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Japanese X-linked Juvenile Retinoschisis: Conflict of Phenotype and Genotype With Novel Mutations in the XLRS1 Gene
Arch Ophthalmol. 2001;119:1553-1554.
INTRODUCTION
X-linked juvenile retinoschisis (XRS) is a relatively rare X-linked recessive vitreoretinal dystrophy that is characterized by a tangential splitting of the superficial layers of the sensory retina. Most cases demonstrate a foveal schisis or cystlike stellate maculopathy, and approximately half of the cases have peripheral retinoschisis. The clinical features of this disorder are variable, resulting in occasional difficulties in diagnosis. Since 1997, when XLRS1, the gene responsible for XRS was identified,1 more than 100 mutations in XLRS1 have been reported.2
We report 3 cases of XRS with novel point mutations of the XLRS1 gene, namely Ala101Pro and Pro193Ser. The mutations were notable because the patients with these mutations had atypical phenotypes and were diagnosed only by molecular genetic analysis.
Informed consent was obtained from the patients. DNA was obtained from peripheral leukocytes, and all of the exons of the XLRS1 gene were analyzed by polymerase chain reaction and direct sequencing. No base change substitutions were detected in 100 alleles of healthy control subjects.
Report of Cases
Case 1
When the patient in case 1 was first seen at age 36 years in 1986, ophthalmoscopic examination revealed a bull's-eye maculopathy in both eyes, and his uncorrectable visual acuity was 20/100 OU.3 In 2000, the chorioretinal macular degeneration had enlarged into a nonspecific shape (Figure 1A and B), and the classical bull's-eye maculopathy was not present in both eyes. His best-corrected visual acuity was reduced to 20/300 OU. The mixed rod-cone electroretinogram (ERG) was the negative type, with a normal a-wave and a reduced b-wave, which is one of the characteristics of XRS (Figure 2). His was previously reported as 1 of 4 cases with a bull's-eye maculopathy with a negative ERG.3 Despite the negative ERG, we could not diagnose him as a patient with XRS because no case of XRS with a classic bull's-eye maculopathy had been reported at that time. Also, the patient had stated that his best-corrected visual acuity had been good in his childhood. His family history was unclear because most relatives had died, and he had no children. During the 14-year follow-up, no peripheral retinoschisis was noted in either eye.
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Figure 1. Fundus photographs (A, C, D) and a fluorescein angiogram (B) of patients with mutations of the XLRS1 gene. A and B, Left eye of case 1. C, Left eye of case 2. D, Right eye of case 3. The case number, the age (in years), and the mutations found in the XLRS1 gene are indicated in each photograph.
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Figure 2. Full-field ERGs recorded after 30 minutes of dark adaptation in a healthy subject, case 1, and case 3. The rod-cone mixed electroretinogram is the negative type in case 1, but normal in case 3. The arrows indicate the stimulus onset.
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With the availability of molecular biological examinations, the patient was tested, and a novel missense mutation, Ala101Pro (c.301G to C) in the XLRS1 gene, was identified from his genomic DNA. He was thus diagnosed as having XRS. Of the 3 other patients who were reported to have a bull's-eye maculopathy and a negative ERG, no mutation in the gene was found in 2 of them, and the other patient could not be contacted.
Case 2
A 22-year-old man was seen who had the usual characteristics of XRS of foveal retinoschisis in both eyes (Figure 1C) and negative ERGs. We present this patient with XRS with the same XLRS1 mutation, Ala101Pro (c.301G to C), as in case 1, for the purpose of comparison. No peripheral retinoschisis was seen in either eye, and his best-corrected visual acuity was 20/60 OD and 20/30 OS.
Case 3
A 26-year-old man was first examined at age 7 years because of reduced visual acuity, and cystic spaces were noticed in the fovea of both fundi. In 2000, his best-corrected visual acuity was still relatively good at 20/30 OU, and foveal cysts were observed in both eyes (Figure 1D). There was no other sign of retinoschisis. During the 19-year follow-up, full-field ERGs were recorded 6 times, and the mixed rod-cone ERGs always showed a normal b-wave amplitude as was the a-wave (Figure 2). His parents were unaffected, his maternal grandfather had died, and the remaining family history could not be obtained. In spite of the normal ERGs, he was diagnosed as having XRS because a novel missense mutation in the XLRS1 gene, namely, Pro193Ser (c.577C to T), was found in his blood DNA. We are following up another male patient with a retinoschisis-like foveal cyst and normal ERGs who showed no mutation in the XLRS1 gene.
Comment
It is well known that some older patients with XRS show nonspecific atrophic macular lesions, and it was recently reported that some cases of classical bull's-eye maculopathy were found in families with XRS, with the XLRS1 gene mutation.4 Taking all of these observations together, a patient with a bull's-eye lesion or chorioretinal macular atrophy with negative ERGs should be considered to be possibly affected by XRS, especially when the family history is unclear. A case of XRS with preserved b-wave has already been reported in a 13-year-old boy.5 He was a member of a family affected by XRS, with an Arg213Try mutation in the XLRS1 gene. His affected 54-year-old grandfather showed negative ERGs. Our results suggest that we cannot exclude a diagnosis of XRS in patients with foveal cysts, even for an adult showing normal ERGs with no affected relatives. However, our results also indicate that all such cases do not necessarily indicate XRS. It is only with molecular genetic analysis that we can identify patients whose clinical phenotype is somewhat ambiguous. In the future, molecular genetic examination should permit more accurate diagnoses and resolve cases where there is a conflict between phenotype and genotype.
AUTHOR INFORMATION
The authors have no financial or proprietary interest in any product or procedure mentioned in this article.
Makoto Nakamura, MD;
Sei Ito, MD;
Hiroko Terasaki, MD;
Yozo Miyake, MD
Nagoya, Japan
Correspoding author and reprints: Makoto Nakamura, MD, Department of Ophthalmology, Nagoya University School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan (e-mail: makonaka{at}med.nagoya-u.ac.jp).
REFERENCES
1. Sauer CG, Gehrig A, Warneke-Wittstock R, et al. Positional cloning of the gene associated with X-linked juvenile retinoschisis. Nat Genet. 1997;17:164-170.
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2. The 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.
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3. Miyake Y, Shiroyama N, Horiguchi M, Saito A, Yagasaki K. Bull's-eye maculopathy and negative electroretinogram. Retina. 1989;9:210-215.
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4. Inoue Y, Yamamoto S, Okada M, et al. X-linked retinoschisis with point mutations in the XLRS1 gene. Arch Ophthalmol. 2000;118:93-96.
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5. 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.
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SECTION EDITOR: W. RICHARD GREEN, MD
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