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Phenotypic Subtypes of Stargardt Macular Dystrophy–Fundus Flavimaculatus
Noemi Lois, MD, PhD;
Graham E. Holder, PhD;
Catey Bunce, MSc;
Fredrick W. Fitzke, PhD;
Alan C. Bird, MD
Arch Ophthalmol. 2001;119:359-369.
ABSTRACT
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Objective To determine if phenotypic subtypes exist in Stargardt macular dystrophy–fundus
flavimaculatus (SMD-FFM).
Methods A cross-sectional study of 63 patients with autosomal recessive SMD-FFM
was undertaken. The age of onset, duration of symptoms, visual acuity, and
clinical features on fundus examination, color fundus photographs, and fundus
autofluorescence images were recorded. Electrophysiological tests, including
pattern, focal, and full-field electroretinogram (ERG), electro-oculogram,
and color-contrast sensitivity measurement, were also performed.
Results Based on electrophysiological attributes (ERG), patients with SMD-FFM
could be classified into 3 groups. In group 1, there was severe pattern ERG
abnormality with normal scotopic and full-field ERGs. In group 2, there was
additional loss of photopic function, and in group 3, there was loss of both
photopic and scotopic function. Differences in scotopic or photopic function
among groups were not explained on the basis of differences in age of onset
or duration of disease.
Conclusions Patients with SMD-FFM can be classified into 3 groups based on the absence
or presence of generalized loss of either photopic or photopic and scotopic
function. It appears that these 3 groups may represent distinct phenotypic
subtypes in SMD-FFM.
INTRODUCTION
SINCE THE initial descriptions by Stargardt1
and Franceschetti,2 there has been controversy
in the literature as to whether Stargardt macular dystrophy (SMD) and fundus
flavimaculatus (FFM) represent different clinical entities.3-13
There is currently no agreement on a clinical classification of this macular
dystrophy3-4,7, 10;
some authors have favored the concept of a single disorder,4-8,10, 12
and others have tried to separate them based on clinical findings.9, 11, 13
Previously, fundus features have been used in an attempt to subclassify
SMD-FFM and to seek phenotype-genotype correlations,3, 7, 9-11,13-15
although many have acknowledged that the criteria used were imperfect. It
is well recognized that the fundus appearance, such as the presence or absence
of macular atrophy and the distribution of flecks, changes over time in these
patients.3, 6-8,10, 13, 16
In addition, it is often difficult to determine objectively the extent and
distribution of fundus lesions without fluorescein angiography, fundus photography,
or fundus autofluorescence images. Finally, the fundus appearance does not
always correlate well with the retinal function.6-7,10
In a recent study,17 we did not find
consistent concordance between siblings with respect to age of onset or fundus
appearance. However, there appeared to be good concordance with respect to
electrophysiological attributes. In some families, there was loss of macular
function alone, whereas in others there was additional loss of photopic or
photopic and scotopic function. The isolated abnormality of full-field responses
driven by cones is now plausible given the recent identification of ABCR in cones.18
On this basis, the purpose of the present study was to test the hypothesis
that the different phenotypes, based on electrophysiological attributes, represent
different stages of progression of the same disorder. This would be supported
by finding a strong association between the degree of functional loss and
the duration of symptoms. If this could not be demonstrated, it would be likely
that the different electrophysiological phenotypes represent distinct subtypes
of SMD-FFM. The study also provided the opportunity to examine other attributes
of the disease in this large group of patients.
SUBJECTS AND METHODS
Patients with SMD-FFM examined between July 1997 and October 1998 were
asked to join this study. The diagnosis of SMD-FFM was based on the presence
of white-yellow flecks at the level of the retinal pigment epithelium involving
the posterior pole or extending to the midperipheral retina, with or without
overt atrophic macular lesions. In all cases, the diagnosis was verified by
fundus autofluorescence imaging.19 A total
of 103 patients with recessive SMD-FFM were examined during the period of
the study. Only patients who underwent electrodiagnostic tests at our institution
were included. In no family was there evidence of autosomal dominant inheritance.
Patient demographics (age, race, and sex), age of onset, duration of
the disease, best-corrected visual acuity, and fundus appearance on slitlamp
biomicroscopy (distribution of flecks and presence or absence of atrophic
macular lesion) were recorded. Color fundus photographs, fundus autofluorescence
images, and International Society for Clinical Electrophysiology of Vision
(ISCEV) standard electrophysiological studies were also undertaken.
The age of onset was defined as the age at which visual loss was first
noted. The duration of the disease was defined as the difference between age
at the time of the examination and age of onset of symptoms.
Best-corrected visual acuity was measured with Snellen visual acuity
charts. Images of fundus autofluorescence were obtained with a confocal scanning
laser ophthalmoscope (cSLO; Zeiss, Jena, Germany) using published techniques.20-21 The findings of fundus autofluorescence,
fundus examination, and color fundus photography were compared.
The term active fleck was used to define flecks
that on biomicroscopy appeared to be composed of white-yellow material at
the level of the retinal pigment epithelium. Resorbed flecks were defined as small areas of depigmentation at the level of the
retinal pigment epithelium. Flecks were designated to be "in the posterior
pole" when they were present only within the vascular arcades, with or without
few flecks nasal to the optic disc, and "in the midperipheral retina" when
they extended beyond that limit.
Electrophysiological investigations were performed according to the
protocols recommended by the ISCEV.22-23
Full-field electroretinogram (ERG), including rod-specific response, bright
white flash mixed response, 30-Hz flicker response, and the photopic single-flash
ERG, and electro-oculogram (EOG) were undertaken. In addition, color-contrast
sensitivity, pattern ERG (PERG), and focal ERG (FERG) were also performed.24 Patients were classified based on amplitudes of scotopic
rod B wave, photopic B wave, and 30-Hz flicker. Values obtained from the right
eye were arbitrarily chosen for classification. Amplitudes of scotopic B wave,
maximal response A and B waves, photopic B wave, and 30-Hz flicker were considered
to be abnormal when their values were smaller than the mean -2 SDs of
an age-matched control group. This assumes a normal distribution, as has been
shown previously in a large series of healthy individuals without retinal
disease.25 Our control group was composed of
35 individuals, 13 women and 22 men, between the ages of 23 and 70 years.
For comparison purposes, the mean and SD of each parameter studied were calculated
for the subgroup of healthy individuals younger than 50 years (range, 23-50
years) and for the subgroup of normal individuals older than 50 years (range,
51-70 years). Electrophysiological data in these subgroups of normal individuals
are summarized in Table 1.
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Table 1. Electrophysiological Data in a Group of 35 Normal Volunteers*
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The Spearman rank correlation test was used to assess the relations
within the groups between (1) age of onset and the amplitudes of scotopic
rod B wave, scotopic maximal A and B waves, and photopic B wave and (2) duration
of the disease and the amplitudes of scotopic rod B wave, scotopic maximal
A and B waves, and photopic B wave. The rank sum test was used to evaluate
differences in age of onset and duration of disease among groups. Univariate
and multiple regression analyses were used to study the influence of age of
onset and duration of disease in the classification. Two patients in whom
ERG was performed using a limited pediatric protocol and 1 patient in whom
periorbital or facial electrodes was used were not included in the analysis.
This study was approved by the ethics committee of Moorfields Eye Hospital,
London, England. Informed consent was obtained from all patients.
RESULTS
Sixty-three patients with SMD-FFM were included in the study. There
were 34 female patients (54%) and 29 male patients (46%). The median age of
onset was 21 years (range, 5-50 years), and the median duration of the disease
was 7 years (range, 0-30 years). At presentation, the median age of the patients
was 30 years (range, 8-65 years). Sixty patients were white Europeans (95%),
2 patients were black (3%), and 1 patient was Indian (2%).
Based on electrophysiological abnormalities, patients were classified
into 3 groups. Patients in SMD-FFM group 1 had normal full-field amplitudes.
Patients in SMD-FFM group 2 had normal scotopic rod ERG but reduced 30-Hz
and photopic B wave amplitudes. Lastly, patients in SMD-FFM group 3 had ERG
abnormalities involving both rod- and cone-driven responses.
Demographics, age of onset, duration of the disease, and findings on
clinical examination, fundus autofluorescence, and electrophysiological studies
are presented separately for each group.
GROUP 1
There were 43 patients (68%) in SMD-FFM group 1, 20 were male (46%)
and 23 female (53%) (Table 2).
The median age of onset was 23 years (range, 5-50 years), and the median duration
of the disease was 7 years (range, 0-30 years) (Figure 1). At the time of examination, the median age of the patients
was 30 years (range, 8-65 years). Five patients had an age of onset at 10
years or earlier.
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Table 2. Demographics, Age at Onset, and Duration of the Disease in
Stargardt Macular Dystrophy-Fundus Flavimaculatus
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Figure 1. Age at onset (A) and duration
of the disease (B) (median and quartiles) in years for Stargardt macular dystrophy–fundus
flavimaculatus groups (group 1, normal full-field amplitudes; group 2, normal
scotopic rod electroretinogram [ERG] but reduced 30-Hz and photopic B wave
amplitudes; group 3, ERG abnormalities involving both rod- and cone-driven
responses). The boxes show the median and 25% and 75% confidence interval
(lower and upper quartiles). The whiskers extend to what could be considered
the 95% confidence interval. Circles represent values outside the 95% confidence
interval.
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In 14 patients (32%), visual acuity in the better-seeing eye was 20/40
or better, in 27 patients (63%), it was 20/50 to 20/200, and in 2 patients
(5%), visual acuity was worse than 20/200 (Table 3).
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Table 3. Visual Acuity and Clinical Findings on Slitlamp Biomicroscopy
and Autofluorescent Images in Stargardt Macular Dystrophy-Fundus Flavimaculatus*
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Fundus examination revealed central macular atrophy bilaterally in 26
patients (60%) (Table 3). Twenty-three
patients (53%) had flecks confined to the posterior pole, and in 19 patients
(44%) flecks extended toward the midperipheral retina, in 3 of whom they extended
to the equator (Table 3). One
had macular atrophy but no flecks. He was included in the study because his
older brother had macular atrophy and flecks. Two had an area of subretinal
fibrosis, 1 of whom reported a history of trauma.
Fundus autofluorescence images were obtained in all but 1 patient (98%).
In all patients with atrophic macular lesions detected on fundus examination,
there was a corresponding moderately well-defined area or multiple foci of
low-intensity signal compared with background in fundus autofluorescence images.
In 7 patients, evidence of macular atrophy was detected only by cSLO. Active
flecks appeared as foci of increased signal on cSLO images, and resorbed flecks
were seen as foci of decreased signal compared with background on cSLO images
(Figure 2A-B). Active flecks were
seen in all but 1 patient, and resorbed flecks were seen in all but 2. In
no patient with flecks confined to the posterior pole (n = 23) did fundus
autofluorescent images disclose abnormality in the peripheral retina. In 3
patients (7%), a moderately well-defined area of increased autofluorescence
was observed at the center of the macula, where only mild pallor could be
detected biomicroscopically (Figure 2A-B).
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Figure 2. Fundus photograph (A), autofluorescence
image (B), and electrophysiological findings (C) of a 48-year-old woman in
Stargardt macular dystrophy–fundus flavimaculatus group 1 (normal full-field
amplitudes). Active and resorbed flecks appeared as foci of high- and low-intensity
signal compared with background, respectively. Pattern electroretinogram (PERG)
was abolished and full-field electroretinograms were normal.
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Color-contrast thresholds were measured in 35 patients (81%). One patient
had normal color vision, 2 (6%) had involvement only of protan and deutan
axes, and 32 (91%) had additional elevation of the tritan axis. The elevation
in the tritan axis tended to be less marked than that on the protan and deutan
axes.
All patients tested (n = 39, 90%) had abolished or residual PERG and
FERG. Six patients with abolished PERG had a visual acuity of 20/40 or better
in the better-seeing eye. Full-field ERG was performed in all patients (n
= 43), and EOG was performed in 38 patients (88%) and was reduced in 4 patients
(10%). Figure 2C shows the electrophysiological
findings (PERG and ERG) corresponding to one of the patients from this group.
Increasing duration of disease was associated with lower photopic B
wave amplitude (P = .006,  = -0.43) but
not scotopic rod B wave amplitude (P = .65,
= -0.07) or scotopic maximal A (P = .49,
= 0.11) or B wave (P = .74, = -0.05)
amplitudes (Figure 3). When 3 subjects
examined at the onset of symptoms were removed from the analysis, the reduction
of photopic function became smaller (P = .02,
= -0.37). There was no evidence of any association between age of onset
and scotopic rod B wave amplitude (P = .15,
= -0.23), scotopic maximal A (P = .06,
= 0.29) or B wave (P = .47, = 0.11) amplitude,
or photopic (P = .61, = 0.08) function.
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Figure 3. Plots of scotopic and photopic
amplitudes (% normal mean -2 SDs) and duration of disease for group
1 (normal full-field amplitudes).
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GROUP 2
Nine patients (14%) were classified as SMD-FFM group 2, 4 were male
(44%) and 5 female (55%) (Table 2).
The median age of onset was 18 years (range, 6-32 years), and the median duration
of the disease was 5 years (range, 2-18 years) (Figure 1). At the time of the examination, the median age of the
patients was 26 years (range, 11-42 years). Four had an age of onset at 10
years or earlier.
In 2 patients (22%), visual acuity in the better-seeing eye was 20/40
or better, in 6 (67%), it was 20/50 to 20/200, and in 1, it was less than
20/200 (Table 3).
Fundus examination disclosed central macular atrophy bilaterally in
5 patients (Table 3). In 1 patient,
macular atrophy was seen only in the left eye. Two patients had flecks confined
to the posterior pole, and in 6 patients, flecks extended toward the midperipheral
retina, in 2 of whom flecks extended to the equator (Table 3). One other patient had no flecks detected on biomicroscopic
examination, although flecks were seen in cSLO images.
Fundus autofluorescence images were obtained in all but 1 patient (89%).
In all patients, with or without macular atrophy detected on slitlamp biomicroscopy,
there was either an area with low-intensity signal or multiple foci of decreased
autofluorescence compared with background in the cSLO images. In the one in
whom no flecks were detected on slitlamp biomicroscopy, autofluorescence images
disclosed active and resorbed flecks confined to the posterior pole. All patients
had active and resorbed flecks. In 2 patients with flecks confined to the
posterior pole, fundus autofluorescent images disclosed no abnormalities in
the peripheral retina.
In the 6 patients tested, color-contrast sensitivity demonstrated increased
thresholds in all axes, although relative sparing of the tritan axis was observed
in 5 patients.
All patients had abolished PERG and FERG, and EOG results were abnormal
in 4 of the 7 patients tested. Figure 4
shows cSLO images and electrodiagnostic findings from one of the patients
corresponding to this group.
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Figure 4. Fundus autofluorescence images,
showing multiple active flecks with high-intensity signal (A) and electrodiagnostic
findings (B) of a 15-year-old boy in Stargardt macular dystrophy–fundus
flavimaculatus group 2 (normal scotopic rod electroretinogram but reduced
30-Hz and photopic B wave amplitudes). There was decreased amplitude of photopic
and 30-Hz flicker with normal rod electroretinogram. PERG indicates pattern
electroretinogram.
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There was little evidence of progressive loss of scotopic (scotopic
rod B wave: P = .07, = -0.63; scotopic
maximal A wave: P = .87, = -0.06; scotopic
maximal B wave: P = .23, = -0.44) or
photopic (P = .73, = -0.14) function
with duration of symptoms, although the photopic responses were abnormally
low (Figure 5). There was no relation
between scotopic function and age of onset (scotopic rod B wave: P = .72, = 0.14; scotopic maximal A wave: P = .39, = 0.33; scotopic maximal B wave: P = .39, = 0.33), although photopic abnormality was less marked
with later onset of symptoms (P = .003, = 0.87).
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Figure 5. Plots of scotopic and photopic
amplitudes (% normal mean values -2 SDs) and duration of disease for
group 2 (normal scotopic rod electroretinogram but reduced 30-Hz and photopic
B wave amplitudes).
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GROUP 3
Ten patients were classified as SMD-FFM group 3 (17%), 5 were male and
5 female (Table 2). The median
age of onset was 9 years (range, 5-42 years), and the median duration of the
disease was 19 years (range, 7-29 years) (Figure 1). At the time of the examination, the median age of the
patients was 31 years (range, 16-50 years). Five patients had an age of onset
earlier than 10 years.
Visual acuity in the better-seeing eye was 20/50 to 20/200 in 2 patients
and worse than 20/200 in 8 patients (Table
3).
Fundus examination disclosed central macular atrophy in all cases (Table 3). In all patients, flecks extended
into the midperipheral retina. In 1 patient, flecks were present just anterior
to the vascular arcades, whereas in 9 they extended to the equator (Table 3). In 1 patient, an area of subretinal
fibrosis was detected. No striking narrowing of the retinal vessels or optic
nerve pallor was observed.
Fundus autofluorescence images were obtained in all patients. All had
an area of low-intensity signal compared with background at the macula. Five
patients had active and resorbed flecks, and 5 had resorbed flecks only. In
1 patient with flecks that extended just anterior to the vascular arcades,
fundus autofluorescent images disclosed no abnormalities in the peripheral
retina beyond that limit. Well-circumscribed areas or patches of decreased
autofluorescence compared with background were detected in the midperipheral
retina in 6 patients (Figure 6).
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Figure 6. Color fundus photograph (A) and
fundus autofluorescence image (B) of the left eye of a 31-year-old woman in
Stargardt macular dystrophy–fundus flavimaculatus group 3 (electroretinogram
abnormalities involving both rod- and cone-driven responses). Large patches
with low-intensity signal were detected in the autofluorescence images, whereas
only mild pallor was observed on slitlamp biomicroscopy.
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A measurable threshold for the tritan axis only was found in 2 of the
4 patients tested. All patients had abolished PERG and FERG, and EOG results
were abnormal in 4 of the 5 patients tested. Figure 7 shows fundus autofluorescence images (A) and electrodiagnostic
findings (B) from one of the patients in this group.
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Figure 7. Fundus autofluorescence images
(A) and electrodiagnostic findings (B) of a 30-year-old man in Stargardt macular
dystrophy–fundus flavimaculatus group 3 (electroretinogram abnormalities
involving both rod- and cone-driven responses). Areas of low-intensity signal
corresponded with atrophy on biomicroscopy and foci of decreased autofluorescence
with resorbed flecks (A). There was decreased amplitude of scotopic, photopic,
and 30-Hz flicker that was also delayed (B). PERG indicates pattern electroretinogram.
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Despite the small numbers, in group 3 there appeared to be a relation
between deterioration in the amplitude of scotopic rod B wave and duration
of the disease (P = .03, = -0.74), although
this could not be demonstrated with respect to scotopic maximal A (P = .48, -0.27) or B wave (P =
.67, = -0.16) amplitudes or photopic function (P = .12, = -0.59) (Figure
8). We found no evidence of any relation between age of onset and
scotopic (scotopic B wave: P = .72, = 0.14;
scotopic maximal A wave: P = .90, = -0.05;
scotopic maximal B wave: P = .53, = 0.22) or
photopic (P = .39, = 0.36) function.
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Figure 8. Plots of scotopic and photopic
amplitudes (% normal mean -2 SDs) and duration of disease for group
3 (electroretinogram abnormalities involving both rod- and cone-driven responses).
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UNCLASSIFIED
One patient could not be classified according to the criteria used.
This patient had reduced scotopic B wave amplitude and normal photopic B wave
amplitude. Maximal B wave amplitude was normal, and 30-Hz flicker amplitude
was abnormal.
COMPARISON BETWEEN GROUPS
Univariate analysis showed that there were differences in scotopic function
between groups 1 and 3 (P<.001) but not between
groups 1 and 2 (P = .48) and differences in photopic
function between groups 1 and 2 (P<.001) and groups
1 and 3 (P<.001).
To test the possibility that electrophysiological groups represent different
stages of the progression of the disease rather than different phenotypic
subtypes, differences in duration of disease and age of onset among groups
were studied. The influence of these parameters (duration of disease and age
of onset) on the classification was assessed.
At the univariate level, duration of disease appeared to have an effect
on scotopic (P<.001) and photopic (P = .002) function. To assess if differences observed among groups
in scotopic and photopic function could be explained only by the different
duration of disease among groups, a multiple regression analysis was used.
When correcting for duration of disease, differences in scotopic and photopic
function between groups 1 and 3 (P<.001) and photopic
function between groups 1 and 2 (P<.001) still
existed, indicating that differences in retinal function cannot be explained
only by differences in duration of disease alone.
In this model, the median age of onset was found to be lower in group
3 (P = .005) than group 1, and the length of history
was found to be longer in group 3 than in groups 1 and 2 (P = .001 and .003, respectively). Age of onset appeared to have an
effect only in photopic (P = .01) but not scotopic
(P = .50) function. When correcting for age of onset,
differences in photopic function between groups 1 and 2 and groups 1 and 3
were still present (P<.001), suggesting that the
classification is not explained by different age of onset among groups.
We sought correlation between other attributes of disease with the classification
(Table 3). In this series, patients
in group 1 tended to have better visual acuity and more restricted distribution
of flecks and atrophy, whereas those in group 3 had the worst visual acuity
and more widespread flecks. Macular atrophy was universal in group 3. However,
there was considerable overlap of these attributes between the groups. The
only feature that was exclusively seen in one group was the presence of atrophy
peripheral to the vascular arcades as detected with the cSLO in group 3. Figure 2, Figure 4, Figure 6, and Figure 9 show autofluorescence images in
patients from groups 1 through 3 and demonstrate the similarity of fundus
phenotype that exists between groups.
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Figure 9. Autofluorescence in patients of
group 1 (A, B), group 2 (C), and group 3 (D). See Figure 1 legend for explanation
of groups.
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COMMENT
Three patterns of functional loss were recognized in patients with SMD-FFM.
Patients in group 1 had severe pattern ERG abnormality with normal scotopic
and photopic ERG B wave amplitudes. Patients in group 2 had additional loss
of photopic ERG, and those in group 3 had abnormality of both the photopic
and scotopic ERG.
The results of this study do not support the concept that these 3 groups
represent different stages in the progression of disease. If this were the
case, patients in group 1 would have markedly shorter duration of disease
than those in group 2, and patients in group 2 would have a shorter duration
of disease than those in group 3. In addition, a strong correlation between
loss of scotopic or photopic function and duration of symptoms would have
been expected in patients in group 1. These were not observed. The fact that
differences in scotopic and photopic function among groups were not explained
on the basis of differences in duration of disease or age of onset among groups
supports the concept that these electrophysiological groups may represent
different phenotypic subtypes in SMD-FFM.
Previous studies3, 7, 9-11,13-14
have addressed the issue of classifying patients with SMD-FFM according to
the presence and distribution of fundus lesions. It has been reported by some
that patients with lesions confined to the macula tend to have normal ERGs,
whereas those with widespread retinal involvement often have peripheral functional
abnormalities.6-7,10, 13
By contrast, it has been shown that generalized cone or cone and rod involvement
can occur in patients with visible manifestation of the disease restricted
to the macula and that a normal ERG may be obtained in patients with peripheral
retinal changes.6-7,10
Little evidence has been presented that demonstrates correlation of function
with the centrifugal extension of morphological changes. Aaberg10
described 3 patients in whom fundus changes initially confined to the macula
extended to the peripheral retina. These patients had peripheral cone and
rod dysfunction at the initial visit. Armstrong and colleagues13
and Moloney and associates9 found deterioration
of retinal function over time in some patients, although it was not specified
how this related to preexisting functional abnormalities. One observation
that is in conflict with a strict segregation of patients is that of Hadden
and Gass,6 who reported 2 cases with apparently
normal electrophysiological responses at the initial visit who had an abnormal
ERG on follow-up. Although this finding supports the possibility of progression
from normal to abnormal peripheral function in some patients, it preceded
the introduction of ISCEV standards for electrophysiology, and the existence
of previous and undocumented ERG abnormalities in those cases cannot be excluded.
In the present series, it was not possible to predict the pattern of
functional loss based on findings of fundus examination. A high percentage
of patients in group 1 (Table 3)
with functional loss restricted to the macular area had widespread retinal
abnormalities similar to those found in groups 2 and 3. The only clinical
characteristic that distinguished our groups was the presence of patches of
atrophy outside the vascular arcades, which was seen in some but not all patients
in group 3 as detected by fundus autofluorescence imaging. This
highlights the value of fundus autofluorescence studies in the characterization
of patients with SMD-FFM. This novel technique, which can be used to assess
the status of the retinal pigment epithelium, and, in an indirect manner of
the photoreceptors, allows simultaneous imaging of active flecks and areas
with photoreceptor cell loss. In several cases, areas of atrophy and flecks
were only detected in cSLO images.
We used PERG to assess functional abnormalities at the macula. Severe
PERG abnormalities were present in all patients studied, even when the visual
acuity was still good. In our experience, this is unusual in other inherited
macular dystrophies and confirms our previous findings.17
As in other proposed classifications,14, 26
we acknowledge that the differences observed among groups might not be absolute
and that it is possible that some patients may change from one group to another.
We have used age of onset and duration of the disease to test our hypothesis,
and, further, we acknowledge that these parameters are subjective and dependent
on the patient's ability to recognize visual symptoms. Only prospective studies
over a long period using consistent electrophysiological recordings would
provide a definitive answer. However, the results of this study provide no
evidence to suggest that SMD-FFM is a single progressive disorder. Functional
characteristics in SMD-FFM, as demonstrated by electrophysiological studies,
may correlate with the nature of the mutation within the ABCR gene.17 However, while mutation
detection is far from complete,15, 27-28
such an exercise is unlikely to be very fruitful.
AUTHOR INFORMATION
Accepted for publication September 8, 2000.
This study was supported by the Macular Disease Society (Dr Lois), the
Medical Research Council (grant G9301094), and the British Retinitis Pigmentosa
Society.
Corresponding author and reprints: Alan C. Bird, MD, Medical Retina
Service, Moorfields Eye Hospital, City Road, London EC1V 2PD, England.
From the Medical Retinal Service (Drs Lois and Bird) and Departments
of Electrodiagnostics (Dr Holder) and Epidemiology (Ms Bunce), Moorfields
Eye Hospital, and Department of Visual Science, Institute of Ophthalmology
(Dr Fitzke), London, England. Dr Lois is now with the Retina Service, Aberdeen
Royal Infirmary, Foresterhill, Aberdeen, Scotland.
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der Deutschen Ophthalmologischen Gesellschaft, Hamburg 1962. In: Sautter H, ed. Entwicklung und Fortschrift
in der Augenhielkunde. Stuttgart, Germany: Enke; 1963:107-120.
3. Klien BA, Krill AE. Fundus flavimaculatus: clinical, functional, and histopathologic observations. Am J Ophthalmol. 1967;64:3-23.
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