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Clinical Course and Visual Function in a Family With Mutations in the RPE65 Gene
Joost Felius, PhD;
Debra A. Thompson, PhD;
Naheed W. Khan, PhD;
Eve L. Bingham;
Jeffrey A. Jamison;
Jennifer A. Kemp;
Paul A. Sieving, MD, PhD
Arch Ophthalmol. 2002;120:55-61.
ABSTRACT
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Objective To evaluate the phenotype of affected and carrier members of a family
with mutations in RPE65 (a retinal pigment epithelium
gene).
Methods RPE65 mutation screening was performed on DNA
from 2 affected brothers, 1 unaffected brother, both parents, and 3 surviving
grandparents using cycle sequencing. Ophthalmic examinations included ophthalmoscopic
fundus examination; visual function testing; 2-color, static, dark-adapted
threshold perimetry; and rod electroretinographic a-wave phototransduction
analysis.
Results The 2 affected brothers carried RPE65 mutations
in compound heterozygous form: a maternal Y368H (1156T C) missense mutation
and a paternal IVS1 + 5ga splice-site mutation. Severe visual deficits
and an absence of rod and cone electroretinographic responses were diagnosed
in both affected boys before the age of 5 years. Visual acuities of about
20/100 during grade school declined to hand movements by the teenage years,
and only a rudimentary peripheral temporal visual field remained by the ages
of 25 and 29 years. Both parents had normal central visual function, as measured
by visual acuity, contrast sensitivity, color vision, and Humphrey 10-2 fields.
However, the 50-year-old father showed hundreds of tiny whitish hard drusen
in both eyes and had abnormal peripheral function on dark-adapted perimetry,
with extended field defects of 15 to 20 dB outside 30° eccentricity. His
rod photoreceptor sensitivity and amplitude, calculated by fitting the rod
a waves by a model of activation of phototransduction, were normal, but the
flicker electroretinographic response was delayed.
Conclusions The RPE65 mutations Y368H and IVS1 + 5ga
present in compound heterozygous form cause severe visual compromise in childhood
and progress to nearly total vision loss by the second to third decades of
life. The retinal and functional changes in the father carrying a presumed
functional null allele suggest that some RPE65 heterozygous
carriers may manifest visual symptoms.
INTRODUCTION
GENETIC mutations that disrupt vitamin A processing in the retinal pigment
epithelium (RPE) result in a spectrum of retinal dystrophies and dysfunctions.1-8
Among the known disease genes in this pathway, mutations in RPE65 seem to be the most common and are associated with a severe phenotype.
The RPE65 gene encodes a unique protein necessary
for the conversion of vitamin A to 11-cis retinal,9 the chromophore of the visual pigments. Mutations
in RPE65 result in autosomal recessive retinal degeneration
that is often diagnosed as Leber congenital amaurosis type II.2, 10-11
However, a range of disease severity has been reported, from congenital blindness
to adult-onset retinitis pigmentosa.12
Genetic defects in vitamin A metabolism are, in theory, attractive targets
for therapeutic intervention in several ways, including gene therapy, RPE
transplantation, and survival factor therapy. In the case of RPE65, advances in such treatments are hoped to be rapid, because mouse
and dog models of the disease are available.9, 13
Characterization of patients with RPE65 mutations
is, therefore, an important goal, because these patients may be expected to
be candidates for future therapeutic trials. We report findings in a family
with 2 different RPE65 disease alleles that together
result in early-onset, severe, and rapidly progressing retinal degeneration.
One of the affected family members was followed up from the age of 5 years
until the present (age 29 years) and shows a prominent macular component to
the disease. In addition, there is evidence of macular changes in one of the
heterozygous carrier parents.
SUBJECTS AND METHODS
SUBJECTS
Four individuals were studied in a family in which an RPE65 splice-site mutation (IVS1 + 5ga) and a missense mutation
(Y368H [1156TC]) segregate in compound heterozygous form with a retinal
degeneration phenotype (Figure 1).
Two brothers, aged 25 and 29 years, carry both mutations and are severely
visually impaired. Their mother, aged 49, carries the Y368H mutation, and
their father, aged 50, carries the IVS1 + 5ga mutation. The RPE65 mutations in this family have been reported14;
herein, we describe the associated phenotype. Informed consent was obtained
from all participating subjects in accordance with the University of Michigan
Medical School Institutional Review Board.
MUTATION SCREENING
DNA from the 2 affected brothers, 1 unaffected brother, both parents,
and 3 surviving grandparents was screened for sequence changes in all RPE65 exons and adjacent intronic regions by cycle sequencing
using primer pairs and conditions published previously.1
VISUAL EXAMINATION
The best-corrected distance visual acuity was determined using the Early
Treatment Diabetic Retinopathy Study letter charts at a 4-m viewing distance,
and results are given in logMAR units. Contrast sensitivity was determined
using the Pelli-Robson Contrast Sensitivity Charts15
at a viewing distance of 1 m and at a luminance of 85 candela (cd)/m2. The central visual field was examined using standard Humphrey 10-2
automated perimetry. Color vision, Goldmann visual fields, and standard clinical
electroretinograms (ERGs) were measured according to methods previously described.16 Color vision was evaluated using the Ishihara plates
and the Farnsworth dichotomous D-15 test. Goldmann kinetic visual fields were
obtained using targets V-4-e, II-4-e, and I-4-e on a standard 10-cd/m2 background. After 60 minutes of dark adaptation, dark-adapted thresholds
were measured at fixation and at several locations along the horizontal meridian
on a Goldmann-Weekers Darkadaptometer (Haag-Streit, Bern, Switzerland). Dark-adapted
static visual fields were determined on a customized Humphrey perimeter. The
apparatus and protocols were adopted from Jacobson et al.17
Visual fields were measured after 60 minutes of dark adaptation using a 500-nm
size V target and then measured again with a 650-nm stimulus to determine
whether thresholds were set by rods or cones. The grid of test locations extended
to 72° eccentricity temporally, 48° nasally, 36° superiorly, and
48° inferiorly.
Electroretinograms were recorded according to the International Society
for Clinical Electrophysiology of Vision standard,18
beginning after 1 hour of dark adaptation, using 10-microsecond xenon flashes
in a Ganzfeld bowl. Pupils were fully dilated using 10% phenylephrine hydrochloride
and 1% tropicamide, and bipolar corneal electrodes (Burian-Allan; Hansen Ophthalmic
Instruments, Iowa City, Iowa) were used. Responses were amplified at 0.1 to
1000 Hz (-3 dB), digitized, and stored. Rod-predominant responses were
recorded first, using 0.5-Hz dim blue stimuli (440-nm peak, 70-nm half width, -1.86
log cd · s/m2). Photopic responses were recorded after light
adaptation for at least 5 minutes with a 43-cd/m2 background light
in the Ganzfeld bowl, and cone responses were elicited with single "white"
flashes (0.5 Hz, 1.0 log cd/m2). Population normal values were
obtained from 50 control subjects. Photopic 32-Hz flicker computer-averaged
responses were recorded after at least 10 minutes of light adaptation to the
43-cd/m2 background, and cycle-by-cycle analysis was used to determine
the amplitude and phase angle of the fundamental component of the flicker
response.19 This phase angle is related, but
not identical, to the usual flicker implicit time, because the higher harmonic
components can modify the time to peak of the full response beyond that of
the fundamental component alone. The range of normal flicker implicit times
depends on the stimulus rate and is different for the 32-Hz flicker compared
with the 30-Hz stimulation. For clinical examinations, the 32-Hz responses
are determined 3 times, and the population normal values are from 40 eyes
of 20 healthy subjects without ocular or known systemic disease.
Photoresponse characteristics of the rod ERG were determined from a-wave
responses to bright flash stimuli. Bright 1-millisecond photostrobe flashes
(model 283; Vivitar, Santa Monica, Calif) were presented in a Ganzfeld bowl,
with a maximal intensity of 2.7 log cd · s/m2, which produced
a maximal retinal intensity of 4.7 log scotopic td (troland) · s, and
were attenuated by neutral density filters with 0.3–log unit steps.
Flashes were spaced at intervals of 2 minutes to avoid adapting the a wave.
Responses were amplified at 10 000 gain from 1 to 1000 Hz and digitized
at 20 kHz. Cone responses were recorded across the same intensity range on
a rod-saturating background of 3.3 log td and were computer subtracted from
the mixed rod-cone response to obtain the rod response.20
The leading edge of the a wave (P3) of the ERG response
to a flash of intensity I was fitted with the Hood
and Birch21 version of the Lamb and Pugh22 phototransduction model:
with a-wave termination chosen just before the upturn of the a wave
or limited to 20 milliseconds after flash onset. Rmax is the maximum amplitude; S, the sensitivity
variable that scales I; t,
time; and td, a brief time delay.20 The effective td
between the flash and a-wave onset was fixed at the beginning of the saturated
a wave elicited by the brightest flash.23 The
response to the brightest flash was fitted first, allowing Rmax and S to be free parameters.
The remaining individual curves for dimmer intensities were fitted, allowing S to vary but with Rmax
and td held constant.
RESULTS
Findings in the 2 affected brothers and their parents are summarized
in Table 1.
THE 29-YEAR-OLD PROPOSITUS (III:1)
This affected brother related a lifelong history of severe vision loss
but completed normal school and obtained a university degree despite progressive
vision loss and blindness by his early 20s. Clinical records from the age
of 5 years indicate 20/100 visual acuities with 3 diopters of hyperopic correction.
Intermittent nystagmus was seen. Both fundi had micropigment clumping in the
posterior pole and a grayish retinal sheen in the middle and far periphery,
with attenuated arterioles. Optic nerve heads were described as unremarkable.
He was diagnosed as having severe cone-rod dystrophy. During grade school,
he read regular books held close under bright fluorescent lights. He played
outdoors on sunny days, but his vision was markedly decreased in dimmer conditions.
At the age of 6, ERG recordings showed essentially no rod or cone responses
and dark-adapted thresholds were elevated by 4.5 log units. His visual acuities
were 20/200 by the age of 12 and 20/800 by the age of 16. Color discrimination
was quite limited at both ages.
When examined at the present age of 29, his visual acuity in both eyes
was reduced to hand movements. Nystagmus was noted. The anterior segments
were normal, and the lenses and media were clear. The retina had a whitish
gliotic reticular RPE appearance across the entire fundus (Figure 2A). The vessels were markedly attenuated. The central macula
had a 1.5–disc diameter area of RPE atrophy. On visual field testing,
he perceived only the V-4-e target in the inferotemporal region between 50°
and 70° for each eye. This measurement is approximate, as nystagmus was
present, although care was taken to monitor the eye position during field
testing. Electroretinographic testing showed no rod or cone responses, except
for 0.3-µV responses to a 32-Hz flicker on computer-averaged recordings.
This is at or barely above noise levels. Further details of ophthalmic examination
results at the age of 29 years are given in Table 1, and Figure 3
summarizes the visual fields between the ages of 12 and 29 years.
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Figure 2. Fundus photographs. A, Right eye
of the 29-year-old propositus. B, Right eye of the 25-year-old affected brother.
C, Macula of the right eye of the 50-year-old father. D, Dark-adapted visual
field abnormalities from the carrier mother (top) and the carrier father (bottom),
obtained with a 500-nm target. Data for left eyes are shown on the left; and
for right eyes, on the right. A comparison of the 500- and 650-nm data indicated
that the detection threshold was mediated by rod photoreceptors in the mother,
but cones mediated some of the peripheral sensitivity in the father. The color
bar indicates deviations from the normal mean. S indicates superiorly; N,
nasally; I, inferiorly; and T, temporally.
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Figure 3. Progression of Goldmann V-4-e
visual field loss in the propositus from the age of 12 years (stippled area)
to the age of 29 years (solid gray area). The black line represents the typical
extent of a normal V-4-e visual field. A, Left eye. B, Right eye.
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THE 25-YEAR-OLD AFFECTED BROTHER (III:2)
This affected brother was given the clinical diagnosis of Leber congenital
amaurosis at the age of 22 months, and ophthalmic examination records from
that time indicate "cellophane maculopathy." His visual function was markedly
diminished; acuities were not specifically tested. He recalls that he could
play basketball in sunlight during grade school. Despite limited vision, he
completed normal school and is pursuing a postgraduate degree. He reports
that he can see only the edge of the sidewalk highlighted against the grass,
and this is seen more easily on overcast days than in direct sunlight.
On ophthalmic examination, the RPE appeared thinned across the entire
fundus (Figure 2B), and both maculae
had a 1–disc diameter central atrophic area. The vessel caliber was
greatly constricted, and the optic cup showed gliotic filling. Sparse fine
bone spicule pigment was present in the periphery, but the predominant feature
was a gliotic white appearance across most of the fundus. Results of the ophthalmic
examination at the age of 25 years are found in Table 1.
THE 50-YEAR-OLD FATHER (II:2)
The father carries the IVS1 + 5ga splice-site mutation on 1 RPE65 allele. He reports no vision complaints. No relatives
are known to have vision complaints. He is in good health but had a myocardial
infarction at the age of 42 years. His medications include amiodarone hydrochloride,
amlodipine besylate, alprazolam, and aspirin, none of which are known to affect
the full-field ERG. Both fundi had normal discs, but the retinal vessels had
slight hypertensive narrowing. Both maculae were abnormal, having many tiny,
hard, drusenoid RPE lesions that extended beyond the macular arcade vessels
into the near peripheral retina (Figure 2C). Such lesions are not typically associated with residual from
a myocardial infarction. Results of the ophthalmic examination are given in Table 1. Functional abnormalities were
found in dark-adapted thresholds tested by 2-color perimetry with the modified
Humphrey perimeter. The threshold sensitivity was normal across the posterior
pole, but elevations of as much as 1.5 to 2.0 log units were present in the
periphery at eccentricities greater than 30°, with 64% of these abnormalities
located outside 45° (Figure 2D).
Cones mediated the abnormal thresholds for 44% of these locations, based on
the difference values of the 500- and 650-nm data. The pattern of findings
was similar for both eyes. Despite this, the rod ERG amplitudes were normal,
as were cone single-flash responses. However, cone function on 32-Hz flicker
testing showed a 5-millisecond timing delay of the fundamental component19 to 32 milliseconds despite normal amplitudes (Table 1). The normal timing of the 32-Hz
flicker fundamental component is 27 milliseconds (SD, 1.04 milliseconds; range,
25.5-30.6 milliseconds) (40 eyes of 20 subjects). This flicker delay was robust
on 3 repeated measurements that were different than those of healthy subjects
(P<.001; 2-tailed unpaired t test). Cone flicker timing delay reportedly can occur when the rod
dark adaptation process is impaired.24 Electroretinographic
changes of this type are not reported to be associated with hypertension.25-26
Rod phototransduction of the father was evaluated in 2 ways. First,
the peak a-wave amplitude to the brightest flash intensity (4.77 log scotopic
td · s)20 was normalized as shown in Figure 4, and the leading edge of the rod
a wave was within the normal range, indicating that rod phototransduction
was not affected. However, the onset of the rising phase of the b wave was
delayed beyond the envelope of the 11 healthy subjects. Second, the rod a
wave was analyzed with the phototransduction model (given in the "Visual Examination"
subsection of the "Subjects and Methods" section), which gave a maximum amplitude
Rmax of 427 µV, which was not different from the normal mean
of 365 µV (SD, 80 µV). The sensitivity, as determined from the
phototransduction model, was within the normal range and was not reduced (log
sensitivity = 0.48; mean ± SD log sensitivity of healthy subjects,
0.53 ± 0.11).
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Figure 4. Normalized rod a-wave responses
at the brightest flash intensity (4.77 log scotopic td · s).
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THE 49-YEAR-OLD MOTHER (II:1)
The mother carries the Y368H missense mutation on 1 RPE65 allele. She has no vision complaints except for a vague statement
of worse vision at night, but this could not be documented objectively. She
is healthy and takes no medications. There is no history of eye disease in
her family. The macula, disc, vessels, and retinal periphery appeared normal,
with the sole exception of a collection of 8 to 10 tiny hard drusen inferonasal
to the disc in the right eye only, with none seen in the left eye. The RPE
appearance was otherwise normal in both eyes across the macula and the peripheral
fundus. Her ophthalmic examination yielded normal results for visual acuity,
light- and dark-adapted visual fields, and ERGs (Table 1).
THE PATERNAL GRANDFATHER (I:4)
Visual testing was not possible in the paternal grandfather because
he is deceased. Optometric records at the age of 72 years indicate a visual
acuity of 20/20 OU, but a retinal and macular examination was not done.
COMMENT
More than 50 disease-causing mutations in the RPE65 gene have been reported,11, 14, 27-28
with estimates indicating that RPE65 mutations are
responsible for 7% to 15% of the cases of early-onset autosomal recessive
severe retinal dystrophy. Although it is generally agreed that most patients
are seen with a relatively homogeneous severe phenotype in early childhood,
few clinical details are given in the literature. Our study of a family carrying
2 different RPE65 disease alleles further documents
the association of RPE65 mutations in compound heterozygous
form with severely compromised vision due to rod-cone involvement at young
ages. In addition, we report the finding of macular drusen and peripheral
rod visual dysfunction in a parent carrying a presumed RPE65 functional null allele in heterozygous form.
The IVS1 + 5ga splice-site mutation carried by the father of the
2 affected brothers in our study is the most common of the known RPE65 mutations, occurring on at least 2 genetic backgrounds.14 Although the father has good corrected visual acuity
and normal visual fields, our studies show subtle changes in his rod absolute
dark-adapted threshold sensitivities and in his cone ERG flicker responses.
In addition, both his maculae were covered with hundreds of tiny hard drusen
extending into the rod-rich retina beyond the macular arcades. His history
of severe heart disease may have contributed to these lesions. Hypertensive
vascular narrowing is associated with cardiac disease; however, a myriad of
tiny hard drusen typically are not associated with cardiac disease. In addition,
he is too young to ascribe these drusen to aging changes. Such RPE level abnormalities
in an individual carrying one copy of a presumed RPE65
null allele suggest that the resulting decrease in expression may produce
mild pathogenic effects. Interruption of the visual cycle by mutations in
the RDH5 (a retinol dehydrogenase gene) that encodes
for the visual cycle enzyme 11-cis retinol dehydrogenase29 results in fundus albipunctatus,6, 30
in which the principal findings are a myriad of tiny yellowish drusenlike
RPE deposits across the fundus and impaired dark adaptation.
The Y368H mutation carried by the mother of the 2 affected brothers
was previously reported as pathogenic in another patient in whom the mutation
was present in compound heterozygous form.31
The mother had only a few tiny drusenlike lesions in 1 eye, suggesting the
possibility that her missense mutation may not be fully inactivating or may
affect a different aspect of RPE65 function. Consistent
with this notion are reports10, 12
of 2 patients with relatively mild forms of retinal degeneration associated
with compound heterozygous RPE65 missense mutations.
This does not seem to be the case for RPE65 missense
mutations in general, however, as a large-scale study14
failed to find differences in the clinical descriptions and best visual acuities
of several age-matched patients carrying 2 presumed null mutations, 2 missense
mutations, or a combination of both.
Both affected brothers in our study had profound night blindness, impaired
cone function, and unrecordable ERG responses at young ages. Their residual
visual function, however, was sufficient to succeed in regular school. This
clinical picture is similar to 4 other patients diagnosed as having RPE65 mutations in early childhood,1, 31
in whom rod ERGs were undetectable and cone ERGs were severely diminished
even at the earliest ages tested (approximately 1 year); cone ERGs were unrecordable
by the age of 5 to 7 years. Both brothers experienced a progressive disease
course that culminated in complete loss of central vision and most peripheral
vision before the ages of 25 and 29 years. Their fundus appearance showed
severe peripheral degeneration and prominent atrophic macular scars indicative
of extensive macular degeneration in the middle- to late-stage disease process.
These findings, and the macular involvement present in their carrier father,
suggest that, over time, loss of RPE65 function resulting
in decreased 11-cis retinal synthesis, accumulation
of vitamin A metabolic intermediates, or both has a major effect in the central
retina, possibly due to unique metabolic requirements and physiological features.
Previous genetic studies of the adenosine triphosphate–binding
cassette transporter (ABCR) that is involved in transport
of all-trans retinal in the photoreceptors32 demonstrated a correlation between disease severity
and mutation type, with different classes and combinations of ABCR mutations shown to result in autosomal recessive Stargardt disease,
fundus flavimaculatus, cone-rod dystrophy, and autosomal recessive retinitis
pigmentosa.33 In addition, although it is controversial,
certain ABCR missense mutations are proposed to increase
susceptibility to age-related macular degeneration.34-36
The extent of phenotypic variability associated with mutations in RPE65 is certainly less than that associated with mutations in ABCR. Our findings, however, add to the evidence that the RPE65 mutation type may factor into disease phenotype,
and further suggest that RPE65 mutations may be linked
to macular abnormalities in affected and carrier individuals. It remains to
be determined whether RPE65 heterozygous individuals,
in general, are at increased risk for vision loss in later life, especially
in association with aging. Sorting out these possibilities, and validating
the connections of defects in vitamin A metabolism to late-onset disease,
will require mutation studies in many more patient families. Nevertheless,
the hope of progress toward therapeutic intervention in RPE diseases affecting
vitamin A metabolism37 provides impetus for
additional observational studies.
AUTHOR INFORMATION
Accepted for publication August 22, 2001.
This study was supported by grants R01-EY06094, R01-EY12298, and P30-EY07003
from the National Eye Institute, National Institutes of Health, Bethesda,
Md; the Foundation Fighting Blindness, Hunt Valley, Md; Senior Scientific
Investigator (Dr Sieving) and Lew Wasserman (Dr Thompson) Awards from Research
to Prevent Blindness Inc, New York, NY; an Alcon Research Institute Award,
Fort Worth, Tex (Dr Sieving); and a research gift from Thyssen Steel, NA,
Detroit, Mich (Dr Sieving).
Corresponding author and reprints: Paul A. Sieving, MD, PhD, National
Eye Institute, 31 Center Dr, MSC, Bethesda, MD 20892-2110.
From the Departments of Ophthalmology and Visual Sciences (Drs Felius,
Thompson, Khan, and Sieving, Mss Bingham and Kemp, and Mr Jamison) and Biological
Chemistry (Dr Thompson), University of Michigan Medical School, Ann Arbor.
Dr Sieving is now with the National Eye Institute, Bethesda, Md.
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