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Electroretinographic Abnormalities in Parents of Patients With Leber Congenital Amaurosis Who Have Heterozygous GUCY2D Mutations
Robert K. Koenekoop, MD, PhD;
Gerald A. Fishman, MD;
Alessandro Iannaccone, MD;
Hany Ezzeldin, PhD;
Maria L. Ciccarelli, COMT, CO;
Alfonso Baldi, MD;
Janet S. Sunness, MD;
Andrew J. Lotery, MD;
Monica M. Jablonski, PhD;
Steven J. Pittler, PhD;
Irene Maumenee, MD
Arch Ophthalmol. 2002;120:1325-1330.
ABSTRACT
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Background Leber congenital amaurosis (LCA) is an infrequently encountered congenital
form of retinitis pigmentosa with marked genetic and clinical heterogeneity.
Thus far, 10 genes have been identified in this disorder since 1996. In the
future, LCA may become treatable by gene and/or pharmacological intervention,
and these therapies will likely be gene specific, giving major significance
to rapid gene identification and gene-phenotype studies.
Objective To test the hypothesis that parents of patients with LCA have identifiable
electroretinographic and psychophysical changes.
Subjects, Materials, and Methods Complete eye examinations and electroretinographic studies were performed
on 2 sets of parents whose offspring were diagnosed as having LCA and who
were found to carry a mutation in 1 of the 10 LCA genes—GUCY2D. One set of parents also underwent static perimetry threshold
measurements.
Results We found that single flash-light–adapted a- and b-wave amplitudes,
30-Hz flicker, or both cone signals were significantly decreased in amplitude
in 4 heterozygotes, while 2 parents showed delayed 30-Hz flicker implicit
times. Electroretinographic rod-mediated signals were normal in 2 of the heterozygotes,
but subnormal in 2. Static perimetry testing showed normal thresholds in the
2 heterozygotes tested.
Main Outcome Measures Single flash-light–adapted a- and b-wave amplitudes and implicit
times, 30- or 32-Hz flicker amplitudes and implicit times, rod-mediated signals,
and dark-adapted, rod-mediated thresholds.
Conclusions Some carrier parents of patients with LCA and a GUCY2D mutation develop measurable, cone and possibly rod abnormalities most
consistent with a mild cone-rod dysfunction. This correlates well with the
known retinal expression pattern of GUCY2D, which
is considerably higher in cone compared with rod photoreceptor cells.
INTRODUCTION
LEBER CONGENITAL amaurosis (LCA) (MIM 204 000) is a congenital,
retinal blinding disease with a worldwide prevalence of 3 in 100 000
neonates.1 It accounts for 5% or more of all
inherited retinal degenerations and for approximately 20% of the children
attending schools for the blind around the world.1-2 Leber
congenital amaurosis was described by Theodor Leber over 130 years ago as
a congenital form of retinitis pigmentosa (RP),3 and
represents one of the most severe forms of inherited retinal diseases. It
is defined and characterized by severely impaired vision in the first 6 months
of life, sensory nystagmus, poorly reactive pupils,3 and
severely diminished or nondetectable cone-rod photoreceptor responses on the
electroretinogram (ERG) in the first year of life.4 Leber
congenital amaurosis is genetically heterogeneous,5 and
since 1996, 10 separate genes have been implicated in the cause of LCA.6-15 In
the future, LCA may be treatable by pharmacological intervention16 and/or
gene replacement therapy,17 and these therapies
will likely be gene specific, giving major significance to gene identification
and gene-phenotype studies.
The first causal LCA gene discovered was the gene for retinal guanylate
cyclase, GUCY2D,6 which
encodes a transmembrane enzyme found in rod-cone outer segment disc membranes.18-19 Light exposure initiates the rod-cone
phototransduction cascades, which results in the activation of  -phosphodiesterase,
and hydrolysis of cyclic guanosine monophosphate (cGMP). This results in the
closure of cGMP-gated ion channels, and a decrease in intracellular calcium
concentration that, in turn, activates the enzyme guanylate cyclase–activating
protein (GCAP). Guanylate cyclase–activating protein activates retinal
guanylate cyclase, which replenishes the level of cGMP to its prelight exposure
levels, and restores the opening of the cGMP-gated ion channels. Mutant retinal
guanylate cyclase probably results in abnormally low levels of cGMP and permanent
closure of the channels, a situation that corresponds to chronic light exposure.6 GUCY2D mutations have been
found in recessive LCA,6, 20-21 as
well as in dominant cone-rod degeneration.22
We identified mutations in the GUCY2D gene
in patients with LCA20 and studied their effects
in a cell culture system.23-24 We
observed that the mutations negatively influence the wildtype allele in vitro
(dominant negative effects). These findings prompted us to test the hypothesis
of in vivo dominant negative effects by using ERG and psychophysical analyses
of parents of children with LCA who have a GUCY2D mutation.
We report significant and repeatable cone ERG abnormalities in parents of
patients with LCA.
SUBJECTS, MATERIALS, AND METHODS
GENOTYPING
Family 1
As part of an ongoing evaluation of LCA phenotypes and genotypes, we
are studying 250 patients with LCA from around the world. Mutation analysis
of all known LCA genes (GUCY2D, RPE65, CRX, AIPL-1, TULP-1, CRB-1, RPGRIP-1,
and LRAT) is routinely performed in our laboratory
by polymerase chain reaction, single-stranded conformational polymorphism.20 Single-stranded conformational polymorphism variants
are further analyzed by direct nucleotide sequencing, and/or by automated
sequencing on an ABI prism 377 (Applied Biosystems, Warrington, England).
To confirm mutations, we perform DNA-based diagnostics by restriction enzyme
digests and exclusion in 100 ethnically matched control patients. Informed
consents were obtained for venous blood sampling, according to the guidelines
from the McGill University Montreal Children's Hospital's ethical review board.
Family 2
The proband of this family was part of another large mutation screening
of all known LCA genes at the University of Iowa, Iowa City, by polymerase
chain reaction, single-stranded conformational polymorphism, and automated
sequencing, as previously documented.21 The
parents were genotyped by denaturing high-pressure liquid chromatography at
the University of Alabama at Birmingham as part of an ongoing parallel study.
ELECTROPHYSIOLOGICAL ASSESSMENTS
Detailed eye examinations, including Snellen visual acuities, slitlamp
biomicroscopy, and dilated indirect ophthalmoscopy were done on all parents.
Electroretinograms were done on both eyes and performed in accord with a standard
recommended by the International Society for Clinical Electrophysiology of
Vision,25 using procedures previously described
by Peachey et al.26 In this article, we analyzed
the ERGs of both parents of the child with a leucine to proline substitution
(L954P mutation) in GUCY2D (family 1). Previously,
we identified and reported this mutation in the proband with LCA and her mother
(subject 1), but were unable to identify a GUCY2D mutation
in the proband's father (subject 2).20 We determined,
in vitro, that the mutation causes a complete loss of retinal guanylate cyclase
activity and inability to respond to GCAP (C. L. Tucker, PhD, V. Ramamurthy,
PhD, A. L. Pina, PhD, unpublished data, June 2000).23
We compared our ERG findings from our heterozygous carriers to the range
of normative data, which include ERG average values and 2 SDs above and below
the mean (our reference range). We also sought to determine whether these
ERG changes could be observed in LCA carriers in whom we were unable to identify
mutations in the GUCY2D gene. We, therefore, performed
ERGs on 12 additional parent pairs of offspring with LCA, according to procedures
previously reported by Hébert et al.27 In
these patients with LCA, we screened, but were unable to identify, pathogenic
mutations in GUCY2D, RPE65, CRX, or AIPL-1.
Electroretinograms were also performed on another set of parents of
a patient with LCA who also harbors a single mutation in GUCY2D (family 2). A mutation predicting a proline to leucine substitution
(P575L) was found in the proband who had LCA and his mother (subject 3), while
no GUCY2D mutation was found in the proband's father
(subject 4) (Figure 1). These ERGs
were done in Rome, Italy, according to a previously reported procedure.28 For these ERGs, monopolar Henkes' type contact lens
electrodes were used to record the responses. Up to 40 responses were averaged
off line for each testing condition. Maximal ERG responses and cone responses
were recorded with a flash at the low end of the standard range (about 1.5
candela [cd]-s/m2), which is the standard intensity for this laboratory.
A set of transient cone-driven ERGs was also recorded at approximately 3.5
cd-s/m2 (same as the University of Illinois at Chicago [UIC], standard).
Each of our 3 ERG laboratories (located in Montreal, Quebec [McGill University],
Chicago [UIC], and Rome [Regina Elena Institute]) has its own reference range
of ERG values, uses different light intensities, and uses different electrodes.
To make meaningful comparisons between the 3 sets of data, we decided to normalize
ERG values by expressing them as percentages of the lowest limit of each of
our reference ranges.
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Figure 1. The P575L mutation in GUCY2D of family 2. The DNA sequence of a segment of exon 8 of GUCY2D is shown. Lanes 1 through 3 represent the proband,
proband's father, and proband's mother, respectively. Lanes 4 and 5 are from
unrelated patients. The arrow on the left marks the position of a heterozygous
cytidine to thymidine change that translates to a P575L amino acid change.
Lane order for all sequences is from left to right: adenosine cytidine, guanosine,
and thymidine. The sequence change was not observed in more than 100 samples
tested.
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PSYCHOPHYSICS
To assess sensitivity losses across the retina, we performed static
threshold perimetry with 500- and 650-nm stimuli after 1 hour of dark adaptation
using a Tubinger perimeter (Oculus, Inc, Tubinger, Federal Republic of Germany)
on subjects 1 and 2 of family 1 as previously described.29
RESULTS
We found abnormal ERGs in all 4 subjects from both families, while we
did not find any ERG abnormalities in the 12 additional LCA-affected parent
pairs who were negative on our GUCY2D, RPE65, CRX, and AIPL-1 genetic screening (data not shown). Of interest are the similarities
in the cone ERG abnormalities in the 4 parents.
ELECTROPHYSIOLOGICAL ASSESSMENTS AND PSYCHOPHYSICS FOR THE PARENTS
OF FAMILY 1 (L954P MUTATION IN GUCY2D)
The 47-year-old mother (subject 1) has mild asthma. She reported difficulties
driving at night, and photoaversion during the day. Her vision was correctable
to 20/30 OD with –0.50 +0.75 x 105°, and 20/25-1 OS with +0.50
+0.50 x 105°. The results of her retinal examination showed no abnormalities.
Her ERGs were performed at The Johns Hopkins University (Baltimore, Md) when
the patient was 45 and 46 years old (data not shown) and were repeated at
UIC when the patient was 47 years old (Figure
2). Results of the ERGs at the 2 institutions were similar. At UIC,
we found distinctly reduced 32-Hz flicker and single flash-light–adapted
a- and b-wave amplitudes (Figure 2A).
The flicker amplitudes were reduced to 137 µV, which represents 80%
of the lower limit of normal. The value 230 µV represents the normal
average, with a range of 171 to 350 µV in this laboratory. The 32-Hz
white flicker responses were significantly delayed to 36 milliseconds (our
normal average is 26 milliseconds, with a range of 22.3-31.6 milliseconds).
The single flash-light–adapted a- and b-wave amplitudes were also reduced
below the normal range, but their implicit times were normal. The a-wave amplitudes
were reduced to 60 µV, which represents 86% of the lower limit of normal.
Our normal average is 98 µV, with a range of 70 to 138 µV. The
b-wave amplitudes were reduced to 126 µV, which represents 95% of the
lower limit of normal. Our normal average is 225 µV, with a range of
132 to 320 µV. For the dark-adapted ERG responses, including both the
rod isolated and rod dominant waveforms, we found subnormal values, while
the implicit times were normal (Figure 2A).
Static threshold perimetry (Figure 3)
showed normal rod thresholds.
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Figure 2. Scotopic (A) and photopic (B)
electoretinograms (ERGs) done at the University of Illinois at Chicago. Healthy
subject; right eye of the carrier mother (subject 1); and father (subject
2) of family 1, respectively. The a and b indicate a wave and b wave, respectively.
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Figure 3. Static perimetry testing using
650-nm and 500-nm stimuli on the carrier mother (subject 1 of family 1) at
the University of Illinois at Chicago.
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The 55-year-old father (subject 2) reported a recent onset of impaired
vision. He denied having nyctalopia and side vision loss. His vision was correctable
to 20/20-1 OD with -2.50 +0.50 x 60° and 20/20-1 OS with a
-2.50 +0.50 x 100°. We found a normal retinal appearance.
His ERGs were performed at The Johns Hopkins University when he was 53 years
old and again when he was 54 years old (data not shown); when he was 55 years
old, we repeated ERGs and performed static perimetry thresholds (Figure 2 and Figure 4) at UIC. The results of the ERGs at both institutions were
very similar, therefore, we only report the most recent results from UIC.
The timing and amplitudes of the rod-mediated ERGs were subnormal (Figure 2A), while the cone-mediated ERGs,
especially the 32-Hz flicker were again markedly decreased (Figure 2B). The 32-Hz flicker (Figure 2B) amplitudes were decreased to 152 µV, which represents
89% of the lower limit of normal. Our normal average is 230 µV, with
a range of 171 to 350 µV. The flicker responses were also slightly delayed
to 32 milliseconds, while our normal average is 26 milliseconds, with a range
of 22 to 31.6 milliseconds. The single light-adapted response was within the
lower limit of normal for the b-wave amplitude with a normal implicit time.
The a-wave amplitude, however, was reduced to 60 µV, which represents
86% of the lower limit of normal. Our normal average is 98 µV, with
a range of 70 to 138 µV. Static threshold perimetry (Figure 4) revealed normal rod thresholds.
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Figure 4. Static perimetry testing using
650-nm and 500-nm stimuli on the carrier father (subject 2 of family 1) at
the University of Illinois at Chicago. cd indicates candela.
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ELECTROPHYSIOLOGICAL ASSESSMENT FOR THE PARENTS OF FAMILY 2 (P575L
MUTATION IN GUCY2D)
The 48-year-old mother (subject 3)has a history of myopia and a lifelong
history of photoaversion. She denied having difficulties with night vision.
Visual acuities were 20/15 with -1.50 +1.00 x 90° OU. Findings
from her retinal examinations were remarkable for mild arteriolar narrowing
and mild pigmentary mottling at the level of the retinal pigment epithelium
inferior and superior to the arcades. The rod-mediated responses were within
normal limits (Figure 5) as were
the maximal ERG responses. Light-adapted, cone-driven, transient and 30-Hz
flicker responses to a 1.5–cd-s/m2 stimulus were normal in
timing (interocular average, transient: 30.5 milliseconds [reference range,
27-32 milliseconds]; flicker, 32 milliseconds [reference range, 28-32 milliseconds]),
but subnormal in amplitude (Figure 5)
(interocular average, 42 µV for the transient and 30 µV for the
flicker response, which correspond to about 60%-65% of the lowest limit of
normal for this laboratory [ie, >65 µV for the transient and >50 µV
for the flicker response]). Responses to 3.5–cd-s/m2 stimuli
(not shown) were proportionally larger in amplitude (interocular average,
88 µV, which is about 85% of the lowest limit of normal at this intensity
[>102 µV]) and remained normal in timing (29 milliseconds; reference
range, 28-33 milliseconds), suggesting again a loss in cone-mediated sensitivity.
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Figure 5. Electroretinogram done in Rome,
Italy, with a healthy subject, mother (subject 3), and father (subject 4)
of family 2, respectively. A indicates rod isolated; B, maximal rod and cone;
C, cone isolated electroretinogram; and D, 30-Hz flicker.
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The 48-year-old father of the proband (subject 4) has a history of amblyopia
of the left eye, but no elicitable symptoms of nyctalopia, photoaversion,
or adaptation problems. His visual acuity was 20/15 OD with +0.50+1.00 x
180°, and 20/100 OS with +2.75. The findings from his retinal examination
were unremarkable, except for a cluster of small hard drusen, temporal to
the fovea in each eye. The rod-mediated responses of subject 4 were within
normal limits (Figure 5) as were
the maximal ERG responses. Light-adapted, cone-driven, transient and 30-Hz
flicker responses to the 1.5–cd-s/m2 stimuli were normal
in timing (interocular average: transient, 31 milliseconds; flicker, 32 milliseconds),
but again subnormal in amplitude (interocular average: 52 µV for the
transient and 36 µV for the flicker response, which correspond to about
70%-75% of the lowest limits of normal). The responses to 3.5–cd-s/m2 stimuli (not shown) were proportionally larger in amplitude (90.5
µV, which is 88% of the lowest limit of normal) and remained normal
in timing (29.5 milliseconds), suggesting a loss in cone-mediated sensitivity.
COMMENT
We performed a functional assessment on heterozygous parents of offspring
with LCA who have mutations in GUCY2D and found significant
diffuse cone-mediated ERG abnormalities in 4 parents, and subnormal rod isolated
amplitudes in 2. To our knowledge, this is the first report of abnormalities
of the cone-rod systems in parents of subjects with LCA. We found these abnormalities
in 2 sets of parents whose offspring were diagnosed as having LCA and who
each carry 1 identified GUCY2D mutation. There were
no significant differences in the electrophysiological abnormalities of the
2 families, despite the distinct locations of the mutations, 1 in the catalytic
and 1 in the kinase homology domain of the GUCY2D protein.
Cone amplitudes were decreased in both parents of both families, while cone-mediated
signals were delayed in 2 of the parents (subjects 1 and 2). The electrophysiological
changes of the LCA carriers are most consistent with a mild cone-rod dysfunction.
Not all carrier parents of children with LCA have abnormal ERGs; we found
normal ERGs in 12 parent pairs who were negative for GUCY2D as well as RPE65, CRX, and AIPL-1.
The observed cone ERG abnormalities in these 2 sets of parents are quite
similar to one another and these in vivo findings correlate well with our
previous in vitro experiments (C. L. Tucker, PhD, V. Ramamurthy, PhD, A. L.
Pina, PhD, unpublished data, June 2002).22-23 In
these experiments, we co-expressed the GUCY2D L954P
mutation with the wild type allele and found dose-dependent, dominant-negative
effects. As we increased the dose of the mutant, the ability of the wildtype
allele to synthesize cGMP under GCAP1 and GCAP2 stimulation was progressively
impaired in our HEK293 cell culture system (C. L. Tucker, PhD, V. Ramamurthy,
PhD, A. L. Pina, PhD, unpublished data, June 2002).22 Our
cone photoreceptor–mediated abnormalities also correlate well with the
known expression profile of GUCY2D in the human retina,
which is expressed at considerably higher levels in cone photoreceptor outer
segments than in rod outer segments.18-19 Using
immunocytochemical methods, Liu et al18 and
Dizhoor et al19 showed that the cone outer
segments were more densely labeled with an antibody to GUCY2D than the rods were. Also, a cone-specific dystrophy was found
when the GUCY2D gene was knocked out in the mouse.
Yang et al30 showed that GUCY2D knockout mice develop a severe and rapid cone degeneration with
cone ERG loss, while the rods remained morphologically normal.
There are several limitations to the specificity of our findings that
must be noted. Our inability to find the second mutant GUCY2D allele in patients with LCA identified as having one probable
disease-associated mutation in a known LCA gene is
a relatively frequent finding reported by several other investigators who
study LCA genes.31-35 For
example, in the study by Lotery et al21 probable
disease causing mutations in GUCY2D were identified
in both alleles in only 2 of 11 patients. This example underscores the challenge
posed by identifying both disease-causing mutations in autosomal recessive
retinal diseases, for example, those that are located in midintrons and in
promoter regions. The possibility that LCA may be caused by a digenic mechanism
in our 2 families cannot be excluded, although the likelihood of this is low.21
Heterozygous mutations in GUCY2D can cause
an early-onset, severe dominant form of cone-rod dystrophy,22 unlike
the clinical phenotype of the 4 heterozygous parents evaluated in this study.
While it cannot be excluded that the GUCY2D mutations
in our patients exhibited incomplete penetrance or effect modification owing
to differences in genetic background between the mothers and their affected
offspring, the negative family history suggests that our patients with LCA
most likely carry 2 disease-causing GUCY2D mutations
in the compound heterozygous state, and that we were only able to identify
the recessive mutation on the mother's allele in both families, but not the
mutation on the father's allele. We also propose that LCA in our patients
is the result of 2 recessive mutations (in our cases compound heterozygotes),
and in single dose, these heterozygous mutations (L954P and P575L) may cause
a mild cone-rod dysfunction.
Electoretinographic abnormalities have been previously reported in parents
of children with other recessive retinal degenerations. For example, Rosenfeld
et al36 found small rod-mediated abnormalities
in carriers of patients with autosomal recessive RP and the rhodopsin genotype.
Felius et al37 found extensive dark-adapted
visual field defects (1-2 log units above normal) and delayed 30-Hz flicker
ERG in 1 parent of a child with LCA who has the RPE65 genotype,
while Swaroop et al38 found small rod-cone
abnormalities in parents of a child with LCA who has the CRX genotype. Parents of children who have recessive Bardet-Biedl were
found to have small cone ERG abnormalities (Elise Heon, MD, oral communication,
June 1, 2001) and small rod ERG abnormalities.39 While
we have found mainly cone abnormalities in the parents of the child with LCA
who has the GUCY2D genotype, ERG changes in parents
of children with LCA who have the AIPL-1, TULP-1, CRB-1,
RPGRIP-1, and LRAT genotype have not yet been
reported. Whether these novel and subtle ERG changes in parents with LCA are
gene specific and can point us to the pathogenic gene must await confirmation
after more extensive genotype-phenotype correlations.
CONCLUSIONS
We documented the occurrence of predominantly cone ERG abnormalities
in heterozygous parents of patients with LCA, likely attributable to the carrier
state for GUCY2D mutations. The abnormalities are
most consistent with a mild cone-rod dysfunction. Given the substantial genetic
heterogeneity of LCA (10 genes so far), and the possible gene-specific nature
of future treatments, rapid genotyping of patients with LCA is essential.
It would be helpful if gene-specific ERG changes could be consistently demonstrated
in obligate carriers and point to the defective gene of a patient with LCA.
The purpose of a future study will be to test the hypothesis that gene-specific
changes can be consistently demonstrated by simple ERG testing in carrier
parents of patients with LCA. Future findings from such studies might be useful
for more focused molecular genetic testing.
AUTHOR INFORMATION
Submitted for publication November 6, 2001; final revision received
April 26, 2002; accepted May 14, 2002.
This study was supported in part by grants from Medical Research Council
Canada (Canadian Institute of Health Research), Ottawa, Ontario; Foundation
Fighting Blindness Canada, Toronto, Ontario; the Federation de Recherche en
Santée du Quebec, Montreal; and start-up funds from the Montreal Children's
Hospital Research Institute (Dr Koenekoop); Foundation Fighting Blindness,
Baltimore; a grant from Grant Healthcare Foundation, Chicago; and the Knights
Templar Foundation, Chicago (Dr Fishman); an unrestricted grant from Research
to Prevent Blindness Inc, New York, NY, to the University of Tennessee Health
Sciences Center, Department of Ophthalmology (Drs Iannaccone and Jablonski).
Dr Lotery is a recipient of a Research to Prevent Blindness Career Development
Award.
We thank all of the patients and parents involved. We also thank Ana
Luisa Pina, PhD, Magali Loyer, MSc, Chandra Tucker, PhD, Vishy Ramamurthy,
PhD, Jim Hurley, PhD, and Debra Derlacki, BS, for their support.
Corresponding author and reprints: Robert K. Koenekoop MD, PhD (e-mail: robert.koenekoop{at}muhc.mcgill.ca).
From the McGill Ocular Genetics Laboratory, Montreal Children's Hospital,
McGill University, Montreal, Quebec (Dr Koenekoop); Department of Ophthalmology,
University of Illinois at Chicago (Dr Fishman); Retinal Degeneration Research
Center, University of Tennessee Health Sciences Center, Memphis (Drs Iannaccone
and Jablonski); Vision Science Research Center, University of Alabama, Birmingham
(Drs Ezzeldin and Pittler); Division of Ophthalmology, Fatebenefratelli Hospital
(Ms Ciccarelli), and the Regina Elena Institute (Dr Baldi), Rome, Italy; Lions
Vision Center of the Wilmer Eye Institute (Dr Sunness), and The Johns Hopkins
Center for Hereditary Eye Diseases (Dr Maumenee), The Johns Hopkins University,
Baltimore, Md; and the Department of Ophthalmology, University of Iowa, Iowa
City (Dr Lotery).
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