juvenile x - linked retinoschisis ( xlrs ) is a hereditary , vitreoretinal degeneration that was initially described in 1898 by haas   and subsequently recognized to have an x - linked recessive inheritance in 1938 by mann and mac rae . it is characterized by decreased visual acuity within the first to second decade of life and cystic - appearing lesions within the fovea [ 35 ] . approximately 50% of patients will also show peripheral retinoschisis [ 35 ] . a selective or predominant b - wave amplitude reduction on full - field electroretinogram ( erg ) testing is a distinctive feature of the disease . in other x - linked diseases , such as x - linked retinitis pigmentosa , choroideremia and x - linked ocular albinism , because of the principle of lyonisation , which predicts a random inactivation of one x chromosome within each cell , female carriers can express some features of the diseases [ 79 ] . as a rule , female carriers of xlrs do not exhibit any clinically apparent fundus abnormalities [ 3 , 4 ] . isolated observations of foveal cystic - appearing lesions in female carriers from families with xlrs have been reported . there were six such female carriers noted out of a total of 13 who were examined in two different families with consanguineous marriages reported by two previous studies [ 10 , 11 ] . foveal changes , described as wrinkling of the internal limiting membrane , of one eye was reported in one female xlrs carrier from a non - consanguineous marriage by wu et  al . . one study did find that 11 out of 11 obligate carriers showed an abnormal rod - cone interaction by psychophysical testing . nevertheless , carrier detection of xlrs currently can most reliably be successful by identifying genetic mutations in a gene that codes for a protein referred to as retinoschisin ( rs1 ) [ 14 , 15 ] . in the current study , we evaluated the possible role of multifocal erg ( mferg ) testing as a means of detecting functional abnormalities in obligate carriers of xlrs . nine obligate carriers ( eight parents , one offspring ) of xlrs patients were enrolled in the study . they were selected on the basis of their availability and willingness to participate in the study . each had at least one male family member who was diagnosed as having characteristic xlrs findings by one of the authors ( gaf ) . none of the carriers had any other medical or ocular conditions that might have affected their retinal function . after each carrier was counseled regarding the study , they signed a written informed consent approved by the institutional review board at the university of illinois at chicago . all carriers were examined at the department of ophthalmology , university of illinois at chicago by two of the authors ( gaf , lsk ) . best - corrected visual acuity ( bcva ) was measured in each carrier with a snellen projection chart . a dilated fundus examination and slit - lamp biomicroscopy of the lens and anterior segment of both eyes were performed on all carriers as were mferg ( electro - diagnostic imaging , san mateo , ca ) measurements . multiple retinal areas were stimulated to record local cone responses using a stimulus array of 103-scaled hexagons subtending a retinal area of approximately 40 in diameter . each hexagon was scaled with eccentricity to obtain approximately equal amplitudes of local erg responses . individual stimulus elements were modulated between black ( 0.45  cd / m ) and white ( 280  cd / m ) for a time averaged luminance of 140.23  cd / m(approximately 3.8 log td ) . the stimulus was displayed on a black - and - white monitor driven at a frame rate of 75  hz ( nortec , plymouth , mn ) . each subject s vision was optimally corrected with a refractor / camera system for the fixed viewing distance of 40  cm . to ensure equal magnification of the stimulus array , the distance between a subject s eye and the refractor / camera was adjusted for each subject to obtain a sharp image on a control monitor . each carrier s pupil was dilated with 2.5% phenylephrine and 1% tropicamide to obtain a pupil diameter of at least 7  mm . multifocal ergs were recorded only for the right eye for each of the xlrs carriers . a burian - allen bipolar contact lens electrode ( hansen ophthalmic laboratories , iowa city , ia ) was used and grounded to the ipsilateral ear . before insertion of the contact lens electrode , a carrier s cornea segments with large eye movements , losses of fixation , or blinks were discarded and re - recorded . the raw data were filtered at a bandpass of 10 to 300  hz , amplified at a gain of 100,000 ( astro - med / gass model cp11 amplifier ) , and digitized at 1200  hz . each local response was isolated by a cross correlation between the m - sequence and response cycle according to the veris algorithm . the amplitude ( a - scale ) and implicit time ( t - scale ) of all local ( first - order ) mferg responses were derived using the algorithm of hood and li . for the current analysis , raw waveforms were exported from the veris 3.0 for each of the 34 ( 15  male , 19  female ) age - similar ( 3079  years ) normally sighted control subjects . template wave forms were constructed for each hexagon from the average of all the control subjects data . these averaged templates were fitted using a least - squares fitting procedure to each control subject s data by stretching horizontally ( timing ) and vertically ( amplitude ) . for each hexagon , the a - scale values each carrier s data were then fit by the control templates and the resulting values for the a - scale and t - scale were plotted for each hexagon . for the a - scale , a number less than one indicates an amplitude lower than for the average control subjects and for the t - scale , a number greater than one indicates a timing delayed compared to the average control subjects . the statistical probability of each value was calculated using the control subjects mean and 3 standard deviations ( sd ) for the a - scale and t - scale respectively and at each hexagon . for the 99.7% confidence level ( grey hexagons ) five control subjects had one abnormal amplitude and two subjects had two abnormal grey hexagons on the a - scale . for implicit time , six control subjects had one abnormal grey hexagon and two had two abnormal grey hexagons . therefore , for this analysis , any carrier exhibiting a total of three or more grey hexagons were considered abnormal . a black hexagon indicated that a measurable signal could not be detected from the noise level . we used a criterion of two or more black hexagons for a carrier as highly likely to represent a local abnormality . the nine xlrs carriers ranged in age from 2370  years , with a mean age of 46.2  years . all showed a normal exam of the anterior segment of the eye , including the lens . seven of the nine obligate carriers were observed to have varying degrees , from mild to moderate , of situs inversus of their temporal retinal vessels . in ocular situs inversus , the temporal vessels leave the optic disc directed towards the nasal retina before making a sharp temporal turn . the fundus photograph for carrier # 1 with situs inversus is shown in fig .  1 . in a study of fundus findings for xlrs patients , situs inversus was observed in 32% of patients with xlrs . to our knowledge , situs inversus of the retinal vessels has not been emphasized as a possible finding in carriers of xlrs . table  1the age , visual acuity for the right eye ( od ) and left eye ( os ) and fundus findings for each of the x - linked retinoschisis carrierscarrierage ( years)va odva osfundus findings13520/1520/15mild situs inversus ou24720/2020/20normal ou32320/2020/20 normal ou45320/2020/20mild situs inversus ou54820/2520/20situs inversus ou65820/2020/20situs inversus ou73920/2020/20mild situs inversus ou84320/20 20/20situs inversus inferior vein os , anomalous branching os  >  od97020/20 20/20 anomalous branching ou , situs inversus superior artery od , inferior artery osfig . 1fundus photograph of xlrs carrier # 1 demonstrating situs inversus of the retinal veins the age , visual acuity for the right eye ( od ) and left eye ( os ) and fundus findings for each of the x - linked retinoschisis carriers fundus photograph of xlrs carrier # 1 demonstrating situs inversus of the retinal veins two of nine carriers demonstrated a mosaic pattern of statistically significant amplitude reductions ( figs . 2a , 3a ) and implicit time delays ( figs .  2b , 3b ) . the actual mferg tracings and hexagon analysis for these two carriers are shown in figs .  2 and 3 . 2multifocal electroretinogram ( mferg ) results of x - linked retinoschisis ( xlrs ) carrier # 8 exhibiting a mosaic pattern of retinal dysfunction . mferg amplitudes ( a ) and implicit times ( b ) for the right eye . in this figure , as in figure 3 , the white hexagons show regions falling within 2 standard deviations ( sd ) of the normal mean . the grey hexagons represent locations that are more than 3 sd from the normal mean while the black hexagons indicate a non - measurable response . 3multifocal electroretinogram ( mferg ) results of xlrs carrier # 3 exhibiting a mosaic pattern of retinal dysfunction . mferg amplitudes ( a ) and implicit times ( b ) for the right eye . mferg waveform traces are illustrated below ( c ) multifocal electroretinogram ( mferg ) results of x - linked retinoschisis ( xlrs ) carrier # 8 exhibiting a mosaic pattern of retinal dysfunction . mferg amplitudes ( a ) and implicit times ( b ) for the right eye . in this figure , as in figure 3 , the white hexagons show regions falling within 2 standard deviations ( sd ) of the normal mean . the grey hexagons represent locations that are more than 3 sd from the normal mean while the black hexagons indicate a non - measurable response . mferg waveform traces are illustrated below ( c ) multifocal electroretinogram ( mferg ) results of xlrs carrier # 3 exhibiting a mosaic pattern of retinal dysfunction . mferg amplitudes ( a ) and implicit times ( b ) for the right eye . our findings support the conclusion that the presence of a functional abnormality on mferg testing , in the absence of other causes for retinal dysfunction in a female at risk , should suggest the presence of a carrier state for xlrs , which could then be further confirmed by genetic testing . however , a normal mferg result would not , by itself , rule out the carrier state . piao and co - workers   showed that mferg cone - mediated responses were more impaired centrally than in the more peripheral retina in their study of seven male patients with xlrs . they also observed a higher frequency of delayed implicit times than reduced amplitudes in their patients . the presence of situs inversus of the retinal vessels in a female from a family with xlrs is also suggestive of the carrier state . our findings on mferg testing demonstrate the effect of lyonisation on retinal function in carriers of xlrs . a similar finding on mferg testing multifocal erg testing may be a useful technique for the detection and monitoring of localized retinal dysfunction in some carriers of xlrs .
purpose to determine whether retinal dysfunction in obligate carriers of x - linked retinoschisis ( xlrs ) could be observed in local electroretinographic responses obtained with the multifocal electroretinogram ( mferg ) . 
 methods nine obligate carriers of xlrs ( mean age , 46.2  years ) were examined for the study . 
 examination of each carrier included an ocular examination 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 were compared with the corresponding values determined for a group of 34 normally - sighted , age - similar control subjects . 
 results mapping of 103 local electroretinographic response amplitudes and implicit times within a central 40 area with the mferg showed regions of reduced mferg amplitudes and delayed implicit times in two of nine carriers . 
 conclusions the mferg demonstrated areas of retinal dysfunction in two carriers of xlrs . when present , retinal dysfunction was evident in the presence of a normal - appearing fundus . 
 multifocal erg testing can be useful for identifying some carriers of xlrs .