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Different mutation of the XLRS1 gene causes juvenile retinoschisis with retinal white flecks
  1. YOSHIHIRO HOTTA,
  2. MAKOTO NAKAMURA,
  3. YOKO OKAMOTO,
  4. RYOJI NOMURA,
  5. HIROKO TERASAKI,
  6. YOZO MIYAKE
  1. Department of Ophthalmology, Nagoya University School of Medicine, Nagoya, Japan
  1. hotta{at}hama-med.ac.jp

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Editor,—Juvenile retinoschisis is an X linked inherited vitreoretinal degeneration that results in splitting of the superficial layers of the retina.1 Retinal white flecks are rarely present in retinoschisis.2 Because we have three families with retinoschisis with retinal white flecks, the clinical features and genetic analysis of bothXLRS1 and RDH5genes were investigated in these families to characterise this unusual fundus finding.

CASE REPORT

Case 1

A 17 year old young man was diagnosed as having retinoschisis at 11 months of age. We have reported some of his clinical findings at the age of 10 years.2 His maternal grandfather and his younger brother (case 2) are also known to have this condition (Fig 1a). Both fundi showed the typical star-shaped configuration in the macula and peripheral retinoschisis inferiorly with multiple small white flecks scattered in the temporal posterior pole (Fig 2a). Full field ERG recordings showed markedly reduced scotopic response and even greater reduction in the photopic responses and a negative-type ERG with a single bright flash stimulus. Corrected visual acuity at the age of 17 years was right eye 20/200 with S+4=C−2×160°, and left eye 20/100 with S+4=C−2.5×20°.

Figure 1

Genotype of four cases. (a, b) Pedigrees of cases 1, 2, and 4. Solid symbols indicate retinoschisis patients; open symbols, unaffected family members. Arrows indicate proband and Xs indicate examined cases. (a) III-1 and III-2 correspond to cases 1 and 2, respectively. (b) III-4 corresponds to case 4. Both pedigrees showed X linked inheritance pattern. (c–f) Nucleotide sequences of the XLRS1 gene using sense primer in four patients with retinoschisis. Arrows indicate the position of the mutation. (c) Case 1, hemizygotic mutant (Glu72Lys). (d) Case 2, hemizygotic mutant (Glu72Lys). (e) Case 3, hemizygotic mutant (Glu72Lys). (f) Case 4, hemizygotic mutant (Arg200Cys).

Figure 2

Posterior pole in the four cases. (a) Right eye of case 1. (b) Right eye of case 2. (c) Left eye of case 3. (d) Left eye of case 4. All cases showed foveal schisis. Cases 1, 3, and 4 showed retinal white flecks.

Case 2

A 14 year old boy, a brother of case 1, was found to have poor visual acuity at the age of 5 years. He was diagnosed by us as having retinoschisis at the age of 13 years. Both fundi showed the typical star-shaped configuration in the macula and peripheral retinoschisis inferiorly without the multiple small white flecks (Fig 2b). The full field ERG showed a similar pattern as in case 1. During the 6 year follow up, the white flecks did not appear. Corrected visual acuity at the age of 14 years was: right eye 10/20 with S+3=C−1.5×110°, and left eye 20/100 with S+4=C−1×160°.

Case 3

A 9 year old boy was found to have poor visual acuity, and was referred to us. He was diagnosed as having retinoschisis at the age of 5 years. Both fundi showed the typical star-shaped configuration in the macula. Multiple small, white flecks were scattered in the posterior pole of the left eye (Fig 2c). The white flecks were not present in the right eye. The full field ERG showed a similar pattern as in case 1. Visual fields showed a large scotoma in the left eye. Corrected visual acuity at the age of 9 years was: right eye 10/20 with S+2.25=C−1×75°, and left eye 10/1000.

Case 4

A 22 year old man was found to have hypermetropia and was corrected by glasses at the age of 1 year. He was diagnosed as having retinoschisis and esotropia and consulted us at the age of 13 years. Pedigrees of case 4 showed an X linked inheritance pattern (Fig 1b). Although the left fundus showed the typical star-shaped configuration in the macula, the right macula showed degenerative changes. Multiple small, white flecks were scattered in his left temporal posterior pole (Fig 2d). The full field ERG showed a similar pattern to case 1. Corrected visual acuity at the age of 22 years was: right eye 30/500 with S+7, and left eye 40/200 with S+5.25=C−1.75 × 90°.

Informed consent was obtained from the patients after an explanation of the study. Genomic DNAs were extracted from leucocytes of peripheral blood. Exons 1–6 of the XLRS1 gene and exons 2–5 of the RDH5 gene were amplified by polymerase chain reaction (PCR) using primers and condition described before.34 The PCR products were purified and directly sequenced using an automated DNA sequencer, Model 373 (Applied Biosystems, USA). The hemizygous XLRS1 gene mutations were recognised in all four patients as shown in Figure 1. No mutation of the RDH5 gene was detected in exons 2–5 as well as flanking intron sequences.

COMMENT

Retinal flecks are sometimes observed in different types of retinal dystrophies.56 We have already reported that the retinal white flecks rarely accompany retinoschisis.2 Recently, a report indicated that mutations of the RDH5gene, which is highly expressed in the retinal pigment epithelium, causes fundus albipunctatus.4 To assess them at the genetic level, we investigate both the XLRS1and RDH5 genes in four cases of retinoschisis including three patients with retinal white flecks. Although we could not detect any mutations of theRDH5 gene, two kinds ofXLRS1 gene mutations, including the most common mutation, were found. The mutations are presumed to be responsible for the disease because no base substitution within the codons of XLRS1 gene was detected in over 100 alleles from normal individuals. In addition, a number of cases of retinoschisis caused by a Glu72Lys mutation and several cases of retinoschisis caused by a Arg200Cys mutation have been reported.378

The clinical features, besides the white flecks of the three patients, were very common. All three cases showed hypermetropia, poor corrected visual acuity, foveal schisis, and negative ERG configuration. We believe that the retinal white flecks in retinoschisis may be a phenotypic variation because of the intrafamilial variation, unilaterality, and detection of the commonXLRS1 gene defect. We were able to follow case 1 for 17 years and no remarkable change in numbers, shape, and size of the white flecks was observed. Because the punctate lesions in his right eye were found in part of the inner layer, the flecks are probably located in the neuroretina.

Acknowledgments

This study was supported in part by grants for the research committee on chorioretinal degenerations from the Ministry of Health and Welfare of Japan, and grant in aid for scientific research (Dr Miyake, B11470363, Dr Hotta, C05807166) from Ministry of Education, Science, Sports and Culture, Japan.

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