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Butterfly-Shaped Pattern Dystrophy
A Genetic, Clinical, and Histopathological Report
Kang Zhang, MD, PhD;
Daniel C. Garibaldi, MD;
Yang Li, MD;
W. Richard Green, MD;
Donald J. Zack, MD, PhD
Arch Ophthalmol. 2002;120:485-490.
ABSTRACT
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Objectives To identify the disease-causing mutation in a large family segregating
dominantly inherited butterfly-shaped pattern dystrophy (BPD) and to describe
the microscopic pathological changes observed in a member of this family.
Methods Seventeen individuals at risk for dominantly inherited BPD in a family
were examined and blood samples obtained. Linkage analysis and mutation screening
of the human retinal degeneration slow (RDS)/peripherin locus were performed.
Light and electron microscopic examinations were performed on 1 postmortem
eye of 1 affected individual.
Results Four individuals demonstrated macular degenerative changes with diminished
visual acuity, and 3 others exhibited early signs of atrophy without visual
deficits. Microscopic examination of the left eye of 1 patient revealed an
area of total loss of the retinal pigment epithelium (RPE) and photoreceptor
cell layer with intact choriocapillaris and lipofuscin-containing cells in
the subretinal space. Outside the area of RPE atrophy, the RPE was greatly
distended by lipofuscin. The disease locus in this family was mapped to 6p21.2,
the region of the RDS/peripherin gene. Further analysis identified a G A
change at nucleotide position 637 of RDS/peripherin,
predicting a novel Cys213Tyr substitution in all affected members of the family.
Conclusions This study describes a new RDS/peripherin mutation for BPD and provides
the first combined genetic-pathological study of this condition, to our knowledge.
Clinical Relevance Accumulation of lipofuscin in RPE is a prominent feature of several
retinal disorders, including age-related macular degeneration. Further elucidation
of the cellular and molecular mechanism of BPD may provide insight into pathogenesis
and lead to novel treatment approaches for this and other macular degenerations.
INTRODUCTION
BUTTERFLY-SHAPED pattern dystrophy (BPD) was first described by Deutman
et al,1 in a white family who had a peculiar
bilateral butterfly-shaped pigmentation in the macular region at the level
of the retinal pigment epithelium (RPE). In BPD, the central lesion is readily
demonstrated by fluorescein angiography, which helps to distinguish this condition
from other pattern dystrophies of the macula.2
Although Deutman et al1 originally suggested
a relatively benign course for the disease and described patients whose sole
pathological features were abnormal electro-oculograms, further studies described
BPD as a chronic progressive disorder. Patients are generally asymptomatic
when diagnosed as having BPD in their second or third decade and retain relatively
normal visual acuity for most of their lives. However, the disease can progress
with age, and older individuals may exhibit atrophic, depigmented lesions
extending into the peripapillary region with markedly reduced visual acuity.3 In general, patients exhibit normal dark adaptation,
color vision, and electroretinograms; have intact peripheral fields; and may
have reduced electro-oculograms.1-6
In recent years, BPD has been linked to various mutations in the human
retinal degeneration slow (RDS)/peripherin gene on chromosome 6p21.2-cen,
including a large deletion in exon 3,4 missense
mutations (Gly167Asp,5 Arg172Trp,7-10
Cys213Arg,10 Lys197Glu, Gly208Asp, Trp246Arg,
and Ser289Leu8), nonsense mutations (Gln239ter and Tyr285ter),8
and a 2–base pair deletion affecting codons 299 and 300.11
Mutations at this locus have also been linked to related pattern dystrophies
of the macula, retinitis pigmentosa, and fundus flavimaculatus.9, 12-17
The RDS/peripherin gene encodes a photoreceptor-specific glycoprotein that
may play a role in the development and maintenance of photoreceptor outer
segment discs.18-20
Mutation in this gene could lead to various disease phenotypes by interfering
with the integrity of the photoreceptor membrane.
We report here the clinical evaluation of 17 members of a large white
family at risk for a dominantly inherited BPD. Six patients were affected
as determined by ophthalmoscopic examination. The light and transmission electron
microscopic examination of the left eye of an affected member of this cohort
revealed an area of total loss of the RPE and photoreceptor cell layer, with
intact choriocapillaris and lipofuscin-containing cells in the subretinal
space in the macula. Outside the area of RPE atrophy, the RPE was greatly
distended by lipofuscin. Genotype analysis revealed linkage between the disease
phenotype and the RDS/peripherin locus. Sequence analysis of the RDS/peripherin
gene identified a GA change at nucleotide position 637, predicting a
novel Cys213Tyr substitution.
SUBJECTS AND METHODS
Approval from the Johns Hopkins Hospital Joint Committee on Clinical
Investigation was obtained for this study, and informed consent was obtained
from all patients. Seventeen individuals at risk for a dominantly inherited
BPD in a large white family, initially described by Singerman et al21 in 1977, participated in this study (Figure 1).
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Figure 1. A, Autosomal dominant inheritance
of a butterfly-shaped pattern dystrophy in a large family. Individuals are
identified by a generation and pedigree number. Squares indicate males; circles,
females; slashed symbols, deceased; solid symbols, affected; and open symbols,
unaffected. B, Cosegregation analysis of the Cys213Ser mutation with disease
phenotype as determined by restriction enzyme digestion of polymerase chain
reaction–amplified genomic DNA. DNA fragments correspond to individuals
with a "+" sign in the pedigree. A 312–base pair genomic DNA fragment
was amplified using primers 2a and 2b. The GA change at nucleotide 637
in affected patients eliminated a PvuII site, resulting in a
312–base pair fragment instead of the wild-type 224–base pair
fragment.
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A history of the patient's vision was obtained from all patients, and
best-corrected visual acuities were assessed. Slitlamp biomicroscopy, ophthalmoscopic
examination, and fluorescein angiography were performed. Light and electron
microscopic examinations were performed on 1 postmortem eye of 1 affected
individual using previously described methods.22
Blood samples were obtained by venipuncture, and genomic DNA was extracted.
Genetic linkage to the RDS/peripherin locus was assessed using the short tandem
repeat polymorphism DNA markers D6S1549 and D6S1557.12-15
Mutation screening was performed by direct sequencing of polymerase chain
reaction–amplified DNA fragments corresponding to the 3 exons of the
gene using published primer pairs.12-13
The primer pairs used for polymerase chain reaction amplification were as
follows: for exon 1, 1a 5'-GCTGTGCTGTGGGAAGCAAC-3', 1b 5'-TCTGACCCCAGGACTGGAAG-3';
for exon 2, 2a5'AGCCCATCTCCAGCTGTCTG-3', 2b5'CTTACCACTCTACCCCCAGCG-3';
and for exon 3, 3a5'-GATTGCCTCTAAATCTCCTCTCCC-3', 3b5'ATGGTGCCCTCCTTGGGAG-3'.
The nucleotide change at position 637 that was identified by DNA sequencing
was independently confirmed by demonstration of elimination of a predicted PuvII restriction enzyme site.
RESULTS
CLINICAL CHARACTERIZATION
Seventeen individuals who were at risk for a dominantly inherited BPD
in a large family were examined. Of these, 6 individuals had diminished visual
acuity and funduscopic abnormalities, and 3 additional individuals demonstrated
pigmentary mottling without accompanying deficits in visual acuity, suggestive
of the early stages of this disorder (Table
1). Although the extent of pigmentary abnormalities varied, we noted
a degree of RPE atrophy in every affected individual. Several family members
had been previously evaluated,21 and reevaluation
during this study demonstrated progressive geographic atrophy of the RPE.
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Clinical Characteristics of Family Members at Risk for Autosomal Dominant
Butterfly-Shaped Pattern Dystrophy
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Ophthalmoscopic examination of individual IV:7, a 52-year-old woman
who had an initial visual acuity of 20/30 OD and 20/70 OS, demonstrated butterfly-shaped
lesions in the central macula associated with yellow pigment deposits at the
level of RPE and numerous flecks at the RPE level in the posterior pole for
both eyes (Figure 2A). These lesions
were strikingly similar to those observed in the individual's father (III:14)
and his cousin (III:2) in a previous study.21
Patient III:1, then 53 years old, with a visual acuity of 20/40 OD and 20/20
OS, also demonstrated bilateral butterfly-shaped accumulations of yellowish
deposits at the level of the RPE with yellow flecks in the posterior pole
(Figure 2B). Fluorescein angiography
revealed a central, dark, butterfly-shaped lesion surrounded by a region of
hyperfluorescence, with dark spots in the posterior pole corresponding to
the observed yellow flecks (Figure 2C).
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Figure 2. A, Fundus examination of the right
eye of individual IV:7 showing a typical butterfly-shaped pigmentary lesion
in the macula with yellow flecks in the posterior pole. B, Fundus examination
of the right eye of individual III:1. Butterfly-shaped accumulation of yellowish
retinal pigment epithelium (RPE) deposits with flecks in the posterior pole.
C, Fluorescein angiogram of the right eye of individual III:1 showing a large,
hypofluorescent, butterfly-shaped macular lesion. The yellow flecks observed
funduscopically in the posterior pole are noted to block fluorescence. D,
Fundus examination of the right eye of individual III:6, showing widespread
retinal atrophy with pigment clumping.
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In patients of the oldest surviving generation, including the patient
for whom we have obtained pathological studies, we observed more extensive
retinal atrophy. In an 80-year-old man (III:6) with a visual acuity of 20/800
OU, we observed bilateral geographic atrophy of the central retina and RPE,
which was clearly demarcated from healthy-appearing tissue in the periphery
(Figure 2D). This was confirmed
by fluorescein angiography, which demonstrated marked RPE atrophy centrally
and healthy tissue in the periphery (not shown).
CLINICOPATHOLOGICAL CASE REPORT
In 1961, a 45-year-old white woman (III:20) had bilateral blurred vision
and a doughnut-shaped, depigmented area inferior to the right macula and a
faint discoloration in the left macula. In 1964, she was noted to have an
additional depigmented area superior to her left fovea and, in the following
year, 2 new areas of depigmentation were observed inferior and superior to
the fovea of this eye. Although her vision was still 20/20 OU at the time,
a central scotoma was discovered in her left eye later that same year, at
which point her visual acuity was still measured at 20/20 OS.
In 1974, when she was initially examined by Singerman et al,21 her visual acuity was 20/30 OU, and funduscopic examination
of the right eye revealed an ovoid area of RPE disturbance surrounding a central
grayish-yellow round area with a dark, slightly refractile material that was
deep to the retina at its center. This ovoid area was adjacent to a region
of dark yellow subretinal material around the right fovea. Examination of
the left macula revealed similar changes, although the RPE abnormalities and
the central dark refractile material were less well defined. Fluorescein angiography
of the right eye demonstrated an early, vertically oriented, ovoid area of
hyperfluorescence, corresponding to the RPE disturbances observed funduscopically.
An angiogram of the left eye revealed similar abnormalities, and neither showed
hyperfluorescent spots peripheral to the central lesion.
In August 1997, the patient was reexamined as part of a cohort used
to map the family's genetic defect to the RDS/peripherin locus. At that time, her visual acuity was 20/64 OD and 20/800 OS.
Ophthalmoscopic examination revealed atrophy of the RPE, left eye more than
the right eye. She died of complications from chronic obstructive pulmonary
disease on October 31, 1997, at which time her left globe was harvested within
12 hours for histopathological examination.
Internal examination disclosed a 3 x 2.5-mm depigmented area with
sharp margins located at the center of the macula (Figure 3). Microscopic examination of 545 serial sections through
the macula disclosed a 3.5-mm area of loss of RPE and photoreceptor cell layer
(Figure 4A, left margin, 4B, right
margin). Peripheral to this region, the RPE cells were distorted and greatly
distended by lipofuscin, whereas the photoreceptors were partially atrophic
(Figure 4C and D). A few large,
round pigmented cells containing lipofuscin were present in the subretinal
space and in the outer aspect of retina (Figure 4E). Immunological staining for factor 8 disclosed normal
staining of the choriocapillaris endothelium outside the area of atrophy,
while about 75% of the capillaries in the area of atrophy of the RPE and photoreceptor
cell layer demonstrated endothelial staining (Figure 4F).
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Figure 3. Gross examination of the left
eye of individual III:20, demonstrating a 3 x 2.5-mm atrophic lesion
with depigmention and sharp margins located at the center of the macula.
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Figure 4. Light microscopic analysis of
left retina from individual III:20. The nasal (A) and temporal (B) margins
of the lesion show an abrupt transition between areas of photoreceptor and
RPE atrophy and areas of relatively intact retina A (hematoxylin-eosin, original
magnification x40). C, A higher-power view of the margin of the lesion
discloses RPE cells distended with lipofuscin and partial atrophy of the photoreceptor
layer (hematoxylin-eosin, original magnification x100). D, An area outside
the atrophic lesion demonstrating RPE cells that are distended with lipofuscin
(hematoxylin-eosin, original magnification x400). E, Area of outer retina
showing melanophages containing lipofuscin (hematoxylin-eosin, original magnification
x400). F, Immunological staining using Factor VIII antibodies demonstrating
relatively intact choriocapillaris endothelium (original magnification x100).
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Ultrastructural examination revealed a 11-µm-thick section of
Bruch's membrane composed of vesicular materials distended from its normal
thickness of 2 µm (Figure 5).
Small mound-shaped deposits of granular material with wide-spaced collagen
and basal laminar deposits were present along the internal aspect of Bruch's
membrane. In some areas of the atrophic zone, residual RPE basement membrane
was present. The choriocapillaris was examined extensively and were intact,
except for 1 vessel that had no endothelium (Figure 5). Outside the area of atrophy, the RPE was greatly distended
by melanin, melanolipofuscin, and especially by lipofuscin granules (Figure 5).
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Figure 5. Electron micrograph demonstrating
a retinal pigment epithelium cell containing lipofuscin (large arrowhead)
and melanolipofuscin (small arrowhead), Bruch's membrane with vesicular material
(arrow), and intact endothelium (star).
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LINKAGE ANALYSIS AND MUTATION DETECTION
Genotype analysis using short tandem repeat markers D6S1549 and D6S1557
revealed a positive linkage between the disease phenotype and the RDS/peripherin locus (data not shown). Sequence analysis of the RDS/peripherin coding region in 6 affected patients revealed
a GA change at the nucleotide position 637, predicting a novel Cys213Tyr
substitution. This change also eliminated a PvuII
restriction enzyme site and therefore was used as a rapid screening assay
for the presence of the mutation. The PvuII site
change segregated with the disease phenotype in all affected members of the
cohort, giving a positive logarithm of the odds (lod) score of 3.37 (Figure 1B). The lack of a PvuII site was not found in 102 control chromosomes examined.
COMMENT
This report provides, to our knowledge, the first clinicopathological
correlate of BPD caused by a defined mutation in the RDS/peripherin gene.
The disease is characterized clinically by the ophthalmoscopic observation
of macular atrophy associated with deposits at the level of the RPE. Our light
microscopic and transmission electron microscopic studies demonstrated that
this atrophy was limited to the outer retina, with loss of the RPE and photoreceptor
cell layer, engorgement of surrounding RPE cells with lipofuscin, and sparing
of the choriocapillaris. These histopathological findings stand in contrast
to the clinical observations of other groups such as Prensky and Bresnick3 who described peripapillary abnormalities in 3 older
members of a large cohort with BPD, which they compared with the peripapillary
variant of choroidal dystrophy, in which the choriocapillaris atrophies focally.
Previous studies have demonstrated that mutations in the RDS/peripherin
gene can yield retinal disease phenotypes and, specifically, that mutations
in the cysteine residue at position 213 can lead to pattern dystrophy.10 We have identified a novel Cys213Tyr mutation in
the RDS/peripherin gene responsible for BPD in this family. The cysteine residue
at codon 213 is highly conserved between human, bovine, mouse, and rat. It
has been suggested that this cysteine residue may play an important role in
intrachain and/or interchain disulfide bond formation.20, 23
One can postulate that the Cys213Tyr mutation could interrupt disulfide bond
formation and thereby disrupt the integrity of the photoreceptor disc membrane,
leading initially to degeneration of photoreceptor cells and ultimately resulting
in an accumulation of lipofuscin in the RPE. In turn, this could result in
the degeneration of the RPE cell layer, with sparing of the choriocapillaris,
as we observed on histopathological examination.
A mutation in the amino acid residue next to Cys213, Cys214Ser, has
been reported in a family with autosomal dominant retinitis pigmentosa rather
than BPD.16 It is not clear why these adjacent
mutations produce distinct clinical pictures, although it is well known that
RDS/peripherin mutations can cause numerous distinct phenotypes.9, 17
Future studies will hopefully help elucidate the molecular mechanisms that
determine clinical phenotype, including the relative importance of primary
structural mutations and modifier gene effects.
AUTHOR INFORMATION
Submitted for publication July 4, 2000; final revision received October
25, 2001; accepted December 3, 2001.
This study was supported by funds from the National Eye Institute, Bethesda,
Md; Foundation Fighting Blindness, Owings Mills, Md; Macula Vision Research
Foundation, Bala Cynwyd, Pa; Milton and Ruth Steinbach Foundation, New York,
NY; Helen Keller Foundation for Research and Education, Birmingham, Ala; and
unrestricted funds from Research to Prevent Blindness, New York, NY.
Dr Zack is the Guerrieri Professor of Genetic Engineering and Molecular
Ophthalmology, Johns Hopkins University, Baltimore, Md.
Drs Zhang, Garibaldi, and Li contributed equally to this article.
We thank our family members for their participation; Larry Singerman,
MD, Arnold Patz, MD, and Andy Goldberg, PhD, for critical review of the manuscript;
and Carol Applegate, Michelle Kerrigan, and Zhengya Yu, MD, for their able
assistance.
Corresponding authors and reprints: W. Richard Green, MD, and Donald
J. Zack, MD, PhD, Department of Ophthalmology, Johns Hopkins University School
of Medicine, 809 Maumenee, 600 N Wolfe St, Baltimore, MD 21287 (e-mail: dzack{at}bs.jbmi.edu).
From the Wilmer Eye Institute and the Departments of Ophthalmology
(Drs Zhang, Garibaldi, Li, Green, and Zack), Molecular Biology and Genetics,
and Neuroscience (Dr Zack), Johns Hopkins University School of Medicine, Baltimore,
Md. Dr Zhang is now with the Department of Ophthalmology and Visual Sciences,
Moran Eye Center, University of Utah School of Medicine, Salt Lake City. Dr
Li is now with Tong Reng Eye Hospital, Beijing, China.
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