Bietti Crystalline Retinopathy and Juvenile Retinoschisis in a Family With a Novel RS1 Mutation

Bietti crystalline retinopathy is a rare degenerative disease that features bilateral retinal crystals, progressive atrophy of the retinal pigment epithelium and choriocapillaris, and severe visual loss. X-linked retinoschisis (XLRS) is a more common retinal disease characterized by cystic schisis at the fovea and variable peripheral retinoschisis. The gene responsible for XLRS has been identified on the X chromosome and designated RS1.¹ We describe a family of Chinese origin in which a man, his daughter, and his grandson have novel mutations in the RS1 gene. Findings from examination of the grandfather are characteristic of Bietti crystalline retinopathy, the daughter is phenotypically normal, and the grandson has classic XLRS. We believe that RS1 is a candidate gene for some cases of Bietti crystalline retinopathy.

A 60-year-old Chinese man with poor vision in both eyes since childhood was evaluated. Visual acuity was counting fingers OD and 20/200 OS. There were no corneal or conjunctival crystals. Fundus examination showed the presence of intraretinal crystals, mostly concentrated in the posterior poles of both eyes (Figure 1). There was atrophy of the retinal pigment epithelium. The retinal vessels were mildly attenuated and the optic nerves appeared normal. No retinoschisis was present. Fluorescein angiography revealed patchy atrophy of the retinal pigment epithelium and choriocapillaris. Electroretinogram responses were severely attenuated but retained some high-intensity white scotopic b-wave amplitude and were not electronegative. The diagnosis of Bietti crystalline retinopathy was made.

A 22-month-old boy (the son of the proband's daughter) was seen because of esotropia in the left eye. The child was the result of an uncomplicated pregnancy and a full-term spontaneous vaginal delivery. Both parents were Chinese and had normal eye examination results. His only sibling was a reportedly normal half-brother (paternal).

Examination revealed a large retinoschisis cavity in the right inferotemporal quadrant, extending to 1 disc diameter from the fovea. The fovea displayed cystic schisis. In the left eye a large schisis cavity involved the entire inferotemporal quadrant, including the macula. The patient was reexamined at age 5 years. Visual acuity was 20/125 OD and 1/150 OS. The electroretinogram was markedly attenuated, with an electronegative B wave in the high-intensity white scotopic response. Examination revealed partial collapse of the large schisis cavity in the right eye and enlargement of inner layer holes in the left eye (Figure 2).

The RS1 gene was sequenced from the child, both parents, and both maternal grandparents. The grandfather and grandson were hemizygous for a T to C transition mutation at nucleotide 667 in exon 6 of the RS1 gene. The daughter was heterozygous for the same mutation, which substitutes arginine for cysteine at residue 223 (C223R) in the predicted protein.

The gene responsible for X-linked retinoschisis was recently identified and designated RS1.¹ The gene consists of 6 exons and encodes a 224–amino acid protein. Exons 4 through 6 encode a highly conserved discoid domain believed to participate in cell-to-cell adhesion. The Retinoschisis Consortium recently reported 82 different RS1 mutations among 91% of 234 cases clinically diagnosed as having retinoschisis.² An additional 12 novel mutations have recently been described, including that occurring in the grandson in this family.³ The vast majority of mutations occur in exons 4 through 6 and those that eliminate or create a cysteine are common.

It is possible that this is a coincidental polymorphism rather than a disease-causing mutation. However, the evidence supports that this mutation resulted in retinoschisis in our patient. The child has the classic phenotype of XLRS, with no other abnormalities in the XLRS1 gene. The mutation occurs in an exon associated with numerous disease-causing mutations, and involves an amino acid substitution likely to alter the protein conformational structure in or near the crucial discoid domain. This mutation was not found in 100 unrelated phenotypically normal patients whose X chromosomes were sequenced.²

Bietti crystalline retinopathy is a rare hereditary retinal degeneration. The defining feature is the presence of crystals throughout the posterior retina. Vision loss accompanies progressive atrophy of the retinal pigment epithelium and choriocapillaris. The gene responsible for Bietti crystalline retinopathy has not been previously identified. Although generally believed to be autosomal recessive, the predominance of male cases has led some authorities to suggest an X-linked inheritance.^4,5 An autosomal dominant pedigree with phenotypic resemblance to Bietti crystalline retinopathy has also been reported.⁶ It seems likely that Bietti crystalline retinopathy is a phenotypic description reflecting more than one genotype.

The pedigree in this report has 2 male members who carry a novel mutation in the RS1 gene. The grandson has a phenotypic expression typical for XLRS and the phenotype exhibited by the grandfather is a crystalline retinal degeneration typical of Bietti crystalline retinopathy. It is not clear why the 2 affected male members of the family, who share the same RS1 mutation, have such different phenotypic expressions. Perhaps some other, as yet unidentified, heritable or nonheritable factor influences the expression of the gene.

The findings in our pedigree suggest that the C233R mutation has variable phenotypic expression, including crystalline retinal deposition and typical retinoschisis. This or other mutations in the RS1 gene may be responsible for some cases of Bietti crystalline retinopathy.

This study was supported by grant R01-EY10259 from the National Institutes of Health, Bethesda, Md (Dr Sieving), the DiMattia and Sovel families (Dr Sieving), and an unrestricted grant from Research to Prevent Blindness Inc, New York, NY (Northwestern University, Chicago).

We wish to thank Kelaginamane T. Hiriyanna, PhD, Radha Ayygagari, PhD, and Beverly M. Yashar MS, PhD, for discussions.

Corresponding author and reprints: David V. Weinberg, MD, 645 N Michigan Ave, Suite 440, Chicago, IL 60611 (e-mail: d-weinberg2@northwestern.edu).