year (p = 1.22 × 10(-4)). There was a significant difference between VA of patients <50 years of age and those >50 years (0.27 ± 0.39 vs. 0.61 ± 0.81, p = 2.90 × 10(-5)). When we compared the rate of VA loss for patients <50 years vs. those >50 years, we also found a significant difference (0.01 ± 0.04 vs. 0.06 ± 0.08, p = 1.23 × 10(-2)). The average age of female carriers was 36.4 ± 17.7 years, with an average logMAR VA of 0.36 ± 0.6. There was no significant correlation between VA of female carriers and age (p = 0.12) with 46% of female carriers having a VA better than 20/20 at an average age of 33 years compared to 25% of affected males at 30 years., Conclusion: In affected males with CHM, VA decreases very slowly until subjects reach 50 years of age, at which time the rate and extent of vision loss become significantly higher. Additionally, VA decreases more rapidly as individuals get older. In contradistinction to affected males, VA loss in female carriers is much milder.

Purpose: To evaluate the presence of peripapillary retinal nerve fiber layer (RNFL) defects in patients with choroideremia by using spectral-domain optical coherence tomography (SD-OCT)., Methods: Twenty-nine eyes of 16 patients with choroideremia underwent peripapillary RNFL thickness measurements by using SD-OCT., Results: The mean (±SD) age of the study population was 44.0 ± 16.0 years (range, 13-63 years). Thirteen eyes (45%) showed a thinning of the peripapillary RNFL in at least 1 quadrant in either 1 or both eyes. Thinning was most commonly found in the superior (13 eyes) and inferior (10 eyes) quadrants. Twenty-one eyes (72%) showed a thickening of the peripapillary RNFL in at least 1 quadrant in either 1 or both eyes. Of these 21 eyes, all had thickening in the temporal quadrant. Additionally, 2 eyes in each of the other 3 quadrants were found to be abnormally thick., Conclusion: Our study demonstrated the presence of defects in the peripapillary RNFL thickness in patients with choroideremia by using SD-OCT. It would be clinically prudent that choroideremia patients considered for various treatment options be considered for RNFL thickness measurements.

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.

Background: Choroideremia is an X-linked recessive disorder characterized by vision loss with progressive atrophy of the retinal photoreceptors, retinal pigment epithelium (RPE), and choriocapillaris. Ectodermal dysplasia is a heterogeneous group of disorders characterized by a deficiency of two or more ectodermal derivatives. We report on the phenotypic and genetic characteristics of a 29-year-old woman with both choroideremia and ectodermal dysplasia., Materials and Methods: Observational case report with physical and ophthalmic examination, fluorescein angiography (FA), visual field testing, electroretinography, and cytogenetic analysis. This study adhered to the tenets of the Declaration of Helsinki and The New York Eye and Ear Infirmary Institutional Review Board guidelines., Results: Physical and ocular examination revealed hypotrichosis, hypohidrosis, full dentures, meibomian gland hypoplasia, and a decrease in corneal tear film. Visual acuity was hand motions in the right eye and 20/50 in the left eye. Fundus examination and fluorescein angiography were consistent with advanced choroideremia and revealed diffuse bilateral RPE and chorioretinal atrophy with sparing of the fovea. Visual field testing had less than 10-degree central islands in both eyes. Scotopic electroretinogram (ERG) was flat with a small flicker response. Cytogenetic analysis showed a complex translocation involving chromosomes X, 1, and 3: 46,X,t(X;1;3)(q13;q24;q21),inv(9)(p11q13). Selective inactivation of the normal X chromosome was present in blood and skin. Chromosomal analyses of the proband's family (mother and two brothers) were normal., Conclusion: An X-autosome chromosomal translocation combined with non-random inactivation of the normal X-chromosome in a woman resulted in the phenotypic findings of choroideremia and ectodermal dysplasia.

Purpose: To define the retinal pathology in a 91 year-old affected matriarch of a three-generation choroideremia family with multiple manifesting carriers., Methods: Tissue from three different retinal areas was processed for immunohistochemistry. The macular area was processed for transmission electron microscopy. Cryosections were studied by indirect immunofluorescence, using well-characterized antibodies to cone cytoplasm, rhodopsin and cone opsins. The affected donor eyes were compared to a postmortem matched normal eye., Results: The retina displayed areas of severe degeneration, with no photoreceptor outer segments, photoreceptor nuclear atrophy, and atrophy of the inner retina. Other retinal areas were near to normal. The RPE was severely degenerated, with thinning, pigment clumping and sub-epithelial debris deposition in all the areas examined. The choroid displayed depigmentation. Labeling with cone opsin antibodies revealed that cones were drastically affected: blue opsin was almost completely absent, while red/green opsins were distributed along the entire plasma membrane of the cell. Rhodopsin was also distributed along the entire rod plasma membrane. Ultrastructural analysis of the affected macula revealed the absence of RPE apical microvilli and basal infoldings. Instead, RPE's basal surface and choroid displayed the presence of banded fibers composed of clumps of wide-spacing collagen. Bruch's membrane was filled with vesicular structures, some smooth and others with bristle-like projections., Conclusions: The histological data suggests that the clinical manifestation in this donor is related to degenerative changes in the retina, RPE, and choroid.

The intracellular distribution of proteins, compartments, substrates, and products is an active process called intracellular traffic. Control of intracellular traffic is established by small GTP-binding proteins (Rab proteins). Rab proteins are modified by geranyl-geranyl moieties necessary for membrane association and target-protein recognition. Geranyl-geranyl groups are transferred to Rab proteins by geranyl-geranyl transferase 2 (GGTase2). GGTase2 requires Rab escort protein 1 (REP1) to bind Rab proteins. REP1 null mutations underlie an X-linked retinal degeneration called choroideremia (CHM). This review summarizes the current biochemical and clinical knowledge on REP1 and CHM.

Purpose: To perform genotype-phenotype correlations in a family with choroideremia., Methods: A three-generation family with two affected males and five carriers was the subject of the study. Molecular genetic analysis using single-strand conformation polymorphism analysis (SSCP) was conducted in all subjects, while electroretinography (ERG), multifocal ERG (mfERG), scanning laser ophthalmoscope microperimetry (SLO perimetry), fluorescein angiography, and Arden contrast color testing were performed in one male and three carriers., Results: The findings in the affected male were typical for advanced choroideremia. The three carriers demonstrated a variable clinical phenotype including reduction of visual acuity and ERG and angiographic changes in one. Molecular genetic analysis revealed a functional null mutation (1388delCCinsG) in the REP-1 gene., Conclusions: A severe retinal pathology was found in the affected male, indicating that the 1388delCCinsG is a severe mutation. Varying phenotypes were present in the three carriers examined. The phenotype in carriers has been explained by random X-inactivation with varying expression of the inactivated and activated gene copy inside the same cell of both the retinal pigment epithelium and the rods. This thesis is in agreement with the clinical data obtained here.

We present clinical and cytogenetic studies of a female patient affected with choroideremia, mild sensorineural deafness, and primary amenorrhea showing a balanced translocation between chromosomes X and 4. The breakpoint was precisely defined applying FISH techniques: 46,X,t(X;4)(q21.2;p16.3).ish t(X;4)(D4S96+, D4F26+; wcpX+). The X-chromosomal breakpoint was located within a region where both the choroideremia locus and a deafness locus (DFN3/POU3F4) have been mapped. The presence of X-linked disorders in this balanced carrier of X-autosomal translocations (XAT) can be explained either by the disruption of the structural coding or regulatory sequences of the gene(s) or by the submicroscopic deletion of this region leading to a contiguous gene deletion syndrome. The primary ovarian failure (POF) found in the present case has been already observed in XAT when the breakpoint is within a previously defined critical region (Xq13-26). A position effect is postulated as a possible explanation.

Purpose: To elucidate the status of a previously described missense mutation (1442A>T) reported in the Rab Escort Protein 1 gene of a patient with choroideremia., Methods: The base substitution previously described by Donnelly et al. (Hum Mol Genet 1994;3:1017) was first confirmed by direct genomic DNA sequencing. The REP-1 cDNA region encompassing exons 10-14 was then specifically amplified from lymphocyte-derived mRNA. The effect on mRNA splicing of the mutation was analyzed by RT-PCR and cDNA sequencing., Results: The 1442A>T change located at the penultimate nucleotide of exon 11 causes complete skipping of this exon during the processing of REP-1 mRNA. Loss of exon 11 leads to the translation of a premature termination codon within exon 12., Conclusion: RT-PCR analyses demonstrated that the 1442A>T transversion previously described as a possible causative missense mutation does act as a splice-site error and gives rise to a truncated REP-1 protein. The virtual absence of any missense mutation found to be responsible for choroideremia makes the RT-PCR-based protein truncation test the most relevant genotypic diagnostic procedure for identifying mutations in the CHM gene.

Choroideremia (CHM), an X-linked recessive hereditary disease, is an intractable chorioretinal dystrophy. The rate of disease progression of CHM reportedly shows considerable variability. A number of mutations involving the gene that codes for Rab escort protein-1 (REP-1) have been detected in CHM patients. We have analyzed REP-1 gene mutations of Japanese CHM patients. The present study was designed to investigate the clinical variability and the genotype to phenotype relationship in 15 Japanese CHM patients referred to the Department of Ophthalmology of Juntendo University Hospital. The clinical investigation of visual acuity, visual field, color vision and refraction revealed inter-individual variability. Mutation analyses of the REP-1 gene revealed 10 types of mutations in 13 patients from 11 families, including an insertion, small deletions, nonsense mutations and an A to CC mutation. In 13 CHM patients with detectable REP-1 gene mutations, no relationship of genotype to phenotype was detected. At present, we consider the REP-1 genotype to be an unreliable prognostic factor for counseling of CHM patients. In two patients from one family, no mutations were detected in coding regions of the REP-1 gene. These patients may have intron mutations of the REP-1 gene, not detectable by the techniques employed in this study, or other causative genes. Both were observed to have somewhat slower disease progression than the other 13 patients. More advanced analyses are necessary to answer questions regarding the genotype-phenotype relationship in CHM patients.

Choroideremia (CHM) is an X-linked heritable progressive dystrophy of the choroid and retina. The condition predominantly affects males beginning in early childhood and eventually results in blindness after a period of 30-40 years. The CHM gene was localized to Xq21 and cloned in the past few years. The gene encodes for Rab escort protein-I, a protein involved in the isoprenylation of intracellular proteins. With the isolation of the gene, a number of mutations have been identified in patients affected by CHM using molecular techniques. Our group reports the characterization of mutations in four Canadian families affected by CHM. In addition, an intragenic polymorphism was identified in exon 5. Finding the mutations in these families will result in accurate predictive testing for carriers, avoid unnecessary repeated examination of at-risk individuals, and add to our understanding of the cause of this disorder.

A Swedish family with choroideremia and a deletion of the CHM gene has been studied with ophthalmological examination, full-field electroretinography, and DNA analysis in order to characterize the phenotype of the disease. Although all four patients studied had a complete deletion of the gene, they showed a considerable variability regarding the phenotype, including the electroretinogram tracings. Two of the affected males demonstrated a severe form of choroideremia with low or nondetectable ERG recordings, while the other two affected males showed a less severe phenotype with only a slight reduction of the ERG amplitudes. The variation of the clinical phenotype among family members carrying the same mutation indicates that the severity of choroideremia is not solely a function of the CHM gene.

Electrooculographic studies were performed in 77 carriers of tapetoretinal dystrophies: Usher syndrome (20), retinitis pigmentosa (32), neuronal ceroid lipofuscinosis (6), Senior syndrome (2), and choroideremia (17). The carriers were matched for sex and age with normal controls. In carriers of Usher syndrome the EOG Lp/Dt ratio was significantly lowered with 30% of the recordings having a subnormal value. There was a trend in carriers of retinitis pigmentosa to a subnormal EOG. In contrast to previous studies there was no decrease in the EOG Lp/Dt ratio in carriers of neuronal ceroid lipofuscinosis. Two carriers of Senior's syndrome had a normal EOG. Carriers of choroideremia did not differ significantly from normal controls; however, the Lp/Dt ratio decreased with increasing age. An abnormal EOG may be indicative of the carrier state in relatives of patients with tapetoretinal dystrophies.