Inner Retinal Abnormalities in X-linked Retinitis
Pigmentosa with RPGR Mutations
Tomas S. Aleman,1Artur V. Cideciyan,1Alexander Sumaroka,1Sharon B. Schwartz,1
Alejandro J. Roman,1Elizabeth A. M. Windsor,1Janet D. Steinberg,1Kari Branham,2
Mohammad Othman,2Anand Swaroop,2and Samuel G. Jacobson1
PURPOSE. To investigate in vivo the retinal microstructure in
X-linked retinitis pigmentosa (XLRP) caused by RPGR muta-
tions as a prelude to treatment initiatives for this common form
METHODS. Patients with RPGR-XLRP (n ? 12; age range, 10–56
years) were studied by optical coherence tomography (OCT)
in a wide region of central retina. Overall retinal thickness and
outer nuclear layer (ONL) and inner retinal parameters across
horizontal and vertical meridians were analyzed and compared.
RESULTS. Retinal architecture of all patients with RPGR muta-
tions was abnormal. At the fovea in younger patients, the ONL
could be normal; but, at increasing eccentricities, there was a
loss of photoreceptor laminar structure, even at the youngest
ages studied. At later ages and advanced disease stages, the
ONL was thin and reduced in extent. Inner retinal thickness, in
contrast, was normal or hyperthick. Inner retinal thickening
was detectable at all ages studied and was strongly associated
with ONL loss.
CONCLUSIONS. Inner retinal laminar abnormalities in RPGR-XLRP
are likely to reflect a neuronal–glial retinal remodeling re-
sponse to photoreceptor loss and are detectable relatively early
in the disease course. These results should be factored into
emerging therapeutic strategies for this form of RP. (Invest
showed that more than one X chromosomal locus causes XLRP,6
and now five XLRP loci are suspected.7RP3, the most common
molecular form, is caused by mutations in the RPGR (retinitis
pigmentosa GTPase regulator) gene.8RPGR encodes two major
isoforms. The ORF15-containing isoform of RPGR is localized to
cilia in photoreceptors and other postmitotic cells and to centro-
of inherited retinal degeneration.1–5
somes in dividing cells.9–11Interaction with other centrosomal
basal body or axonemal proteins implicated in abnormal micro-
tubular transport makes RPGR a partner in a complex set of
pathways implicated in many syndromic and nonsyndromic reti-
nal degenerative diseases.7,11–13
Preclinical progress has prompted thoughts of translational
research leading to clinical trials in RPGR-XLRP.14Canine and
mouse models are available,9,15–17and evidence in transgenic
mice points to the possible value of gene replacement.18A
potential problem for therapy in RPGR-XLRP was recently
identified in the canine XLRPA2 model. Retinal remodeling was
detected in these dogs whether untreated19or treated with
intravitreal neurotrophic factor.20Neuronal–glial remodeling
of the retina in response to photoreceptor injury has been
documented in many rodent models of retinal degenera-
tion,21–23in human postmortem retinal tissue from some forms
of RP,24and most recently in humans, by means of in vivo
high-resolution optical microscopy in choroideremia and Leber
congenital amaurosis.25–27The retinal laminar architecture in
human RPGR-XLRP, however, has not been studied in detail.
We used in vivo retinal microscopy to analyze a cohort of
patients with RPGR-XLRP as a first step toward understanding
the factors that may determine feasibility and efficacy in future
clinical trials of treatment for this form of RP.
MATERIALS AND METHODS
There were 12 patients with RPGR mutations, representing 11 families
(Table 1). Molecular methods have been reported.29,30Patients under-
went a complete eye examination including Goldmann kinetic visual
fields, dark-adapted chromatic static threshold perimetry, and electro-
retinography (ERG). Techniques, methods of data analysis, and normal
results have been described.31–34Normal subjects were included for
optical coherence tomography (n ? 28; age range, 5–58 years). In-
formed consent was obtained from all subjects. Procedures adhered to
the Declaration of Helsinki and were approved by the institutional
Optical Coherence Tomography
In vivo microscopy of the retinal cross-section was obtained with OCT
(Carl Zeiss Meditec, Inc., Dublin, CA). The principles of the method
and our recording and analysis techniques have been published.35–37
Most data were acquired with the OCT3 (Carl Zeiss Meditec, Inc.) with
a theoretical axial resolution in retinal tissue of ?8 ?m; in three
patients, data were acquired with the OCT1, with an axial resolution of
?10 ?m. In all subjects, overlapping OCT scans of 4.5-mm length were
used to cover horizontal and vertical meridians up to 9 mm eccentric-
ity from the fovea. At least three OCTs were obtained at each retinal
location. In a subset of patients, dense raster scans were performed to
sample an 18 ? 12-mm2region of the retina centered on the fo-
vea.25,26,36,37A video fundus image was acquired by the commercial
software and saved with each OCT scan. In addition, the fundus video
visible during the complete session was recorded continuously on a
video cassette recorder.
From the1Department of Ophthalmology, Scheie Eye Institute,
University of Pennsylvania, Philadelphia, Pennsylvania; and the2De-
partment of Ophthalmology and Visual Sciences and Biological Chem-
istry, University of Michigan Medical School, Ann Arbor, Michigan.
Supported by The Foundation Fighting Blindness, the Macula
Vision Research Foundation, Hope for Vision, the Chatlos Foundation,
the National Institutes of Health/National Eye Institute, the Macular
Disease Foundation, the Ruth and Milton Steinbach Fund, and Alcon
Submitted for publication April 17, 2007; revised June 6, 2007;
accepted August 10, 2007.
Disclosure: T.S. Aleman, None; A.V. Cideciyan, None; A.
Sumaroka, None; S. B. Schwartz, None; A.J. Roman, None; E.A.M.
Windsor, None; J.D. Steinberg, None; K. Branham, None; M. Oth-
man, None; A. Swaroop, None; S.G. Jacobson, None
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be marked “advertise-
ment” in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Corresponding author: Samuel G. Jacobson, Scheie Eye Institute,
University of Pennsylvania, 51 N. 39th Street, Philadelphia, PA 19104;
Investigative Ophthalmology & Visual Science, October 2007, Vol. 48, No. 10
Copyright © Association for Research in Vision and Ophthalmology
Postacquisition processing of OCT data was performed with cus-
tom programs (MatLab 6.5; MathWorks, Natick, MA). Longitudinal
reflectivity profiles (LRPs) making up the OCT scans were aligned by
using a dynamic cross-correlation algorithm with a manual override
when crossing structures (for example, intraretinal pigment) that in-
terrupted local lateral isotropy of signals. Repeat scans were laterally
aligned and averaged to increase signal-to noise-ratio and allow better
definition of retinal laminae.36
Overall retinal thickness was defined as the distance between the
signal transition at the vitreoretinal interface (labeled T1 in Ref. 35) and
the major signal peak corresponding to the RPE.25In normal subjects,
the RPE peak was assumed to be the last peak within the two- or
three-peak scattering signal complex (labeled ORCC in Ref. 35) deep in
the retina. In patients, the presumed RPE peak was sometimes the only
signal peak deep in the retina; at other times, it was apposed by other
major peaks. In the latter case, the RPE peak was specified manually by
considering the properties of the backscattering signal originating from
layers vitread and sclerad to it. Nuclear layers were defined as previ-
ously published.25–27,35–37Outer photoreceptor nuclear layer (ONL)
thickness was defined as the major intraretinal signal trough delimited
by the signal slope maxima. In some patients and at some retinal
locations, ONL thickness was not measurable. An inner retinal
thickness parameter was defined as the distance between the signal
transition at the vitreoretinal interface and the slope maximum
sclerad to the signal trough that corresponds to the inner nuclear
For topographic analysis, the precise location and orientation of
each scan relative to retinal features (blood vessels, intraretinal pig-
ment, and optic nerve head) were determined with video images of the
fundus. LRPs were allotted to regularly spaced bins in a rectangular
coordinate system centered at the fovea. The waveforms in each bin
were aligned and averaged. For two-dimensional maps, 0.3 ? 0.3-mm2
bins were used for sampling, whereas 0.15 ? 0.15-mm2bins were used
for analysis along the horizontal and vertical meridians. Overall retinal,
ONL, and inner retinal thickness were measured as just described.
Missing data were interpolated bilinearly, thicknesses were mapped to
a pseudocolor scale, and the locations of blood vessels and optic nerve
head were overlaid for reference.25–27,37
Clinical Characteristics of the Patients
Of the RPGR mutations in our cohort of patients (Table 1), five
were novel. The others have been reported to be associated
with RP.5,29,30,38–42All patients showed clinical and visual
function features of RP (Table 1). Visual acuities were abnor-
mal but more mildly affected in the first three decades of life
than at older ages. The extent of the kinetic visual field was
nearly full in response to a large bright target (V-4e) in patient
(P)1, the youngest patient studied, but was diminished by at
least 45% from the normal mean visual field extent in all other
patients. Patterns of field loss included complete midperiph-
eral scotomas with residual central and temporal peripheral
islands (P2, P5–P7, and P9), incomplete midperipheral scoto-
mas with residual field connecting central and temporal pe-
ripheral islands (P4 and P8), loss of peripheral field detection
completely (P3, P11, and P12), and only a detectable temporal
peripheral island (P10). Dark-adapted chromatic perimetry
showed measurable, albeit reduced, rod function in central
and/or far peripheral fields (P1, P2, and P5–P7), and the re-
mainder of the patients had reduced cone-mediated detection
of stimuli, mainly in the central field. Rod ERGs were measurable
but reduced in b-wave amplitude (by ?75% of normal mean
amplitude) in some of the younger patients (P1, P2, P5, P6); cone
ERGs were present but abnormally reduced (Table 1).
Topographical Maps of Retinal Thickness in
Maps across a wide expanse of central retina illustrate thick-
ness topography for the full cross-section of retina, the ONL,
TABLE 1. Molecular and Clinical Characteristics of the Patients with RPGR-XLRP
(% Normal Mean)?
ND, not detectable; HM, hand motions.
* Nucleotide positions based on References 8 and 28.
† Best corrected visual acuity; similar in the two eyes, unless specified.
‡ Spherical equivalent; average of both eyes.
§ Average of both eyes; expressed as a percentage of normal mean; 2 SD below normal equals 90%.32
? Expressed as a percentage of normal mean amplitude (rod, 292 ?V; cone flicker, 172 ?V); 2 SD below normal equals 67% for rod b-wave
and 60% for cone flicker.33
¶ Recorded 2 to 5 years (P1, P2, P5, and P7) or 12 to 19 years (P8 and P10) before OCTs.
# Novel mutation.
** Patients are siblings.
†† Patient had cataract extraction and intraocular lens implants, both eyes.
4760 Aleman et al.
IOVS, October 2007, Vol. 48, No. 10
and the inner retina in a normal subject (Fig. 1A) and three
patients with RPGR-XLRP of different ages and disease stages
(Figs. 1B–D). In the normal retina, there was a foveal depres-
sion surrounded by parafoveal thickening and then a decline in
thickness with increasing eccentricity. The crescent-shaped
thickening at superior and inferior poles of the optic nerve
represent converging axons (Fig. 1A, left). P1, a 10-year-old
patient with RPGR-XLRP (Fig. 1B, left), showed a similar pat-
tern of retinal thickness to that of normal, but there appeared
to be thinning across much of the central retina except at the
fovea. Two older hemizygotes, P8 and P12, also showed
thinned retina and thinning included the fovea (Figs. 1C, 1D,
left). The ONL of the normal retina peaked centrally and
declined with distance from the fovea. Parafoveal thinning
occurred more gradually in the superior retina (Fig. 1A, mid-
dle). P1 retained a small central island of ONL that was sur-
rounded by undetectable photoreceptor layer and then detect-
able but reduced ONL eccentric to the vascular arcades (Fig.
1B, middle). P8 and P12 also showed central ONL islands, but
these were of decreased extent and thickness compared with
the results in P1 (Figs. 1C, 1D, middle).
Inner retinal thickness topography in the normal retina had
a foveal depression surrounded by an annulus of increased
thickness and a crescent-shaped thickening extending toward
the optic nerve head from the superior and inferior retina (Fig.
1A, right). Inner retinal topography in the patients with RPGR-
XLRP approximated normal, but there were differences. There
appeared to be greater thickening of the inner retina at most
eccentricities from the fovea, with the older (P12) showing
more thickening than the younger (P1) subject (Figs. 1B–D,
right). The observations in these maps prompted us to perform
locus-by-locus quantitation of thickness of overall retina, ONL,
and inner retina along horizontal and vertical meridians in all
12 patients with RPGR-XLRP and to compare the results to
those in normal subjects (Fig. 2).
Inner Retinal Architecture in
Cross-sectional images in a normal subject and P2, a 15-year-old
with RPGR-XLRP, are shown (Figs. 2A, 2B). The normal retinal
cross-section had a foveal depression and the surrounding
retina was laminated with two prominent low-reflectivity cel-
lular layers (ONL and INL; highlighted) and intervening hyper-
reflective synaptic laminae. P2 also showed a foveal depression
with normal-appearing foveal ONL thickness. The ONL, how-
ever, diminished in thickness with eccentricity from the fovea
and became abnormally thin. The inner retina, including the
INL and the more vitread hyperreflective layer, appeared thick-
ened at the eccentricities with reduced ONL.
Retinal thickness, ONL, and inner retinal thickness for the
12 patients with RPGR-XLRP are quantified across the horizon-
tal and vertical meridians (Figs. 2C–E). Data are plotted in
relation to normal limits (defined as ?2 SD from the mean).
Patients are identified by individual symbols and colors distin-
guish younger (10–23 years) from older (31–56 years) age
groups. Retinal thickness in the younger patients was normal
or abnormally reduced, whereas the older group of patients
had thinner retinas at nearly all loci across the two meridians
examined (Fig. 2C). Only the youngest patients had normal
ONL thickness at the fovea (Fig. 2D). In contrast to the gradual
decline of ONL with eccentricity in normal data, RPGR-XLRP
ONL became abnormally thin within the central 2 to 4 mm and
remained subnormal in thickness or not detectable at further
eccentricities. Inner retinal thickness was normally at a mini-
mum in the fovea. Parafoveal thickening, a feature of the
raphy of RPGR-XLRP. Topographical
maps of retinal thickness (left), ONL
thickness (middle), and inner retinal
thickness (right) in a normal 22-year-
old man (A) and three patients with
RPGR-XLRP (P1, P8, and P12) of dif-
ferent ages and disease stages (B–D).
Traces of major blood vessels and
location of optic nerve head are over-
laid on each map (depicted as right
eyes). Note that pseudocolor scales
(shown beneath the normal maps)
for (A) and (C) are the same but the
scale for (B) is different. T, temporal;
N, nasal; S, superior; I, inferior.
Retinal thickness topog-
IOVS, October 2007, Vol. 48, No. 10
Inner Retina in RPGR Mutations 4761
normal retina, was also present in RPGR-XLRP. At eccentrici-
ties beyond approximately 2 mm eccentric to the fovea, some
younger patients showed normal inner retinal thickness,
whereas many had hypernormal thickness. Nearly all older
patients had hyperthick retinas in these paracentral regions of
measurement (Fig. 2E).
We explored further the association between the primary
photoreceptor loss in RPGR-XLRP and the observed inner
ture in RPGR-XLRP (A, B). Cross-sec-
tional scans along the horizontal
(left) and vertical (right) meridians in
a normal subject (A) and a 15-year-
old patient (B). Brackets defining
ONL and inner retina are labeled
(left) and a bracket showing total ret-
inal thickness is at the right. Nuclear
layers are colored (ONL, blue; inner
nuclear layer, purple). OCTs are in
grayscale with lowest reflectivity as
black and highest reflectivity as
white. Insets: schematic location of
the scans. (C–E) Thickness of the ret-
ina (C), ONL (D), and inner retina (E)
along the horizontal and vertical me-
ridians in the 12 patients, identified
by symbols and grouped by age. Ver-
tical axes in (D) and (E) start at the
axial resolution of the OCT system.
Shaded areas: normal limits; mean ?
2 SD; (C), n ? 27; (D), n ? 26; (E),
n ? 14. T, temporal; S, superior.
Retinal laminar architec-
mutant retina. Inner retinal thickness as a function of ONL thickness at
extrafoveal (?2 mm of eccentricity; 0.15 mm bins) retinal locations in
patients with RPGR-XLRP and normal subjects. Both inner retinal and
ONL thicknesses are specified as change from the mean normal value
calculated at each retinal location. Vertical dashed line: lower normal
limit (?2 SD from normal mean) for ONL thickness; horizontal dashed
line: upper normal limit (?2 SD from normal mean) for inner retinal
Relationship of outer and inner laminar features in RPGR-
4762 Aleman et al.
IOVS, October 2007, Vol. 48, No. 10
retinal thickening (Fig. 3). Loci used in this analysis were
outside the highly specialized foveal and parafoveal architec-
ture43in the temporal, superior, and inferior retina, beginning
at 2 mm eccentric from the fovea. The ONL in patients with
RPGR-XLRP showed the expected differences from normal at
these eccentricities with almost all loci (1614/1615) abnor-
mally reduced in ONL thickness, to various degrees. The inner
retina showed no loci with thinning. At the sampled loci, inner
retinal thickness was either within normal limits (256/1615,
16%), or was hyperthick (84%). The younger age group had
79% (771/970) of loci with hyperthick inner retina and re-
duced ONL. The older age group had 91% (587/644) of loci
with hyperthick inner retina and reduced ONL. In summary,
the predominant finding in both younger and older patients
was reduction in ONL thickness with associated thickening of
the inner retina.
Evidence that RP can be inherited as an X-linked trait dates
back nearly a century (reviewed in Ref. 1). Ensuing decades
have led to many studies of disease expression in XLRP hem-
izygotes of unknown genotype by investigators using clinical
observation (for example, Refs. 4,44) and histopathology of
rare donor retinas (for example, Refs. 24,45–49). The steady
progress toward understanding human XLRP was accelerated
by identification of causative genes and mutations (reviewed in
Ref. 7). Now, there are small and large animal models of human
diseases. Specifically for RPGR-XLRP, there are both murine
and canine disease models.9,16,17,19This background of clinical
and molecular information should help in the development of
therapeutic strategies for these incurable severe blinding reti-
nal degenerations, whether to arrest disease progression or
even restore vision.
With the advent of therapeutic concepts, questions about
human retinal degenerative disease have become more re-
fined.50Noninvasive tools to measure retinal structure are now
available to inquire whether there is treatment potential, with
what possible treatment, and what age may be most appropri-
ate.51In vivo microscopy by OCT permits quantitation of
human retinal laminae and has been used to understand the
cross-sectional micropathology of molecularly defined retinop-
athies.25–27,36,37,52–55OCT in our cohort of RPGR-XLRP pa-
tients revealed the expected result of retinal thinning, a well-
known histopathological feature of retinal degenerative
diseases in general and in XLRP in particular.47–49Morphomet-
ric study in XLRP donor retinas (age range, 24–84 years; mean,
62 years47) has reported dramatic reductions in foveal photo-
receptors. Our in vivo results at the fovea showed that there
can be normal ONL thickness in the first decade of life, but this
becomes reduced in hemizygotes in later decades. Eccentric to
the fovea, there was abnormally reduced photoreceptor lami-
nar thickness even in the first decade of life. At late ages and
more advanced stages, only a small island of central ONL
Inner retinal lamination did not simply follow the ONL
pattern of loss and become abnormally thin. In contrast, there
was thickening of inner retinal structure. This was evident in
topographical maps obtained in hemizygotes of different ages
and also in most of the profiles across horizontal and vertical
meridians. In general, ONL loss outside the fovea was associ-
ated with inner retinal thickening, and it was present even in
the youngest ages studied. The inner retinal hyperthickness
persisted into later decades. It is of interest that morphometric
studies of donor retinas from patients with RP of unknown
genotype (including XLRP) reported less profound cell loss in
the INL than in photoreceptors or ganglion cells, both centrally
and in extramacular regions, and even at late ages.48,49
What inner retinal abnormalities have been reported in
murine or canine animal models of RPGR deficiency? A murine
model of RPGR dysfunction, with or without an RPGR ORF15
transgene, showed slow but progressive ONL reduction, but
inner retinal changes were not specifically mentioned.9,17Ca-
nine studies in XLRPA2, caused by a microdeletion in RPGR
ORF15 with a resultant frameshift16have specifically studied
inner retinal changes. In addition to progressive ONL thinning,
the dogs had rod photoreceptor neurite sprouting that could
extend deep into the inner retina, rod bipolar cell dendrite
retraction, increased GABA-immunoreactive amacrine cells,
and Mu ¨ller glial cell reactivity that increased but later de-
creased. The authors concluded that such inner retinal remod-
eling changes occurred early rather than only late in the dis-
ease.19Peripheral retinal thickening and disorganization was
observed in the same canine XLRP model treated with intra-
vitreal injections of ciliary neurotrophic factor (CNTF). There
was an apparent increase in the number of rod cells in the
treated eyes. Also, bipolar cells had increased dendritic sprout-
ing into the ONL. Photoreceptor nuclear phenotype abnormal-
ities suggested dedifferentiation of rods.20
The exact basis of the inner retinal thickening that we
observed in human RPGR-XLRP is not known. We speculate
that the inner retinal abnormalities represent a detectable non-
invasive marker for the neuronal–glial remodeling response
secondary to photoreceptor stress or loss, a well-documented
process in rodent models of retinal degeneration.22,23A clue
about the basis of the RPGR-XLRP inner retinal abnormalities
comes from similar changes noted recently in Leber congenital
amaurosis (LCA) caused by CEP290 mutations.56Inner retinal
thickening in CEP290-LCA was interpreted in the context of
retinal histologic abnormalities in the rd16 mouse, a model for
the human disease.13Rd16 mouse retina had photoreceptor
loss, but there was also inner nuclear and inner plexiform layer
thickening. Surprisingly, the nuclei of the inner retinal cell
types appeared enlarged; and Mu ¨ller cell activation by GFAP
immunolabeling was notably increased.56Intra- or extracellular
edema may also play a role in the increased thickness of the
pericentral inner retina in RPGR-XLRP; there was no OCT
evidence of cystoid macular changes in any of the patients in
the present study.
The results in our cohort of patients with RPGR-XLRP
should be extended to larger populations of this relatively
common form of RP. Focal therapeutic strategies, such as
subretinal gene delivery, will require retinal structural data to
determine where in the retina to deliver the treatment and
what age or stage of disease is most sensible for therapy. Trials
of systemically administered treatments will also gain from
clear expectations of outcomes based on measurable retinal
structure. An investment in understanding which patients
should be included or excluded in a trial based on retinal
anatomic criteria could reduce the time taken to perform a
trial. Further, the exact molecular and cellular bases of the
remodeling response must be elucidated in the animal models.
Key unanswered questions remain, such as whether the ob-
served inner retinal structural changes have visual functional
consequences. If secondary dysfunction further complicates
the primary photoreceptor disease effects and if this is not
reversible, then expectations from treatment may have to be
The authors thank Elaine Smilko, Mary Nguyen, Anjani Naidu, Michelle
Doobrajh, Malgorzata Swider, and Waldo Herrera-Novey for critical
IOVS, October 2007, Vol. 48, No. 10
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