X-linked retinitis pigmentosa: functional phenotype of an RP2 genotype.

Abstract

Rod- and cone-mediated function was studied with psychophysics and electroretinography in members of an X-linked retinitis pigmentosa pedigree with the RP2 genotype. An asymptomatic hemizygote with an early stage of the disease had cone dysfunction in the mid-periphery and an abnormal cone electroretinogram (ERG); rod function was normal. Hemizygotes with more advanced disease had cone and rod dysfunction in the mid-peripheral retina and cone dysfunction in the far periphery; cone and rod ERGs were abnormal. At very advanced stages, there was an absolute mid-peripheral scotoma and marked cone and rod dysfunction in the far peripheral and central retina. Cone and rod ERGs were severely abnormal or not detectable. Heterozygotes showed tapetal-like reflexes, patches of pigmentary retinopathy, and a range of functional findings from no detectable abnormalities to moderate levels of retinal dysfunction. There were regions of normal function adjacent to dysfunctional patches that had greater cone than rod sensitivity losses or comparable cone and rod losses. The results suggest that the phenotype of this RP2 genotype of X-linked retinitis pigmentosa, unlike other forms of retinitis pigmentosa, is first expressed as a cone photoreceptor system dysfunction, and as the disease progresses, both rod and cone systems are involved.

Full text

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December 1992 Vol. 33/13
Investigative Ophthalmology
& Visual Science
Articles
X-Linked Retinitis Pigmenfosa: Functional Phenotype
of an RP2 Genotype
Samuel G. Jacobson, Alejandro J. Roman, Arrur V. Cideciyan, Marcia G. Robey,
Takeshi Iwara, and George Inana
Rod- and cone-mediated function was studied with psychophysics and electroretinography in members
of an X-linked retinitis pigmentosa pedigree with the RP2 genotype. An asymptomatic hemizygote with
an early stage of the disease had cone dysfunction in the mid-periphery and an abnormal cone electroret-
inogram (ERG); rod function was normal. Hemizygotes with more advanced disease had cone and rod
dysfunction in the mid-peripheral retina and cone dysfunction in the far periphery; cone and rod ERGs
were abnormal. At very advanced stages, there was an absolute mid-peripheral scotoma and marked
cone and rod dysfunction in the far peripheral and central retina. Cone and rod ERGs were severely
abnormal or not detectable. Heterozygotes showed tapetal-like reflexes, patches of pigmentary retinop-
athy, and a range of functional findings from no detectable abnormalities to moderate levels of retinal
dysfunction. There were regions of normal function adjacent to dysfunctional patches that had greater
cone than rod sensitivity losses or comparable cone and rod losses. The results suggest that the
phenotype of this RP2 genotype of X-linked retinitis pigmentosa, unlike other forms of retinitis pig-
mentosa, is first expressed as a cone photoreceptor system dysfunction, and as the disease progresses,
both rod and cone systems are involved. Invest Ophthalmol Vis Sci 33:3481-3492, 1992
Molecular genetic studies have demonstrated that
at least two different subregions of the short arm of
the X chromosome are responsible for X-linked retini-
tis pigmentosa (XLRP). The two genotypes have been
termed RP2, corresponding to the Xpl 1.2-3 region,
and RP3, corresponding to the Xp21 region.1"11 Al-
though there have been many studies of the pheno-
types of XLRP hemizygotes and heterozygotes with
unknown genotypes,12"24 the phenotypic expression
of the retinal disease in XLRP patients known to have
the RP2 or RP3 genotypes is not well understood. In
one of two reports to date, an XLRP family with link-
age to the RP3 locus showed diverse fundus abnormal-
ities in the hemizygotes.25 The other study reported an
From the Department of Ophthalmology, University of Miami
School of Medicine, Bascom Palmer Eye Institute, Miami, Florida.
Supported in part by Public Health Service research grants
EY05627 (SGJ) and EY02180 (Core), the National Retinitis Pig-
mentosa Foundation, Inc., Baltimore, Maryland, and The Chatlos
Foundation, Inc., Longwood, Florida. Dr. Jacobson is a Research
to Prevent Blindness Dolly Green Scholar, and Dr. Inana has an
RPB Eye Research Professorship.
Submitted for publication: March 12, 1992; accepted June 12,
1992.
Reprint requests: Dr. S.G. Jacobson, Bascom Palmer Eye Insti-
tute, 1638 N.W. 10th Avenue, Miami, FL 33136.
association of the RP2 genotype with early onset of
myopia and an association of the RP3 genotype with
the visual symptom of late onset of night blind-
ness.26*27
We examined 70 members of a large XLRP family
using molecular genetic techniques and ophthalmos-
copy. In a subset of family members, we performed
tests of visual function. Molecular genetic results indi-
cated that this family has an RP2 genotype. The oph-
thalmoscopic examinations revealed tapetal-like re-
flexes28 in most of the heterozygotes and pigmentary
retinopathy typical of RP in the hemizygotes. The vi-
sual function tests led to the definition of a functional
phenotype for this family and provided insight into
the nature and progress of this retinal degenerative
disease. A brief report of some of this work has been
published.29
Materials and Methods
Seventy members of a family with XLRP were in-
cluded in this study. All 70 members were examined
with ophthalmoscopy, and their blood samples were
collected for molecular genetic analysis. A subset of
10 family members, five hemizygotes and their
mothers, had complete ocular examinations, Gold-
3481

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INVESTIGATIVE OPHTHALMOLOGY 6 VISUAL SCIENCE / December 1992
Vol. 33
mann kinetic perimetry, dark- and light-adapted
static threshold perimetry, and full-field rod and cone
electroretinography. Data from dark- and light-
adapted static perimetry in 17 patients with autoso-
mal dominant (AD) RP with rhodopsin muta-
tions3031 were analyzed and compared with those
from the XLRP patients. Informed consent was ob-
tained from the subjects after the nature of the proce-
dures had been explained fully.
Molecular genetic analysis was achieved through ge-
nomic Southern blot analyses of leukocyte DNA from
the family members using Xp markers known to be
RP2 markers (TIMP, DXS426, DXS7) or RP3
markers (OTC, DXS84)32 and the ornithine amino-
transferase (OAT)-related sequences in the proximal
short arm of the X chromosome.33'34 Linkage analy-
sis was performed with the computer program
LINKAGE.35
Goldmann kinetic perimetry was performed in one
eye of hemizygotes and both eyes of heterozygotes us-
ing targets V (64 mm2 area) and I (0.25 mm2 area) at
intensity 4e (318 cd/m2) on a 10 cd/m2 white back-
ground. The visual field extent was quantified by a
published method.25
Static threshold perimetry was performed in one
eye of hemizygotes, both eyes of heterozygotes, and
one eye of the ADRP patients with rhodopsin muta-
tions using monochromatic stimuli (target area 64
mm2) in the dark- and light-adapted states. Dark-
adapted perimetry was performed with 650 and 500
nm targets and light-adapted (10 cd/m2) perimetry
was performed with a 600 nm target using a full field
test strategy of 75 loci (12° grid) and a profile test
along the horizontal meridian (2° spacing). Details of
the technique, analysis methods, and normal results
have been published.36"38 For the dark-adapted test-
ing, the sensitivity difference between the 500 and 650
nm stimuli at each test location determines whether
rods (>28 dB), cones (<12 dB), or both rods and
cones (13-27 dB) are mediating detection of the stimu-
lus. Sensitivity losses were calculated for rods (based
on 500 nm test results, dark-adapted) and for cones
(based on 600 nm test results, light-adapted) by com-
parison to normal mean values. At loci with no detect-
able function, maximum rod or cone sensitivity losses
(ie, based on the mean normal sensitivities at that
locus) were used in any further calculations. Dark-
and light-adapted spectral sensitivity measurements
and dark adaptometry were performed in some of the
patients using procedures described previously.3031
Full-field rod and cone electroretinograms (ERGs)
were performed in one eye of hemizygotes and both
eyes of heterozygotes using previously described
methods.2339 Two conventional suprathreshold stim-
uli were used to elicit rod and cone ERGs. The rod
ERG was elicited with a dim blue flash in the dark-
adapted state (-0.1 log scot-tr-s), and the cone ERG
was elicited with white light (0.64 cd-sec/m2) flicker at
29 Hz on a white background light (6.9 cd/m2). In
addition, intensity series were performed in the dark-
adapted state with blue light flashes over a 3 log unit
range, and in the light-adapted state with white light
over a 2.8 log unit range flickering at 29 Hz on the
white background.2324'29 Waveforms were measured
conventionally and the Naka-Rushton equation, V
= Vmax*In/(P + Kn) was fit to the measured ampli-
tudes from the rod intensity series.40 In the equation,
V is rod b-wave amplitude; Vmax is the amplitude at
response saturation; I is the stimulus intensity; K is
the intensity at half Vmax; and n is the exponent re-
sponsible for the slope of the function.232439 To estab-
lish the relationship between rod and cone ERG am-
plitudes, rod Vmax was plotted against the amplitude
of the cone flicker response to our maximum lumi-
nance white flash for this stimulus condition (4.8 cd-
sec/m2).
Results
Figure 1 is a pedigree that shows all of the subjects
in this study. Female family members with tapetal-
like reflexes, patches of pigmentary retinopathy, or
both are shown as heterozygotes, as are obligate het-
erozygotes with or without funduscopic abnormali-
ties. Those female and young male family members
with normal-appearing fundi (even though they may
have a 50/50 chance of being heterozygotes or hemi-
zygotes, respectively) are shown as unaffected.
The results of the DNA linkage analysis suggested
linkage of the disease in this family with Xp markers
that are at DXS7 or proximal, including DXS426 and
TIMP (maximum lod scores >2), whereas markers
distal to DXS7, such as OTC and DXS84, did not
show linkage (maximum lod scores < 1). The OAT-
related loci originally mapped at Xpll.2 and later
proximal to TIMP showed cosegregation with the dis-
ease without recombination (Family M-441). Thus,
the results were consistent with the genotype of the
disease being RP2.9
Table 1 lists some clinical findings in the subset of
10 family members (denoted by underlined numbers
in Figure 1) studied with complete eye examinations
and retinal function tests. The hemizygotes are listed
in the order of their age. The order of heterozygotes
corresponds to that of their sons. The hemizygotes
had varying degrees of myopia and astigmatism.
There was no obvious relationship of age to degree of
severity, as assessed by visual acuity or kinetic perime-
try. Of interest, patient IV/14, the hemizygote with
the largest visual field extent, had a tapetal-like reflex

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X-LINKED RP: PHENOTYPE OF RP2 GENOTYPE / Jocobson er ol
3483
iv
V
4
3 4 5 6 | 7 8 ± 10 11 12 13 14 13 16
2 3 4 5 6 7
4 T. T
19 20 T 21 722 23 T24 25
19 T20 21
26 27 28 29 30 31
8 9 10 11 12 13
Fig. 1. Pedigree of the XLRP family in the present study. Filled squares are affected men. Circles that enclose a dot are obligate heterozygotes
or female members with fundus features of the heterozygous state. Unfilled symbols are family members without fundus features of the
hemizygous or heterozygous states of the disease. The underlined patient numbers are those of the 10 family members who underwent
complete eye examinations and retinal function tests.
across most of his fundus.42 This reflex had the un-
usual feature of appearing and disappearing with
change in the direction of fundus illumination. The
other hemizygotes showed attenuated retinal vessels
and pigmentary abnormalities (bone spicule-like pig-
ment, depigmentation, atrophy) mainly in the mid-pe-
ripheral and far peripheral retina. These findings are
associated with typical RP of any genetic type. Cen-
tral retinal pigmentary changes were less severe than
those in the more peripheral retina. The heterozy-
gotes had interocular asymmetries in fundus appear-
ance and visual field extent.23 All five heterozygotes
had a tapetal-like reflex and all but one showed
patches of pigmentary retinopathy.
Figure 2 (upper) shows rod and cone ERG ampli-
tude and timing results from the hemizygotes and het-
erozygotes. Rod ERG b-waves to a dim blue light in
the dark-adapted state were reduced in amplitude and
delayed in timing in all hemizygotes except patient
IV/14. The rod ERG in patient IV/9 was not detect-
able. Cone flicker ERGs were measurable in all hemi-
zygotes and had reduced amplitude and delayed tim-
ing. One heterozygote (patient III/6) showed normal
rod and cone ERG parameters in both eyes. Two het-
Table 1. Clinical findings in XLRP hemizygotes and heterozygotes
Patient no.
Hemizygotes
V/2
IV/2
IV/14
IV/4
IV/9
Heterozygotes
IV/17
III/1
111/6
III/2
III/4
Age
8
11
21
25
27
33
39
42
51
46
Eye
RE
LE
RE
LE
RE
LE
RE
LE
RE
LE
RE
LE
RE
LE
RE
LE
RE
LE
RE
LE
Refraction
-2.00+ 1.25 X 100
-1.25+ 1.25X092
-7.00 + 2.75 X 105
-5.50+ 1.00X060
-4.25 + 2.25 X 145
-3.00 + 2.00X017
-3.00 +0.25 X 127
-3.00 + 0.75X015
-6.00 +2.50 X 135
-5.50 + 2.50 X 060
-2.00 + 0.25 X 075
-1.50 + 0.50x005
+0.25 + 2.75 X 090
-0.75 + 2.00 X 105
-0.25
-0.25
-0.25 + 1.50X090
piano + 1.75 X 083
-1.75 +3.50 X 110
+ 1.00 + 0.50x080
Visual acuity
20/60
20/60
20/25
20/25
20/25f
20/25f
20/20
20/20
20/200
20/100
20/25t
20/20t
2O/8OOt
20/20f
20/20f
20/15f
20/251
20/20t
20/300f
20/20|
Kinetic visual field
extent (%)*
V-4e
80
89
91
56
83
88
89
86
71
100
100
99
95
95
94
I-4e
3
4
72
8
<1
59
74
69
52
96
99
82
100
43
77
* Expressed as a percent of normal mean. Two standard deviations below
normal equals 90% for V-4e and 88% for I-4e.
t Tapetal-like reflex.

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INVESTIGATIVE OPHTHALMOLOGY 6 VISUAL SCIENCE / December 1992
Vol. 33
ROD ERG
N XY XX
1UU
95
90
"in
oi-
-
75
70
• i
: i
N
i f
i
>8 L R
N XY XX
CONE FLICKER ERG
N XY XXN XY XX
•1 -0.8 -0.6 -0.4 -0.2
LogK
0 0.2 0.<!
-0.5 0
Rod Vmax (normalized, log units)
Fig. 2. Rod and cone elec-
troretinogram (ERG) results
in one eye of hemizygotes
(XY, circles) and both eyes of
heterozygotes (XX, triangles).
Upper four graphs compare
rod ERG amplitude and tim-
ing and cone flicker ERG am-
plitude and timing in the pa-
tients and normal subjects (n
= 37, ages 13-64 years39).
Mean ± two standard devia-
tions (SD) for the normal pa-
rameters are denoted by the
hatched bars. Lines connect
the left (L) and right (R) eye
data from the heterozygotes
to highlight interocular asym-
metries. Lower left graph
shows rod ERG b-wave Vmax
versus K in the patients.
Hatched area is mean ± two
SD for the two parameters.
Lower right graph is the rod
ERG b-wave Vmax versus
cone flicker maximum ampli-
tude for the patients. The
hatched area encompasses
95% of the normal population
based on the assumption of a
bivariate Gaussian distribu-
tion.
erozygotes (patients III/1 and III/2) had reduced rod
b-wave amplitudes with or without timing abnormali-
ties and had reduced and delayed cone ERGs in both
eyes. In the remaining two heterozygotes (patients IV/
17 and III/4), one eye had abnormal rod and cone
ERGs, while the other eye showed normal rod param-
eters, but cone ERGs delayed in timing with normal
or abnormal amplitude. The lines connecting the
right and left eye data of the same heterozygote high-
light interocular asymmetries of function.23
The relationship between Vmax and K from the rod
ERG b-wave intensity-response functions is shown
for hemizygotes and heterozygotes (Fig. 2, lower left).
Only three of the hemizygotes had sufficient re-
sponses for calculation of Naka-Rushton parameters.
Patient IV/14 had normal Vmax, K, and n. In patients
IV/2 and IV/4 Vmax was reduced. K was normal in
patient IV/4, but slightly abnormal in IV/2, and n was
normal in both patients (normal mean = 0.87; stan-
dard deviation = 0.1239). Heterozygotes showed ei-
ther normal or reduced rod ERG b-wave Vmax. K was
normal in 9 of 10 eyes, and n was normal in all eyes.
The relationship of rod and cone ERGs in the hemi-
zygotes and heterozygotes is quantified in Figure 2
(lower right). Vmax of the rod ERG b-wave intensity-
response function is plotted against the maximum
amplitude cone flicker ERG. These amplitude data
are normalized to the mean amplitude of control sub-
jects and expressed in log units.21'39 Based on this
graph, it is evident that some hemizygotes show
greater cone than rod ERG amplitude reduction,
whereas others have results that fall close to the line
expected when reduction is equal.2139 The heterozy-
gotes fall within the range of normal data, show rela-
tively equal reduction of responses, or have greater
cone than rod amplitude reduction.
Figure 3 shows gray scale maps of cone and rod
sensitivity losses, determined from results of light-
and dark-adapted static perimetry, in one eye of four
hemizygotes. Patient IV/14, age 21 yr, has no rod sen-
sitivity loss at any of the loci tested, but many extrafo-
veal loci show cone sensitivity loss (mean loss for ab-
normal loci = 5.2 dB; SD = 1.1 dB). Sensitivity at the
foveal locus was normal. Patient IV/2, age 11 yr, has
marked cone sensitivity losses in the superior and
mid-peripheral fields with less pronounced cone dys-
function in the more peripheral field. Sensitivity at
the foveal locus was normal. Mean cone sensitivity
loss is 15.7 dB (SD = 7.6 dB). There is considerable
rod sensitivity loss in the mid-peripheral field, but sen-
sitivities in the central and peripheral fields are within
the normal limits. Mean rod sensitivity loss is 24.2 dB
(SD =17.1 dB). Patient IV/4, age 25 yr, shows a simi-
lar pattern of cone dysfunction to patient IV/2, but

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X-UNKED RP: PHENOTYPE OF R.P2 GENOTYPE / Jocobson er ol
3485
HEMIZYGOTES
PATIENT IV/14
CONE SENSITIVITY LOSS
PATIENT IV/2
PATIENT IV/4
PATIENT IV/9
-1
L
1
ECCENTRICITY (degrees)
Fig. 3. Dark- and light-adapted static threshold perimetry in one eye of four hemizygotes. Results of static perimetry are displayed as gray
scales of rod and cone sensitivity losses. Gray scales have 16 levels of gray, ranging from 0-54 dB for rods and 0-30 dB for cones. Black
indicates no detection of the stimulus. White indicates test result was within two standard deviations of the mean normal sensitivity for that
locus. Physiologic blind spot is shown as a black square at 12° in the temporal field.
has a slightly greater extent of severe cone dysfunction
in the mid-periphery (mean = 16.3 dB; SD = 8.1 dB).
Rod dysfunction in patient IV/4 is greater than in
patient IV/2. In the superior field, there is no measur-
able rod function, and no peripheral loci fall within
the normal limits (mean = 29.7 dB; SD = 14.3 dB).
Patient IV/9 has an extensive mid-peripheral scotoma
with only a residual central island of impaired cone
function and far peripheral islands of severely im-
paired rod and cone function. Mean cone sensitivity
loss is 23 dB (SD = 5.6 dB) and mean rod sensitivity
loss is 46 dB (SD = 8.6 dB).
The profile tests in Figure 4 provide greater detail of
the rod- and cone-mediated function in the central
60° of the hemizygotes. The two-color (500 and 650
nm stimuli) dark-adapted profiles in patient IV/14
show there is rod mediation or mixed rod and cone
mediation at the loci tested and that rod sensitivities
to the 500 nm stimulus are within two standard devia-
tions of the normal mean. The light-adapted (600 nm
stimulus) profile indicates that cone sensitivity is nor-
mal at fixation, but at extrafoveal loci sensitivities are
just below or at the normal limit. Patient IV/2 also
shows rod or mixed mediation across the field. Rod
sensitivity is within the normal limits only in the cen-
tral 20°. At greater eccentricities, sensitivities are re-
duced by about 3 log units. Cone sensitivity is normal
only at fixation, and there is decreasing sensitivity
with increasing eccentricity from fixation. Patient
V/2 retains rod sensitivity in the central 20-30°, but it
is reduced by at least 1 log unit; rod function is even
further reduced or unmeasurable at greater eccentrici-
ties. Cone sensitivity is substantial only in the central
few degrees. In patient IV/9, there is no measurable
rod sensitivity in the central 60°, and the residual
cone-mediated function by dark- or light-adapted pe-
rimetry is severely reduced.
Figure 5 shows gray scale maps of cone and rod
sensitivity losses in both eyes of two heterozygotes.
These maps illustrate a number of points. First, the
retinopathy is patchy, with regions of normal func-
tion adjacent to regions of dysfunction. Second, these
heterozygotes show interocular asymmetry in visual
field location and percentage of abnormal loci in each
eye. Third, the percentage of loci with cone sensitivity
loss is greater than the number with rod sensitivity
loss. In the left eye of patient III/1,75% of loci showed
abnormally reduced cone sensitivity, while 58% of
loci had abnormally reduced rod sensitivity. In the
right eye, 56% of loci had abnormal cone sensitivity,
while 27% had abnormal rod sensitivity. Patient IV/
17's left eye showed 72% of loci with abnormal cone
sensitivity versus 34% with abnormal rod sensitivity.
The relationship in the right eye was 56% versus 27%.
The findings from dark- and light-adapted perime-
try that there are retinal regions in hemizygotes and
heterozygotes that exhibit normal or slightly reduced
rod sensitivity and moderately impaired cone sensitiv-
ity are supported further in Figure 6, which shows
measurements of dark-adapted (upper) and light-

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INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / December 1992
Vol. 33
HEMIZYGOTES
m
0)z
UJ
PATIENT IV/14
40
MM RHR RRRHR R R RMMRR R R R \SVRRRMRR
PATIENT IV/2
40
PATIENT V/2
40
PATIENT IV/9
40
10 20 30
T
30
N
20 10
ECCENTRICITY (degrees)
Fig. 4. Dark-adapted (left)
and light-adapted (right) static
threshold perimetric profiles
along the horizontal meridian
for the central 60° in four
hemizygotes. For clarity, all
data are displayed as right
eyes; the physiologic blind
spot is shown as a hatched
bar. (Left) For the dark-
adapted profiles, squares indi-
cate thresholds determined
with the 500 nm stimulus and
triangles with the 650 nm stim-
ulus. The letters above the
thresholds are the photore-
ceptor mediations for detec-
tion of the 500 and 650 nm
stimuli. R, rods detect both
colors. M, mixed rod and
cone detection. C, cones de-
tect both colors.36"38 For pa-
tients IV/4, IV/2, and V/2,
the dashed lines delimit ± two
standard deviations
from the mean normal (n
= 10, ages 14-56 yr) for 500
nm. For patient IV/9, the
dashed lines delimit two SD
from the mean normal (n = 5,
ages 29-54) for 650 nm at the
cone plateau.2728 (Right) For
the light-adapted profiles, cir-
cles indicate the 600 nm stim-
ulus. The dashed lines delimit
± two SD from the mean nor-
mal (n = 10, ages 14-56 yr). N
is nasal and T is temporal in
the visual field.
(SD)
adapted (lower) spectral sensitivity at select loci in the
inferior field of one hemizygote and two heterozy-
gotes. In patient IV/14, the hemizygote, the dark-
adapted spectral sensitivity function corresponds to
that of the rod system and is within the normal range
of values for this locus. Light-adapted spectral sensitiv-
ity is reduced below the normal at all wavelengths
greater than 480 nm. This finding of decreased sensi-
tivity at longer wavelengths and normal short wave-
length sensitivity was examined further in patient IV/
14 with light-adapted (10 cd/m2) perimetry at 24 loci
in the central 48° using 440 and 600 nm stimuli.43 In
the right eye, 7 of 24 loci had abnormally reduced
sensitivities (>2 SD below the mean normal at each
locus) with the 440 nm stimulus, whereas 20 of the 24
loci were abnormal with the 600 nm stimulus. In the
left eye, 4 of 24 loci were abnormally reduced in sensi-
tivity with the 440 nm stimulus, whereas 17 of 24 loci
were abnormal with the 600 nm stimulus.
Heterozygote III/4 also has normal dark-adapted
(rod) sensitivity; light-adapted (cone) sensitivity is re-
duced at all wavelengths tested. Heterozygote IV/17

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X-LINKED RP: PHENOTYPE OF RP2 GENOTYPE / Jocobson er ol
3487
Fig. 5. Dark- and light-adapted static thresh-
old perimetry in both eyes of two heterozygotes.
The data are displayed in gray scale as in Fig-
ure 3.
2
Ul
O
36-i
24-
W , 2 -
HETEROZYGOTES
PATIENT Ml/1
CONE SENSITIVITY LOSS
T 72 60 48 36 24 12 0 12 24 36 48 NN 48 36 24 12 0 12 24 36 48 60 72 T
PATIENT IV/17
CONE SENSITIVITY LOSS
ROD SENSITIVITY LOSS
RF
--J
Hi
T 72 60 48 36 24 12 0 12 24 36 48 NN 48 36 24 12 0 12 24 36 48 60
ECCENTRICITY (degrees)
has a relatively small reduction of rod sensitivity, but
pronounced cone sensitivity loss at this test locus.
There was no detection of shorter wavelength stimuli.
Dark adaptometry was performed in heterozygotes
III/4 and IV/17 at the same loci that were tested for
spectral sensitivity; the time course was normal.
Analyses of the relationship between rod and cone
sensitivity losses determined from results of dark- and
light-adapted perimetry are shown in Figure 7 for
hemizygotes and heterozygotes. Data from patients
with known genotypes of ADRP3031 are presented for
comparison. In Figure 7 (upper eight panels), double
histogram gray scales show rod versus cone sensitivity
losses for one eye of two hemizygotes (IV/14 and IV/
2), both eyes of one heterozygote (IV/17), and one eye
of four ADRP patients with different rhodopsin mu-

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INVESTIGATIVE OPHTHALMOLOGY 6 VISUAL SCIENCE / December 1992
Vol. 30
PATIENT IV/14
PATIENT HI/4
PATIENT IV/17
CO
x>
£ 2 0
>
CO
z
UJ
0
500 600 700 400 500 600 700 400
WAVELENGTH (nm)
500 600
Fig. 6. Spectral sensitivity
measurements in the dark-
adapted (upper panels) and
light-adapted (lower panels)
states in a hemizygote (patient
IV/14) and two heterozygotes
(patients III/4 and IV/17)
compared to normal results
(area between solid lines repre-
sents ±2 SD from the mean
normal; n = 10, ages 20-45
yr). For patients IV/14 and
III/4, the test locus was 20° in
the inferior field. For patient
IV/17, the test locus was 38°
inferiorly.
tations. Each of the eight double histograms is a 16
X 16 matrix wherein the filled cells represent the rela-
tion between statistically significant (>2 SD from the
mean normal at that locus) cone sensitivity loss or rod
sensitivity loss at the same retinal location. In general,
the patterns in the double histograms of the XLRP
patients show greater cone than rod sensitivity losses
(especially patient IV/14 and the left eye of patient
IV/17) or relatively comparable cone and rod losses.
The patterns in these XLRP patients appear to differ
from those in the four ADRP patients with rhodopsin
mutations, who show more rod than cone sensitivity
losses.30'31
Figure 7 (lower graph) shows the relationship of
mean rod and cone sensitivity losses in all 10 XLRP
patients and, for comparison, in 17 ADRP patients
with rhodopsin mutations. The graph suggests a sepa-
ration between the two groups; this was tested statisti-
cally. Rod and cone sensitivity losses were considered
to be equally important dependent variables. For that
reason, Hotelling's T-squared, a multivariate proce-
dure,44 was employed to test for differences in the val-
ues of these parameters between XLRP and ADRP
patients. The two groups were significantly different
(P < 0.001). Density ellipses45 calculated to encom-
pass 67% of the distributions for each group are used
to display the variability within and correlation be-
tween rod and cone sensitivity losses. The choice of
67% is arbitrary and does not affect the statistical sig-
nificance of the results.
Discussion
This study characterized the functional phenotypes
of hemizygotes and heterozygotes in an XLRP family
with a defined gene locus, RP2, on the short arm of
the X chromosome. The phenotypes show intrafami-
lial consistency in the sense that patterns of rod and
cone dysfunction in the more severely affected hemi-
zygotes appear to reflect progression of patterns in
more mildly affected members. Also, the dysfunction
in patches of retinopathy of heterozygotes is like that
in retinal regions of hemizygotes at various stages of
the disease. The results suggest that the retinal degen-
eration in this XLRP RP2 family is expressed first as a
cone photoreceptor system dysfunction and, as the
disease progresses, the rod system also becomes in-
volved. At many stages of the disease, cone and rod
systems show comparable degrees of dysfunction, a
pattern that is distinguishable from the pattern of
greater rod than cone dysfunction found in many
other forms of RP.
Based on the functional phenotypes of the five
hemizygotes with different degrees of disease severity,
we propose that in this family the following sequence
of changes in visual function may occur as the retinal
degeneration progresses. At an early stage, a hemizy-
gote has cone dysfunction in the mid-peripheral ret-
ina and an abnormal cone ERG. Rod function mea-
sured by dark-adapted perimetry, dark-adapted spec-
tral sensitivity, and rod ERGs is within normal limits.

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No. 13
X-UNKED RP: PHENOTYPE OF RP2 GENOTYPE / Jocobson er ol
3489
IV/2
CD
•D
I
•
•
858
• no
• •
•
•
•
B • HUBI fcl
• •
•
•
• •
•
K
m
• • • • •
Mi
I ••••
•
•HH
•
•
H
Fig. 7. Relationship of psy-
chophysically determined rod
and cone sensitivity losses in
XLRP patients compared to
ADRP patients with muta-
tions in the gene encoding
rhodopsin. Upper two rows
are double histograms of rod
versus cone sensitivity losses
from dark- and light-adapted
perimetry results in one eye of
two hemizygotes (patients IV/
14 and IV/2), left (LE) and
right (RE) eyes of one hetero-
zygote (I V/l 7), and one eye of
four patients from four differ-
ent ADRP families with rho-
dopsin gene mutations. Each
cell in the double histogram
has a gray scale that corre-
sponds to the number of vi-
sual field loci with a specific
rod and cone sensitivity loss.
White represents no loci,
black represents >25 loci, and
the 16 levels of gray are
mapped linearly to number of
loci between 0 and 25. Lower
graph plots the mean values
for rod and cone sensitivity
losses in 10 XLRP patients
and 17 ADRP patients with
rhodopsin mutations. The
XLRP and ADRP groups
were significantly different in
the values of these parame-
ters. The density ellipses were
calculated to encompass 67%
of the distributions for each
group. ADRP patients are des-
ignated by the amino acid
substitutions resulting from
their rhodopsin gene muta-
tion. The first letter is the
XLRP
I V / t 4 IV/17, LE IV/17, RE
amino acid usually present at that position, followed by the position number, followed by the amino acid present in the mutant rhodopsin.
P23H, proline-23-histidine. T58R, threonine-58-arginine. R135W, arginine-135-tryptophan. Q344*, stopcodon mutation at glutamine-344.
ROD SENSITIVITY LOSS (dB)
25
CD
2,
(I)
CO
O
D XLRP HEMIZYGOTES
O XLRP HETEROZYGOTES
• ADRP P23H
• ADRP T58R
• ADRPR135W
* ADRP 0.344'
1 5
1
CO
Z
UJ
CO
UJ
z
o
o
ROD SENSITIVITY LOSS (dB)
At a further stage, there is an absolute scotoma for
cone function in the superior field, the mid-periphery
has both rod and cone dysfunction, and the peripheral
retina begins to show cone dysfunction, but still has
no rod dysfunction. Rod and cone ERGs both are
reduced in amplitude. With increasing severity of ex-
pression, the mid-peripheral annular scotoma be-
comes complete and absolute and there is rod and
cone dysfunction in the far periphery and central ret-
ina. Rod and cone ERGs are further reduced in am-
plitude. At an advanced stage, severely abnormal rod
and cone function exists in islands of the far periph-
ery, and only very reduced cone function is measur-
able centrally. A markedly diminished cone ERG is
detectable. This functional pattern in the advanced
stage is like that described previously in a study of two
XLRP hemizygotes.15
Heterozygotes in this pedigree can show a tapetal-
like reflex or patches of pigmentary retinopathy.
There can be a range of findings on retinal function
tests, from normal results to considerable rod and
cone dysfunction. The perimetric results suggest there
can be large regions of retinal dysfunction as well as
more isolated loci of dysfunction. The patches and the
loci show comparable rod and cone dysfunction or
greater cone than rod abnormalities. The types of ab-
normalities in rod and cone ERG parameters that we
found in the heterozygotes of this study are like those

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3490INVESTIGATIVE OPHTHALMOLOGY b VISUAL SCIENCE / December 1992
Vol. 33
found in earlier studies of XLRP heterozygotes of un-
known genotype.141618'20'21'23'24 Furthermore, we con-
cur with previous observations that there can be equiv-
alent reductions in cone and rod ERG amplitudes in
XLRP heterozygotes.21'24 However, we also found
that some heterozygotes in this family exhibit greater
cone than rod ERG dysfunction.
When the results of the clinical, psychophysical,
and electroretinographic tests are taken together, the
phenotypic expression in this X-linked pedigree is not
exactly like the phenotypes of other retinal degenera-
tive diseases that have been studied with similar meth-
ods. The ERG results alone can lead to the impression
that this family has a cone-rod dystrophy.39-46 Interest-
ingly, "cone-rod" patterns of ERG results have been
reported previously in XLRP patients with unknown
genotype.19>22>47'48 The reduced rod b-wave Vmax but
normal or slightly abnormal K in our patients resem-
ble the findings in some patients with cone-rod dys-
trophy and are unlike those usually described for
j^p 29,42,47 jn e reiationship between rod and cone sen-
sitivities determined psychophysically also could be
found in cone-rod dystrophy,39-50 and we demon-
strated that it differs from the result in ADRP patients
with rhodopsin mutations, the only other RP geno-
types that have been studied with the same tech-
niques.30-31
When the regional retinal variation of the disease is
considered, however, the XLRP hemizygotes have
patterns more like those found in typical RP than in
cone-rod dystrophy. The hemizygotes show mid-pe-
ripheral funduscopic and functional abnormalities
before peripheral and central changes. They do not
manifest the early and severe central retinal degenera-
tive and functional abnormalities and relative preser-
vation of mid-peripheral function found in the cone-
rod dystrophies.39'50-51 The finding of greater mid-
spectral than S cone dysfunction in patient IV/14, the
hemizygote with the mildest disease expression,
differs from the finding in cone dystrophy and typical
RP that S cone dysfunction precedes dysfunction in
the other photoreceptor-mediated mechanisms.52'53
Also, although there are some similarities in the find-
ings for patient IV/14 and young hemizygotes re-
ported as having X-linked cone dystrophy with a ta-
petal-like sheen,54-55 our hemizygotes with more ad-
vanced disease were unlike the more advanced
patients with this entity.54
An early onset of myopia recently has been re-
ported to be associated with the RP2 locus in
XLRP.26-27 The five hemizygotes in our study had
various degrees of myopia, a finding consistent with
previous reports of myopia in XLRP.5657 However,
the age of onset of the myopia in our patients is not
known. Three other issues raised in earlier reports are
worth noting. First, the suggestion that the tapetal-
like reflex may be a funduscopic feature of XLRP
heterozygotes exclusively in families with the RP3
locus58 is not supported by the findings in the present
family. Second, the finding of "cone-rod" and "rod-
cone" ERG patterns in the same XLRP family may
not be evidence of "inconsistency" or clinical hetero-
geneity4748 but may result from regional retinal varia-
tions of the disease at different stages of progression,
such as was evident from results of rod and cone pe-
rimetry in the hemizygotes of the present study.
Third, the observation based on clinical examinations
alone that there can be intrafamilial variability of ex-
pression in XLRP25 is confirmed by the clinical re-
sults from the family in this study. However, more
detailed testing of retinal function in this family led to
the identification of a definite pattern of retinal dys-
function that showed intrafamilial consistency. Thus,
understanding the relationship between phenotype
and the newly identified genotypes in RP may require
not only clinical examinations but also specialized
tests aimed at defining the underlying pathophys-
iology.
Key words: cone photoreceptor, electroretinogram, retinitis
pigmentosa, rod photoreceptor, X chromosome
Acknowledgments
We thank Mr. W. Feuer for statistical analyses; Dr. C.
Kemp and Dr. R. Knighton for critical review of the data;
Dr. J. Nathans and Dr. C.-H. Sung for molecular genetic
analyses of the ADRP patients; Ms. M. Roman, Mr. P.
Apathy, Ms. K. Stewart, and Ms. V. Zwaan for data collec-
tion; and Mrs. B. Koernig for help with clinical coordina-
tion of the study.
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