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, Color fundus photograph of
the left eye of the proband. Intraretinal crystals are seen in the posterior
pole. B, Fluorescein angiogram of the left eye of the proband demonstrates
attenuation of the pigment epithelium and patchy atrophy of the choriocapillaris.
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).
Color photograph of the left eye
of the grandson (unaltered digital image). Note the prominent inferior schisis
cavity with large inner-layer holes.
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
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
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: email@example.com).
Weinberg DV, Sieving PA, Bingham EL, Jampol LM, Mets MB. Bietti Crystalline Retinopathy and Juvenile Retinoschisis in a Family With a Novel RS1 Mutation. Arch Ophthalmol. 2001;119(11):1719-1721. doi: