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Electroretinographic Testing as an Aid in Detection of Carriers of X-Chromosome-Linked Retinitis Pigmentosa
E L E C T R O R E T I N O G R A P H I C TESTING AS AN AID IN D E T E C T I O N O F CARRIERS O F X-CHROMOSOME-LINKED RETINITIS PIGMENTOSA E L I O T L. B E R S O N , M.D.,
Jo B E R N I C E R O S E N , M.D., Boston,
Approximately 35% of our patients with retinitis pigmentosa are males with no family history of disease, or males with one or more affected male relatives and no affected female relatives. It has been difficult to determine whether the mode of inheritance in these cases is X-chromosome-linked or autosomal re cessive. An approach to classification of these males with respect to genetic type has been examination of female relatives to determine whether they show the carri er state of X-chromosome-linked retinitis pigmentosa. Carriers of X-chromosome-linked reti nitis pigmentosa can be asymptomatic with good visual acuity, normal darkadaptation thresholds, and full visual fields. 1-8 Some have been detected on the basis of patches of bone spicule pigmen tation in the periphery, 5 , 9 " 1 3 or a tapetallike reflex in the macula and perimacHowever, many obligate u j a 4,i2,i4,i5 carriers of X-chromosome-linked disease, identified through pedigree studies, have shown no visible fundus abnormali ties. 1,2,6 ~ 8 Visual pigment concentrations as monitored with retinal densitometry 16 or the early receptor potential 1 7 have been reported as subnormal in those carriers tested. From the Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Mas sachusetts. This study was supported by Specialized Research Center Grant EY02014 and Research Ca reer Development Award EY70800 (Dr. Berson), from the National Eye Institute, and by the National Retinitis Pigmentosa Foundation, Baltimore, Mary land, and the George Gund Foundation, Cleveland, Ohio. Reprint requests to Eliot L. Berson, M.D., Berman-Gund Laboratory, 243 Charles St., Boston, MA 02114. 460
AND E M I L Y A. S I M O N O F F ,
B.A.
Massachusetts
Electroretinograms (ERGs) of carriers of X-chromosome-linked retinitis pig mentosa have been either normal in amplitude, 5 ' 8 , 1 1 ' 1 5 subnormal in ampli tude, 8 ' 1 0 ' 1 3 , 1 8 or even nondetectable. 1 5 De tection of the carrier state with ERG test ing was unsuccessful in one attempt in which known carriers were partially darkadapted for five to ten minutes before testing. 7 No studies of the carrier state have been reported in which a group of carriers were fully dark-adapted before testing and in which full-field ERG re sponses were evaluated with respect to cone and rod amplitudes and implicit times. We evaluated full-field ERGs of obli gate carriers from nine families with known X-chromosome-linked retinitis pigmentosa, and in some cases, daugh ters of these obligate carriers. In a tenth family with several affected males and possible X-chromosome-linked retinitis pigmentosa, we tested suspected female carriers to determine whether they showed ERGs similar to those seen in obligate carriers. Electroretinograms from obligate carriers of X-chromosome-linked retinitis pigmentosa were compared with those from female carriers of autosomal recessive disease to determine whether the full-field ERG could be used to differ entiate these carrier states. S U B J E C T S AND M E T H O D S
Full-field (ganzfeld) ERGs were re corded as previously described. 19 Patients were dark-adapted for 45 minutes before testing. In our ganzfeld test system the ranges for peak-to-peak amplitudes for 100 normal subjects between ages 6 and 55 years with 6 or less diopters of myopia
AMERICAN JOURNAL O F OPHTHALMOLOGY 87:460-468, 1979
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X-CHROMOSOME-LINKED RETINITIS PIGMENTOSA
were as follows: blue light (Wratten 47, 47A and 47B with 8 ft-L white light source) under dark-adapted conditions, 125 to 250 |JLV; white light (8 ft-L) under dark-adapted conditions, 350 to 700 |xV; and white (8 ft-L) flicker at 30 cycles per second (cps or Hz), 50 to 125 n-V. The time interval between stimulus onset and the major cornea-positive peak of the rod or cone response was used for measure ment of b-wave implicit times in these studies. For these normal subjects, rod b-wave implicit times to white light ranged from 71 to 108 msec, and cone b-wave implicit times to 30 Hz white flicker ranged from 25 to 32 msec. The blue light elicited a rod-isolated response, the white light (dark-adapted) elicited a rod-dominated response, and the white 30 Hz flicker a cone-isolated response. Twenty-three obligate white carriers were examined in nine families with Xchromosome-linked retinitis pigmentosa. The mode of inheritance was considered X-chromosome-linked only if one or more males were affected with widespread reti nitis pigmentosa, and at least one mother or daughter of an affected male showed a patch of bone spicule pigmentation in the periphery, or an abnormal tapetal-like re flex in the macula and perimacula. None of these families showed father-to-son transmission. In these families obligate female carriers were defined as those women who had either an affected son or an affected father or both. A representa tive family is shown in Figure lA.Ten daughters of obligate carriers from six of these families were also examined for the carrier state. All obligate carriers except Patients 6 and 22 (Table 1), and daughters of obli gate carriers (Table 2), had visual acuities of 6/12 (20/40) or better, normal dark-ad aptation thresholds in the GoldmannWeekers dark adaptometer to an 11 degree white test light presented 7 degrees above
461
the fovea, and normal color vision on the Farnsworth D-15 panel. Patient 6 had visual acuity of 6/9 (20/30) in the right eye, and counting fingers at 6 feet in the left eye, dark-adapted thresholds elevated 0.5 log unit above normal in the right eye, and 3 log units above normal in the left eye, and a tritan axis of confusion in the left eye on the Farnsworth D-15 panel. Patient 22 had visual acuity reduced to hand motions in the right eye and 6/120 (20/400) in the left eye, dark adaptation thresholds elevated 2 log units above normal, and normal color vision on the Farnsworth D-15 panel in both eyes. A tenth family (Fig. 1,B) with retinitis pigmentosa was examined to see if the mode of inheritance was X-chromosomelinked. This family had several affected males; the oldest affected male had vision reduced to counting fingers by age 30 years. The mothers of affected males (1-2 and II-8) had no visual symptoms and showed neither bone spicule pigmenta tion nor a tapetal-like reflex. A sister of the propositus (11-11) showed a patch of bone spicule pigmentation in the periphery but her sons were reported to be normal. All women examined except Patients 6 and 8 (Table 3) had visual acuities of 6/12 (20/40) or better, normal dark-adap tation thresholds, and normal color vi sion. Patient 6 had visual acuities reduced to 6/60 (20/200) in the right eye because of anisometropia and amblyopia. Patient 8 had visual acuity of R.E.: 6/60 (20/200) and L.E.: 6/30 (20/100) because of bilat eral atrophic macular scars. Full-field ERGs from obligate carriers were compared with those of 20 obligate white female carriers of autosomal reces sive retinitis pigmentosa. Families with autosomal recessive disease were defined as those in which male and female sib lings or two or more female siblings were comparably affected with widespread ret initis pigmentosa, and in which no older
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TABLE ]L FUNDI AND ELECTRORETINOGRAMS IN OBLIGATE CARRIERS OF X-CHROMOSOME-LINKED RETINITIS PIGMENTOSA
Electroretinograms t Right Eye Patient
Age
Family No.
No.
(yrs)
R.E.
3081
1 2 3 4
21 25 36 51
977
5
159
Blue
White
White
(30 Hz)
Blue
White
White
(30 Hz)
L.E.
l*V
^v
(*V
msec
xV
xV
nv
msec
B N N N
B N N N
50 150 225 75
200 340 525 210
40 50 75 30
33.5 32 30.5 32
50 150 225 50
200 340 525 130
40 50 75 20
33.5 32 3233.5
45
B
N
68
212
25
38
150
400
50
36
6 7
49 52
B B
B B
ND 123
50 275
25 50
39 39
ND 65
50 288
32 48
39 37.5
1194
8 9 10
41 48 49
B B B
B B B
200 125 50
375 230 175
35 25 25
36 34.5 36
125 175 50
300 300 150
30 40 25
36 34.5 36
403
11 12 13 14
14 18 20 65
N N N B
N N N N
106 29 147 40
330 208 412 150
47 26 71 15
32 37.5 30.5 37.5
NA 32 115 60
NA 159 294 300
NA 29 60 20
NA 35 30.5 36
1705
15 16
39 47
N B
N B
160 100
330 200
58 75
28 32
162 120
412 300
59 100
28 32
410
17 18 19
9 9 51
N N B
N N B
150 175 100
375 375 300
75 50 25
33.5 34.5 36
175 175 75
375 375 375
75 50 50
33.5 33.5 33.5
125
20 21 22
38 64 70
T T B
B.T T B
180 200 ND
335 400 ND
50 50 ND
36 33.5
—
120 200 ND
300 400 ND
25 50 ND
36 33.5
23
52
T
T
100
224
35
34.5
100
224
35
34.5
1924
Fundi*
Left Eye
—
*N designates normal; B, bone spicule pigmentation in one or more quadrants in the periphery;.T, tapetal-like reflex in macula. tNormal range for amplitudes: blue 125 to 250 (xV; white (dark-adapted) 350 to 700 (xV; white 30 Hz, 50 to 125 (xV. Normal range for white 30 cps b-wave implicit times, 25 to 32 msec. ND designates nondetectable ERG to single flashes of light; NA, not available.
relatives were affected. In these families mothers and daughters of affected pa tients were considered obligate carriers. RESULTS
Of the 23 obligate carriers, 14 showed signs of the carrier state in at least one eye by ophthalmoscopic examination; the re maining nine had a normal fundus ap
pearance in each eye (Table 1). Twentytwo of the 23 obligate carriers, except Patient 3, had abnormal amplitudes to white light under dark-adapted condi tions (<350 |xV), or delayed cone b-wave implicit times (> 32 msec), or both. Pa tients 17, 18, and 21 had normal ERG amplitudes with delays in cone b-wave implicit times as the only abnormality in
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X-CHROMOSOME-LINKED RETINITIS PIGMENTOSA
463
TABLE 2 FUNDI AND ELECTRORETINOGRAMS IN DAUGHTERS OF OBLIGATE CARRIERS OF X-CHROMOSOME-I.INKED RETINITIS PIGMENTOSA
E lectroretinogram s f Right Eye Patient
Age
No.
(yrs)
Family No.
Left Eye
Blue
White
White
(30 Hz)
Blue
White
White
(30 Hz)
R.E.
L.E.
txV
>*v
y.V
msec
pV
M.V
nv
msec
Fundi*
977
1 2 3
20 21 23
N N N
N B N
118 106 218
294 230 530
41 47 76
36 39 26
76 88 J206
230 170 700
38 20 88
36 39 26
403
4 5
30 32
N N
N N
112 194
334 418
41 82
28 25
100 194
329 435
35 82
28 25
1705
6 7
15 20
N N
N N
200 112
500 262
88 74
26 26
200 126
494 265
100 60
26 26
125
8
43
B,T
B,T
147
323
29
32
59
282
20
37.5
1194
9
21
N
N
123
318
70
30.5
106
341
70
30.5
1924
10
22
B,T
B,T
47
135
23
33.5
47
135
23
33.5
*N designates normal; B, bone spicule pigmentation in one or more quadrants in the periphery; T, tapetal-like reflex in macula. tNormal range for amplitudes: blue 125 to 250 JJIV; white (dark-adapted) 350 to 700 jiV; white 30 Hz, 50 to 125 (AV. Normal range for white 30 Hz b-wave implicit times, 25 to 32 msec.
A FAMILY 3081
I.
T 55
55
33 71
68 065 63
60
20
| a 25 60
40
58
»
/
62
38
' — 71 J 7 2
•6
B. FAMILY 844 I.
52
»
47
60 |
14
'25~ 21 "' 24 " 29~ 27" « - 29~ 26™ 24"'25
"•
-
■'
M
<5 *
fl^.'
-
I 42 22
ff
*
39^/ 36
12*
9
23" « - 24 22
6
^
^45 6$ LT
23 27
|73 T T 4
EMnMMd, offedtd
Q j ftft«cteo bj hit lory 0
Ewmln*d,nornialERG,agt<5
["I
"Ofmol by h«»fy, * t d 64
(V) ONigote corner by hi»ttr, ( 2 ) ObligaW carrier, clinically detected by fundm emm wvi/or ERG (•)
SuJMttedcoffier.jwWii
,X
P'OpOMtut
Fig. 1 (Berson, Rosen, and Simonoff). (A) Pedigree of family 3081 with X-chromosome-linked retinitis pigmentosa. Family number identifies the number of the propositus (111-29) in the files of the Berman-Gund Laboratory for the Study of Retinal Degenerations. (B) Pedigree of family 844 with suspected Xchromosome-linked retinitis pigmentosa. Family number identifies the number of the propositus (11-13) in the files of the Berman-Gund Laboratory. Findings of fundus examinations and measurements of ERGs are included in the Results (Tables 1 and 3).
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AMERICAN JOURNAL OF OPHTHALMOLOGY
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TABLE 3 FUNDI AND ELECTRORETINOGRAMS IN FEMALES IN A FAMILY* WITH SUSPECTED X-CHROMOSOME-LINKED RETINITIS PIGMENTOSA
EleetroretinogramsJ Right Eye Patient
Age
Fundit
No.
(yrs)
R.E.
1 2 3 4 5 6 7 8
9 12 15 16 22 42 44 77
N N N N N B N
§
Left Eye
Blue
White
White
(30 Hz)
Blue
White
White
(30 Hz)
L.E.
uV
^v
uV
msec
nv
M.V
t*v
msec
N N N N B B N
138 79 176 106 53 30 88 65
588 106 530 341 132 88 318 312
106 17 120 59 29 18 47 29
25 32 25
191 141 159 112 56 82 129 59
530 294 430 306 141 210 276 197
88 75 82 47 47 53 42 29
25
§
30.5 33.5
32 29 39
30.5
25 32
33.5
28 28 39
*Family 844, See Figure 1,B. f N designates normal; B, bone spicule pigmentation in one or more quadrants in the periphery. iNormal range for amplitudes: blue 125 to 250 u-V; white (dark-adapted) 350 to 700 u.V; white 30 Hz, 50 to 125 |xV. Normal range for white 30 Hz b-wave implicit times, 25 to 32 msec. §Atrophic macular scar.
the ERG. Although cone b-wave implicit times were delayed in many carriers, rod b-wave implicit times to blue light fell within the normal range. Figure 2 shows normal full-field ERGs (top row) and representative ERGs from four obligate carriers included in Table 1. Rows 2 and 4 illustrate abnormal ERGs in carriers who had a normal appearance to their fundi. Rows 3 and 5 illustrate abnor mal responses from obligate carriers who had an abnormal appearance to their fundi. Intensity-amplitude functions for blue and white light for five normal subjects and five carriers of X-chromosome-linked retinitis pigmentosa are shown in Figure 3. These carriers were among those who could be separated from normal subjects on the basis of ERG amplitudes to rela tively bright white light under darkadapted conditions. Whereas the range of amplitudes from normals and these carri ers overlapped for most intensities of blue light and for low intensities of white light, no overlap was observed for the
Fig. 2 (Berson, Rosen, and Simonoff). Electroretinograms from a normal subject and four obligate female carriers of X-chromosome-linked retinitis pigmentosa. Two to three responses to the same stimulus are represented. Stimulus onset is desig nated by the vertical hatched lines for columns 1 and 2, and vertical shock artifacts for column 3. Cornea-positivity is an upward deflection. Arrows in column 3 designate cone b-wave implicit times.
V O L . 87, N O . 4
X-CHROMOSOME-LINKED RETINITIS PIGMENTOSA
465
WHITE LIGHT
BLUE LIGHT 250
?oo
_
600
t<
100 _
150
I
I
50 0
(
i
1
\
700
\
i i
^ > a
■r
50C
£ 400 j
300
<
200
-
I*4 I
100
f
0
i
i -1.5
i -1.2
i
-0.9
i -0.6
i -0,3
i
0.0
LOG STIMULUS INTENSITY
1 -3.3
1 -3.0
i
-27
i
-2.4
I i
-2.1
|1
'
i1
i -1.8
i
-1.5
-1.2
1 -09
'
i 1 1 1 -0.6
1 -0.3
1 0.0
LOG STIMULUS INTENSITY
Fig. 3 (Berson, Rosen, and SimonofF). Intensity amplitude functions for blue light stimuli (left) and white light stimuli (right) under dark-adapted conditions for five normal subjects and five carriers of Xchromosome-linked retinitis pigmentosa. Mean amplitudes for each intensity are indicated by solid circles for normal subjects and open circles for patients; vertical bars designate ranges. Arrows designate stimulus intensities used in the ERG testing reported in Tables 1 to 3.
higher intensities of white light. The mean normal functions for blue and white light displaced horizontally did not fit respectively the mean functions gener ated by carriers, in that normal subjects individually and as a group showed steeper slopes than carriers. Three out of ten daughters of obligate carriers of X-chromosome-linked retinitis pigmentosa were identified as carriers on the basis of patches of peripheral bone spicule pigmentation or a tapetal-like re flex in the macula, or both; seven of ten, including the three with abnormal ap pearances to their fundi, could be iden tified on the basis of abnormal ERGs (Table 2). Each of these patients had a 50% chance of inheriting the carrier state. Representative ERGs from a normal sub ject (top row) and daughters of obligate carriers are shown in Figure 4. Daughters of obligate carriers either had normal ERGs (row 2) or ERGs that Were reduced in amplitude with or without delays in cone b-wave implicit times (bottom three rows). One daughter (rows 3 and 4) showed reduced amplitudes to white light under dark-adapted conditions and delayed cone b-wave implicit times in
both eyes, even though fundus abnormal ities were seen only in one eye. Data on eight women in a family are summarized in Table 3. On the basis of fundus examinations alone, the mode of
Fig. 4 (Berson, Rosen, and SimonofF). Electroretinograms for a normal subject and three daugh ters of obligate carriers of X-chromosome-linked retinitis pigmentosa. Horizontal arrows (column 3) designate cone b-wave implicit times.
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AMERICAN JOURNAL OF OPHTHALMOLOGY
inheritance could not be established as no woman with affected sons had the charac teristic bone spicule pigmentation or tapetal-like reflex sometimes seen in the carrier state. Two women (Fig. 1,B: 11-11 and 111-18) showed bone spicule pigmen tation in the periphery and had abnormal ERGs, but neither had an affected son or an affected father. Those women with affected sons (1-2 and II-8) showed abnor mal ERGs comparable to those recorded from obligate carriers; these ERGs estab lished that the mode of inheritance in this family was X-chroinosome-linked. Two daughters of carriers (111-15 and 111-22) with no diagnostic findings on ophthal moscopic examination showed abnormal ERGs. Two other daughters of carriers (111-20 and 111-23) had normal fundus findings and normal ERGs. Representa tive ERGs from a normal subject (top row) and some of the abnormal women in this family are illustrated in Figure 5. Normal ERGs were found in 20 female carriers of autosomal recessive retinitis pigmentosa, ages 6 to 55 years. Ampli tudes to blue light ranged from 125 to 250 M-V, white light 358 to 654 jxV, and white flicker 64 to 125 ixV. B-wave im plicit times to blue light were 79 to 103 msec and b-wave implicit times to 30 Hz white flicker were 25 to 32 msec. None of these women showed bone spicule pig mentation or a tapetal-like reflex. DISCUSSION
In our study, 22 out of 23 or 96% of obligate carriers of X-chromosome-linked retinitis pigmentosa could be detected through reductions in amplitudes of dark-adapted full-field ERG responses or through delays in cone ERG b-wave im plicit times, or both. Three of 22 carriers were identified on the basis of delayed cone b-wave implicit times alone. Only 60% of these obligate carriers would have been detected by ophthalmoscopic exam ination alone. Among women of child-
APRIL, 1979 Whitel30cpsl
II Fig. 5 (Bcrson, Rosen, and Simonoff). Eleetroretinograms for a normal subject and four suspected carrier women in a family with possible Xchromosome-linked retinitis pigmento*sa. Horizon tal arrows (column 3) designate cone b-wave implic it times. Genetic typing of this family as Xchroinosome-linked was established through the ERGs.
bearing age (15 to 40 years old) only three out of seven obligate carriers and two out of five carrier daughters of obligate carri ers were detected by ophthalmoscopic examination. That less than 50% of carri ers of X-chromosome-linked retinitis pig mentosa of child-bearing age could be identified on the basis of the ophthalmo scopic examination emphasizes the im portance of the ERG as an aid in detect ing carriers in this age group. In the case of affected males with no affected female relatives (about 35% of our population with retinitis pigmentosa), the question often arises as to whether they have X-chromosome-linked or auto somal recessive retinitis pigmentosa. Males with X-chromosome-linked disease are usually virtually blind by age 30 to 40 years, whereas males and females with autosomal recessive disease usually retain
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X-CHROMOSOME-LINKED RETINITIS PIGMENTOSA
vision until age 45 to 60 years. Evidence derived from this study indicates that the mode of inheritance and visual prognosis can be determined in almost all cases through ERG testing of the mother or daughter of an affected male. Once car rier females are identified on the basis of ERG or fundus abnormalities, affec ted male relatives would know they have X-ehromosome-linked disease and all of their daughters would be carriers and all of their sons would be normal. Female relatives identified as carriers of X-chromosome-linked retinitis pigmen tosa would know that they have a 50% chance of having an affected son or a 50% chance of having a carrier daughter with each childbirth. Rod and cone ERGs ranged from nor mal amplitudes to nondetectable respons es, suggesting wide variability in the area of retina involved in carriers. The ERGs indicated not only differences among car riers, but also differences between two eyes of the same carrier. Three obligate carriers could only be identified by ab normal ERG recordings in one eye; we therefore recommend that both eyes of a suspected female carrier be evaluated when deciding if she is abnormal. Addi tional precautions included interpreta tions of ERGs considering that increasing age, 20 high axial myopia, 2 1 - 2 3 miotic pu pils, hazy media, and extensive uveal pig mentation have been associated with de creases in ERG amplitudes. Whether photoreceptors are completely absent in parts of the retina or whether some or all photoreceptors contain less visual pigment is not certain. Retinal densitometric studies have shown decreases in rhodopsin concentrations within ten degree areas of retina, 7 ' 16 but these meas urements could reflect reductions in visu al pigment concentrations in some or all rods, loss of rods in the area tested, or both. The reduced rod ERG amplitudes with normal rod b-wave implicit times
467
observed in about two-thirds of the carri ers could not be simulated in normal subjects tested with neutral density filters interposed between the stimulus and the eye, as normal subjects showed responses that were both reduced in amplitude and delayed in b-wave implicit times. 2 4 The slopes of intensity-amplitude func tions for rod-isolated responses to blue light and rod-dominated responses to white light were steeper for normal sub jects than for carriers; this difference also could not be explained by a neutral density effect involving all rods. These findings are inconsistent with the idea that these carriers have the same decrease in visual pigment concentration in all rods, and raise the possibility that they have decreased visual pigment concentra tions in some rods, or loss of some rods, or both. These ERGs suggest patchy in volvement of rods and are therefore con sistent with the Lyon hypothesis 2 5 of ran dom inactivation of one X chromosome during embryogenesis. SUMMARY
Twenty-two of 23 obligate female car riers in nine families with known Xchromosome-linked retinitis pigmentosa were detected on the basis of abnormal full-field electroretinograms (ERGs). On ly 14 of these carriers had fundus find ings characteristic of the carrier state. Electroretinograms of carriers were either reduced in amplitude to white light un der dark-adapted conditions or delayed in cone b-wave implicit time, or both. Daughters of obligate carriers had either normal ERGs or abnormal ERGs simi lar to those recorded from obligate car riers. Abnormal ERGs of carriers of Xchromosome-linked retinitis pigmentosa contrasted with the normal ERGs record ed from female carriers of autosomal re cessive disease. These data support the idea that ERG testing of female relatives of males with retinitis pigmentosa can
468
AMERICAN JOURNAL OF OPHTHALMOLOGY
help to establish for a given family whether the mode of inheritance is Xchromosome-linked or autosomal reces sive. REFERENCES 1. Nettleship, E.: The Bowman lecture on some hereditary diseases of the eye. Trans. Ophthalmol. Soc. U.K. 29:57, 1909. 2. Usher, C. H.: On a few hereditary eye affec tions. Trans. Ophthalmol. Soc. U.K. 55:164, 1935. 3. McKenzie, D. S.: The inheritance of retinitis pigmentosa in one family. Trans. Ophthalmol. Soc. N.Z. 5:79, 1951. 4. Weiner, R. L., and Falls, H. F.: Intermediate sex-linked retinitis pigmentosa. Arch. Ophthalmol. 53:530, 1955. 5. Goodman, G., Ripps, H., and Siegal, I. M.: Sex-linked ocular disorders. Trait expressivity in males and carrier females. Arch. Ophthalmol. 73: 387, 1965. 6. Kobayashi, V. A.: Genetic study on retinitis pigmentosa. Jpn. J. Ophthalmol. 4:82, 1960. 7. Bird, A. C.: X-linked retinitis pigmentosa. Br. J. Ophthalmol. 59:177, 1975. 8. Schappert-Kimmijser, J.: Les degenerescences tapetoretiniennes du type X chromosomal aux PaysBas. Bull Mem. Soc. Fr. Ophthalmol. 76:122, 1963. 9. Klein, D., Franceschetti, A., Hussels, I., Race, R. R., and Sanger, R.: X-linked retinitis pigmentosa and linkage studies with Xg blood-groups. Lancet 1:974, 1967. 10. Krill, A. E.: Observations of carriers of Xchromosomal-linked chorioretinal degenerations. Do these support the "inactivation hypothesis"? Am. J. Ophthalmol. 64:1029, 1967. 11. Berson, E. L., Gouras, P., Gunkel, R. K., and Myrianthopoulos, N.C.: Rod and cone responses in sex-linked retinitis pigmentosa. Arch. Ophthalmol. 81:215, 1969. 12. Falls, H. F., and Cotterman, C. W.: Choroido-retinal degeneration. A sex linked form in
APRIL, 1979
which heterozygous women exhibit a tapetal-like reflex. Arch. Ophthalmol. 40:685, 1948. 13. Jay, B., and Bird, A. C.: X-linked retinitis pigmentosa. Trans. Am. Acad. Ophthalmol. Otolaryngol. 77:641, 1973. 14. Cicarelli, E. C.: A new syndrome of tapetallike reflexes with ring scotomata. Arch. Ophthalmol. 67:316, 1962. 15. Francois, J.: Chorioretinal degeneration with retinitis pigmentosa of intermediate sex-linked he redity. Doc. Ophthalmol. 16:111, 1962. 16. Bird, A. C., and Hyman, V.: Detection of heterozygotes in families with X-linked pigmentary retinopathy by measurement of retinal rhodopsin concentration. Trans. Ophthalmol. Soc. U.K. 92:221, 1972. 17. Berson, E. L., and Goldstein, E. B.: Early receptor potential in sex-linked retinitis pigmentosa. Invest. Ophthalmol. 9:58, 1970. 18. Franceschetti, A., Frangois, J., and Babel, J.: Chorioretinal Heredodegenerations. Springfield, Charles C Thomas, pp. 589-600, 1974. 19. Rabin, A. R., and Berson, E. L.: A full-field system for clinical electroretinography. Arch. Ophthalmol. 92:59, 1974. 20. Karpe, G., Rickenback, K., and Thomasson, S.: The clinical electroretinogram. The normal electroretinogram above 50 years of age. Arch. Oph thalmol. 28:301, 1950. 21. Dhanda, R. P.: ERG in myopic retinal degen erations. Jpn. J. Ophthalmol. [Suppl.] 10:325, 1966. 22. Pallin, O.: The influence of the axial length of the eye on the size of the recorded b- potential in the clinical single-flash electroretinogram. Acta Oph thalmol. [Suppl.] 101, 1969. 23. Black, R. K., Jay, B., and Kolb, H.: Electrical activity in the eye in high myopia. Br. J. Ophthal mol. 50:629, 1966. 24. Berson, E. L., and Kanters, L.: Cone and rod responses in a family with recessively inherited retinitis pigmentosa. Arch. Ophthalmol. 84:288, 1970. 25. Lyon, M. F.: Gene action in the X-chromosome of the mouse (Mus musculus), Nature 190:372, 1961.
Jo B E R N I C E R O S E N , M.D., Boston,
Approximately 35% of our patients with retinitis pigmentosa are males with no family history of disease, or males with one or more affected male relatives and no affected female relatives. It has been difficult to determine whether the mode of inheritance in these cases is X-chromosome-linked or autosomal re cessive. An approach to classification of these males with respect to genetic type has been examination of female relatives to determine whether they show the carri er state of X-chromosome-linked retinitis pigmentosa. Carriers of X-chromosome-linked reti nitis pigmentosa can be asymptomatic with good visual acuity, normal darkadaptation thresholds, and full visual fields. 1-8 Some have been detected on the basis of patches of bone spicule pigmen tation in the periphery, 5 , 9 " 1 3 or a tapetallike reflex in the macula and perimacHowever, many obligate u j a 4,i2,i4,i5 carriers of X-chromosome-linked disease, identified through pedigree studies, have shown no visible fundus abnormali ties. 1,2,6 ~ 8 Visual pigment concentrations as monitored with retinal densitometry 16 or the early receptor potential 1 7 have been reported as subnormal in those carriers tested. From the Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Mas sachusetts. This study was supported by Specialized Research Center Grant EY02014 and Research Ca reer Development Award EY70800 (Dr. Berson), from the National Eye Institute, and by the National Retinitis Pigmentosa Foundation, Baltimore, Mary land, and the George Gund Foundation, Cleveland, Ohio. Reprint requests to Eliot L. Berson, M.D., Berman-Gund Laboratory, 243 Charles St., Boston, MA 02114. 460
AND E M I L Y A. S I M O N O F F ,
B.A.
Massachusetts
Electroretinograms (ERGs) of carriers of X-chromosome-linked retinitis pig mentosa have been either normal in amplitude, 5 ' 8 , 1 1 ' 1 5 subnormal in ampli tude, 8 ' 1 0 ' 1 3 , 1 8 or even nondetectable. 1 5 De tection of the carrier state with ERG test ing was unsuccessful in one attempt in which known carriers were partially darkadapted for five to ten minutes before testing. 7 No studies of the carrier state have been reported in which a group of carriers were fully dark-adapted before testing and in which full-field ERG re sponses were evaluated with respect to cone and rod amplitudes and implicit times. We evaluated full-field ERGs of obli gate carriers from nine families with known X-chromosome-linked retinitis pigmentosa, and in some cases, daugh ters of these obligate carriers. In a tenth family with several affected males and possible X-chromosome-linked retinitis pigmentosa, we tested suspected female carriers to determine whether they showed ERGs similar to those seen in obligate carriers. Electroretinograms from obligate carriers of X-chromosome-linked retinitis pigmentosa were compared with those from female carriers of autosomal recessive disease to determine whether the full-field ERG could be used to differ entiate these carrier states. S U B J E C T S AND M E T H O D S
Full-field (ganzfeld) ERGs were re corded as previously described. 19 Patients were dark-adapted for 45 minutes before testing. In our ganzfeld test system the ranges for peak-to-peak amplitudes for 100 normal subjects between ages 6 and 55 years with 6 or less diopters of myopia
AMERICAN JOURNAL O F OPHTHALMOLOGY 87:460-468, 1979
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X-CHROMOSOME-LINKED RETINITIS PIGMENTOSA
were as follows: blue light (Wratten 47, 47A and 47B with 8 ft-L white light source) under dark-adapted conditions, 125 to 250 |JLV; white light (8 ft-L) under dark-adapted conditions, 350 to 700 |xV; and white (8 ft-L) flicker at 30 cycles per second (cps or Hz), 50 to 125 n-V. The time interval between stimulus onset and the major cornea-positive peak of the rod or cone response was used for measure ment of b-wave implicit times in these studies. For these normal subjects, rod b-wave implicit times to white light ranged from 71 to 108 msec, and cone b-wave implicit times to 30 Hz white flicker ranged from 25 to 32 msec. The blue light elicited a rod-isolated response, the white light (dark-adapted) elicited a rod-dominated response, and the white 30 Hz flicker a cone-isolated response. Twenty-three obligate white carriers were examined in nine families with Xchromosome-linked retinitis pigmentosa. The mode of inheritance was considered X-chromosome-linked only if one or more males were affected with widespread reti nitis pigmentosa, and at least one mother or daughter of an affected male showed a patch of bone spicule pigmentation in the periphery, or an abnormal tapetal-like re flex in the macula and perimacula. None of these families showed father-to-son transmission. In these families obligate female carriers were defined as those women who had either an affected son or an affected father or both. A representa tive family is shown in Figure lA.Ten daughters of obligate carriers from six of these families were also examined for the carrier state. All obligate carriers except Patients 6 and 22 (Table 1), and daughters of obli gate carriers (Table 2), had visual acuities of 6/12 (20/40) or better, normal dark-ad aptation thresholds in the GoldmannWeekers dark adaptometer to an 11 degree white test light presented 7 degrees above
461
the fovea, and normal color vision on the Farnsworth D-15 panel. Patient 6 had visual acuity of 6/9 (20/30) in the right eye, and counting fingers at 6 feet in the left eye, dark-adapted thresholds elevated 0.5 log unit above normal in the right eye, and 3 log units above normal in the left eye, and a tritan axis of confusion in the left eye on the Farnsworth D-15 panel. Patient 22 had visual acuity reduced to hand motions in the right eye and 6/120 (20/400) in the left eye, dark adaptation thresholds elevated 2 log units above normal, and normal color vision on the Farnsworth D-15 panel in both eyes. A tenth family (Fig. 1,B) with retinitis pigmentosa was examined to see if the mode of inheritance was X-chromosomelinked. This family had several affected males; the oldest affected male had vision reduced to counting fingers by age 30 years. The mothers of affected males (1-2 and II-8) had no visual symptoms and showed neither bone spicule pigmenta tion nor a tapetal-like reflex. A sister of the propositus (11-11) showed a patch of bone spicule pigmentation in the periphery but her sons were reported to be normal. All women examined except Patients 6 and 8 (Table 3) had visual acuities of 6/12 (20/40) or better, normal dark-adap tation thresholds, and normal color vi sion. Patient 6 had visual acuities reduced to 6/60 (20/200) in the right eye because of anisometropia and amblyopia. Patient 8 had visual acuity of R.E.: 6/60 (20/200) and L.E.: 6/30 (20/100) because of bilat eral atrophic macular scars. Full-field ERGs from obligate carriers were compared with those of 20 obligate white female carriers of autosomal reces sive retinitis pigmentosa. Families with autosomal recessive disease were defined as those in which male and female sib lings or two or more female siblings were comparably affected with widespread ret initis pigmentosa, and in which no older
462
AMERICAN JOURNAL OF OPHTHALMOLOGY
APRIL, 1979
TABLE ]L FUNDI AND ELECTRORETINOGRAMS IN OBLIGATE CARRIERS OF X-CHROMOSOME-LINKED RETINITIS PIGMENTOSA
Electroretinograms t Right Eye Patient
Age
Family No.
No.
(yrs)
R.E.
3081
1 2 3 4
21 25 36 51
977
5
159
Blue
White
White
(30 Hz)
Blue
White
White
(30 Hz)
L.E.
l*V
^v
(*V
msec
xV
xV
nv
msec
B N N N
B N N N
50 150 225 75
200 340 525 210
40 50 75 30
33.5 32 30.5 32
50 150 225 50
200 340 525 130
40 50 75 20
33.5 32 3233.5
45
B
N
68
212
25
38
150
400
50
36
6 7
49 52
B B
B B
ND 123
50 275
25 50
39 39
ND 65
50 288
32 48
39 37.5
1194
8 9 10
41 48 49
B B B
B B B
200 125 50
375 230 175
35 25 25
36 34.5 36
125 175 50
300 300 150
30 40 25
36 34.5 36
403
11 12 13 14
14 18 20 65
N N N B
N N N N
106 29 147 40
330 208 412 150
47 26 71 15
32 37.5 30.5 37.5
NA 32 115 60
NA 159 294 300
NA 29 60 20
NA 35 30.5 36
1705
15 16
39 47
N B
N B
160 100
330 200
58 75
28 32
162 120
412 300
59 100
28 32
410
17 18 19
9 9 51
N N B
N N B
150 175 100
375 375 300
75 50 25
33.5 34.5 36
175 175 75
375 375 375
75 50 50
33.5 33.5 33.5
125
20 21 22
38 64 70
T T B
B.T T B
180 200 ND
335 400 ND
50 50 ND
36 33.5
—
120 200 ND
300 400 ND
25 50 ND
36 33.5
23
52
T
T
100
224
35
34.5
100
224
35
34.5
1924
Fundi*
Left Eye
—
*N designates normal; B, bone spicule pigmentation in one or more quadrants in the periphery;.T, tapetal-like reflex in macula. tNormal range for amplitudes: blue 125 to 250 (xV; white (dark-adapted) 350 to 700 (xV; white 30 Hz, 50 to 125 (xV. Normal range for white 30 cps b-wave implicit times, 25 to 32 msec. ND designates nondetectable ERG to single flashes of light; NA, not available.
relatives were affected. In these families mothers and daughters of affected pa tients were considered obligate carriers. RESULTS
Of the 23 obligate carriers, 14 showed signs of the carrier state in at least one eye by ophthalmoscopic examination; the re maining nine had a normal fundus ap
pearance in each eye (Table 1). Twentytwo of the 23 obligate carriers, except Patient 3, had abnormal amplitudes to white light under dark-adapted condi tions (<350 |xV), or delayed cone b-wave implicit times (> 32 msec), or both. Pa tients 17, 18, and 21 had normal ERG amplitudes with delays in cone b-wave implicit times as the only abnormality in
VOL. 87, N O . 4
X-CHROMOSOME-LINKED RETINITIS PIGMENTOSA
463
TABLE 2 FUNDI AND ELECTRORETINOGRAMS IN DAUGHTERS OF OBLIGATE CARRIERS OF X-CHROMOSOME-I.INKED RETINITIS PIGMENTOSA
E lectroretinogram s f Right Eye Patient
Age
No.
(yrs)
Family No.
Left Eye
Blue
White
White
(30 Hz)
Blue
White
White
(30 Hz)
R.E.
L.E.
txV
>*v
y.V
msec
pV
M.V
nv
msec
Fundi*
977
1 2 3
20 21 23
N N N
N B N
118 106 218
294 230 530
41 47 76
36 39 26
76 88 J206
230 170 700
38 20 88
36 39 26
403
4 5
30 32
N N
N N
112 194
334 418
41 82
28 25
100 194
329 435
35 82
28 25
1705
6 7
15 20
N N
N N
200 112
500 262
88 74
26 26
200 126
494 265
100 60
26 26
125
8
43
B,T
B,T
147
323
29
32
59
282
20
37.5
1194
9
21
N
N
123
318
70
30.5
106
341
70
30.5
1924
10
22
B,T
B,T
47
135
23
33.5
47
135
23
33.5
*N designates normal; B, bone spicule pigmentation in one or more quadrants in the periphery; T, tapetal-like reflex in macula. tNormal range for amplitudes: blue 125 to 250 JJIV; white (dark-adapted) 350 to 700 jiV; white 30 Hz, 50 to 125 (AV. Normal range for white 30 Hz b-wave implicit times, 25 to 32 msec.
A FAMILY 3081
I.
T 55
55
33 71
68 065 63
60
20
| a 25 60
40
58
»
/
62
38
' — 71 J 7 2
•6
B. FAMILY 844 I.
52
»
47
60 |
14
'25~ 21 "' 24 " 29~ 27" « - 29~ 26™ 24"'25
"•
-
■'
M
<5 *
fl^.'
-
I 42 22
ff
*
39^/ 36
12*
9
23" « - 24 22
6
^
^45 6$ LT
23 27
|73 T T 4
EMnMMd, offedtd
Q j ftft«cteo bj hit lory 0
Ewmln*d,nornialERG,agt<5
["I
"Ofmol by h«»fy, * t d 64
(V) ONigote corner by hi»ttr, ( 2 ) ObligaW carrier, clinically detected by fundm emm wvi/or ERG (•)
SuJMttedcoffier.jwWii
,X
P'OpOMtut
Fig. 1 (Berson, Rosen, and Simonoff). (A) Pedigree of family 3081 with X-chromosome-linked retinitis pigmentosa. Family number identifies the number of the propositus (111-29) in the files of the Berman-Gund Laboratory for the Study of Retinal Degenerations. (B) Pedigree of family 844 with suspected Xchromosome-linked retinitis pigmentosa. Family number identifies the number of the propositus (11-13) in the files of the Berman-Gund Laboratory. Findings of fundus examinations and measurements of ERGs are included in the Results (Tables 1 and 3).
464
AMERICAN JOURNAL OF OPHTHALMOLOGY
APRIL, 1979
TABLE 3 FUNDI AND ELECTRORETINOGRAMS IN FEMALES IN A FAMILY* WITH SUSPECTED X-CHROMOSOME-LINKED RETINITIS PIGMENTOSA
EleetroretinogramsJ Right Eye Patient
Age
Fundit
No.
(yrs)
R.E.
1 2 3 4 5 6 7 8
9 12 15 16 22 42 44 77
N N N N N B N
§
Left Eye
Blue
White
White
(30 Hz)
Blue
White
White
(30 Hz)
L.E.
uV
^v
uV
msec
nv
M.V
t*v
msec
N N N N B B N
138 79 176 106 53 30 88 65
588 106 530 341 132 88 318 312
106 17 120 59 29 18 47 29
25 32 25
191 141 159 112 56 82 129 59
530 294 430 306 141 210 276 197
88 75 82 47 47 53 42 29
25
§
30.5 33.5
32 29 39
30.5
25 32
33.5
28 28 39
*Family 844, See Figure 1,B. f N designates normal; B, bone spicule pigmentation in one or more quadrants in the periphery. iNormal range for amplitudes: blue 125 to 250 u-V; white (dark-adapted) 350 to 700 u.V; white 30 Hz, 50 to 125 |xV. Normal range for white 30 Hz b-wave implicit times, 25 to 32 msec. §Atrophic macular scar.
the ERG. Although cone b-wave implicit times were delayed in many carriers, rod b-wave implicit times to blue light fell within the normal range. Figure 2 shows normal full-field ERGs (top row) and representative ERGs from four obligate carriers included in Table 1. Rows 2 and 4 illustrate abnormal ERGs in carriers who had a normal appearance to their fundi. Rows 3 and 5 illustrate abnor mal responses from obligate carriers who had an abnormal appearance to their fundi. Intensity-amplitude functions for blue and white light for five normal subjects and five carriers of X-chromosome-linked retinitis pigmentosa are shown in Figure 3. These carriers were among those who could be separated from normal subjects on the basis of ERG amplitudes to rela tively bright white light under darkadapted conditions. Whereas the range of amplitudes from normals and these carri ers overlapped for most intensities of blue light and for low intensities of white light, no overlap was observed for the
Fig. 2 (Berson, Rosen, and Simonoff). Electroretinograms from a normal subject and four obligate female carriers of X-chromosome-linked retinitis pigmentosa. Two to three responses to the same stimulus are represented. Stimulus onset is desig nated by the vertical hatched lines for columns 1 and 2, and vertical shock artifacts for column 3. Cornea-positivity is an upward deflection. Arrows in column 3 designate cone b-wave implicit times.
V O L . 87, N O . 4
X-CHROMOSOME-LINKED RETINITIS PIGMENTOSA
465
WHITE LIGHT
BLUE LIGHT 250
?oo
_
600
t<
100 _
150
I
I
50 0
(
i
1
\
700
\
i i
^ > a
■r
50C
£ 400 j
300
<
200
-
I*4 I
100
f
0
i
i -1.5
i -1.2
i
-0.9
i -0.6
i -0,3
i
0.0
LOG STIMULUS INTENSITY
1 -3.3
1 -3.0
i
-27
i
-2.4
I i
-2.1
|1
'
i1
i -1.8
i
-1.5
-1.2
1 -09
'
i 1 1 1 -0.6
1 -0.3
1 0.0
LOG STIMULUS INTENSITY
Fig. 3 (Berson, Rosen, and SimonofF). Intensity amplitude functions for blue light stimuli (left) and white light stimuli (right) under dark-adapted conditions for five normal subjects and five carriers of Xchromosome-linked retinitis pigmentosa. Mean amplitudes for each intensity are indicated by solid circles for normal subjects and open circles for patients; vertical bars designate ranges. Arrows designate stimulus intensities used in the ERG testing reported in Tables 1 to 3.
higher intensities of white light. The mean normal functions for blue and white light displaced horizontally did not fit respectively the mean functions gener ated by carriers, in that normal subjects individually and as a group showed steeper slopes than carriers. Three out of ten daughters of obligate carriers of X-chromosome-linked retinitis pigmentosa were identified as carriers on the basis of patches of peripheral bone spicule pigmentation or a tapetal-like re flex in the macula, or both; seven of ten, including the three with abnormal ap pearances to their fundi, could be iden tified on the basis of abnormal ERGs (Table 2). Each of these patients had a 50% chance of inheriting the carrier state. Representative ERGs from a normal sub ject (top row) and daughters of obligate carriers are shown in Figure 4. Daughters of obligate carriers either had normal ERGs (row 2) or ERGs that Were reduced in amplitude with or without delays in cone b-wave implicit times (bottom three rows). One daughter (rows 3 and 4) showed reduced amplitudes to white light under dark-adapted conditions and delayed cone b-wave implicit times in
both eyes, even though fundus abnormal ities were seen only in one eye. Data on eight women in a family are summarized in Table 3. On the basis of fundus examinations alone, the mode of
Fig. 4 (Berson, Rosen, and SimonofF). Electroretinograms for a normal subject and three daugh ters of obligate carriers of X-chromosome-linked retinitis pigmentosa. Horizontal arrows (column 3) designate cone b-wave implicit times.
466
AMERICAN JOURNAL OF OPHTHALMOLOGY
inheritance could not be established as no woman with affected sons had the charac teristic bone spicule pigmentation or tapetal-like reflex sometimes seen in the carrier state. Two women (Fig. 1,B: 11-11 and 111-18) showed bone spicule pigmen tation in the periphery and had abnormal ERGs, but neither had an affected son or an affected father. Those women with affected sons (1-2 and II-8) showed abnor mal ERGs comparable to those recorded from obligate carriers; these ERGs estab lished that the mode of inheritance in this family was X-chroinosome-linked. Two daughters of carriers (111-15 and 111-22) with no diagnostic findings on ophthal moscopic examination showed abnormal ERGs. Two other daughters of carriers (111-20 and 111-23) had normal fundus findings and normal ERGs. Representa tive ERGs from a normal subject (top row) and some of the abnormal women in this family are illustrated in Figure 5. Normal ERGs were found in 20 female carriers of autosomal recessive retinitis pigmentosa, ages 6 to 55 years. Ampli tudes to blue light ranged from 125 to 250 M-V, white light 358 to 654 jxV, and white flicker 64 to 125 ixV. B-wave im plicit times to blue light were 79 to 103 msec and b-wave implicit times to 30 Hz white flicker were 25 to 32 msec. None of these women showed bone spicule pig mentation or a tapetal-like reflex. DISCUSSION
In our study, 22 out of 23 or 96% of obligate carriers of X-chromosome-linked retinitis pigmentosa could be detected through reductions in amplitudes of dark-adapted full-field ERG responses or through delays in cone ERG b-wave im plicit times, or both. Three of 22 carriers were identified on the basis of delayed cone b-wave implicit times alone. Only 60% of these obligate carriers would have been detected by ophthalmoscopic exam ination alone. Among women of child-
APRIL, 1979 Whitel30cpsl
II Fig. 5 (Bcrson, Rosen, and Simonoff). Eleetroretinograms for a normal subject and four suspected carrier women in a family with possible Xchromosome-linked retinitis pigmento*sa. Horizon tal arrows (column 3) designate cone b-wave implic it times. Genetic typing of this family as Xchroinosome-linked was established through the ERGs.
bearing age (15 to 40 years old) only three out of seven obligate carriers and two out of five carrier daughters of obligate carri ers were detected by ophthalmoscopic examination. That less than 50% of carri ers of X-chromosome-linked retinitis pig mentosa of child-bearing age could be identified on the basis of the ophthalmo scopic examination emphasizes the im portance of the ERG as an aid in detect ing carriers in this age group. In the case of affected males with no affected female relatives (about 35% of our population with retinitis pigmentosa), the question often arises as to whether they have X-chromosome-linked or auto somal recessive retinitis pigmentosa. Males with X-chromosome-linked disease are usually virtually blind by age 30 to 40 years, whereas males and females with autosomal recessive disease usually retain
VOL. 87, NO. 4
X-CHROMOSOME-LINKED RETINITIS PIGMENTOSA
vision until age 45 to 60 years. Evidence derived from this study indicates that the mode of inheritance and visual prognosis can be determined in almost all cases through ERG testing of the mother or daughter of an affected male. Once car rier females are identified on the basis of ERG or fundus abnormalities, affec ted male relatives would know they have X-ehromosome-linked disease and all of their daughters would be carriers and all of their sons would be normal. Female relatives identified as carriers of X-chromosome-linked retinitis pigmen tosa would know that they have a 50% chance of having an affected son or a 50% chance of having a carrier daughter with each childbirth. Rod and cone ERGs ranged from nor mal amplitudes to nondetectable respons es, suggesting wide variability in the area of retina involved in carriers. The ERGs indicated not only differences among car riers, but also differences between two eyes of the same carrier. Three obligate carriers could only be identified by ab normal ERG recordings in one eye; we therefore recommend that both eyes of a suspected female carrier be evaluated when deciding if she is abnormal. Addi tional precautions included interpreta tions of ERGs considering that increasing age, 20 high axial myopia, 2 1 - 2 3 miotic pu pils, hazy media, and extensive uveal pig mentation have been associated with de creases in ERG amplitudes. Whether photoreceptors are completely absent in parts of the retina or whether some or all photoreceptors contain less visual pigment is not certain. Retinal densitometric studies have shown decreases in rhodopsin concentrations within ten degree areas of retina, 7 ' 16 but these meas urements could reflect reductions in visu al pigment concentrations in some or all rods, loss of rods in the area tested, or both. The reduced rod ERG amplitudes with normal rod b-wave implicit times
467
observed in about two-thirds of the carri ers could not be simulated in normal subjects tested with neutral density filters interposed between the stimulus and the eye, as normal subjects showed responses that were both reduced in amplitude and delayed in b-wave implicit times. 2 4 The slopes of intensity-amplitude func tions for rod-isolated responses to blue light and rod-dominated responses to white light were steeper for normal sub jects than for carriers; this difference also could not be explained by a neutral density effect involving all rods. These findings are inconsistent with the idea that these carriers have the same decrease in visual pigment concentration in all rods, and raise the possibility that they have decreased visual pigment concentra tions in some rods, or loss of some rods, or both. These ERGs suggest patchy in volvement of rods and are therefore con sistent with the Lyon hypothesis 2 5 of ran dom inactivation of one X chromosome during embryogenesis. SUMMARY
Twenty-two of 23 obligate female car riers in nine families with known Xchromosome-linked retinitis pigmentosa were detected on the basis of abnormal full-field electroretinograms (ERGs). On ly 14 of these carriers had fundus find ings characteristic of the carrier state. Electroretinograms of carriers were either reduced in amplitude to white light un der dark-adapted conditions or delayed in cone b-wave implicit time, or both. Daughters of obligate carriers had either normal ERGs or abnormal ERGs simi lar to those recorded from obligate car riers. Abnormal ERGs of carriers of Xchromosome-linked retinitis pigmentosa contrasted with the normal ERGs record ed from female carriers of autosomal re cessive disease. These data support the idea that ERG testing of female relatives of males with retinitis pigmentosa can
468
AMERICAN JOURNAL OF OPHTHALMOLOGY
help to establish for a given family whether the mode of inheritance is Xchromosome-linked or autosomal reces sive. REFERENCES 1. Nettleship, E.: The Bowman lecture on some hereditary diseases of the eye. Trans. Ophthalmol. Soc. U.K. 29:57, 1909. 2. Usher, C. H.: On a few hereditary eye affec tions. Trans. Ophthalmol. Soc. U.K. 55:164, 1935. 3. McKenzie, D. S.: The inheritance of retinitis pigmentosa in one family. Trans. Ophthalmol. Soc. N.Z. 5:79, 1951. 4. Weiner, R. L., and Falls, H. F.: Intermediate sex-linked retinitis pigmentosa. Arch. Ophthalmol. 53:530, 1955. 5. Goodman, G., Ripps, H., and Siegal, I. M.: Sex-linked ocular disorders. Trait expressivity in males and carrier females. Arch. Ophthalmol. 73: 387, 1965. 6. Kobayashi, V. A.: Genetic study on retinitis pigmentosa. Jpn. J. Ophthalmol. 4:82, 1960. 7. Bird, A. C.: X-linked retinitis pigmentosa. Br. J. Ophthalmol. 59:177, 1975. 8. Schappert-Kimmijser, J.: Les degenerescences tapetoretiniennes du type X chromosomal aux PaysBas. Bull Mem. Soc. Fr. Ophthalmol. 76:122, 1963. 9. Klein, D., Franceschetti, A., Hussels, I., Race, R. R., and Sanger, R.: X-linked retinitis pigmentosa and linkage studies with Xg blood-groups. Lancet 1:974, 1967. 10. Krill, A. E.: Observations of carriers of Xchromosomal-linked chorioretinal degenerations. Do these support the "inactivation hypothesis"? Am. J. Ophthalmol. 64:1029, 1967. 11. Berson, E. L., Gouras, P., Gunkel, R. K., and Myrianthopoulos, N.C.: Rod and cone responses in sex-linked retinitis pigmentosa. Arch. Ophthalmol. 81:215, 1969. 12. Falls, H. F., and Cotterman, C. W.: Choroido-retinal degeneration. A sex linked form in
APRIL, 1979
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