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Gyrate Atrophy of the Choroid and Retina
Further Experience With Long-term Reduction of Ornithine Levels in Children
Muriel I. Kaiser-Kupfer, MD;
Rafael C. Caruso, MD;
David Valle, MD
Arch Ophthalmol. 2002;120:146-153.
ABSTRACT
Objective To determine whether the long-term reduction of plasma ornithine levels
by way of an arginine-restricted diet in patients with gyrate atrophy will
slow the progression of this chorioretinal degeneration.
Design Natural history study of 2 pairs of siblings with gyrate atrophy treated
with an arginine-restricted diet.
Main Outcome Measures Fundus photography and electrophysical and psychophysical retinal function
tests.
Results After 16 to 17 years of receiving an arginine-restricted diet, the younger
sibling in each pair, who was prescribed the diet at an earlier age than the
older sibling, demonstrated a slower progression of lesions compared with
the older sibling.
Conclusions If started at an early age, long-term substantial reduction of plasma
ornithine levels may appreciably slow the progression of the chorioretinal
lesions and, to a lesser extent, the progressive loss of retinal function
in patients with gyrate atrophy.
INTRODUCTION
GYRATE ATROPHY (GA) of the choroid and retina is a rare, autosomal recessive,
chorioretinal dystrophy.1 The initial symptoms
are myopia and reduction of peripheral vision and in some patients, reduction
of night vision in the first decade of life. Correspondingly, sharply demarcated
circular patches of chorioretinal atrophy appear in the peripheral retina.
With increasing age, these lesions increase in size and number, eventually
coalescing and involving the entire posterior pole. Loss of visual function
accompanies the chorioretinal degeneration, with decreased visual acuity or
severe visual field constriction occurring in the fourth to seventh decade.
Almost all patients demonstrate impaired peripheral vision by age 10 years.
The primary defect causing GA is a deficiency of the enzyme ornithine- -aminotransferase
(OAT),2 which results in markedly elevated
levels (10- to 15-fold) of ornithine in plasma and other body fluids.
Multiple efforts to treat GA have resulted in conflicting reports, in
part due to the difficulties in evaluating therapies for a rare, slowly progressing
genetic disorder.3-6
The patients often vary in their genotype at the disease gene locus, their
genetic background, and their compliance with and age at the time of institution
of treatment. These variables, together with the small number of patients,
make objective evaluation of therapeutic trials difficult.
In 1991, we described the effects of long-term reduction of ornithine
levels on the progression of the chorioretinal degeneration in GA.7 To minimize the variables mentioned above, we concentrated
on sibling pairs. Siblings with autosomal recessive disorders like GA have
identical genotypes at the disease gene locus and, on average, half of all
of their genes are identical by descent. Thus, to the extent that genetic
factors influence phenotypic variation, affected siblings can be expected
to be more similar than unrelated patients, ie, intrafamilial variability
should be less than interfamilial variability. Our comparison of phenotypic
severity in 6 GA sibling pairs confirmed this expectation.7
In the current study, we focused on the 2 youngest sibling pairs. The retina
of the younger sibling in each pair (<10 years old) was largely normal
appearing and functioning at the time the treatment was instituted.
We present the long-term follow-up of these subjects. At the time of
this report, the sibling pairs had been receiving the diet for 16 to 17 years.
Our results further support the conclusion that long-term reduction of ornithine
levels slows the progression of chorioretinal lesions and to a lesser extent,
loss of retinal function.
PATIENTS AND METHODS
PATIENTS
Two sibling pairs with GA were studied. The younger sibling in each
pair was younger than 10 years at entry into the study. The 2 sisters in pedigree
GA 008 are Americans of German/Italian ancestry. The brother and sister in
pedigree GA 021 are Lebanese.
THE OPHTHALMIC EXAMINATION
The 4 patients underwent at least yearly complete ophthalmic examinations.
Best-corrected visual acuity was determined using the standard Early Treatment
Diabetic Retinopathy Study chart.8 Slitlamp
biomicroscopy, funduscopic examination, and fundus photography were performed
at each visit. Visual fields were tested with manual kinetic perimetry (Goldmann
perimeter; Haag Streit, Bern, Switzerland) and automated static perimetry
(Humphrey Field Analyzer, program 30-2; Zeiss Instruments, Jena, Germany).
A global visual field score was obtained by summing the sensitivity values
of the 76 points tested by this program. Dark adaptation was measured with
a Goldmann-Weekers adaptometer (Haag Streit, Bern), modified to use the von
Békésy threshold tracking method. Patients underwent light adaptation
for 5 minutes with a Ganzfeld background with a luminance of 2700 cd/m2. The luminance threshold was then measured for a minimum of 30 minutes
during dark adaptation, using a central 11°-diameter circular stimulus
with a 0.6-Hz flicker rate. Final thresholds below a luminance of –4.24
log cd/m2 were considered normal; this value was the upper limit
of a tolerance interval estimated using a control sample of 20 subjects with
normal dark adaptation. This tolerance interval was calculated to include
95% of the population with 95% confidence.
Color vision was evaluated using the Hardy-Rand-Rittler plates (American
Optical Co, Buffalo, NY),9 the Farnsworth panel
D-15 (Luneau, Ophthalmologie, Paris, France),10
and the Lanthony desaturated panel D-15 (Luneau, Ophthalmologie, Paris).11 When age permitted, the Farnsworth Munsell 100 Hue
test was used and the scores were compared with the scores for normal subjects
reported by Verriest et al.12 Electroretinography
(ERG) was performed as described previously13
following the recommendation of the International Society for Clinical Electrophysiology
of Vision.14 In brief, ERGs were elicited after
30 minutes of dark adaptation by dim and bright white stimuli (rod-mediated
ERG and maximal retinal responses). After 10 minutes of light adaptation,
ERGs elicited by 0.3-Hz and 30-Hz white stimuli were recorded (cone and flicker
response). The electro-oculogram was recorded using the standard technique
of the International Society for Clinical Electrophysiology of Vision.15 All ERG and electro-oculographic recordings were
obtained using the same recording system (Universal Testing and Analysis System,
model E-2000; LKC Technologies, Gaithersburg, Md) and the same type of bipolar
electrode (Burian-Allen lens, Hansen Instruments, Iowa City, Iowa), although
different lenses were used. Fluorescein angiography was performed when possible
owing to age and cooperation.
To quantify the rate of change of the main outcome variables (static
perimetry and ERG), the half-life of the outcome variable, ie, the number
of years required for the field score or ERG amplitude to decline to 50% of
its value, was used.13 Half-lives were calculated
by fitting the data points with the model: Vt = V0 x 2-(k/t), where t represents time (in years); Vt, the magnitude
of the outcome variable at t; and k, half-life (in years). This method also
provides an unbiased approach to deal with the test-retest variability of
our results.
The study was approved by the National Eye Institute (Bethesda, Md)
clinical institute review board and the Johns Hopkins Joint Committee on Clinical
Investigation (Baltimore, Md). The patients were admitted to the study after
obtaining parental consent or patient consent if aged 18 years or older.
RESULTS
Our initial evaluations of each of the affected children were reported
previously7 and are summarized and updated
as follows.
PATIENT GA008-1
This female patient, born in April 1977, was found to have GA at age
4 years 6 months, and was first evaluated in August 1983 at age 6 years, 4
months (Table 1). At that time,
the diagnosis was confirmed and she was prescribed an arginine-restricted
diet and followed at yearly intervals. Photographic montages of both retinas
were constructed at each visit. The right and left retinas are shown for August
1983 (age 6 years 4 months) and most recently in August 2000 (age 23 years
4 months) (Figure 1) after adhering
to the diet for 17 years. At the time of diagnosis, there were scattered chorioretinal
atrophic lesions typical for GA. During the following 17 years, there were
alterations in the pigmentation of some lesions and in general, an increase
in size and number of atrophic lesions. The right and left retinas in August
2000 reflect the progression of the chorioretinal atrophic lesions. These
fundus changes were paralleled by a gradual decline in sensitivity in the
central 30° visual field and in the amplitude of the ERG maximal response
(Figure 2). The half-lives of these
variables were 24.6 and 20.1 years, respectively; they were both abnormal
in our initial evaluation. In contrast, the final threshold of dark adaptation
as assessed with a central 11° target remained in the normal range. The
Lens Opacities Classification System II16 at
age 23 years revealed that there was only a trace posterior subcapsular opacity
bilaterally, although she had been receiving an arginine-restricted diet for
the entire 17 years. Her compliance had been poor and her plasma ornithine
concentration had been consistently elevated (mean ± SD, 4.9 ±
1.7 mg/dL [370 ± 129 µmol/L] [normal, 120 ± 65 µmol/L]).
Measurements were obtained at intervals of about 6 months.
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Pairs of Siblings With Gyrate Atrophy
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Figure 1. Photographic montages of the eyes
of patient GA 008-1. Right eye (A) and left eye (B) at age 6 years 4 months,
and right eye (C) and left eye (D) at age 23 years 4 months. Comparison of
top and bottom shows progression in both size and number of atrophic lesions
after receiving an arginine-restricted diet for 17 years.
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Figure 2. Patient 008-1. Graph of central
30° field sensitivity measured with static perimetry (decibels, open circles)
and electroretinogram (ERG) maximal response amplitude (microvolts, solid
circles) as a function of time. The line passing through the data points is
an exponential curve.
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PATIENT GA008-2
The sister of patient GA008-1, born in October 1980, was first examined
at age 2 years 10 months (Table 1).
With confirmation of the diagnosis of GA, she was prescribed an arginine-restricted
diet in December 1982 at age 2 years 10 months. Right and left retinas were
first successfully photographed in August 1986 (age 5 years 10 months) (Figure 3) and yearly thereafter. The last
montage was obtained in August 2000 at age 19 years 10 months (Figure 3). In 1986, there was diffuse mottling of the retinal pigment
epithelium (RPE) in the mid and far periphery but with no evidence of atrophic
lesions. This was in sharp contrast to her older sister who, at age 6 years
10 months, already had extensive chorioretinal atrophy typical of GA. By August
2000, a fine dusting of pigment was noted peripherally in both eyes. In addition,
a discrete atrophic lesion was noted at the 2-o'clock position in the right
eye and at the 3-o'clock position in the left eye. The final threshold of
dark adaptation, as assessed with a central 11° target, remained normal.
However, a moderate gradual decline in sensitivity in the central 30°
visual field was observed, associated with an even milder reduction in amplitude
of the ERG maximal response (Figure 4).
The half-lives of these variables were 35.3 and 150.9 years, respectively.
At age 19 years, the Lens Opacities Classification System II revealed that
there was only a trace posterior subcapsular opacity bilaterally. The mean
± SD plasma ornithine level was 3.4 ± 1.0 mg/dL (256 ±
76 µmol/L), with measurements obtained at roughly 6-month intervals.
Her values have been consistently lower than those of her older sibling.
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Figure 3. Photographic montages of the eyes
of patient GA 008-2. Right eye (A) and left eye (B) at age 5 years 10 months,
and right eye (C) and left eye (D) at age 19 years 10 months. There is a solitary
atrophy lesion in each eye (arrow) at age 19 years 10 months, after the patient
had been receiving the diet for 17 years (beginning at age 2 years 10 months).
The small depigmented area (left) at the 3-o'clock position may be an additional
early atrophic lesion. The apparent lesion at the 11-o'clock position does
not indicate atrophy but is a discrete area of depigmentation. This minimal
involvement should be compared with the multiple lesions in her sibling, patient
GA-008-1, at age 6 years 4 months (Figure 1, A and B).
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Figure 4. Patient 008-2. Graph of central
30° field sensitivity measured with static perimetry (decibels, open circles)
and electroretinogram (ERG) maximal response amplitude (microvolts, solid
circles) as a function of time. The line passing through the data points is
an exponential curve.
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PATIENT GA021-1
This female patient, born in October 1975, was found to have GA at age
8 years 9 months, and was first evaluated at age 8 years 11 months, at which
time the diagnosis of GA was confirmed. The arginine-restricted diet was begun
at age 9 years 4 months, by which time the ERG maximal response was already
considerably reduced. Photographic montages of the right and left retinas
are shown for October 1984 (age 9 years) and September 2000 (age 24 years
11 months) (Figure 5). At the commencement
of the diet, the retinas showed chorioretinal atrophy typical for GA. During
the ensuing 16 years of follow-up, there was mild progression and coalescence
of a few lesions while others became more pigmented with apparent reduction
in size. However, both static and kinetic perimetry demonstrated progressive
loss of the visual field (Figure 6);
the half-life of her visual field score was 14.9 years. Dark adaptation showed
a gradual elevation of final threshold. The amplitude of the ERG maximal response
declined from 1990 to 1992 and has since remained stable (Figure 6); the half-life of her ERG amplitude was 20.0 years. She
first showed early posterior subcapsular opacities bilaterally at age 13 years.
By age 25 years, these opacities had progressed to P2 on the Lens
Opacities Classification System II. These changes have occurred despite excellent
control of plasma ornithine levels (mean ± SD, 1.9 ± 0.8 mg/dL
[144 ± 62 µmol/L]).
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Figure 5. Photographic montages of the eyes
of patient GA021-1. Right eye (A) and left eye (B) at age 9 years 4 months,
at the time the arginine-restricted diet was started, and right eye (C) and
left eye (D) at age 24 years 11 months. Note the multiple scattered atrophic
and pigmented chorioretinal lesions (A and B). There was minimal progression
and coalescence of some lesions that occurred during the ensuing 16 years.
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Figure 6. Patient 021-1. Graph of central
30° field sensitivity measured with static perimetry (decibels, open circles)
and electroretinogram (ERG) maximal response amplitude (microvolts, solid
circles) as a function of time. The line passing through the data points is
an exponential curve.
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PATIENT GA021-2
The brother of patient GA021-1, born in April 1982, was diagnosed as
having GA in July 1984 at the age of 2 years 3 months. He was first seen at
age 2 years 6 months. Following confirmation of the diagnosis of GA, he began
an arginine-restricted diet at age 2 years 8 months. Photographic montages
of the right and left retinas were prepared in October 1986 at age 4 years
9 months (Figure 7). There was diffuse
mottling of the RPE in the middle and far periphery with multiple, small,
discrete depigmented spots but no areas of atrophy. The ERG amplitude was
decreased. By September 2000, at age 18 years 6 months (Figure 7), the appearance of the retinas had changed, with mottling
of the pigment epithelium and a moderate increase in selected areas of pigmentation.
During the 16 years he received the diet, he had not developed atrophic lesions
but had shown further deposition of pigment, mainly lacy in appearance but
with 2 clumps (Figure 7). During
the follow-up period, the final threshold of dark adaptation remained normal
and the decline in sensitivity of the central 30° visual field was minimal.
The half-life of his visual field score was 120.6 years (Figure 8). However, a gradual reduction in amplitude of the ERG
maximal response had occurred (Figure 8);
the half-life of his ERG amplitude was 9.63 years, shorter than that seen
in his sister. By age 19 years, there was no evidence of any lens opacity.
The mean ± SD plasma ornithine level was 1.6 ± 0.8 (123 ±
64 µmol/L).
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Figure 7. Photographic montages of the eyes
of patient GA021-2. Right eye (A) and left eye (B) at age 4 years 9 months,
and right eye (C) and left eye (D) at age 18 years 6 months. Two pigment clumps
are noted (arrows). There is diffuse mottling and the finer pigment clumping
is more lacy, as seen in the periphery. There is a slight increase in pigmentation;
no atrophic chorioretinal lesions are seen. At a similar age, his older sibling
had multiple scattered atrophic and pigmented lesions (Figure 5, top). Other
linear and circular dark areas at the edge of the figure parts are artifacts
of constructing the montage. This patient began receiving an arginine-restricted
diet at age 3 years.
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Figure 8. Patient 021-2. Graph of central
30° field sensitivity measured with static perimetry (decibels, open circles)
and electroretinogram (ERG) maximal response amplitude (microvolts, solid
circles) as a function of time. The line passing through the data points is
an exponential curve.
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COMMENT
Siblings with GA have the same OAT genotype
and tend to follow a similar course of chorioretinal degeneration.7 In this study, we first asked how the retinas of 2
siblings would differ at the same age if the younger sibling had begun the
diet at an earlier age than the older sibling. This would provide early data
on the effects of a reduction in plasma ornithine levels on retinal degeneration.
The second question asked how retinal degeneration would progress in a younger
sibling who had been receiving the diet for 16 to 17 years and who had not
yet shown any retinal lesions compared with the older sibling, who already
had typical chorioretinal degeneration. This would tell us whether the diet
might be more effective in early cases without retinal lesions compared with
later cases with well-established retinal lesions. The third question we asked
was whether the functional status of the retina, as measured by routine psychophysical
and electrophysiological techniques, could be preserved over time in both
siblings, especially in the younger, with absent or minimal retinal changes.
At the time of our previous report, both sibling pairs had been receiving
the diet for 7 to 8 years7 and each younger
sibling had reached the age of the older sibling at the time of the older
sibling's diagnosis. For both sibling pairs, the younger had not yet developed
any atrophic lesions and had only diffuse mottling of the RPE with some small,
discrete depigmented spots in the periphery. The appearance of the earliest
lesions in the RPE is consistent with the observations of Kuwabara et al17 in rats and monkeys receiving intravitreal injections
of L-ornithine, and with the more recent results of Wang et al,18-19
who produced an OAT-deficient mouse by gene targeting and found that the RPE
cells were the site of the earliest pathologic changes.
After 16 to 17 years of receiving the diet, the appearance of the retinas
in the younger siblings was quite remarkable. Patient GA008-2, who had been
receiving the diet for 17 years with excellent reduction of ornithine levels,
had only a fine dusting of pigment noted peripherally in both eyes, somewhat
reminiscent of the early changes in retinitis pigmentosa. There was only 1
discrete atrophic lesion in each eye. The phenotype of patient GA021-2, who
had been receiving the diet for 16 years with excellent reduction in ornithine
levels, also showed diffuse mottling of the RPE in the mid and far periphery.
Deposition of pigment was found, usually lacy in appearance but occasionally
in clumps and without atrophic lesions. Again, this retinal appearance suggests
early retinitis pigmentosa. Further consideration of our first question suggests
that a different phenotype of retinal changes, more akin to retinitis pigmentosa
than GA, resulted from prolonged and successful reduction of plasma ornithine
levels, with the RPE cells showing the major pathologic changes. This was
probably in process before the diet was instituted.
With respect to the second question, it was apparent that the younger
of the 2 sibling pairs, in whom the retinas appeared considerably less affected
at the start of the diet, appeared to progress more slowly and toward a different
fundus phenotype. The older of the sibling pairs, both of whom had well-established
typical-appearing retinal lesions of GA, continued to experience progression
and coalescence of a few chorioretinal lesions while receiving the diet. Whether
the course of GA reflected the variable nature of the disease or a decrease
in plasma ornithine levels (GA021-1 having a larger decrease than GA008-1
but both having the fundus lesions progressing about the same) could not be
determined at the time. Thus, the younger siblings appeared to have had a
notable slowing of the fundus change. This result is consistent with those
found in the murine study of OAT deficiency produced by gene-targeting in
which an arginine-restricted diet with reduction of plasma ornithine levels
completely prevented retinal degeneration.20
Treatment can be most effective when begun as early as possible when the retina
is free or relatively free of lesions.
The third question is the most important. Even in a retina with no atrophic
lesions and only diffuse mottling of the RPE (patient GA021-2), ERG amplitude
at the time of initial diagnosis, while the patient was receiving general
anesthesia, was reduced. It is unlikely that ERG amplitude was reduced at
birth (as is thought to be the case in retinitis pigmentosa) given that fetal
umbilical cord blood ornithine concentration had been measured in 1 patient
and found to be normal. Furthermore, Wang et al19
reported that ERG amplitudes in mice with GA were found to be normal at age
2 months and did not show a clear decrease until the animals were 6 months
old. It is clear that during the 16- to 17-year follow-up in our study, a
small but slowly progressing measurable decrease in functional status occurred
in the younger member of each sibling pair. These changes were seen in either
ERG amplitude or visual field sensitivity, while psychophysical measurements
of central visual function, such as visual acuity, color vision, and dark
adaptation remained normal. In the 2 older siblings, the rates of change of
ERG amplitude and central 30° visual field sensitivity were similar. In
patient GA008-2, a mild decline in visual field sensitivity was seen despite
the stable ERG maximal response amplitude. However, flicker response amplitude
(data not shown) evidenced a decline comparable with that of the central visual
field. We speculate that the stability of the maximal response amplitude may
be due to preservation of rod-mediated function since the rod response (data
not shown) did not show a declining trend similar to that seen for the flicker
response. In contrast, in patient GA 021-2, the reduction in maximal response
amplitude was more conspicuous than the minimal change in visual field sensitivity
in the central 30° visual field. This was probably because static perimetry
only reflects the function of the posterior pole of the retina (central 30°)
while the ERG also reflects the function of the peripheral retina. The time
course of the ERG amplitude of patient GA021-2 was the only instance in which
the rate of change was greater in the younger than in the older sibling. This
decline in ERG amplitude suggests that, despite the absence of typical chorioretinal
atrophic lesions, a moderate reduction in RPE/photoreceptor function had occurred,
which is possibly reflected by the changes in peripheral fundus pigmentation
seen in this patient. Since the OAT-deficient mice fed an arginine-restricted
diet from age 6 weeks had a normal ERG over a 12-month period,20
it is possible that the retinal function could have been preserved if the
arginine-restricted diet was instituted at an earlier age and had been more
effective in maintaining ornithine levels in the normal range.
Three of the 4 patients included in this study (GA 008-1, GA 008-2,
and GA 021-2) showed final dark adaptation thresholds in the normal range.
This may be because dark adaptation was measured with a large test target
in a single test locus centered on the fovea. Therefore, this finding does
not rule out a patchy distribution of functional loss that could have been
detected using a smaller target in multiple test loci. It does, however, suggest
that these 3 patients have rod-mediated function, at least in some areas of
their central retinas, which allows them to detect very dim stimuli. In accord,
patients did not report difficulties seeing at night or in dim illumination.
In summary, commencing an arginine-deficient diet to reduce plasma ornithine
levels at an early age before any chorioretinal changes have occurred would
seem to slow the development of retinal lesions and to result in a different
phenotype similar to early retinitis pigmentosa. However, there is still a
progressive, relatively small loss in some aspects of retinal function despite
excellent dietary compliance as seen in patient GA 021-2. Continued follow-up
of these patients may provide further insights into the development of new
and improved methods of treatment. This suggests that other factors, such
as genetic heterogeneity, local requirements for OAT activity in retinal cells,
or other modifying genes may also play a role in the pathophysiology of GA.
AUTHOR INFORMATION
Accepted for publication October 17, 2001.
This work was supported in part by grant RR-0052 from the National Institutes
of Health, Bethesda (Pediatric Clinical Research Unit, The Johns Hopkins University
Hospital, Baltimore), and a grant from the National Eye Institute, National
Institutes of Health (Dr Valle). Dr Valle is an investigator with the Howard
Hughes Medical Institute, The Johns Hopkins University, School of Medicine.
We thank the nurses and nutritional staff of The Johns Hopkins Hospital
Pediatric Clinical Research Unit, especially Celide Barnes Koerner, MS, research
nutritionist, and Ernest Kuehl, Patrick Ciatto, and Marilois Palmer, for photography
and preparation of photographic montages. We are grateful for the hard work
and dedication of our patients and their families.
Corresponding author and reprints: Muriel I. Kaiser-Kupfer, MD, NEI-NIH,
10 Center Dr MSC 1860, Bldg 10, Room 10N226, Bethesda, MD 20892-1860 (e-mail: kaiserm{at}nei.nih.gov).
From the National Eye Institute, National Institutes of Health, Bethesda,
Md (Drs Kaiser-Kupfer and Caruso); and the McKusick-Nathans Institute of Genetic
Medicine and Howard Hughes Medical Institutes, Johns Hopkins University School
of Medicine, Baltimore, Md (Dr Valle).
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