73 Juvenile X-Linked Retinoschisis

J X- retinoschisis (XLRS, OMIM 31270) is a vitreoretinal dystrophy that manifests early in life (as early as 3 months of age)22 and has no associated nonocular findings. Intraretinal cysts form in the macula, and splitting of the retinal layers occurs in peripheral retina (figures 73.1 and 73.2). The macular changes frequently are in the form of a spoke-wheel pattern of perifoveal cysts and may result in a visual acuity of 20/60 or less. Patients tend to be hyperopic.11 Substantial peripheral visual field loss can occur. The term retinoschisis was introduced by Wilczek in 1935.28

The condition is limited nearly exclusively to males. Female carriers essentially never show macular or retinal pathology or suffer visual symptoms, but in rare cases, carriers may have macular or peripheral retinal changes, presumably on the basis of Lyonization of the trait.9

XLRS is one of the more common causes of juvenile macular degeneration in males, with a prevalence of 1 : 5,000 to 1 : 25,000. Affected males typically are identified by early grade-school age owing to reduced visual acuity. Males initially complain of reduced visual acuity, not poor night vision or loss of peripheral vision. In many cases, the reduced visual acuity stabilizes by the teenage years in affected males and then remains constant into middle age. Macular atrophy may begin in late middle age and progress toward legal blindness (20/200) in affected males. Vitreous hemorrhage and full-thickness retinal detachment occurs occasionally, and successful surgical repair is infrequent.

While the fundus appearance of XLRS may be diagnostic in affected males, the presentation can be confusing in some cases, requiring additional testing with electroretinography. This will be most helpful in the males who have progressed beyond the typical spoke-wheel pattern and present with a bilateral maculopathy, with or without areas of peripheral schisis. A fluorescein angiogram may also be helpful in differentiating XLRS from autosomal-recessive Stargardt macular dystrophy, which exhibits a silent or dark choroid. Younger patients typically show a normal angiogram, although older patients with XLRS may exhibit changes in the retinal pigment epithelium, including relative window defects in the macula (figure 73.3). Occasionally, patients exhibit a change in color immediately or shortly after light onset with dark adaptation (Mizuo phenomenon).5 This phenomenon disappears with vitrectomy and removal of the posterior vitreous face.15

Differential diagnosis

A careful review of the family history will assist in establishing a diagnosis in which an index case presents with a bilateral maculopathy and an electronegative ERG. Conerod dystrophy and Stargardt macular dystrophy have a macular phenotype but do not show either an X-linked pattern of inheritance or selective b-wave reduction of the ERG that occurs with XLRS.

Goldmann-Favre syndrome is an autosomal-recessive vitreoretinal disorder in which macular cysts and peripheral lattice degeneration are seen. Patients complain of nyctalopia, unlike in XLRS, and have a markedly reduced ERG.6 Wagner disease is an autosomal-dominant disorder that maps to 5q13–143 and is characterized by myopia, vitreous syneresis, and frequent retinal detachment. The macula may show pigmentary changes. While the ERG may be abnormal in patients with Wagner disease, selective b- wave reduction is not seen.

Gene identification

XLRS was mapped to Xp22.1–22.3 by linkage analysis of many pedigrees.1,4,17,18,24,26,27 The XLRS gene was cloned in 1997 and was designated RS1.22 RS1 gene structure consists of six exons coding for 224 amino acid residues. The C- terminal discoidin domain mediates cell-cell adhesion. The RS1 protein is heavily expressed in inner segments of both rod and cone photoreceptors and is also seen in cells of the inner nuclear layer.7

Penetrance of mutations is virtually 100%. There is significant intrafamilial variability in the phenotype. Clinically useful genotype-phenotype correlations have not been found. Mutations result in loss of function. Exons 1–3 tend to have nonsense mutations, whereas exons 4–6 (encoding the discoidin domain) have missense mutations, which draws attention to its functional importance.20

Classical ERG studies

The electroretinogram (ERG) is the single most useful test for confirming a diagnosis of XLRS. Significant abnormality of dark-adapted thresholds is uncommon. The Arden ratio of the electro-oculogram is usually normal in affected

F 73.1 Fundus photograph of XLRS-affected male with juvenile retinoschisis showing spoke-wheel pattern of foveal cysts covering an area of approximately one disk diameter. (See also color plate 47.)

F 73.2 Fundus photograph of XLRS-affected male with peripheral schisis cavity, which occurs in 50% of affected males. (See also color plate 48.)

individuals.12,19 The ERG frequently shows an electronegative configuration, in which a-wave amplitude remains substantially normal but the b-wave is reduced (figure 73.4A). Since the b-wave historically was thought to arise from Müller cell depolarization following release of potassium by activity of depolarizing bipolar cells,10 the presumption was that Müller cells might harbor the primary defect in XLRS. Other diseases that can cause an electronegative ERG configuration include congenital stationary night blindness,2 which has a normal fundus, whereas XLRS has an abnor-

mal fundus and is not associated with symptomatic night blindness. Other ERG abnormalities in XLRS include the scotopic threshold response (STR).16 The STR originates in the proximal retina owing to potassium release by amacrine cells and a subsequent depolarization of the Müller cells from this excess potassium. One study suggested that the STR was a sensitive test for identifying XLRS.16 Despite this apparent sensitivity, however, female carriers exhibited no STR abnormality. Female carriers have normal a- and b- waves. Consequently, female carriers can be identified only by pedigree analysis (daughter of an affected father or woman having an XLRS-affected son).

Although an electronegative ERG is the most frequent presentation in XLRS, exceptions have been reported. In one study of an XLRS family with an Arg213Trp mutation, one affected male retained a normal scotopic b-wave response (figure 73.4B).23 This indicates that caution is advised in placing complete reliance on the ERG for differential diagnosis of this condition. In this case, genotyping was particularly helpful to confirm the diagnosis of XLRS.

Analysis of photoreceptor and inner retinal responses in XLRS

In a study of 15 males with retinoschisis who had been genotyped for RS1 mutations,8,20 the ERG was evaluated to determine whether RS1 protein expression in photoreceptors affected their function.13 When the phototransduction model was applied to dark-adapted a-wave responses elicited by high-intensity flashes, no significant differences were found in XLRS subjects for the parameters Rmax and log S compared with normal subjects. Seven of these affected males had normal rod values of Rmax and log S. This indicated that the photoreceptors were not inherently affected, even though these cells express the RS1 protein. Dark-adapted b-wave responses were considerably reduced under rodisolating conditions, implicating defective signaling by the depolarizing bipolar cells of the rod pathway.21

Normal cone phototransduction in XLRS was demonstrated by normal scaling of the photopic cone a-wave compared with the leading edge of the normals’ a-wave (figures 73.5 and 73.6).13 However, the XLRS a-wave amplitudes were significantly lower than normals by a relatively consistent amount across all intensities, suggesting that secondorder hyperpolarizing neurons (hyperpolarizing bipolar cells and horizontal cells) were not contributing to the response. This effect is also found in the monkey a-wave after applying APB + PDA, which isolates the photoreceptor activity.

Additional studies were then performed to investigate possible ONand OFF-pathway sites of dysfunction by recording photopic ON-OFF responses to 150-ms long-duration

F 73.3 Intravenous fluoroscein angiogram of XLRSaffected male with abnormal RPE and showing a typical central fluoroscein staining due to RPE thinning.

stimuli. This demonstrated reduced b-wave amplitude but normal d-wave amplitude, which caused the ratio of the b/d amplitudes to be less than 1, which is invariably abnormal for this particular stimulus condition.25 However, we also found a similar reduction of the b/d ratio in a number of other retinal degenerations; consequently, this appears to be a nonspecific finding in retinal degenerations and is nonspecific for localizing the defect in retinal signaling to either the ON or the OFF pathway.

Photopic flicker ERG responses were elicited at 32 Hz, and the fundamental component showed reduced amplitude and delayed phase, consistent with abnormal signaling by both the ON and OFF pathway components.14 This may be useful in the clinical assessment of XLRS.

The aggregate of these results indicated that, although the expression of RS1 protein is heavily concentrated in the inner segments of both rods and cones, it does not inherently affect the photoreceptor function of either cell type. Immunohistochemical studies localizing the RS1 protein show involvement of retinal cells in the inner nuclear layer, but precise subcellular localization has not yet been performed to learn whether both depolarizing and hyperpolarizing bipolar cells are involved. However, from these ERG studies, it currently is reasonable to propose that retinal signaling by ERG generators associated with both the ON and OFF pathways is defective.

The authors thank Dr. Deborah Carper, Ms. Terry Green, and Ms. Maria Macotto for technical and editorial assistance.

A

B

F 73.4 Electronegative full-field ERG in XLRS. A, Twelve- year-old XLRS-affected male shows typical ERG, with selective b-wave reduction but a-wave preservation in dark-adapted recordings, compared with unaffected brother. Photopic b-wave and flicker are also reduced. (Figure modified from Pawar et al: Hum Hered 1996; 46:329–335.) Used by permission from S. Karger AG, Basel.) B, Atypical ERG in XLRS male with an ARG213Trp mutation in the RS1 gene shows preservation of b-wave for darkadapted and light-adapted conditions, compared with unaffected male relative. All parameters were recorded according to International Society for Clinical Electrophysiology of Vision standards. (Figure modified from Sieving PA, Bingham EL, Kemp J, et al: Am J Ophthalmol 1999; 128:179–184. Used by permission from Elsevier Science, UK).

F 73.5 Rod-driven a-wave analysis in XLRS. A, Darkadapted ERG responses from a representative XLRS-affected male show preservation of the a-wave but suppression or loss of the b-wave. B, Phototransduction modeling of rod a-wave responses (after subtraction of cone-driven components) elicited by highintensity flashes gave normal Rmax and log S parameters for XLRS. C, Normalized rod a-wave XLRS responses (averaged from nine affected males, heavy solid curve) at the brightest flash intensity (4.77 log scot td s) overlapped that of 12 control subjects (heavy dashed curve). The data indicated no functional impairment of rod photoreceptor activity compared with normals. (Modified from Khan NW, Jamison JA, Kemp JA, Sieving PA: Vision Res 2001; 41:3931–3942. Used by permission from Elsevier Science, UK.)

REFERENCES

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2.Bornschein H, Schubert G: Das photopische flimmerelektroretinogramm des menschen. Zeit Biol 1953; 106:229–238.

3.Brown DM, Graemiger RA, Hergersberg M, Schinzel A, Messmer EP, Niemeyer G, Schneeberger SA, Streb LM, Taylor CM, Kimura AE, Weingeist TA, Sheffield VC, Stone EM: Genetic linkage of Wagner disease and erosive vitreoretinopathy to chromosome 5q13–14. Arch Ophthal 1995; 113:671–675.

4.Browne D, Barker D, Litt M: Dinucleotide repeat polymorphisms at the DXS365, DXS443 and DXS451 loci. Hum Mol Gen 1992; 1:213.

F 73.6 Photopic ERG analysis in XLRS. A, Photopic conedriven ERG shows relative loss of b-wave versus a-wave. B, Phototransduction modeling of cone a-wave responses. C, Human XLRS a-wave responses are subnormal by a constant amount across the intensities elicited, consistent with the absence of a contribution from hyperpolarizing bipolar and/or horizontal cells, implicating impaired signaling of the retinal OFF pathway. This effect is mirrored in the monkey a-wave (average of four animals) on blocking synaptic output from cones, using APB + PDA. (Modified from Khan NW, Jamison JA, Kemp JA, Sieving PA: Vision Res 2001; 41:3931–3942. Used by permission from Elsevier Science, UK.)

5.de Jong PT, Zrenner E, van Meel GJ, Keunen JE, van Norren D: Mizuo phenomenon in X-linked retinoschisis: Pathogenesis of the Mizuo phenomenon. Arch Ophthalmol 1991; 109: 1104–1108.

6.Fishman GA, Jampol LM, Goldberg MF: Diagnostic features of the Favre-Goldmann syndrome. Br J Ophthalmol 1976; 60: 345–353.

7.Grayson C, Reid SN, Ellis JA, Rutherford A, Sowden JC, Yates JR, Farber DB, Trump D: Retinoschisin, the X-linked retinoschisis protein, is a secreted photoreceptor protein, and is expressed and released by Weri-Rb1 cells. Hum Mol Genet 2000; 9:1873–1879.

8.Hiriyanna KT, Bingham EL, Yashar BM, Ayyagari R, Fishman G, Small KW, Weinberg DV, Weleber RG, Lewis RA, Andreasson S, Richards JE, Sieving PA: Novel mutations in XLRS1 causing retinoschisis, including first evidence of putative leader sequence change. Hum Mutat 1999; 14:423–427.

9.Kaplan J, Pelet A, Hentati H, Jeanpierre M, Briard ML, Journel H, Munnich A, Dufier JL: Contribution to carrier

detection and genetic counselling in X-linked retinoschisis. J Med Genet 1991; 28:383–388.

10.Karwoski CJ, Proenza LM: Relationship between Muller cell responses, a local transretinal potential, and potassium flux. J Neurophysiol 1977; 40:244–259.

11.Kato K, Miyake Y, Kachi S, Suzuki T, Terasaki H, Kawase Y, Kanda T: Axial length and refractive error in X-linked retinoschisis. Am J Ophthalmol 2001; 131:812–814.

12.Kellner U, Brummer S, Foerster MH, Wessing A: X-linked congenital retinoschisis. Graefes Arch Clin Exp Ophthalmol 1990; 228:432–437.

13.Khan NW, Jamison JA, Kemp JA, Sieving PA: Analysis of photoreceptor function and inner retinal activity in juvenile X-linked retinoschisis. Vision Res 2001; 41:3931–3942.

14.Kondo M, Sieving PA: Primate photopic sine-wave flicker ERG: Vector modeling analysis of component origins using glutamate analogs. Invest Ophthalmol Vis Sci 2001; 42:305– 312.

15.Miyake Y, Terasaki H: Golden tapetal-like fundus reflex and posterior hyaloid in a patient with x-linked juvenile retinoschisis. Retina 1999; 19:84–86.

16.Murayama K, Kuo C, Sieving PA: Abnormal threshold ERG response in X-linked juvenile retinoschisis: Evidence for a proximal retinal origin of the human STR. Clin Vis Sci 1991; 6:317–322.

17.Oudet C, Weber C, Kaplan J, Segues B, Croquette MF, Roman EO, Hanauer A: Characterisation of a highly polymorphic microsatellite at the DXS207 locus: Confirmation of very close linkage to the retinoschisis disease gene. J Med Genet 1993; 30:300–303.

18.Pawar H, Bingham EL, Hiriyanna K, Segal M, Richards JE, Sieving PA: X-linked juvenile retinoschisis: Localization between (DXS1195, DXS418) and AFM291 wf5 on a single YAC. Hum Hered 1996; 46:329–335.

19.Peachey NS, Fishman GA, Derlacki DJ, Brigell MG: Psychophysical and electroretinographic findings in X- linked juvenile retinoschisis. Arch Ophthalmol 1987; 105:513– 516.

20.Retinoschisis Consortium: Functional implications of the spectrum of mutations found in 234 cases with X-linked juvenile retinoschisis (XLRS). Hum Mol Genet 1998; 7:1185– 1192.

21.Robson JG, Frishman LJ: Response linearity and kinetics of the cat retina: The bipolar cell component of the dark-adapted electroretinogram. Vis Neurosci 1995; 12:837–850.

22.Sauer CG, Gehrig A, Warneke-Wittstock R, Marquardt A, Ewing CC, Gibson A, Lorenz B, Jurklies B, Weber BH: Positional cloning of the gene associated with X-linked juvenile retinoschisis. Nat Genet 1997; 17:164 –170.

23.Sieving PA, Bingham EL, Kemp J, Richards J, Hiriyanna K: Juvenile X-linked retinoschisis from XLRS1 Arg213Trp mutation with preservation of the electroretinogram scotopic b- wave. Am J Ophthalmol 1999; 128:179–184.

24.Sieving PA, Bingham EL, Roth MS, Young MR, Boehnke M, Kuo CY, Ginsburg D: Linkage relationship of X-linked juvenile retinoschisis with Xp22.1–p22.3 probes. Am J Hum Genet 1990; 47:616–621.

25.Sieving PA: AOS Thesis: Photopic ONand OFF-pathway abnormalities in retinal dystrophies. Trans Am Ophthalmol Soc 1993; 91:701–773.

26.Weber BH, Janocha S, Vogt G, Sander S, Ewing CC, Roesch M, Gibson A: X-linked juvenile retinoschisis (RS) maps between DXS987 and DXS443. Cytogenet Cell Genet 1995; 69:35–37.

27.Wieacker P, Wienker TF, Dallapiccola B, Bender K, Davies KE, Ropers HH: Linkage relationships between retinoschisis, Xg and a cloned DNA sequence from the distal short arm of the X chromosome. Hum Genet 1983; 64:143–145.

28.Wilczek M: Ein der netzhautspaltung (retinoschisis) mit einer offnung. Zeit Augenhlkd 1935; 85:108–116.

T of several kinds of congenital stationary night blindness (CSNB) has been clarified in the last years, following the analysis of the visual function and molecular genetics. This chapter reviews recent knowledge of four kinds of CSNB: complete CSNB, incomplete CSNB, fundus albipunctatus, and Oguchi’s disease. All these types of CSNB show the negative waveform in the dark-adapted single bright-flash (mixed rod-cone) electroretinogram (ERG) after 20–30 minutes of dark adaptation (see below). The identification of the mutant genes causing forms of CSNB in combination with the electrophysiological analysis refines the classification of these diseases and enhances our understanding of the underlying pathophysiology.

Complete CSNB (CSNB 1) and incomplete CSNB (CSNB 2)

The Schubert-Bornschein type of CSNB35 has normal fundi and the mixed rod-cone ERG recorded with a single bright flash shows negative configuration (normal a-wave with smaller b-wave). The associated hereditary pattern can be either X-linked or autosomal-recessive. In 1986, we reported that the X-linked Schubert-Bornschein type CSNB can be divided into two different subtypes: complete CSNB, which has also been termed CSNB 1, and incomplete CSNB, which has also been termed CSNB.24 The distinction between the complete and incomplete types was based on the rod function, evaluated by routine dark adaptometry and rod-mediated ERG; the complete type lacks rod function, while the incomplete type shows residual rod function. Other significant differences between two types include cone ERG,24 long-flash photopic ERG,23 changes of 30-Hz flicker ERG under the light adaptation,16 oscillatory potentials,10,24 scotopic threshold response (STR),19 S-cone ERG,18 refractive error,24 and color vision.42 These differences lead us to confirm that these two types are different clinical entities. Our clinical hypothesis was validated by molecular genetics. In 1998, the a-1-subunit of L-type voltage-gated calcium channel gene (CACNA1F) was identified as the mutated gene in X-linked incomplete CSNB,1,40 and in 2000, NYX gene mutation was identified to cause X-linked complete CSNB.2,33

I C P Table 74.1 shows the initial complaints of our 49 complete CSNB patients and 41 incomplete CSNB patients.15 Many patients visited our clinic with the initial complaint of low visual acuity. It should be noted that only one of the 41 incomplete CSNB patients complained of night blindness, which causes us to overlook this disease because we then tend not to perform the ERG testing.

V A The distribution of corrected visual acuity is shown in figure 74.1. In both types, the visual acuity ranged from 0.1 to 1.0, with a mean of 0.4–0.5. There was no statistical difference in visual acuity between two types.15,24

R E Figure 74.2 shows the distribution of refractive error in patients in the two groups. Many patients with complete CSNB have high or moderate myopic refractive error, while those with incomplete CSNB have mild myopic or hyperopic refractive error. The mean refractive errors are -8.7 and -2.5 diopters in complete CSNB and incomplete CSNB, respectively. The difference in refractive error between the two groups is statistically significant (P < 0.001)15,24 and helps to distinguish the two types of CSNB.

S D A C Figure 74.3 shows the representative subjective dark adaptation curves in patients with complete CSNB, incomplete CSNB, fundus albipunctatus, and Oguchi’s disease. Compared with a normal curve, the rod adaptation is absent, and the cone adaptation shows an elevated threshold in complete CSNB. In incomplete CSNB, rod adaptation is present, although the final threshold is elevated by approximately 1.0–1.5 log units.24

F -F R C ERG Representative examples of standard full-field ERGs are shown in figure 74.4. The mixed rod-cone ERG in a single bright-flash stimulus reveals negative configuration with normal a-wave in both types, but the incomplete CSNB has on the rising b-wave much more prominent oscillatory potentials.24 The rod ERG is absent in complete CSNB but is subnormally present in incomplete CSNB.24 The normal a-wave and subnormal or absent rod

F 74.3 Subjective dark adaptation curve in a normal subject, complete CSNB, incomplete CSNB, fundus albipunctatus

and Oguchi’s disease. Each vertical and horizontal axes indicate threshold (log) and dark adaptation time, respectively.

F 74.5 Exaggerated enhancement of amplitude and change of wave shape of 30-Hz flicker ERG during light adaptation in incomplete CSNB.

ERG suggest that both types of CSNB have a defect not in the rod itself but in the second-order neuron or the synapsis to the second-order neuron in the rod visual pathway. The defect is almost complete in complete CSNB and incomplete in incomplete CSNB.

The cone and 30-Hz flicker ERG appears nearly normal in complete CSNB except for the finding of flattening appearance of the bottom of cone ERG a-wave but are severely deteriorated in incomplete CSNB.24 Although the amplitude of 30-Hz flicker ERG recorded after 30 minutes of dark adaptation is very small in incomplete CSNB, it increases exaggeratedly after 10 minutes of light adaptation16 (figure 74.5).

ERG I S Figure 74.6 shows ERG intensity series, elicited by relatively dim (upper) and intense (lower) stimuli, of a normal subject, a complete CSNB patient, and an incomplete CSNB patient.19 In the normal subject, the cornea-negative STR37 was recorded at -8.2 log units, and

the peak time shortened as the stimuli intensity increased. At the intensity of -5.8 log units, the b-wave becomes clearly visible for the first time. At the intense stimuli (lower panel), the b-wave had saturated at -1.4 log units, and the a-wave (-1.7 log units) and oscillatory potentials (-0.8 log units) started to appear. In complete CSNB, neither STR nor b- wave was recorded when the stimulus intensity was low (upper panel). At the moderate stimulus intensity of -4.4 log units (lower panel), both a- and b-waves began to appear, the former presenting normal and increasing amplitude. However, the b-wave saturated quickly, resulting in a negative configuration when the stimulus intensity was relatively strong. Oscillatory potentials were undetectable. In incomplete CSNB, the STR started to appear at -7.6 log units, showing a slightly higher threshold than that of a normal subject; however, the peak time was approximately 80 ms longer than normal. The b-wave began to appear at -5.8 log units as in the normal subject, with normal amplitude and peak time. At greater intensities, the b-wave amplitude became lower than normal, saturating at -3.4 log units, whereas the a-wave amplitude continued to increase progressively, resulting in a negative configuration. The oscillatory potentials were clearly visible.

L -F P ERG The photopic ERG to square wave light simulation (long-flash) have shown that the cone ON response, which is generated by depolarizing bipolar cells,36 is severely disturbed in complete CSNB, showing the hyperpolarizing pattern23 (figure 74.7). This waveform is similar to the monkey’s ERG when the neurotransmitter blocking agent APB38 was applied to the retina.36 The OFF response, on the other hand, which is generated by hyperpolarizing bipolar cells,36 is intact in complete CSNB, leading us to hypothesize that complete CSNB has a complete defect of ON function in both rod and cone visual pathways.18,36 The incomplete CSNB showed the reduction of ON and OFF responses, and our analysis of large series of patients suggested that incomplete CSNB has an incomplete defect on both ON and OFF responses,23 but the OFF responses are perhaps more severely disturbed.18

Significant differences exist between S- and ML-cones ERG. S-cones connect only with the ON bipolar cells, whereas ML-cones connect with both ON and OFF bipolar cells.41 The full-field S-cone ERG was absent in complete CSNB,14,18 while it was recordable in incomplete CSNB.18

EOG The electro-oculogram (EOG) is normal in both types of CSNB.24 This is a very important finding to differentiate the CSNB with progressive disorder, such as retinitis pigmentosa, which shows abnormal or flattened EOG. The EOG may not be as helpful in differentiating cone-rod dystrophy from incomplete CSNB.

F 74.6 ERG intensity series with relatively dim stimuli (upper) and relatively intense stimuli (lower) in a normal subject

and a patient with complete and incomplete CSNB. STR: scotopic threshold response, bs: scotopic b-wave.

F 74.7 Long-flash photopic ERG in a normal subject, a patient with Oguchi’s disease, complete and incomplete CSNB.

short arm of the X chromosome.26 In 2000, the gene, which is called NYX, was cloned from the Xp11 region by BechHansen et al.2 and Meindl et al.33 The NYX gene, which encodes the glycosylphosphatidyl (GTP)-anchored extracellular protein nyctalopin. Nyctalopin is a new and unique member of the small leucine-rich proteoglycan family, which may be the gene product that guides and promotes the formation and function of the ON pathway within the retina. This mutation was also found in our six original Japanese patients with X-linked complete CSNB.15 The mouse mutant of a natural occurring model of X-linked complete CSNB, the no b-wave (nob), was recently found by Pardue et al.32 The ERG abnormalities are similar to those of complete CSNB patients.

In 1998, the gene for the X-linked incomplete CSNB was identified by Bech-Hansen et al.1 and Strom et al.40 It codes for the pore-forming subunit of an L-type voltage-gated calcium channel (CACNA1F) that is found in the retina. The mutation of CACNA1F was also found in all 15 patients examined in our original study of Japanese patients with incomplete CSNB15,29 (figure 74.8). The loss of the functional channel impairs the calcium flux into photoreceptors (rods and cones) that is needed for sustaining the tonic neurotransmitter release from presynaptic terminals. The knock-out mice without a functional beta subunit of the channel were found to have marked loss of the ribbon synapses of photoreceptor inner segments.34

P P Above-mentioned pathophysiological studies using clinical patients, animal models, and molecular genetics suggested that X-linked complete CSNB has an almost complete defect of the ON bipolar cells or its synapsis in both rod and cone visual pathways, leaving the OFF pathway intact. On the other hand, the X-linked incomplete CSNB has an incomplete defect of the ON and OFF bipolar cells or their synapsis in the rod and cone visual pathways.

C V The color vision in both complete and incomplete type patients is essentially normal.24 It appears curious that in spite of nonrecordable S-cone ERG, psychophysical color vision is essentially normal in complete CSNB. We found that S-cone function in complete CSNB is preserved only in the fovea and becomes abnormal toward the peripheral retina.42 This accounts for the normal color vision that tests mainly foveal function and the nonrecordable S-cone ERGs that arise mainly from peripheral retina.

M G Linkage studies of X-linked complete CSNB localized the gene for complete CSNB to the

Fundus albipunctatus

The fundus albipunctatus is a type of CSNB with autoso- mal-recessive inheritance. This type of CSNB was first differentiated from retinitis punctata albescens, one of the varieties of progressive tapetoretinal degeneration, by Lauber12 in 1910. The fundi of typical patients have a characteristic appearance with a large number of discrete, round or elliptical, yellowish-white lesions at the level of the retinal pigment epithelium. These lesions may change in appearance during long-term follow-up, and some may fade.13 The subjective dark adaptation (see figure 74.3)39 and the dark adaptation time to obtain the maximum ERG response11 is quite delayed. We found that the fundus albipunctatus can

F 74.8 Putative topology of the human retina-specific calcium channel L-type. All mutations found in our study and in other reports. Solid circles: mutations found in our study; circles

be associated with cone dystrophy in many patients.20 In this chapter, the typical fundus albipunctatus and the fundus albipunctatus associated with cone dystrophy are described separately.

T F A The representative fundus picture is shown in figure 74.9 (top). As is shown in the subjective dark adaptation in figure 74.3, the ERG and EOG are also distinctive because an unusually long dark adaptation is needed to obtain the maximum normal scotopic ERG responses (figure 74.10) and normal EOG light rise.5,22 The cone-mediated ERG as well as subjective cone visual functions such as visual acuity, color vision, and visual field is essentially normal. Patients with typical fundus albipunctatus complain of night blindness from early childhood, and the clinical course has been considered to be stationary.

F A A C D

We found that fundus albipunctatus can be associated with cone dystrophy.20 Such patients often show bull’s-eye maculopathy (figure 74.9, bottom) with progressive decrease of visual acuity and color vision deficiency. Although the

with left oblique lines: mutations found by Strom et al.40; circles with right oblique lines: mutations found by Bach-Hansen et al.1

maximum responses are obtained after prolonged dark adaptation, as seen in typical fundus albipunctatus, the maximum amplitude is smaller than normal in some patients, indicating that rod function after a long period of dark adaptation does not recover to a normal level. The cone-mediated ERGs were very abnormal or essentially absent (see figure 74.10).

M G It has been unclear whether the fundus albipunctatus associated with cone dystrophy represents an advanced stage of fundus albipunctatus, a distinct disease entity, or a chance combination of two different diseases. In 1999, the 11-cis-retinol dehydrogenase gene, RDH5, was identified as the mutated gene in patients with typical fundus albipunctatus.44 We analyzed many patients with fundus albipunctatus with or without cone dystrophy. We found either homozygous or compound heterozygous mutations in the RDH5 gene in all of the patients.28 Because some mutations were detected in both groups and because a progressive decline of visual functions was observed in some of the older patients, we concluded that mutations of the RDH5 gene can lead to progressive cone dystrophy as well as congenital night blindness. This result indicates that

F 74.9 Fundus photograph in fundus albipunctatus (upper) and fundus albipunctatus associated with cone dystrophy (lower). (See also color plate 49.)

the fundus albipunctatus is not always stationary but is progressive in about one third of the patients, associating with diffuse cone dysfunction in old age.

P P The delayed dark adaptation in subjective threshold ERG and EOG in fundus albipunctatus either with or without cone dystrophy is understandable in view of the mutations leading to a deficiency of 11-cis- RDH. Accordingly, the production of 11-cis-retinal in the retinal pigment epithelium is compromised, and the deficient supply of chromophore to the photoreceptors delays the rate at which they can recover after bleaching.6

Oguchi’s disease

Oguchi’s disease, first described by Oguchi31 in 1907, is an unusual form of CSNB characterized by a peculiar gray-

white discoloration of the fundus (figure 74.11). In 1913, Mizuo found that this fundus coloration disappeared after a long period of dark adaptation (Mizuo’s phenomenon)25 (see figure 74.11).

Although the rod function is absent both subjectively and electroretinographically after 30 minutes of dark adaptation, it may reappear after 2–3 hours of dark adaptation3,27 (see figures 74.3 and 74.10). It has been reported that mutations in either the arrestin gene9 or the rhodopsin kinase gene45 cause a recessive form of Oguchi’s disease.

F -F ERG Figure 74.10 shows the full-field ERGs in an Oguchi’s disease patient with the mutation in the arrestin gene. When recorded after 30 minutes of dark adaptation, the rod ERG is absent, and cone-mediated (cone, 30-Hz flicker) ERGs are essentially normal. The mixed rod-cone ERG shows a negative configuration with relatively preserved oscillatory potentials, and the a-wave amplitude is reduced in comparison with a normal control. After 3 hours of dark adaptation, however, the mixed rod-cone ERG shows increases in the a-wave and b-wave. Including our seven patients, the ERGs of 26 patients with Oguchi’s disease recorded after 15–30 minutes of dark adaptation were reported in past Japanese literature. All of those ERGs have reduced a-waves, nearly absent b-waves, and relatively preserved oscillatory potentials.17 The pathogenesis of the cone visual system in Oguchi’s disease is different from those of complete CSNB and incomplete CSNB. Unlike in complete and incomplete CSNB, the long-flash photopic ERG shows a normal amplitude and waveform, indicating that the ON and OFF systems in cone visual pathway are functioning normally17,23 (see figure 74.7).

EOG Including our six patients, 16 of 21 Japanese patients have had an extremely low Arden ratio (<1.4) in the EOG (normal > 1.8).17 It should also be noted that even in patients with a normal to subnormal Arden ratio, the a-wave amplitude was significantly smaller than normal.

O O F The visual acuity and color vision are normal. Reviewing all Japanese patients with Oguchi’s disease reported so far, I got the impression that the refractive error in Oguchi’s disease is minor, if any, and I found neither patients with high myopia nor patients with high hyperopia.

M G Rhodopsin kinase and arrestin, of which genes have been proved to be mutated in Oguchi’s disease, act in sequence to deactivate rhodopsin to stop the phototransduction cascade. Most patients reported in the literature with mutations in the arrestin gene are Japanese.

F 74.10 Full-field ERG in a normal subject, a patient with fundus albipunctatus, a patient with fundus albipunctatus associated with cone dystrophy, and a patient with Oguchi’s disease. The

Although the patients with mutations of rhodopsin kinase gene showed no signs of photoreceptor degeneration in literature, some patients with mutations of arrestin were reported to be associated with photoreceptor degeneration similar to retinitis pigmentosa.30 The animal model is not essentially the same as the findings in Oguchi’s disease patients. Elimination of the function of arrestin in fruit flies uniformly causes photoreceptor degeneration, which is dependent on exposure of light.8 Transgenic mice that were homozygous for an arrestin mutation showed prolonged photoresponses.43

P P In 1965, Carr and Gouras3 reported detailed ERG findings in four Caucasian patients with Oguchi’s disease. Their patients’ ERGs, when recorded with a relatively intense stimulus after 10 minutes of dark adaptation, showed a negative form with normal a-waves and small b-waves, similar to those in complete CSNB. In a later study, Carr and Ripps4 restudied one of these patients and found, in addition to the normal a-wave, a normal EOG and normal concentrations and kinetics of visual pigments.

standard ERG was recorded after 30 minutes of dark adaptation, but some ERGs were recorded with longer dark adaptation of 2–3 hours.

The authors concluded that a defect in the postreceptor signals is the cause of night blindness. In 1997, two of their patients were examined by Yamamoto et al.45 in terms of the molecular genetics and the mutations of rhodopsin kinase were detected. It appears slightly difficult to explain the normal a-wave and normal EOG in relation to the mutations of rhodopsin kinase.

In Japanese patients, however, the a-wave amplitude of mixed rod-cone ERG was significantly lower than normal when recorded after 20–30 minutes of dark adaptation.17 Our analysis of three patients with Oguchi’s disease indicated that the rod a-wave is absent.17 Also, many Japanese patients showed abnormal EOG.17 Since most Japanese patients with Oguchi’s disease have mutations of arrestin, these differences may be caused by different gene mutations.

The mechanism of the Mizuo phenomenon is also unknown. Some authors speculate that it is the result of elevated extracellular potassium levels generated in the retina in response to an excessive stimulation of rod photoreceptors.

F 74.11 Fundus photographs of Oguchi’s disease in light adaptation (upper) and after a long period of dark adaptation (lower). (See also color plate 50.)

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