Carriers Of X-linked Retinitis Pigmentosa Research Articles

Asymmetric presentation with a novel RP2 gene mutation in X-Linked retinitis pigmentosa: a case report

BackgroundWe present the detailed multimodal imaging analysis in a case of X-linked retinitis pigmentosa (XLRP) exhibiting a markedly asymmetric presentation with a novel RP2 mutation.Case presentationA 25-year-old woman complained of decreased vision in the right eye as well as night blindness. Her visual acuity was 20/100 (OD) and 20/20 (OS). Fundus examination revealed bone spicule pigmentation with tessellated changes in the fundus within the posterior pole. Optical coherence tomography (OCT) showed generalized disruption of foveal microstructures in the OD. No abnormal findings were identified, but localized ellipsoid zone band losses were observed on OCT in the OS. Fundus autofluorescence revealed multiple patchy hypo-autofluorescent lesions in the OD and a tapetal-like radial reflex against a dark background in the OS. Fluorescein angiography and OCT angiography revealed diffuse mottled hyperfluorescence with reduced retinal vessel density in the OD and no evidence of vascular compromise in the OS. Goldmann perimetry demonstrated a constricted visual field, and electrophysiological assessment revealed an extinguished rod response and a severely impaired cone response in the OD. Molecular genetic tests via next-generation sequencing revealed the pathogenic variant to be a heterozygous frameshift mutation in RP2 (RP2, p.Glu269Glyfs*7), resulting in premature termination of the protein.ConclusionsRandom X-inactivation may be attributed to interocular differences in the severity of XLRP in female carriers. A novel frameshift mutation in the RP2 gene and a comprehensive phenotypic evaluation in the current study may broaden the spectrum of the disease in XLRP carriers.

A novel mutation of RPGR in a Chinese family with X-linked retinitis pigmentosa.

To identify potential mutations and elucidate the clinical findings of male patients and female carriers of X-linked retinitis pigmentosa (XLRP) in a Chinese family. A four generation pedigree was collected that consisted of 20 individuals. Genomic DNA was extracted from peripheral blood, and then the target fragments were amplified by PCR and sequenced directly. In addition, all affected patients and female carriers underwent comprehensively ophthalmic evaluation. A novel mutation c.2865G>A p.W955X in RPGR gene was identified of this family, including four affected individuals and eight carriers. All male patients, aging from 7 to 31y, tended to have more various, even potentially deleterious clinical features of RP. At the same time, individuals with heterozygous mutations (carriers) manifested a wide spectrum of clinical features. Herein, only two male patients and three female carriers manifested pathological myopia (PM). Among the female carriers, half of subjects who harbor poor visual acuity suffered esotropia or exotropia. Additionally, 16.7% and 66.7% of carriers had abnormal electroretinogram (ERG) and fundus, respectively. In this study, a novel mutation of the RPGR gene is identified, which broadens the spectrum of RPGR mutations, and elaborates the relationship between genotype and phenotype.

RPGR-Related X-Linked Retinitis Pigmentosa Carriers with a Severe “Male Pattern”

Background: X-linked retinitis pigmentosa (XLRP) due to mutations in the RPGR gene is a very severe form of RP, resulting in rapid disease progression and retinal dysfunction. Female carriers do not usually report symptoms. However, it has reported that carriers of XLRP can have a significant visual and retinal impairment. Objectives: To report a detailed description of 3 cases of severely affected females who presented with a “male” phenotype and have posed challenges at diagnosis, due to the apparent autosomal dominant family history. Method: Autofluorescence imaging (AF), colour imaging and optical coherence tomography (OCT) were performed. Confirmation of the genetic mutation was obtained by Sanger genetic sequencing. In 1 patient an X-inactivation analysis was performed to detect the X-inactivation ratio, as the percentage of cells tested in which each allele is active. Results: All the patients started suffering from night blindness in early childhood. Colour, fundus AF and OCT images showed the typical pattern of degeneration reported in men. One patient underwent retina implant surgery due to the severe atrophy. Conclusions: This is a small selection of females with a severe phenotype that do not differ from the typical male phenotype. In our opinion gene therapy surgery should be warranted in this scenario.

X-linked Retinitis Pigmentosa in Japan: Clinical and Genetic Findings in Male Patients and Female Carriers.

X-linked retinitis pigmentosa (XLRP) is a type of severe retinal dystrophy, and female carriers of XLRP demonstrate markedly variable clinical severity. In this study, we aimed to elucidate the clinical findings of male patients with and female carriers of XLRP in a Japanese cohort and demonstrate the genetic contribution. Twelve unrelated families (13 male patients, 15 female carriers) harboring pathogenic mutations in RPGR or RP2 were included, and comprehensive ophthalmic examinations were performed. To identify potential pathogenic mutations, targeted next-generation sequencing was employed. Consequently, we identified 11 pathogenic mutations, of which five were novel. Six and five mutations were detected in RPGR and RP2, respectively. Only one mutation was detected in ORF15. Affected male patients with RP2 mutations tended to have lower visual function than those with RPGR mutations. Female carriers demonstrated varying visual acuities and visual fields. Among the female carriers, 92% had electroretinographical abnormalities and 63% had a radial autofluorescent pattern, and the carriers who had higher myopia showed worse visual acuity and more severe retinal degeneration. Our results expand the knowledge of the clinical phenotypes of male patients with and female carriers of XLRP and suggest the possibility that RP2 mutations are relatively highly prevalent in Japan.

The clinical application of preimplantation genetic diagnosis for X-linked retinitis pigmentosa.

To investigate the usefulness of preimplantation genetic diagnosis (PGD) based on mutated allele revealed by sequencing with aneuploidy and linkage analyses (MARSALA) for a pedigree with X-linked retinitis pigmentosa (XLRP). One pathogenic mutation (c.494G > A) of the retinitis pigmentosa GTPase regulator (RPGR) gene was identified in a pedigree affected by XLRP. Then, PGD was carried out for the couple, of which the wife was an XLRP carrier. Three blastocysts were biopsied and then MARSALA was performed by next-generation sequencing (NGS). Prenatal diagnosis was also carried out to confirm the PGD results. Three blastocysts were all unaffected. Then, one of the embryos was chosen randomly to be transferred, and the pregnancy was acquired successfully. The results of prenatal diagnosis were consistent with the PGD results. The fetus did not carry RPGR mutation (c.494G > A) and had normal chromosome karyotype. As a result, a healthy baby free of XLRP condition was born. The PGD method based on MARSALA was established and applied to a family with XLRP successfully. MARSALA will be a valid tool, not only for XLRP families but also for families affected with other monogenetic disorders, to prevent transmission of the genetic disease from parents to offspring.

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.

The Role of X-Chromosome Inactivation in Retinal Development and Disease.

The expression of X-linked genes is equalized between males and females in mammalian species through X-Chromosome inactivation (XCI). Every cell in a female mammalian embryo randomly chooses one X Chromosome for epigenetic silencing at the 8-16 cell stage, resulting in a Gaussian distribution of XCI ratios with a peak at 50:50. At the tail extremes of this distribution, X-linked recessive mutations can manifest in disease in female carriers if the mutant allele is disproportionately active. The role of XCI skewing, if any, in X-linked retinal disease is still unknown, although many have speculated that such skewing accounts for phenotypic variation in female carriers of X-linked retinitis pigmentosa (XlRP). Some investigators have used clinical findings such as tapetal-like reflex, pigmentary changes, and multifocal ERG parameters to approximate XCI patches in the retina. These studies are limited by small cohorts and the relative inaccessibility of retinal tissue for genetic and epigenetic analysis. Although blood has been used as a proxy for other tissues in determining XCI ratios, blood XCI skews with age out of proportion to other tissues and may not accurately reflect retinal XCI ratios. Future investigations in determining retinal XCI ratios and the contribution of XCI to phenotype could potentially impact prognosis for female carriers of X-linked retinal disease.

Radial fundus autofluorescence in the periphery in patients with X-linked retinitis pigmentosa.

PurposeTo describe the peripheral autofluorescence images and clinical features of patients with retinal dystrophy who showed radial fundus autofluorescence (FAF) at the posterior pole.MethodsThe authors retrospectively reviewed pooled wide-field FAF images of 711 patients with retinal dystrophy and 56 family members.ResultsEleven eyes of seven women exhibited radial FAF at the posterior pole. Wide-field FAF showed extension of the radial pattern to the periphery in all eyes except one. One woman showed radial hyper-FAF only in the periphery, not at the posterior pole. These eight individuals were X-linked retinitis pigmentosa patients or carriers. The tapetal-like reflex was not observed in their color fundus photographs. The peripheral visual field showed wedge-shaped restriction in some individuals.ConclusionWide-field FAF imaging can depict radial FAF not only at the posterior pole but also in the periphery in X-linked retinitis pigmentosa carriers. The authors therefore agree with previous reports that radial FAF may be a hallmark of X-linked retinitis pigmentosa.

Visual Function in Carriers of X-Linked Retinitis Pigmentosa

To determine the frequency and severity of visual function loss in female carriers of X-linked retinitis pigmentosa (XLRP). Case series. Two hundred seventy-six XLRP carriers with cross-sectional data (n= 242) and longitudinal data (n= 34; median follow-up, 16 years; follow-up range, 3-37 years). Half of the carriers were from RPGR- or RP2-genotyped families. Retrospective medical records review. Visual acuities, visual field areas, final dark adaptation thresholds, and full-field electroretinography (ERG) responses to 0.5-Hz and 30-Hz flashes. In genotyped families, 40% of carriers showed a baseline abnormality on at least 1 of 3 psychophysical tests. There was a wide range of function among carriers. For example, 3 of 121 (2%) genotyped carriers were legally blind because of poor visual acuity, some as young as 35 years. Visual fields were less affected than visual acuity. In all carriers, the average ERG amplitude to 30-Hz flashes was approximately 50% of normal, and the average exponential rate of amplitude loss over time was half that of XLRP males (3.7%/year vs. 7.4%/year, respectively). Among obligate carriers with affected fathers, sons, or both, 53 of 55 (96%) had abnormal baseline ERG results. Some carriers who initially had completely normal fundi in both eyes went on to experience moderately decreased vision, although not legal blindness. Among carriers with RPGR mutations, those with mutations in ORF15, compared with those in exons 1-14, had worse final dark adaptation thresholds and lower 0.5-Hz and 30-Hz ERG amplitudes. Most carriers of XLRP had mildly or moderately reduced visual function but rarely became legally blind. In most cases, obligate carriers could be identified by ERG testing. Carriers of RPGR ORF15 mutations tended to have worse visual function than carriers of RPGR exon 1 through 14 mutations. Because XLRP carrier ERG amplitudes and decay rates over time were on average half of those of affected men, these observations were consistent with the Lyon hypothesis of random X-inactivation.

Evaluation of multimodal imaging in carriers of X-linked retinitis pigmentosa

The aim of this study was to investigate visualization of the tapetal-like reflex using current imaging modalities and evaluate SD-OCT changes in known carriers of X-linked retinitis pigmentosa (XLRP); the objective being the development of an optimal protocol for clinicians to identify carriers. Ten XLRP carriers (19 eyes) were examined using color fundus photography, 488 nm reflectance (488-R), near-infrared reflectance (NIR-R), autofluorescence (AF) and spectral domain optical coherence tomography (SD-OCT) imaging (Spectralis SLO-OCT, Heidelberg). Horizontal line scans through the fovea were acquired in all subjects and in a group of 10 age-similar controls. Peripheral SD-OCT scans (extending to 27.5° eccentricity) were also acquired in both eyes of 7 carriers. MP-1 microperimetery (10-2 pattern; Nidek) was performed in one eye of each carrier. For the XLRP carriers, a tapetal reflex was observed with all imaging modalities in 8 of 19 eyes. It had the same retinal location on color fundus, 488-R and NIR-R imaging but a different location on AF. The tapetal reflex was most easily detected in 488-R images. The horizontal foveal SD-OCT scans were qualitatively normal, but measurements showed significant outer retinal layer thinning in all eyes. Additionally, the 14 eyes with peripheral SD-OCTs demonstrated patchy loss of the inner segment ellipsoid band. Microperimetry exhibited patchy visual sensitivity loss in 9 eyes. Full field ERGs were variable, ranging from normal to severely abnormal rod and cone responses. Our findings suggest that an optimal protocol for identifying carriers of XLRP should include 488-R imaging in a multimodal approach. Peripheral SD-OCT imaging and central retinal layer quantification revealed significant structural abnormalities.

Cellular imaging demonstrates genetic mosaicism in heterozygous carriers of an X-linked ciliopathy gene

X-linked retinitis pigmentosa (XLRP) is the least common genetic type of retinitis pigmentosa; however, it has extremely devastating consequences to patients' activities of daily living. RPGR and RP2 genes expressed in the photoreceptor sensory cilia are predominantly implicated in XLRP; however, the interpretation of genetic mutations and their correlation with clinical phenotypes remain unknown, and the role of these genes in photoreceptor cilia function is not completely elucidated. Therefore, we evaluated structural characteristics in five female obligate carriers of XLRP by using state-of-the-art non-invasive imaging methods, including adaptive optics (AO) scanning laser ophthalmoscopy (SLO). In all five carriers examined, qualitative and quantitative analyses by AO SLO imaging revealed a mosaic pattern of cone disruption, even in the absence of visual symptoms, normal visual acuity and normal macular thickness, on optical coherence tomography and mildly subnormal full-field cone electroretinographic findings. As the technique is sensitive to the level of a single cone, the ability to visualize the cone cells in vivo should be especially useful in other retinal diseases. In addition, further investigation of XLRP carriers may yield insight into how cone structures change over time and ultimately enable understanding of the role of RPGR and RP2 in cone cell survival.

STRUCTURAL AND FUNCTIONAL CHARACTERISTICS IN CARRIERS OF X-LINKED RETINITIS PIGMENTOSA WITH A TAPETAL-LIKE REFLEX

The purpose of this study was to identify the functional and structural characteristics in three female obligate carriers of X-linked retinitis pigmentosa from the same family by using spectral domain optical coherence tomography, fundus autofluorescence, and microperimetry. Three female obligate carriers with a tapetal-like reflex, 21, 49, and 57 years of age, from a single family of X-linked retinitis pigmentosa that was seen in the ophthalmology department at the University of Illinois at Chicago, were enrolled in the study. All carriers underwent a complete ophthalmic examination. Spectral domain optical coherence tomography measurements, a macular microperimetry examination, and fundus autofluorescence testing were performed. The spectral domain optical coherence tomography examination in all three carriers showed a normal retinal microstructure and thickness. Microperimeter testing showed subnormal retinal sensitivity in the areas of the tapetal-like reflex. Fundus autofluorescence examination showed the presence of speckled areas of enhanced autofluorescence. Our study demonstrates that the carriers of X-linked retinitis pigmentosa with a tapetal-like reflex can show an enhanced reflectance on infrared images, abnormal autofluorescence properties, elevated retinal thresholds, and a normal retinal morphology within the posterior pole on spectral domain optical coherence tomography testing.

Optical coherence tomography and electro-oculogram abnormalities in X-linked retinitis pigmentosa

To determine the correlations between morphological optical coherence tomography (OCT) and electrophysiological electro-oculogram (EOG) alterations in families with X-linked retinitis pigmentosa (XLRP). Observational case series. About 32 eyes of 16 members of four different families: Seven obligate carriers, four affected male homozygotes and five unaffected females underwent ophthalmologic completed exams including EOG and OCT. All the subjects were previously tested with genetic analysis. The results were statistically analysed. The abnormalities in OCT were detected in all carriers and affected males consisting of macular edema and increased RPE reflectivity compared to no alterations in unaffected females. The EOG was flat in all affected males; distinctly abnormal in eight eyes of obligate carriers; normal in two eyes of obligate carriers and in all unaffected females. In two obligate carriers, the EOG was not performed due to a nuclear cataract. The correlations between OCT and EOG alterations were statistically significant. The OCT and EOG were demonstrated to be useful methods to identify the minimal alterations in carriers of X-linked retinitis pigmentosa.

Histopathologic-Genotypic Correlations in Retinitis Pigmentosa and Allied Diseases

This paper reviews the published histopathologic findings of patients with retinitis pigmentosa (RP) or an allied disease in whom the responsible gene defect was identified, including 10 cases with dominant RP (cases with mutations in RHO, PRPC8, and RP1), three with dominant spinocerebellar ataxia (SCA7), three X-linked RP carrier females (RPGR), two with congenital retinal blindness (AIPL1 and RPE65), two with mitochondrial encephalomyopathy overlap syndrome (MTTL1), and one case each with dominant cone degeneration (GCAP1), X-linked cone degeneration (RCP), enhanced S-cone syndrome (NR2E3), and dominant late-onset retinal degeneration (CTRP5). No histopathologic descriptions were found of the vast majority of genetically defined forms of retinal degeneration.

Fundus autofluorescence in carriers of X-linked recessive retinitis pigmentosa associated with mutations in RPGR, and correlation with electrophysiological and psychophysical data.

To describe fundus autofluorescence (AF) in carriers of X-linked retinitis pigmentosa (XLRP) associated with mutations in RPGR (RP3), and to compare the findings on AF with ophthalmoscopy and with electrophysiological and psychophysical data. Eleven carriers from two families with XLRP and mutations in RPGR underwent clinical examination including fundus photography, AF, full-field electroretinography, Goldmann kinetic perimetry and two-colour threshold perimetry (2CT perimetry). An abnormal AF pattern was found in 9 of 11 carriers, with a radial pattern in 6 of 11. In 2CT perimetry patchy rod and cone sensitivity losses were seen in 7 of 8 carriers. Rods tended to be more affected than cones. The areas of sensitivity loss showed some correspondence with the abnormalities seen on AF. AF had a specific pattern in 9 of 11 carriers from two families with mutations in RPGR. The result was independent of the family investigated. The radial pattern may be explained by random X-inactivation early during embryogenesis subsequently preserved in all daughter cells and the centrifugal radial growth pattern of the developing neuroretina. AF may prove to be a rapid and easy clinical test to identify carriers of RP3.

ON-pathway dysfunction and timing properties of the flicker ERG in carriers of X-linked retinitis pigmentosa.

Carriers of X-linked retinitis pigmentosa (XLRP) frequently show prolonged implicit times of the flicker electroretinogram (ERG). This study tested the hypothesis that a preferential response attenuation within the cone depolarizing (ON) bipolar cell (DBC) pathway is a major contributing factor. Light-adapted, full-field ERGs were recorded from 10 XLRP carriers and 12 visually normal control subjects. Fundamental amplitudes and phases of ERG responses to sinusoidally flickering stimuli at temporal frequencies ranging from 8 to 96 Hz were analyzed within the framework of a recent vector summation model of the cone system ERG to test for evidence of a response attenuation within the DBC pathway. In addition, ERG responses to sawtooth flicker were examined for a reduced b- to d-wave amplitude ratio, indicative of ON pathway dysfunction. The carriers' fundamental response phases at 32 Hz correlated significantly with their log ratios of response amplitudes at 32 versus 12 Hz (r = 0.89, P < 0.001) and with their log b- to d-wave amplitude ratios (r = 0.71, P < 0.05), both of which were used as indices of response attenuation within the DBC pathway. A control experiment demonstrated that a reduced sensitivity of cone phototransduction made at most only a minimal contribution to the timing changes in the carriers' flicker ERG responses. The overall pattern of results indicates that a preferential response attenuation within the DBC pathway is the primary source of timing changes in the flicker ERGs of these carriers of XLRP. These findings illustrate the value of analyzing ERG responses to flickering stimuli at multiple temporal frequencies to evaluate mechanisms of disease action in photoreceptor degenerations.

Detection using the multifocal electroretinogram of mosaic retinal dysfunction in carriers of X-linked retinitis pigmentosa

PurposeTo examine whether a mosaic pattern of retinal dysfunction in obligate carriers of X-linked retinitis pigmentosa (XLRP) could be observed in local electroretinographic responses obtained with the multifocal electroretinogram (mfERG). DesignProspective observational case series. ParticipantsFive obligate carriers of XLRP (mean age, 53.2 years) were recruited into the study. MethodsExamination of each subject included a complete ocular examination, Humphrey visual field, standard full-field electroretinogram (ERG), and mfERG testing. For the mfERG, we used a 103-scaled hexagonal stimulus array that subtended a retinal area of approximately 40° in diameter. The amplitudes and implicit times in each location for the mfERG was compared with the corresponding value determined for a group of normally sighted, age-corrected control subjects. Main outcome measuresMapping of 103 local electroretinographic response amplitudes and implicit times within the central 40° with the multifocal electroretinogram. ResultsLocalized regions of reduced mfERG amplitudes and/or delayed implicit times were found in four of five carriers. In one of these four carriers, a mosaic pattern of mfERG dysfunction was present even in the absence of any clinically apparent retinal changes, retinal sensitivity losses on Humphrey field testing, or abnormal full-field cone ERG responses. However, one carrier with a typical tapetal-like reflex demonstrated no deficit on any functional tests. ConclusionsThe mfERG demonstrated patchy areas of retinal dysfunction in some carriers of XLRP. This mosaic pattern of dysfunction may be observed in some patients with a normal-appearing fundus, normal psychophysical thresholds, and normal amplitude and implicit time full-field ERG cone responses.

Phenotypes in Three Swedish Families With X-linked Retinitis Pigmentosa Caused by Different Mutations in the RPGR Gene

To assess the clinical phenotypes in three Swedish families with X-linked retinitis pigmentosa caused by different mutations in the RPGR gene. Three families from different parts of Sweden, including nine patients with retinitis pigmentosa and six female carriers of X-linked retinitis pigmentosa, were examined clinically. Ophthalmologic examination included kinetic perimetry with a Goldmann perimeter using standardized objects I4e and V4e, dark adaptation final thresholds with a Goldmann-Weeker adaptometer, and full-field electroretinograms. The clinical findings in the patients demonstrated a severe form of retinitis pigmentosa with visual handicap early in life. Patients with a microdeletion of exons 8 through 10 of the RPGR gene had a more severe phenotype compared to the patients with single base-pair mutations in the introns 10 and 13 of the RPGR gene, resulting in splicing defects. Furthermore, heterozygous carriers in these families displayed a wide spectrum of clinical features, from minor symptoms to severe visual disability. These three families show a variable clinical phenotype resulting from different mutations in the RPGR gene. A microdeletion spanning at least parts of exons 8 through 10 seems to result in a severe phenotype compared to the splice defects. Heterozygous carriers of X-linked retinitis pigmentosa with these specific RPGR genotypes also show a variability of the phenotype; carriers with the microdeletion may be severely visually handicapped.

ERG and EOG abnormalities in carriers of X-linked retinitis pigmentosa.

The diagnosis of X-linked retinitis pigmentosa (XL-RP) relies on the identification of the female carriers, in whom fundal abnormalities are often minimal and variable. The electroretinogram (ERG) has been reported as abnormal in 54-96% of heterozygote females. This study examines the combined use of electro-oculogram (EOG) and standardised ERG in 31 obligate and 33 non-obligate carriers of XL-RP. In the obligate carrier group, the EOG was abnormal in 13 carriers (41%), the ERG abnormal in 21 carriers (68%) and a combined EOG and ERG abnormality occurred in 24 carriers (77%). An EOG abnormality alone occurred in 2 carriers (6.5%). Fourteen obligate carriers (45%) showed a peak to peak delay of the ERG scotopic b wave, this being a previously unreported phenomenon. Similarly, in the non-obligate carrier group, the EOG was abnormal in 11 carriers (44%) and the ERG abnormal in 19 carriers (73%). The results of this study suggest that the use of both tests, including measurement of the scotopic b wave latency, may increase the carrier detection rate.

X-inactivation pattern in carriers of X-linked retinitis pigmentosa: A valuable means of prognostic evaluation?

In a large family with X-linked retinitis pigmentosa 2 (XLRP2), we reexamined 7 obligate carrier females and 6 daughters of obligate carriers, whose linkage relationships suggested that they carried the XLRP2 gene. The phenotype varied from totally normal eyes through mild retinal changes to complete loss of vision. The X-inactivation analysis was carried out with the highly informative probe M27 beta on DNA from blood lymphocytes. This probe detects a locus DXS255 that is differentially methylated on the active and inactive X chromosomes. In 5 blind heterozygotes (aged 43 to 68 years), we found that the X chromosome carrying the RP2 gene was methylated and active in nearly all their cells. The opposite X inactivation pattern was found in a carrier female (aged 45 years) who gave normal findings on eye examination. Carriers with less skewed X inactivation had a less severe clinical outcome. However, we found little or no correlation between their phenotypes and the methylation status of their X chromosomes. Our results suggest that it may be possible to develop a predictive test that could identify cases with severe outcome and perhaps cases with normal outcome.