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The Usher syndrome type 2A: clinical findings in obligate carriers
INTERNATiO3ALJOURNALOF
Rdiatric International Journal of Pediatric Otorhinolaryngology 31 (1995) 159-174
ELSEVIER
The Usher syndrome type 2A: clinical findings in obligate carriers Annelies van Aarem*a, Cor W.R.J. Cremersa, Alfred J.L.G. Pinckersb, Patrick L.M. Huygen”, Godfried C.J.H. Hornbergen”, Bill J. Kimberling” ‘Department of Otorhinolaryngology. University Hospital Nijmegen. P.O. Box 9101. 6500 HB Nijmegen, The Netherlands bDepartment of Ophthalmology. University Hospital Nijmegen. P.O. Box 9101. 6500 HB Nijmegen, The Netherlands ‘Center for Hereditary Communication Disorders, Boys Town National Research Hospital. Omaha, NE, USA
Received 18 May 1994; accepted 18 July 1994
Abstract Ten obligate carriers of Usher syndrome type 2A from 5 different families with 2 affected persons all underwent audiologic, vestibular and ophthalmologic examinations. They had a sensorineural hearing loss which was in excess of that expected for their age at all of the frequencies (0.25-8 kHz) tested, however, only a 10 dB (average) excess in hearing loss at 0.25-0.5 kHz proved to be significant. The speech discrimination scores obtained conformed with the hearing thresholds. Tympanometry, acoustic reflex and brain stem auditory-evoked potential findings were generally normal. Some vestibular abnormalities were found in a minority of the carrier sample, but not beyond the level of false positivity. Ophthalmologic findings were essentially normal, although in 5 carriers there was a subnormal electrooculography (EOG). These findings are not sufficient specific for carrier detection. Keywords: Genetic deafness; Genetic blindness; Retinitis Autosomal recessive inheritance; Usher syndrome
pigmentosa;
Carrier detection;
1. Introduction
The Usher syndrome is an autosomal recessively inherited syndrome with congenital bilateral sensorineural deafnessand retinitis pigmentosa (RP) [22,29]. This l
Corresponding author, Tel.: 09 1 80 614450; Fax: 09 1 80 540251.
016s5876/95/SO9.50 0 1995Elsevier Science Ireland Ltd. All rights reserved SSDI 0165-5876(94)01081-8
160
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31 (1995) 159-174
leads to progressive visual field loss (tunnel vision); posterior subcapsular cataracts also arise. RP can result in blindness through central visual acuity loss. The Usher syndrome is the most prevalent genetic cause of deafnessand blindness [16,31]. At present, 3 types can be distinguished on clinical grounds. Type I is characterized by RP and profound childhood deafnessand an insensitive or hyposensitive vestibular labyrinth; type II is characterized by RP and a moderate sensorineural hearing loss and a sensitive labyrinth. Type III is like type II, but the sensorineural hearing loss is progressive.A rapid, easyand inexpensive test with a high sensitivity and speciticity for the detection of the carrier state of the Usher syndrome is needed. Based on genelinkage studies, Usher syndrome type I is split up preliminary into type 1A that links to chromosome 14q32 [lO,ll], type 1B that links to chromosome llq13.5 [15,24] and type IC that links to chromosome 1lp [24]. Typ.eII is split up into type 2A linked on chromosome lq32-q41 [4] and a type 2B that is unlinked to lq32-q41 [20]. The literature on this topic is scarceor contradictory. A review is given of the literature and our own results are presented. 2. Materials and methods Ten obligate carriers of the Usher syndrome type II underwent extensive otologic, audiologic, vestibular and ophthalmologic tests. The 5 families studied all counted 2 Usher patients. The diagnosis of the Usher syndrome was based on the medical history, otoscopic, audiologic, vestibular and ophthalmologic findings. Gene linkage studies of the affected and non-affected family membersshowed linkage to chromosomeI and therefore those families are classified showing type 2A Usher syndrome. Pure-tone audiograms were measuredin a special sound-proof room according to the IS0 8253 (1989) [9] standard, testing at 0.5, 1, 2, 4 and 8 kHz for air and bone conduction. All threshold testing used 5 dB intensity increments. The IS0 7029 method (1984) [8] was followed to calculate P50 (50th percentile) threshold values for presbycusisfor each patient individually at each frequency, in relation to his or her age and sex. This method is very similar to that reported by Robinson [23]. Monaural speechdiscrimination scoreswere obtained using the sameset-up and standard Dutch phonetically balanced word lists consisting of ten monosyllables. Maximum speech discrimination scores (D,,,& were derived. Tympanograms and contralateral and ipsilateral acoustic middle-ear muscle reflexes were elicited and recorded. Brain stem auditory-evoked potentials (BAEPs) were obtained. The method has been previously reported in detail [30]. Eye movements were recorded with d.c. electronystagmography (ENG). Calibration of eye movement was obtained before each test. Saccades,smooth pursuit (SP), and optokinetic nystagmus (OKN) responseswere tested; gazepositions were tested to seewhether there was any gaze-evokednystagmus [30]. Vestibular tests were conducted with the patient in the dark with the eyesopen. Velocity step (VS) tests were performed with a Tiinnies rotatory chair and the postrotatory nystagmus response were analysedas previously reported [7] using 90% confidence limits for the parameters initial velocity (V), time constant (T) and ‘Gesamtamplitude’ - cumulative eye displacement- [a] [27] (and classified into the categoriesnormoreflexia, hyporeflex-
A. van Aarem et al. /Ini. J. Pediatr. Otorhinolaryngol.
161
31 (1995) 159-174
ia and hyperreflexia). The values of directional preponderance (DP) parameterswere also calculated (similar to the side effect, seebelow) to assessdirectional asymmetry of the responses.DP values in excessof 25% indicate significant asymmetry [27]. For the caloric side effect (SE), we arbitrarily assumeda relative side difference, i.e. (difference/sum)lOO%,in excessof 20% to indicate unilateral hypofunction. For the 95% confidence limits of the absolute responselevel, we took the values of 7”/5 and 45”/s previously established [19]. All of the carriers underwent a routine ophthalmologic examination. In addition, their visual fields were evaluated with Goldmann perimetry, using test targets I-l-I-4, III-4 and V-4, and they underwent electrooculography (EOG) and electroretinography (ERG) examinations as previously reported [2 1,281. Blood-samples from the patients and their family members as shown in the pedigreeswere collected for gene linkage studies in Boys Town National Research Hospital.
3.Results Fig. 1 shows the pedigrees. In 2 families (B and D), there was a consanguineous mating. Consanguinity was excluded within 5 generations in family A. No genealogic data were available on families C and E. Gene linkage studies performed in Boys Town National Research Hospital showed for all families by linkage to lq32-q42 having Usher syndrome type 2A. Otoscopy was normal in all ten carriers. None had in their medical history any hearing impairment, relevant ear disease,exposition to ototoxic drugs or noise trauma. Table 1 shows the audiometric results and speechdiscrimination data of the 10 affected Usher cases.The hearing loss was symmetrical in all those affected and more A
C
-
- affected
_
= unaffected male - obligate male carrier
@
male
l c @
- affected female = unaffected female = obligate female carrier
Fig. 1. Pedigrees of families with Usher syndrome. The numbers are identification
numbers.
M
M
45
56
41
36
38
27
24
25
21
A2
B3
l34
C5
C6
D7
D8
E9
El0
R L
M
45(-) 45(-) %) 3%) 2%) ‘44 5%) 4%) %, 544 5%) 45f-) 3%) 2%, ‘Of-) % 3%) 45,-) 2of-) ‘OH
0.25 kHz
+ /,a# 1 kHz
6500 + 15) qss + 5) 6500 + 15) 7q55 + 15) 4% + 20) q20 + 0) 35~0 + 15) 35(20 + 15) 30(30+ 0) 75wlf <15) 9q>70 + <20) 65,>,+ <5) g5(,70+ <15) 80(,60 + <20) g5t,70 + <15) 75(50+ 25) q70 + IO) 45(35+ 10) 55(45+ 10) 35(35+ 0) 50(45+ 5) 30(30+ 0) 50(50+ 0) 3000 + 0) 5505 + 0) 5q5cl+ 0) q50 + IO) 65~ + 5) 5Ot50+ 0) 3Ot25+ 5) 3505 + 0) q15 + IO) 4% + 15)
+ 5)
5505 + 20) 60(55+ 5) 55(50+ 0) 15(15+ 0) fO(lO+ 0) 50(35+ 15)
q55
0.5 kHz
dBHL: AC&
65(,+ 5) q6ll+ 0) 50(50+ 0) 5000 + 0)
@%Q + 0)
8000 c IO) (j5(65+ 0) 65~ + 5) 75(65+ IO) 5505 + IO) tq60 + 0) 70(65+ 5) 70(65+ 5) 105(>70+ <35) g5(,,+ <25) 115(,70 + <45) ‘05(>70 + <35) 65(65+ o) 650 t 5) q60 + 0)
2 kHz
95c.60 + <35) 9%60 + <30) 7505 + 20) got55+ 25) @$o + I01 7Ot55+ 15) q.60 + C5) 65~55+ IO) lo5(>60+ <65) g5(,,+ ~25) 12Ot.w + <60) 125,., + C65) 65(>60+ <5) ‘%o t 15) 65wo+ c5) 65~0 +
4 kHz
7$=4l+ <35) 7Ot.46 t <30) 75,>40 + C35) 65~3 + ~25) 65(>4a + <25)
9’4>40+ <50)
> t~wo + <60) > lOOwe + <60) 65,>4e + <25) 75(>40+ <35) 75(>4e + <35) 70,,40 + <30) 95(>4e + <55) g5,,4e + <45) > ‘O”(>4U+<60) > 1~(>40+ c60) ’ ‘OfJ(>4o+ <60) ’ lf%.46 + C60) 70,,4e t <30) 70(>40 + <30)
8 kHz 68 60 63 67 38 30 52 45 90 78 93 87 55 50 48 48 60 58 38 38
PTAb
95 100 95 95 95 95 95 75 75 70 75 90 95 95 95 95 95 95 95
80
D,,,C
Abbreviations: -, not measured; >, outside the range of the audiometer; ahearing loss, air conduction threshold (bone conduction threshold + air-bone gap); bpure tone average of 0.5, 1, 2 kHz (PTA); Cmaximum speech discrimination (D,,,).
;; L
1
R
Id
L R L R
L R L R
R L R L R
Ear
F
F
M
M
F
M
48
F
Age (yr) Sex
Al
Patient No.
Table I Pure tone and speechaudiometry results in 10 Usher patients
A. van Aarem et al. /Int. J. Pediatr. Otorhinolaryngol.
31 (1995) 159-174
163
marked at the higher frequencies. The pure tone average (PTA) at 0.5, 1 and 2 kHz varied from 30 to 93 dB. The maximum speechdiscrimination score was 80% or better, except in Nos 5 and 6. All had normal tympanograms. All except Nos 5 and 6, showed normal acoustic reflexes and BAEP findings. In Nos 5 and 6 who had the most severehearing loss (Table 1), wave V, in as far as it could be identified, showed increased (absolute) latency. Vestibular examination revealed normal caloric responsesbut abnormal rotatory responses(i.e. hyporeflexia or hyperreflexia). The results of the ophthalmologic tests are shown in Table 2. The ERG was nonrecordable. All the patients except for 2 had tunnel vision. Table 3 shows the results of tone audiometry and speech audiometry for the obligate carriers. The air-bone gap (ABG) values are included. The excessin hearing loss for the air conduction (AC) threshold, i.e. AC+, was calculated as AC+ = AC - P50 (seeMethods). Table 4 presents the AC+ values obtained. Probit analyses(not shown) demonstrated that the AC+ values (as well as the ABG values) had approximately normal distributions at all of the frequencies. The statistics for AC+ were calculated for each ear and frequency (Table 5). Table 5 shows the S.E.M. values which were used to test (Student’s t test) whether the mean values differed significantly from zero (P < 0.05). This was found to be the caseat 0.25 and 0.5 kHz for both ears. According to Student’s t test, the mean AC+ value at 0.25 kHz was significantly higher than that at 1 kHz in the right ear and those at 1, 2 and 4 kHz in the left ear; in the right ear, also the AC+ value at 0.5 kHz was significantly higher than that at 1 kHz. Table 3 shows that there was some ABG with a mean value of about 5 dB (Table 6). After calculating S.D. and S.E.M. values for the ABG (not shown), it was found that the mean ABG was significantly different from zero at all frequencies(Student’s t test, P < 0.05). It appeared that AC+ differed significantly from the ABG only at 0.5 kHz (Table 6). Assuming that the statistics for the ABG at 0.25 kHz (measurements were not available) were similar to those found at 0.5 kHz (not shown), it can be concluded from the present measurementsand analyses that the observation of a significant (excess in) sensorineural hearing loss (with reference to the P50 of presbycusis,seeMethods) was present only at 0.25 and 0.5 kHz. This (excessin) sensorineural hearing loss, i.e. AC+ corrected for the apparent conductive loss, was about 5-10 dB on average (Table 6). Analysis of the regression of AC+ at 0.25 or 0.5 kHz on age (not shown) did not reveal any significant correlation. All carriers showed normal tympanograms. Acoustic reflexes were normal in ah except No 7; reflex thresholds were found at levels of between 80 and 100 dB and there was no pathologic reflex decay, i.e. a reflex decline of more than 50% within 10 s. Carrier No 7 showed bilateral threshold elevation at 0.5 and 1 kHz. All the carriers showed normal BAEP results. Table 7 presentsthe vestibular findings. None of the carriers showed spontaneous or gaze-evoked nystagmus or any abnormal Saccades, SP or OKN responses. Caloric abnormalities were found in 2 subjects (Nos 1 and 8), i.e. significantly high responselevels. This feature was linked to the finding of hyperreflexia in the VS test. Abnormal VS responseswere found in 6 of the carriers, i.e. hyperreflexia in cases 1, 3, 5, 8 and 9 and hyporeflexia in case6. None of the DP values were significant.
Normal
RP
OD:l.08 OS:l.O4 OD: 1.22 OS:1.38 OD:0.67 os:o.50 OD1.0 0S:l.O OD:l.ll OS: I .o OD:0.62 OS:O.60 0D:l.O 0S:l.O 0D:l.O OS:O.88 OD:0.86 os:1.12 OD1.10 OS:1.08
0D:TV 5” 0S:TV 5” 0D:TV 10” 0S:TV 5” OD:TV# OS:TV% OD:TV# OS:TV# ODTV 20” OSTV 20” 0D:TV 10” 0S:TV 10” ODTV 20” 0D:TV 20” ODTV 25” ODTV 25” PRS PRS
EOGe
Goldmannd 0D:O OS:0 ODO OS:0 ODO OS:0 0D:O OS:0 ODO OS:0 0D:O OS:0 ODO OS:0 0D:O OS:0 0D:O OS:0 0D:O OS:0
ERG-CF’
0D:O OS:0 0D:O OS:0 0D:O OS:0 0D:O OS:0 0D:O OS:0 ODO OS:0 0D:O OS:0 0D:O OS:0 0D:O OS:0 0D:O OS:0
ERG-AF’
Abbreviations: Y,examined elswhere; avision: S, spherical; C, cylindrical; SC, sine correction; bfundus: RP, retinitis pigmentosa; ‘media: CCP, cataracta corticalis posterior; IO, increased (lens) opacity; CPP, cataracta polaris posterior; CC, cataracta capsularis; dGoldmann perimetry (V-4): TV, tunnel vision; PRS, partial ring scotoma; eelectrooculography (EDG): lower limit normal (5% limit) LpDt (Arden) ratio: 1.80; ‘electro-retinography (ERG): CF, cone function; lower limit normal b-wave: 100 micro Volt; RF, rod function; lower limit normal b-wave: 150 micro Volt (absolute limits).
M
21
El0
Normal
RP
F
25
E9
CPP
RP
F
24
D8
CCP
RP
M
27
D7
cc
RP
M
38
C6
CPP
RP
F
36
CS
IO
RP
M
41
B4
CCP
RP
M
56
B3
CCP
RP
M
45
A2
CCP
RP
0D:S + 0.50, C-2.0, 165YO.2 0S:S + 0.50, C-2.0, So/O.08 ODS-2.0, c-2.0, 50”/0.3 OS:S-2.0, C-1.25, 180”/0.2 OS:S-7.5/0.25# OS:S-7.0, C-1.25, 165”/0.4# ODS-6.5, C-1.0, lO”/l.O# OS:S-6.25, C-1.25, 175”/1.0# OD:S-1 .O, C-O.50 180”/0.5 0s:s + 0.5, c-o.50 180”/0.5 0D:WO.S OS:SC/O.8 OD:S-0.5010.5 OS:!!&1.0/0.4 ODS-0.50, c-0.50, 180”/0.5 os:s-0.50, c-0.50, 1800/0.3 OD:SC/ 1.o OS:SC/O.8 oD:sc/1 .o os:sc/o.8
F
48
Al
Media’
Fundusb
Visiona
Age (yr)
Patient No.
Sex
Table 2 Results of ophthalmologic tests in IO Usher patients
F
F
12
29
31
62
65
54
53
59
49
A2
B3
B4
c5
C6
D7
D8
E9
El0
R L R L R L R L R L R L R L R L R L R L
Ear
‘OH 2o(-l
‘5w
2ot-l 2%) ‘%) 2%) ‘5H 2oi-j 2% 2%) 2oH 2%) 4%) 35H ‘OH ‘%I ‘%I
*5(-)
‘4-l
0.25 kHz
+ 5)
+ 10)
+ 5)
+ 5)
50 + 0)
20(,0
20~15
25(20
5(0+ 5)
+ IO)
+ 5)
20(r5 IO,0
+ 5)
+ 5)
20(15 30(25
+ 5)
2O(lS
15(5+ IO) 5(5+ 0) 5(0+ 5)
%s
q15 + 5)
5(5+ 0) lO(0+ 10) 20(15+ 5) 15(15+ 0) 20(0+ 20)
0.5 kHz
dB HL: AC(Bc + ABG)a
+ 5)
+ IO)
+ 0)
5,o + 5)
5(5 + 0)
3420
q20
50 + 0) fO(10+ 0) to,, + IO) 5(0+ 5) 10(10+ 0) 5(0 + 3) ‘O(S+ 5) O(0+ 0) O(0+ 0) l5(15+ 0) l5(5 + IO) 5(0 + 5) 10, + IO) 5, + 5) 5(0 l 5)
qo
1 kHz
25(20+ 5)
3q15 + 15)
5(0+ 5) ‘5(15 + 0) 5(S+ 0)
5(0+ 5) 50 + 0) qo + 0)
5,5 l 0) 50 + 0) qo
<20)
%-ul+
7q.40 + C30) 10(5+ 5) 55(>4a +
35(30+ 5) o,o + 0) 2% + 15) 50(45+ 5) qso + 0) qs + 5) 100 + IO)
15(5+ IO) 5(5+ 0) If-+5+ 5) q40 + 0) 35(35+ 0) 10(5.5) 5(0+ 5)
+ 0)
+ <60)
q>4rJ
40(40+ 0) 35(2, + IO)
q10 + 0)
3q30 + 0)
90(>40 + <50) 50(45+ 5)
0)
30(30+ 0)
l
+ 20)
q5 4 5) qo
o,o + 0)
h+O)
100 + 5)
+ 15)
25(, + 2oJ 5(0+ 5)
50 + 0)
+ 5)
+ 10)
‘O(lO+ 0)
‘O(5+ 5)
8 kHz
5(0+ 5)
5,
145
35~20
5(S+ 0)
2$25 + 01
‘010+ IO)
5(5+ 0)
4 kHz
O(D +0)
2 kHz
3 7 18 I2 10 10 10 10 3 2 22 18 15 15 7 7 28 28 I2 5
PTAb
100 100 100 100 100 100 100 100 100 100 95 95 95 95 100 95 loo 95 100 100
DmaxC
Abbreviations: -, not measured; >, outside the range of the audiometer; ahearing loss, air conduction threshold (bone conduction threshold + air-bone gap); bPure tone average of 0.5, 1, 2 kHz (PTA); fmaximum speech discrimination (D,,).
F
M
F
M
M
F
F
14
F
Age (yr) Sex
Al
No.
Carrier
Table 3 Pure tone and speech audiometry results in Ii) obligate carriers
F
F
M
F
29
31
62
65
54
53
59
49
B3
B4
CS
C6
D7
D8
E9
El0
F
M
M
F R L R L R L R L R L
R L R L
+I1 +I1 +I4 +24 +14 +I9 +14 +14
R L R L
F
72
+15 +15
R L
F
+I3 +I3 +36 +31 +6 +6 +4 +9 +7 +I7
0.25 kHz
Cl0 +5 +19 +19 +I9 +14 -2 -2 +12 +12 +25 +I5 +5 0 +19 +14 +I6 +I
+5 +lO
0.5 kHz
-1 -1 +4 +9 +4 +9 -8 -8 +6 +6 -I +4 0 0 +I3 +23 +i +I
+5 +5
1 kHz
to the P50 threshold
dB HL: AC+ = AC - PSO
(AC+) in relation
Ear
threshold
Sex
A2
Age (yr)
14
No.
Al
Carrier
Table 4 Excess in hearing loss for the air conduction frequency for his or her age and sex
+3 +3 -7 -12 +14 +l4 0 +5 -3 +2 +28 +23 +4 -1
+I4 +4 +14 +14 -12 +8 +23 +23 +I +I
+3 +3 -13 -18
+lO 0 +3 +3
+I0 +5
0 +5 +8 -2 +4 -1
4 kHz
for each carrier
2 kHz
values for presbyacusis
+41 +51 +31 +41 -9 +36 -12 -2 0 -5
+I0 +10 -II -16 +8 +8 +I7 +2 -15 -25
8 kHz
individually
at each
A. van Aarem et al. /Int. J. Pediatr. Otorhinolaryngol.
167
31 (1995) 159-174
Table 5 AC+ values (dBHL) with their statistics. Student’s t test was applied to identify mean values, which were significantly different from zero Ear R
n Mean SD. S.E.M. i
L
n Mean SD. S.E.M. t
0.25 kH.z
0.5 kHz
1 kHz
2 kHz
4 kHz
8 kHz
10 13.4 8.8 2.8 4.8 IO IS.9 7.4 2.3 6.8
10 12.8 8.3 2.6 4.9 IO 8.8 7.3 2.3 3.8
IO 2.3 5.5 1.8 1.3 IO 4.8 8.2 2.6 1.9
10
10 5.3 11.4 3.6 1.5 10 4.3 10.5 3.3 1.3
10 6.0 19.2 6.1 I.0 IO 10.0 25.1 7.9 1.3
5.1
9.9 3.1 1.6 10 3.6 9.5 3.0 1.2
Significant values in bold italic print. Table 6 Mean values (dBHL) for both ears for AC+ and ABG and their difference
AC+ ABG AC+-ABG
0.25 kHz
0.5 kHz
1 kHz
2 kHz
4 kHz
8 kHz
15 6? 9?
II* 6 5
4 4 0
4 3 I
5 6 -1
8 5 3
Abbreviations: *, significant difference between AC+ and ABG (Student’s t test, P < 0.05); bold italic print indicates values significantly different from zero. Table 7 Clinical and vestibulo-ocular data on the carriers Carrier no.
Age (yrs) Sex
Al
14
A2 B3 B4 c5 C6 D7 D8 E9 El0
VS response
Calories
R nystagmus V,T,G
L nystagmus V,T,G
LC, RC”
F
40, plateau
46. 32, 1472
50, 50
12 29 31 62
F F F F
49, 12, 588 85, 15, 1275 44, 16, 704 71, 28, 1988
52, 13,676 72, 14, 1008 37, 18, 666 68, 24.1632
18.21 13, 14 14. I5 41.52
65 54 53 59 49
M M F M F
23, 14, 322 50, 16, 800 68, 12, 816 56, 14, 784 39, 20, 780
IS, 14,210 48,23, 1104 58, 15, 870 66, 18,1186 39, 19, 741
IO, 9 20, 17 16,21 36, 32 IO. 14
Abbreviations: significant values in bold italic print; “left cold, right cold.
Remarks
Dizziness, nausea, vomiting afterwards
Susceptible to motion sickness Often at sea
F
M
F
72
29
31
62
65
54
53
59
49
A2
B3
I34
C5
C6
D7
D8
E9
El0
ODS + 1.0, c-1.0, 200/1.0 Gs:S + 1.25, C-0.25, 18OVl.O ODC-0.50. 900/l.o OS: c-0.50, 1800/l.o ODS-1.50/1.0 OS:S-2.0. C-1.25, 45-11.0
0S:MCL -4.511 .o OD!S + 2.25, c-0.50. 9oVl.O 0s:s + 1.15/1.0 0D:S + 1.25, C-0.50, 9OVl .O 0s:S + 1.25, C-0.50, 9oYl.O 0D:S + 1.75, C-0.25, 45Vl.O 0s:s + 2.0, c-0.50, 13oV1.0 0D:ll OS:11 OD:9 OS:10 OD:9 OS:10
C.I.
OS:10
OD:9
N
N
N
N
N
N
N
OD: 9
C.C. OS:11
N
OD:13 OS:13
N
NE
N c.c
N
N
N
N
N
N
N
N
N
N
N
N
N
OD1.82 OS1.78 ODZ.47 os:1.30
ODIOO OS:1 10 OD:14O OS:120
OD160 OS:170
OS:150
os:2.0
OD:2.0 os:2.22
OD210
OS:120
0S:I.M OD2.0
ODNE
0S:ca 40# OD:350 OS:210 OD130 OS:140
os:2.14 OD:1.81 OS: 1.93 OD:l.Sl OS:1.61 OD1.53
OS: 150 0D:ca 2OtY
OS:200 OD150
os:2.0!? OD1.65 OS:I.63 OD:2.18
OD280
ERG-CF*
OD2.05
S/We Gold- EOG= mann
OS;18 NE
OD18
NE
10Pd
N
C.I.
N
Media=
ODS: no maculae reflexes, N RPE somewhat coarse aspect, grey arcades in the periphery, blond fundus
ODS: temporal papillae pale, maculae: no reflexes, OD: some golden glistening around the foveola ODS: periphery somewhat coarse aspect, but conforms with age OS: RPE depigmentation
OS: pigment dot in the periphery, not related to RP normal
coarse aspect, but without pigmentation OD: a few greyish specks in the periphery unrelated to RP Normal
vessel
0s:s-0.50/1 .o ODS-0.25, c-0.25, 90’11 .o OS:SC/l .o ODMCL -4.5/l .O
ODS; cilioretinal
Fundus b
ODS: RPE somewhat
carriers
ODS-4.0, c-0.75. 18OVl.O os:s-4.5. c-0.75, 145”I 1.o ODS-l.OIl.0
Visiona
tests on 10 obligate
OD:3Qo OS:290 OD350 OS:350
OD:3SO OS:350
OS:370
OD:3SO
OS:130
0D:NE
OD:350 OS:300 OD:220 OS:210
OS290 NE
OS:340 OD:320
OD410
ERG-RFs
Abbreviations: #, skin electrode ERG, NE, not examined; N, normal; Vision: S, spherical; C, cylindrical; SC, sine correction; WCL, with contact lens; bfundus: RPE, retinitis pigment epithelium; RP, retinitis pigmentosa; ‘media: CL cataracta incipiens; CC, (CPP) cataracta corticalis; dIOP, intra ocular pressure - NE, not examined; %, Schober; W, Worth; ‘Electra-oculography (EOG): lower limit normal (5% limit) LplDt (Arden) ratio: 1.80, abnormal values shown in bold italics; sElectro-retinography (ERG): CF, cone function; lower limit normal b-wave: 100 micro Volt; RF, rod function; lower limit normal b-wave: 150 micro Volt (absolute limits), abnormal values shown in bold italics.
M
M
F
F
F
F
F
14
Al
Sex
tins)
Carrier No.
Age
Table 8 Results of ophthahnologic
A. van Aarem et al. /Int. J. Pediatr. Otorhinolaryngol. 31 (1995) 159-174
169
Vestibular complaints were not mentioned by any of the carriers before examination. Carrier No 5, before being informed about the finding of hyperreflexia, mentioned her susceptibility to motion sickness.Carrier No 1 also showing hyperreflexia complained later about her dizziness, nausea and vomiting after the vestibular examination. Carrier No 6 showed hyporeflexia of the VS responseand was a professional marine at sea. The ophthalmologic test results of the 10 obligate carriers are presented in Table 8. In 5 of the carriers (Nos 2, 5, 6,9 and 10) the EOG was subnormal; one of them was also found to have an abnormal ERG (No 6). 4. Discussion The present results indicate that the carriers had an AC threshold which was in excessof that expected for their age (AC+) by about 10 dB at 0.25-0.5 kHz (Table 6). As they appeared to have about 5 dB conductive hearing loss, which we have no plausible explanation for other than the possibility of systematic error in the measurements,presumably bias introduced by avoidance of threshold values for bone conduction that are apparently higher than thesefor air conduction, the apparent sensorineural hearing loss at those frequencies had to be corrected for the ABG present (i.e. AC+ - ABG, seeTable 6). The latter value was not equivalent to BC, the bone conduction threshold in Table 3. If we had corrected the BC values for (sexrelated) presbycusisin a similar way to that done for AC following the IS0 7029procedure, we might have found similar values. However, as no such procedure has been defined for BC, there was no alternative. We assumedthat the ABG was not agedependent, which indeed appeared to be the case (the regression analyses are not shown). All of the carriers showed normal BAEP and tympanometric results. Acoustic reflexes were generally normal. The significant sensorineural hearing loss, therefore, can be regarded as cochlear in origin. Kimberling et al. [14,16] also performed BAEP, tympanometric and acoustic reflex examinations, but did not report in detail any of the results obtained. The present results and those reported by others indicate that sensorineural hearing loss can be observed among type II carriers. However, it can be distinguished from presbycusis only with some difficulty, for example by applying the present methods. We have no explanation for the present observation that the sensorineural hearing loss manifested itself predominantly at the lower frequencies in the carriers, whereas the affected persons showed their predominant hearing loss at the higher frequencies. The hearing loss of the carriers in this study may represent partial expression of the (more severe)hearing loss shown by the affected persons at the lower frequencies. In view of the above-mentioned normal BAEP findings in the affected persons, one would expect to find normal BAEP examinations only in the obligate carriers, which turned out to be the case.The samewas true for the tympanometric and acoustic reflex examinations. In the literature, very few articles are available on possible clinical abnormalities in carriers of the Usher syndrome [4,17,25]. In other studies, one single family was described [ 1,2,6,12,13,18]or the carriers were only mentioned indirectly [3,14,16,26].
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31 (1995) 159-174
The lack of clinical data and the lack of gene linkage results on affected persons meansthat it is not always clear which type of the Usher syndrome was studied c.q. or in which type of carrier the abnormalities were diagnosed (Table 9). Therefore, no direct comparison can be made between our results in obligate type 2A carriers and previously reported results. Only three earlier studies present the audiograms of obligate (0) c.q. possible carriers (P) [ 1,2,13]. Two additional studies mention either the mean hearing lossesfor the various frequencies [ 171or the mean hearing loss is presented in figures [18]. An overview of the hearing lossesin the various studies is given in Table 10. No technical data on audiometry were reported in the majority of studies, therefore we cannot make any meaningful direct comparisons with our findings. We have already mentioned our reservations about some of the vestibular findings, for example, the responseswhich showed hyporeflexia (low V and G values) in carrier No 6, who might have developed vestibulo-ocular reflex (VOR) suppresTable 9 Overview of clinical studies on carriers in the literature Author
No. + type AudioType Usher of carriersb metry syndrome,
Hal&en [5]
I
Holland [6]
I+IMll
Davenport
II
90 40 28 0 22 P 20 3P 140 SP 80 1P 80 2P 20
?
14 0
Kloepfer [17] I Goode [2]
IMII
de Haas [4]
I+Iulll
McL.eod 1181 XVIII
Vestibular test
III
10 6P Grmdahl [3] I + II + III 35 0 Rimberling I + II 23 0 1141 Kimberling I + II 20 0
ERG/DA
EOG
ERG
-
DA
-
-
-
? ? +
+
+
+
+
+
+
+
-
+
+
ERG+DA
+
+
+
ERG
+
+
-
DA
+ +
-
+
+
+
111 Sondheimer 1251 Karjalainen
Fundus- PeriscOPY metry
?
+
+
?
?
?
?
+ (4) +
? +
?
+
DA ERG
? -
+
+
+
ERG
-
?
ERG
-
Ml31
1161 Tamayo [26] ?
80
t
Abbreviations: +, mentioned in methods, -, not performed; ?, unclear; %ype Usher syndrome: author’s classification is shown in bold italics; bcarrier type: 0, obligate; P, possible.
I
typeb
Usher Syndrome
1I/Mf?d
11/w?d
I/M/adult
I/F/adult
l/F/6
l/F/8
l/M/IO
P
P
0
0
P
P
P
lJFJ49s
1 /M/81
lJM/+’
1/Mf?dJ
0
0
P
P
l/M/54’
18/F/> 14
0
0
10/M/> 14
No&x/age
0
Carrier tYpeC
ADe AS ADe AS= ADe ASe ADe ASe AD AS AD AS AD AS AD AS AD AS AD AS AD AS AD AS AD AS AD AS 10
5
15 10
35
3s
0.125 kHz
dRHL:
5q45
5 IO
IO 5
55wo
+ IS)
+ 5)
+ ABG)~
12.0 13.5 10.5 10.8 15.3 15.0 0.0 2.7 25 15 20 25 20 25 45 40 35 30 10 10 15 10
0.25 kHz
AC(BC
+ 5)
65wl
qMl+
8.0 10.5 5.5 3.1 6.3 4.0 0.5 6.8 15 20 5 IO 5 IO 70 65 50 55 IO 5 10 5 0) + 5)
I kHz
5 5
5
10
IS(l5 + 0) *000 + IO) 20(20+ 0)
;;r++O;o)
50(45
9.0 11.0 6.1 5.2 1.7 9.0 2.2 9.5 20 15 I5 20 15 15 50 45 45 40 5 5 10 0
0.5 kHz
+ 0) + 0)
5
5
25(lS + 10) 2000 + 0)
q,
q60
9.5 14.0 4.4 3.6 6.8 0.4 1.8 8.6 15 IO I5 IO 5 0 75 70 80 70 I5 15 20 5
2 kHz
20 20 40 5
22.0 34.5 12.5 13.6 17.2 IO.4 5.4 4.0
3 kHz
+ 20)
+ IO) + 0)
6s,5
+ 10) 7s(65
75f65
6SVlo+ 5) 7005 + 20)
75C55
30.5 39.0 16.3 16.6 20.4 12.2 5.0 5.0 IO 20 20 10 -5 5 70 65 60 55 55 15 45 10
4 kHz
25 55 15
5s
25
28.5 37.0 18.8 20.8 17.7 10.4 7.2 6.3
8 kHz
75 55
0 5 65 75 65 60 35 5 3s 5 90 85
30.5 32.5 15.0 16.3 12.7 8.6 6.3 0.4 5 IO IS
Abbreviations: ahearing loss, air conduction threshold (bone conduction threshold + air-bone gap); btype Usher syndrome, author’s classification is shown in bold italics; ‘carrier type: 0, obligate; P, possible; d?, age unknown; emean values; ‘noise exposure +; hoise exposure -.
Karjalainen III H31
[ll
Davenport II
Khrepfer I171
Author
Table 10 Results of pure tone audiometry in carriers in the literature
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sion in responseto his professional activities. Hyperreflexia was found in 4 other carriers, of whom at least 2 (Nos 1 and 5) were suspectedof being susceptible to motion sickness.If we exclude these 2 carriers and the above-mentioned carrier No 6 from the present evaluation, hyperreflexia occurred in 3 casesout of the 7, which may have been due to false positivity [27]. It is possible that in carrier Nos 1 and 5, motion sicknesswas secondary to their abnormal VOR behavior. Be this as it may, for the moment it seemsthat the odds are against the type 2A carriers having specific vestibular abnormalities. In the literature, 10 obligate carriers of a presumed type II Usher syndrome were tested by other authors and only 2 of them were found to have reduced caloric responses.If we include the report by Karjalainen et al. [12] the score for hypoexcitability in type II/III carriers is 2 out of 12 and, including the present report, it is 2 out of 22 carriers. This can certainly be reconciliated with false positivity at a presumed level of significance of 5%. Although several authors mentioned employing SP [14], and OKN tests [14,18], no results pertaining to carriers were mentioned in their reports. We could not find any reports about rotatory tests on carriers. Our ophthalmological investigations did not show any RP-specific fundus changes in the carriers; the media were normal for their age. Sondheimer et al. [25] did not find any fundus abnormalities either, in 14 obligate carriers (type unknown). Fundus and media abnormalities in carriers were reported by Kloepfer et al. [ 171in 4 out of the 13 carriers (type unknown); they displayed a fundus picture typical of RP. During re-evaluation, 3 out of the 4 did not have RP, but gyrate atrophy-like fundus abnormalities, with abnormal ERG, the fourth did not have any fundus abnormalities [6]. Thesegyrate atrophy-like findings were later criticized by Sondheimer et al. [251. Conflicting results have been published in the literature on dark adaption (DA) measurements[3,4,25]. In view of these findings and the fact that DA measurement is a subjective method, we chose objective test methods: EOG and ERG. Table 8 shows that the EOG and ERG results of some of the carriers were abnormal: 5 out of the 10carriers had an EOG value of below the 5% lower confidence limit; 1 carrier also had an abnormal ERG result. The literature also mentioned abnormal EOG and ERG results in carriers. The two parents (type II) examined by Davenport et al. [l] underwent general ophthalmologic tests, fundoscopy, perimetry and ERG tests and no abnormalities were found. One of the two carriers displayed subnormal EOG values. Tamayo [26] found subnormal ERG values in 2 out of the 8 obligate carriers (type unknown). Hallgren [5] did not find any abnormal ERG values in 4 obligate carriers tYPe 1. Summarizing, no clear ophthalmologic abnormalities were found in carriers in this study, which supports the lack of abnormalities reported in carriers in the literature. Although EOG and ERG abnormalities were found, these methods do not appear to be sufficient sensitive and specific for the identification of heterozygotes. The fact that the affected persons were found to have vestibular abnormalities (hyporeflexia or hyperreflexia) might suggestthe possibility that the obligate carriers
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31 (1995) 159-l 74
113
also had (some)similar symptoms. As shown above, similar findings (i.e. hyporeflexia or hyperreflexia) were indeed encountered in the present study, but not beyond the level of false positivity. It seemsjustified to attribute the abnormal rotatory responsesin the affected persons to functional impairment of the afferent visual system, causedby abnormalities in the peripheral retina. These features were generally lacking in the obligate carriers. The results of our study on 10 obligate Usher type 2A syndrome carriers and the review of the literature, indicate that it is not (yet) possible to identify carriers using extensive audiovestibular and ophthalmologic tests. Acknowledgements The authors would like to thank the patients and their family members for their help and cooperation. The authors are indebted to Professor E.M. BleekerWagemakers,MD, International Ophthalmic ResearchInstitute, Ophthalmogenetic Department, Amsterdam, The Netherlands, for providing genealogic data. They wish to thank Mrs. P. Folman, Mr. M.G.M. Nicolasen, Mr. J.F.P. Noten, Mrs. E.M. Hoeks and Mr. A.A.I. van ‘t Pad Bosch for their technical assistance.This researchproject was supported in The Netherlands by grants from the following Foundations and Societies: ‘De Drie Lichten’, ‘Heinsius Houbolt’, ‘Voor de Blinden en Slechtzienden’, and ‘De Gelderse Blindenvereniging’. References [I] Davenport, S.L., O’Nuallain, S, Omenn, G.S. and Wilkus, R.J. (1978)Usher syndrome in four hard of hearing siblings. Pediatrics 62, 578-583. [2] Goode, R.L., Rafaty, F.M. and Simmons, F.B. (1967) Hearing loss in retinitis pigmentosa. Pediatrics 40, 875-880. [3] Grottdahl, J. and Mj@n, S. (1986) Usher syndrome in four Norwegian counties. Chn. Genet. 30, 14-28. [4] Haas, E.B., de Lith, G.H., van Rijnders, J., Rumke, A.M., Volmer, C. (1970) Usher’s syndrome, with special reference to heterozygous manifestations. Dot. Ophthalmol. 28, 166-190. [5] Hallgren, B. (1959) Retinitis pigmentosa combined with congenital deafness;with vestibulocerebellar ataxia and mental abnormality in a proportion of cases: a clinical and geneticostatistical study. Acta Psychiatr. Neural. Stand. 34 (Suppl. 138), l-99. [6] Holland, M.G., Cambie, E. and Kloepfer, W. (1972) An evaluation of genetic carriers of Usher’s syndrome. Am. J. Ophthalmol. 74, 940-947. [7] Huygen, P.L.M., van Rijn, P.M., Cremers, C.W.R.J. and Theunissen, E.J.J.M. (1993) The vestibulo-ocular reflex in pupils at a Dutch school for the hearing impaired; findings relating to acquired causes.Int. J. Pediatr. Otorhinolaryngol. 25, 39-47. [8] IS0 7029(1984)Acoustics - Threshold of hearing by air conduction as a function of age and sex for otologically normal persons. Geneva, International Organization for Standardization. [9] IS0 8253-l (1989) Acoustics - Audiometric test methods - Part I: Basic pure tone air and bone conduction threshold audiometry. Geneva, International Organization for Standardization. [IO] Kaplan, J., Gerber, S., Bonneau, D., Rozet, J.M., Dufier, J.L., Munnich, A. and Frezal, J. (1991) Probable location of Usher type I gene on chromosome 14q by linkage with D14S13 (MLJl4 probe). Cytogenet. Cell Genet. 58, A27446, 1991/l Ith International Workshop on Human Gene Mapping, London, 18-22 August.
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[I 1) Kaplan, J,. Gerber, S., Bonneau, D., Roxct, J.M., Dehieu, 0.. Briard, M.L., Dolfus, H., Ghazi, I., Dutier, J.L., F&al, I. and Munnich, A. (1992)A genefor Usher syndrome type I (USHIA) maps to chromosome 14q. Genomics 14, 979-987. [12] Karjalainen, S., Tergsvirta, M., Karja, J. and Kiilriainen, H. (1985) Usher’s syndrome type III: ENG findings in four affected and six unaffected siblings. J. Laryngol. Otol. 99, 43-48. 1131 Karjalainen, S., Teriisvirta, M., Kiirjl, J. and KLiiriHinen, H. (1983) An unusual otological manifestation of Usher’s syndrome in four siblings. Clin. Genet. 24, 273-279. [14] Kimberhng, W.J., Mtiller, C.G., Davenport, S.L. et al. (1989)Usher syndrome:clinical findings and gene localization studies. Laryngoscope 99, 66-72. [IS] Kimberhng, W.J., Miiller, C.G., Davenport, S., Priluck, I.A., Beighton, P.H., Greenberg, J., Reardon, W., Weston, M.D., Kenyon, J.B., Grunkemeyer, J.A., Pieke Dahl S., Overbeck, L.D., Blackwood, D.J., Brower, A.M., Hoover, D.M., Rowland, P. and Smith, R.J.H. (1992) Linkage of Usher syndrome type I gene (USHlB) to the long arm of chromosome 11. Genomics 14, 988-994. [16] Kimberling, W.J., Weston, M.D., Pieke Dahl, S., Kenyon, J.B., Shugart, Y.Y., MBller, C., Davenport, S.L.H., Martini, A., Milani, M. and Smith, R.J.H. (1991)Genetic studies of Usher syndrome. Ann. N.Y. Acad. Sci. 630, 167-175. [17] Kloepfer, H.W. and Laguite, J.K. (1966) The hereditary syndrome of congenital deafness and retinitis pigmentosa. (Usher’s syndrome). Laryngoscope 76, 850-862. 1181 McLeod, AC., McConnell, F.E., Sweeney,A., Cooper, M.C. and Nance, W.E. (1971)Clinical variation in Usher’s syndrome. Arch. Otolaryngol. 94, 321-334. [IS] Nijhuis, B.G. and Huygen, P.L.M. (1980)Single-responsevariability of air and water caloric reactions. Otorhinolaryngol. 42, 196-205. [20] Pieke Dahl, S.A., Kimberling, W.J., Gorin, M.B. et al., (1993) Genetic heterogenicity of Usher Syndrome type II. J. Med. Genet. 30, 843-848. [21] Pinckers, A., Hardus, P. and Nabbe, B. (1983)The EOG in unilateral eye disease:injuries. Graefe’s Arch. Clin. Exp. Ophthalmol. 220, 87-91. [22] Regenbogen, L.S. and Coscas, G.J. (1985) Oculo-auditory Syndromes. Masson, New York. [23] Robinson, D.W. and Sutton, G.J. (1979) Age effect in Hearing - A comparative analysis of published threshold data. Audiology 18, 320-334. [24] Smith, R.J.H., Lee, E.C., Kimberling, W.J., Daiger, S.P., Pelias, M.Z., Keats, B.J.B., Jay, M., Bird, A., Reardon, W., Guest, M., Ayyagari, R. and Hejtmancik, J.F. (1992) Localization of two genes for Usher syndrome type I to chromosome 11. Genomics 14, 995-1002. [25] Sondheimer, S., Fishman, G.A., Young, R.S. and Vasquez, V.A. (1979) Dark adaptation testing in heterozygotes of Usher’s syndrome. Am. J. Ophthalmol. 63, 547-550. [26] Tamayo, M.L., Bemal, J.E., Tamayo, G.E. et al. (1991)Usher syndrome: results of a screeningprogram in Colombia. Clin. Genet. 40, 304-311. [27] Theunissen, E.J.J.M., Huygen, P.L.M. and Folgering, H.T. (1986) Vestibular hyperreactivity and hyperventilation. Clin. Otolaryngol. 11, 161-169. [28] Thijssen, J.M., Pinckers, A. and Otto, A.J. (1974) A multipurpose optical system for ophthalmic diagnosis. Ophthalmologica 168, 308-314. [29] Usher, C.H. (1914) On the inheritance of retinitis pigmentosa, with notes of cases. R. Lond. Ophthalmol. Hosp. Rep. 19, 130-236. [30] Verhagen, W.I.M., Ter Bruggen, J.P. and Huygen, P.L.M. (1992) Oculomotor, auditory and vestibular responsesin myotonic dystrophy. Arch. Neurol. 49, 954-960. [31] Vernon, M. (1969)Usher’s syndrome - deafnessand progressive blindness: clinical cases,prevention, theory and literature survey. J. Chronic Dis. 22, 133-151.
Rdiatric International Journal of Pediatric Otorhinolaryngology 31 (1995) 159-174
ELSEVIER
The Usher syndrome type 2A: clinical findings in obligate carriers Annelies van Aarem*a, Cor W.R.J. Cremersa, Alfred J.L.G. Pinckersb, Patrick L.M. Huygen”, Godfried C.J.H. Hornbergen”, Bill J. Kimberling” ‘Department of Otorhinolaryngology. University Hospital Nijmegen. P.O. Box 9101. 6500 HB Nijmegen, The Netherlands bDepartment of Ophthalmology. University Hospital Nijmegen. P.O. Box 9101. 6500 HB Nijmegen, The Netherlands ‘Center for Hereditary Communication Disorders, Boys Town National Research Hospital. Omaha, NE, USA
Received 18 May 1994; accepted 18 July 1994
Abstract Ten obligate carriers of Usher syndrome type 2A from 5 different families with 2 affected persons all underwent audiologic, vestibular and ophthalmologic examinations. They had a sensorineural hearing loss which was in excess of that expected for their age at all of the frequencies (0.25-8 kHz) tested, however, only a 10 dB (average) excess in hearing loss at 0.25-0.5 kHz proved to be significant. The speech discrimination scores obtained conformed with the hearing thresholds. Tympanometry, acoustic reflex and brain stem auditory-evoked potential findings were generally normal. Some vestibular abnormalities were found in a minority of the carrier sample, but not beyond the level of false positivity. Ophthalmologic findings were essentially normal, although in 5 carriers there was a subnormal electrooculography (EOG). These findings are not sufficient specific for carrier detection. Keywords: Genetic deafness; Genetic blindness; Retinitis Autosomal recessive inheritance; Usher syndrome
pigmentosa;
Carrier detection;
1. Introduction
The Usher syndrome is an autosomal recessively inherited syndrome with congenital bilateral sensorineural deafnessand retinitis pigmentosa (RP) [22,29]. This l
Corresponding author, Tel.: 09 1 80 614450; Fax: 09 1 80 540251.
016s5876/95/SO9.50 0 1995Elsevier Science Ireland Ltd. All rights reserved SSDI 0165-5876(94)01081-8
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leads to progressive visual field loss (tunnel vision); posterior subcapsular cataracts also arise. RP can result in blindness through central visual acuity loss. The Usher syndrome is the most prevalent genetic cause of deafnessand blindness [16,31]. At present, 3 types can be distinguished on clinical grounds. Type I is characterized by RP and profound childhood deafnessand an insensitive or hyposensitive vestibular labyrinth; type II is characterized by RP and a moderate sensorineural hearing loss and a sensitive labyrinth. Type III is like type II, but the sensorineural hearing loss is progressive.A rapid, easyand inexpensive test with a high sensitivity and speciticity for the detection of the carrier state of the Usher syndrome is needed. Based on genelinkage studies, Usher syndrome type I is split up preliminary into type 1A that links to chromosome 14q32 [lO,ll], type 1B that links to chromosome llq13.5 [15,24] and type IC that links to chromosome 1lp [24]. Typ.eII is split up into type 2A linked on chromosome lq32-q41 [4] and a type 2B that is unlinked to lq32-q41 [20]. The literature on this topic is scarceor contradictory. A review is given of the literature and our own results are presented. 2. Materials and methods Ten obligate carriers of the Usher syndrome type II underwent extensive otologic, audiologic, vestibular and ophthalmologic tests. The 5 families studied all counted 2 Usher patients. The diagnosis of the Usher syndrome was based on the medical history, otoscopic, audiologic, vestibular and ophthalmologic findings. Gene linkage studies of the affected and non-affected family membersshowed linkage to chromosomeI and therefore those families are classified showing type 2A Usher syndrome. Pure-tone audiograms were measuredin a special sound-proof room according to the IS0 8253 (1989) [9] standard, testing at 0.5, 1, 2, 4 and 8 kHz for air and bone conduction. All threshold testing used 5 dB intensity increments. The IS0 7029 method (1984) [8] was followed to calculate P50 (50th percentile) threshold values for presbycusisfor each patient individually at each frequency, in relation to his or her age and sex. This method is very similar to that reported by Robinson [23]. Monaural speechdiscrimination scoreswere obtained using the sameset-up and standard Dutch phonetically balanced word lists consisting of ten monosyllables. Maximum speech discrimination scores (D,,,& were derived. Tympanograms and contralateral and ipsilateral acoustic middle-ear muscle reflexes were elicited and recorded. Brain stem auditory-evoked potentials (BAEPs) were obtained. The method has been previously reported in detail [30]. Eye movements were recorded with d.c. electronystagmography (ENG). Calibration of eye movement was obtained before each test. Saccades,smooth pursuit (SP), and optokinetic nystagmus (OKN) responseswere tested; gazepositions were tested to seewhether there was any gaze-evokednystagmus [30]. Vestibular tests were conducted with the patient in the dark with the eyesopen. Velocity step (VS) tests were performed with a Tiinnies rotatory chair and the postrotatory nystagmus response were analysedas previously reported [7] using 90% confidence limits for the parameters initial velocity (V), time constant (T) and ‘Gesamtamplitude’ - cumulative eye displacement- [a] [27] (and classified into the categoriesnormoreflexia, hyporeflex-
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31 (1995) 159-174
ia and hyperreflexia). The values of directional preponderance (DP) parameterswere also calculated (similar to the side effect, seebelow) to assessdirectional asymmetry of the responses.DP values in excessof 25% indicate significant asymmetry [27]. For the caloric side effect (SE), we arbitrarily assumeda relative side difference, i.e. (difference/sum)lOO%,in excessof 20% to indicate unilateral hypofunction. For the 95% confidence limits of the absolute responselevel, we took the values of 7”/5 and 45”/s previously established [19]. All of the carriers underwent a routine ophthalmologic examination. In addition, their visual fields were evaluated with Goldmann perimetry, using test targets I-l-I-4, III-4 and V-4, and they underwent electrooculography (EOG) and electroretinography (ERG) examinations as previously reported [2 1,281. Blood-samples from the patients and their family members as shown in the pedigreeswere collected for gene linkage studies in Boys Town National Research Hospital.
3.Results Fig. 1 shows the pedigrees. In 2 families (B and D), there was a consanguineous mating. Consanguinity was excluded within 5 generations in family A. No genealogic data were available on families C and E. Gene linkage studies performed in Boys Town National Research Hospital showed for all families by linkage to lq32-q42 having Usher syndrome type 2A. Otoscopy was normal in all ten carriers. None had in their medical history any hearing impairment, relevant ear disease,exposition to ototoxic drugs or noise trauma. Table 1 shows the audiometric results and speechdiscrimination data of the 10 affected Usher cases.The hearing loss was symmetrical in all those affected and more A
C
-
- affected
_
= unaffected male - obligate male carrier
@
male
l c @
- affected female = unaffected female = obligate female carrier
Fig. 1. Pedigrees of families with Usher syndrome. The numbers are identification
numbers.
M
M
45
56
41
36
38
27
24
25
21
A2
B3
l34
C5
C6
D7
D8
E9
El0
R L
M
45(-) 45(-) %) 3%) 2%) ‘44 5%) 4%) %, 544 5%) 45f-) 3%) 2%, ‘Of-) % 3%) 45,-) 2of-) ‘OH
0.25 kHz
+ /,a# 1 kHz
6500 + 15) qss + 5) 6500 + 15) 7q55 + 15) 4% + 20) q20 + 0) 35~0 + 15) 35(20 + 15) 30(30+ 0) 75wlf <15) 9q>70 + <20) 65,>,+ <5) g5(,70+ <15) 80(,60 + <20) g5t,70 + <15) 75(50+ 25) q70 + IO) 45(35+ 10) 55(45+ 10) 35(35+ 0) 50(45+ 5) 30(30+ 0) 50(50+ 0) 3000 + 0) 5505 + 0) 5q5cl+ 0) q50 + IO) 65~ + 5) 5Ot50+ 0) 3Ot25+ 5) 3505 + 0) q15 + IO) 4% + 15)
+ 5)
5505 + 20) 60(55+ 5) 55(50+ 0) 15(15+ 0) fO(lO+ 0) 50(35+ 15)
q55
0.5 kHz
dBHL: AC&
65(,+ 5) q6ll+ 0) 50(50+ 0) 5000 + 0)
@%Q + 0)
8000 c IO) (j5(65+ 0) 65~ + 5) 75(65+ IO) 5505 + IO) tq60 + 0) 70(65+ 5) 70(65+ 5) 105(>70+ <35) g5(,,+ <25) 115(,70 + <45) ‘05(>70 + <35) 65(65+ o) 650 t 5) q60 + 0)
2 kHz
95c.60 + <35) 9%60 + <30) 7505 + 20) got55+ 25) @$o + I01 7Ot55+ 15) q.60 + C5) 65~55+ IO) lo5(>60+ <65) g5(,,+ ~25) 12Ot.w + <60) 125,., + C65) 65(>60+ <5) ‘%o t 15) 65wo+ c5) 65~0 +
4 kHz
7$=4l+ <35) 7Ot.46 t <30) 75,>40 + C35) 65~3 + ~25) 65(>4a + <25)
9’4>40+ <50)
> t~wo + <60) > lOOwe + <60) 65,>4e + <25) 75(>40+ <35) 75(>4e + <35) 70,,40 + <30) 95(>4e + <55) g5,,4e + <45) > ‘O”(>4U+<60) > 1~(>40+ c60) ’ ‘OfJ(>4o+ <60) ’ lf%.46 + C60) 70,,4e t <30) 70(>40 + <30)
8 kHz 68 60 63 67 38 30 52 45 90 78 93 87 55 50 48 48 60 58 38 38
PTAb
95 100 95 95 95 95 95 75 75 70 75 90 95 95 95 95 95 95 95
80
D,,,C
Abbreviations: -, not measured; >, outside the range of the audiometer; ahearing loss, air conduction threshold (bone conduction threshold + air-bone gap); bpure tone average of 0.5, 1, 2 kHz (PTA); Cmaximum speech discrimination (D,,,).
;; L
1
R
Id
L R L R
L R L R
R L R L R
Ear
F
F
M
M
F
M
48
F
Age (yr) Sex
Al
Patient No.
Table I Pure tone and speechaudiometry results in 10 Usher patients
A. van Aarem et al. /Int. J. Pediatr. Otorhinolaryngol.
31 (1995) 159-174
163
marked at the higher frequencies. The pure tone average (PTA) at 0.5, 1 and 2 kHz varied from 30 to 93 dB. The maximum speechdiscrimination score was 80% or better, except in Nos 5 and 6. All had normal tympanograms. All except Nos 5 and 6, showed normal acoustic reflexes and BAEP findings. In Nos 5 and 6 who had the most severehearing loss (Table 1), wave V, in as far as it could be identified, showed increased (absolute) latency. Vestibular examination revealed normal caloric responsesbut abnormal rotatory responses(i.e. hyporeflexia or hyperreflexia). The results of the ophthalmologic tests are shown in Table 2. The ERG was nonrecordable. All the patients except for 2 had tunnel vision. Table 3 shows the results of tone audiometry and speech audiometry for the obligate carriers. The air-bone gap (ABG) values are included. The excessin hearing loss for the air conduction (AC) threshold, i.e. AC+, was calculated as AC+ = AC - P50 (seeMethods). Table 4 presents the AC+ values obtained. Probit analyses(not shown) demonstrated that the AC+ values (as well as the ABG values) had approximately normal distributions at all of the frequencies. The statistics for AC+ were calculated for each ear and frequency (Table 5). Table 5 shows the S.E.M. values which were used to test (Student’s t test) whether the mean values differed significantly from zero (P < 0.05). This was found to be the caseat 0.25 and 0.5 kHz for both ears. According to Student’s t test, the mean AC+ value at 0.25 kHz was significantly higher than that at 1 kHz in the right ear and those at 1, 2 and 4 kHz in the left ear; in the right ear, also the AC+ value at 0.5 kHz was significantly higher than that at 1 kHz. Table 3 shows that there was some ABG with a mean value of about 5 dB (Table 6). After calculating S.D. and S.E.M. values for the ABG (not shown), it was found that the mean ABG was significantly different from zero at all frequencies(Student’s t test, P < 0.05). It appeared that AC+ differed significantly from the ABG only at 0.5 kHz (Table 6). Assuming that the statistics for the ABG at 0.25 kHz (measurements were not available) were similar to those found at 0.5 kHz (not shown), it can be concluded from the present measurementsand analyses that the observation of a significant (excess in) sensorineural hearing loss (with reference to the P50 of presbycusis,seeMethods) was present only at 0.25 and 0.5 kHz. This (excessin) sensorineural hearing loss, i.e. AC+ corrected for the apparent conductive loss, was about 5-10 dB on average (Table 6). Analysis of the regression of AC+ at 0.25 or 0.5 kHz on age (not shown) did not reveal any significant correlation. All carriers showed normal tympanograms. Acoustic reflexes were normal in ah except No 7; reflex thresholds were found at levels of between 80 and 100 dB and there was no pathologic reflex decay, i.e. a reflex decline of more than 50% within 10 s. Carrier No 7 showed bilateral threshold elevation at 0.5 and 1 kHz. All the carriers showed normal BAEP results. Table 7 presentsthe vestibular findings. None of the carriers showed spontaneous or gaze-evoked nystagmus or any abnormal Saccades, SP or OKN responses. Caloric abnormalities were found in 2 subjects (Nos 1 and 8), i.e. significantly high responselevels. This feature was linked to the finding of hyperreflexia in the VS test. Abnormal VS responseswere found in 6 of the carriers, i.e. hyperreflexia in cases 1, 3, 5, 8 and 9 and hyporeflexia in case6. None of the DP values were significant.
Normal
RP
OD:l.08 OS:l.O4 OD: 1.22 OS:1.38 OD:0.67 os:o.50 OD1.0 0S:l.O OD:l.ll OS: I .o OD:0.62 OS:O.60 0D:l.O 0S:l.O 0D:l.O OS:O.88 OD:0.86 os:1.12 OD1.10 OS:1.08
0D:TV 5” 0S:TV 5” 0D:TV 10” 0S:TV 5” OD:TV# OS:TV% OD:TV# OS:TV# ODTV 20” OSTV 20” 0D:TV 10” 0S:TV 10” ODTV 20” 0D:TV 20” ODTV 25” ODTV 25” PRS PRS
EOGe
Goldmannd 0D:O OS:0 ODO OS:0 ODO OS:0 0D:O OS:0 ODO OS:0 0D:O OS:0 ODO OS:0 0D:O OS:0 0D:O OS:0 0D:O OS:0
ERG-CF’
0D:O OS:0 0D:O OS:0 0D:O OS:0 0D:O OS:0 0D:O OS:0 ODO OS:0 0D:O OS:0 0D:O OS:0 0D:O OS:0 0D:O OS:0
ERG-AF’
Abbreviations: Y,examined elswhere; avision: S, spherical; C, cylindrical; SC, sine correction; bfundus: RP, retinitis pigmentosa; ‘media: CCP, cataracta corticalis posterior; IO, increased (lens) opacity; CPP, cataracta polaris posterior; CC, cataracta capsularis; dGoldmann perimetry (V-4): TV, tunnel vision; PRS, partial ring scotoma; eelectrooculography (EDG): lower limit normal (5% limit) LpDt (Arden) ratio: 1.80; ‘electro-retinography (ERG): CF, cone function; lower limit normal b-wave: 100 micro Volt; RF, rod function; lower limit normal b-wave: 150 micro Volt (absolute limits).
M
21
El0
Normal
RP
F
25
E9
CPP
RP
F
24
D8
CCP
RP
M
27
D7
cc
RP
M
38
C6
CPP
RP
F
36
CS
IO
RP
M
41
B4
CCP
RP
M
56
B3
CCP
RP
M
45
A2
CCP
RP
0D:S + 0.50, C-2.0, 165YO.2 0S:S + 0.50, C-2.0, So/O.08 ODS-2.0, c-2.0, 50”/0.3 OS:S-2.0, C-1.25, 180”/0.2 OS:S-7.5/0.25# OS:S-7.0, C-1.25, 165”/0.4# ODS-6.5, C-1.0, lO”/l.O# OS:S-6.25, C-1.25, 175”/1.0# OD:S-1 .O, C-O.50 180”/0.5 0s:s + 0.5, c-o.50 180”/0.5 0D:WO.S OS:SC/O.8 OD:S-0.5010.5 OS:!!&1.0/0.4 ODS-0.50, c-0.50, 180”/0.5 os:s-0.50, c-0.50, 1800/0.3 OD:SC/ 1.o OS:SC/O.8 oD:sc/1 .o os:sc/o.8
F
48
Al
Media’
Fundusb
Visiona
Age (yr)
Patient No.
Sex
Table 2 Results of ophthalmologic tests in IO Usher patients
F
F
12
29
31
62
65
54
53
59
49
A2
B3
B4
c5
C6
D7
D8
E9
El0
R L R L R L R L R L R L R L R L R L R L
Ear
‘OH 2o(-l
‘5w
2ot-l 2%) ‘%) 2%) ‘5H 2oi-j 2% 2%) 2oH 2%) 4%) 35H ‘OH ‘%I ‘%I
*5(-)
‘4-l
0.25 kHz
+ 5)
+ 10)
+ 5)
+ 5)
50 + 0)
20(,0
20~15
25(20
5(0+ 5)
+ IO)
+ 5)
20(r5 IO,0
+ 5)
+ 5)
20(15 30(25
+ 5)
2O(lS
15(5+ IO) 5(5+ 0) 5(0+ 5)
%s
q15 + 5)
5(5+ 0) lO(0+ 10) 20(15+ 5) 15(15+ 0) 20(0+ 20)
0.5 kHz
dB HL: AC(Bc + ABG)a
+ 5)
+ IO)
+ 0)
5,o + 5)
5(5 + 0)
3420
q20
50 + 0) fO(10+ 0) to,, + IO) 5(0+ 5) 10(10+ 0) 5(0 + 3) ‘O(S+ 5) O(0+ 0) O(0+ 0) l5(15+ 0) l5(5 + IO) 5(0 + 5) 10, + IO) 5, + 5) 5(0 l 5)
qo
1 kHz
25(20+ 5)
3q15 + 15)
5(0+ 5) ‘5(15 + 0) 5(S+ 0)
5(0+ 5) 50 + 0) qo + 0)
5,5 l 0) 50 + 0) qo
<20)
%-ul+
7q.40 + C30) 10(5+ 5) 55(>4a +
35(30+ 5) o,o + 0) 2% + 15) 50(45+ 5) qso + 0) qs + 5) 100 + IO)
15(5+ IO) 5(5+ 0) If-+5+ 5) q40 + 0) 35(35+ 0) 10(5.5) 5(0+ 5)
+ 0)
+ <60)
q>4rJ
40(40+ 0) 35(2, + IO)
q10 + 0)
3q30 + 0)
90(>40 + <50) 50(45+ 5)
0)
30(30+ 0)
l
+ 20)
q5 4 5) qo
o,o + 0)
h+O)
100 + 5)
+ 15)
25(, + 2oJ 5(0+ 5)
50 + 0)
+ 5)
+ 10)
‘O(lO+ 0)
‘O(5+ 5)
8 kHz
5(0+ 5)
5,
145
35~20
5(S+ 0)
2$25 + 01
‘010+ IO)
5(5+ 0)
4 kHz
O(D +0)
2 kHz
3 7 18 I2 10 10 10 10 3 2 22 18 15 15 7 7 28 28 I2 5
PTAb
100 100 100 100 100 100 100 100 100 100 95 95 95 95 100 95 loo 95 100 100
DmaxC
Abbreviations: -, not measured; >, outside the range of the audiometer; ahearing loss, air conduction threshold (bone conduction threshold + air-bone gap); bPure tone average of 0.5, 1, 2 kHz (PTA); fmaximum speech discrimination (D,,).
F
M
F
M
M
F
F
14
F
Age (yr) Sex
Al
No.
Carrier
Table 3 Pure tone and speech audiometry results in Ii) obligate carriers
F
F
M
F
29
31
62
65
54
53
59
49
B3
B4
CS
C6
D7
D8
E9
El0
F
M
M
F R L R L R L R L R L
R L R L
+I1 +I1 +I4 +24 +14 +I9 +14 +14
R L R L
F
72
+15 +15
R L
F
+I3 +I3 +36 +31 +6 +6 +4 +9 +7 +I7
0.25 kHz
Cl0 +5 +19 +19 +I9 +14 -2 -2 +12 +12 +25 +I5 +5 0 +19 +14 +I6 +I
+5 +lO
0.5 kHz
-1 -1 +4 +9 +4 +9 -8 -8 +6 +6 -I +4 0 0 +I3 +23 +i +I
+5 +5
1 kHz
to the P50 threshold
dB HL: AC+ = AC - PSO
(AC+) in relation
Ear
threshold
Sex
A2
Age (yr)
14
No.
Al
Carrier
Table 4 Excess in hearing loss for the air conduction frequency for his or her age and sex
+3 +3 -7 -12 +14 +l4 0 +5 -3 +2 +28 +23 +4 -1
+I4 +4 +14 +14 -12 +8 +23 +23 +I +I
+3 +3 -13 -18
+lO 0 +3 +3
+I0 +5
0 +5 +8 -2 +4 -1
4 kHz
for each carrier
2 kHz
values for presbyacusis
+41 +51 +31 +41 -9 +36 -12 -2 0 -5
+I0 +10 -II -16 +8 +8 +I7 +2 -15 -25
8 kHz
individually
at each
A. van Aarem et al. /Int. J. Pediatr. Otorhinolaryngol.
167
31 (1995) 159-174
Table 5 AC+ values (dBHL) with their statistics. Student’s t test was applied to identify mean values, which were significantly different from zero Ear R
n Mean SD. S.E.M. i
L
n Mean SD. S.E.M. t
0.25 kH.z
0.5 kHz
1 kHz
2 kHz
4 kHz
8 kHz
10 13.4 8.8 2.8 4.8 IO IS.9 7.4 2.3 6.8
10 12.8 8.3 2.6 4.9 IO 8.8 7.3 2.3 3.8
IO 2.3 5.5 1.8 1.3 IO 4.8 8.2 2.6 1.9
10
10 5.3 11.4 3.6 1.5 10 4.3 10.5 3.3 1.3
10 6.0 19.2 6.1 I.0 IO 10.0 25.1 7.9 1.3
5.1
9.9 3.1 1.6 10 3.6 9.5 3.0 1.2
Significant values in bold italic print. Table 6 Mean values (dBHL) for both ears for AC+ and ABG and their difference
AC+ ABG AC+-ABG
0.25 kHz
0.5 kHz
1 kHz
2 kHz
4 kHz
8 kHz
15 6? 9?
II* 6 5
4 4 0
4 3 I
5 6 -1
8 5 3
Abbreviations: *, significant difference between AC+ and ABG (Student’s t test, P < 0.05); bold italic print indicates values significantly different from zero. Table 7 Clinical and vestibulo-ocular data on the carriers Carrier no.
Age (yrs) Sex
Al
14
A2 B3 B4 c5 C6 D7 D8 E9 El0
VS response
Calories
R nystagmus V,T,G
L nystagmus V,T,G
LC, RC”
F
40, plateau
46. 32, 1472
50, 50
12 29 31 62
F F F F
49, 12, 588 85, 15, 1275 44, 16, 704 71, 28, 1988
52, 13,676 72, 14, 1008 37, 18, 666 68, 24.1632
18.21 13, 14 14. I5 41.52
65 54 53 59 49
M M F M F
23, 14, 322 50, 16, 800 68, 12, 816 56, 14, 784 39, 20, 780
IS, 14,210 48,23, 1104 58, 15, 870 66, 18,1186 39, 19, 741
IO, 9 20, 17 16,21 36, 32 IO. 14
Abbreviations: significant values in bold italic print; “left cold, right cold.
Remarks
Dizziness, nausea, vomiting afterwards
Susceptible to motion sickness Often at sea
F
M
F
72
29
31
62
65
54
53
59
49
A2
B3
I34
C5
C6
D7
D8
E9
El0
ODS + 1.0, c-1.0, 200/1.0 Gs:S + 1.25, C-0.25, 18OVl.O ODC-0.50. 900/l.o OS: c-0.50, 1800/l.o ODS-1.50/1.0 OS:S-2.0. C-1.25, 45-11.0
0S:MCL -4.511 .o OD!S + 2.25, c-0.50. 9oVl.O 0s:s + 1.15/1.0 0D:S + 1.25, C-0.50, 9OVl .O 0s:S + 1.25, C-0.50, 9oYl.O 0D:S + 1.75, C-0.25, 45Vl.O 0s:s + 2.0, c-0.50, 13oV1.0 0D:ll OS:11 OD:9 OS:10 OD:9 OS:10
C.I.
OS:10
OD:9
N
N
N
N
N
N
N
OD: 9
C.C. OS:11
N
OD:13 OS:13
N
NE
N c.c
N
N
N
N
N
N
N
N
N
N
N
N
N
OD1.82 OS1.78 ODZ.47 os:1.30
ODIOO OS:1 10 OD:14O OS:120
OD160 OS:170
OS:150
os:2.0
OD:2.0 os:2.22
OD210
OS:120
0S:I.M OD2.0
ODNE
0S:ca 40# OD:350 OS:210 OD130 OS:140
os:2.14 OD:1.81 OS: 1.93 OD:l.Sl OS:1.61 OD1.53
OS: 150 0D:ca 2OtY
OS:200 OD150
os:2.0!? OD1.65 OS:I.63 OD:2.18
OD280
ERG-CF*
OD2.05
S/We Gold- EOG= mann
OS;18 NE
OD18
NE
10Pd
N
C.I.
N
Media=
ODS: no maculae reflexes, N RPE somewhat coarse aspect, grey arcades in the periphery, blond fundus
ODS: temporal papillae pale, maculae: no reflexes, OD: some golden glistening around the foveola ODS: periphery somewhat coarse aspect, but conforms with age OS: RPE depigmentation
OS: pigment dot in the periphery, not related to RP normal
coarse aspect, but without pigmentation OD: a few greyish specks in the periphery unrelated to RP Normal
vessel
0s:s-0.50/1 .o ODS-0.25, c-0.25, 90’11 .o OS:SC/l .o ODMCL -4.5/l .O
ODS; cilioretinal
Fundus b
ODS: RPE somewhat
carriers
ODS-4.0, c-0.75. 18OVl.O os:s-4.5. c-0.75, 145”I 1.o ODS-l.OIl.0
Visiona
tests on 10 obligate
OD:3Qo OS:290 OD350 OS:350
OD:3SO OS:350
OS:370
OD:3SO
OS:130
0D:NE
OD:350 OS:300 OD:220 OS:210
OS290 NE
OS:340 OD:320
OD410
ERG-RFs
Abbreviations: #, skin electrode ERG, NE, not examined; N, normal; Vision: S, spherical; C, cylindrical; SC, sine correction; WCL, with contact lens; bfundus: RPE, retinitis pigment epithelium; RP, retinitis pigmentosa; ‘media: CL cataracta incipiens; CC, (CPP) cataracta corticalis; dIOP, intra ocular pressure - NE, not examined; %, Schober; W, Worth; ‘Electra-oculography (EOG): lower limit normal (5% limit) LplDt (Arden) ratio: 1.80, abnormal values shown in bold italics; sElectro-retinography (ERG): CF, cone function; lower limit normal b-wave: 100 micro Volt; RF, rod function; lower limit normal b-wave: 150 micro Volt (absolute limits), abnormal values shown in bold italics.
M
M
F
F
F
F
F
14
Al
Sex
tins)
Carrier No.
Age
Table 8 Results of ophthahnologic
A. van Aarem et al. /Int. J. Pediatr. Otorhinolaryngol. 31 (1995) 159-174
169
Vestibular complaints were not mentioned by any of the carriers before examination. Carrier No 5, before being informed about the finding of hyperreflexia, mentioned her susceptibility to motion sickness.Carrier No 1 also showing hyperreflexia complained later about her dizziness, nausea and vomiting after the vestibular examination. Carrier No 6 showed hyporeflexia of the VS responseand was a professional marine at sea. The ophthalmologic test results of the 10 obligate carriers are presented in Table 8. In 5 of the carriers (Nos 2, 5, 6,9 and 10) the EOG was subnormal; one of them was also found to have an abnormal ERG (No 6). 4. Discussion The present results indicate that the carriers had an AC threshold which was in excessof that expected for their age (AC+) by about 10 dB at 0.25-0.5 kHz (Table 6). As they appeared to have about 5 dB conductive hearing loss, which we have no plausible explanation for other than the possibility of systematic error in the measurements,presumably bias introduced by avoidance of threshold values for bone conduction that are apparently higher than thesefor air conduction, the apparent sensorineural hearing loss at those frequencies had to be corrected for the ABG present (i.e. AC+ - ABG, seeTable 6). The latter value was not equivalent to BC, the bone conduction threshold in Table 3. If we had corrected the BC values for (sexrelated) presbycusisin a similar way to that done for AC following the IS0 7029procedure, we might have found similar values. However, as no such procedure has been defined for BC, there was no alternative. We assumedthat the ABG was not agedependent, which indeed appeared to be the case (the regression analyses are not shown). All of the carriers showed normal BAEP and tympanometric results. Acoustic reflexes were generally normal. The significant sensorineural hearing loss, therefore, can be regarded as cochlear in origin. Kimberling et al. [14,16] also performed BAEP, tympanometric and acoustic reflex examinations, but did not report in detail any of the results obtained. The present results and those reported by others indicate that sensorineural hearing loss can be observed among type II carriers. However, it can be distinguished from presbycusis only with some difficulty, for example by applying the present methods. We have no explanation for the present observation that the sensorineural hearing loss manifested itself predominantly at the lower frequencies in the carriers, whereas the affected persons showed their predominant hearing loss at the higher frequencies. The hearing loss of the carriers in this study may represent partial expression of the (more severe)hearing loss shown by the affected persons at the lower frequencies. In view of the above-mentioned normal BAEP findings in the affected persons, one would expect to find normal BAEP examinations only in the obligate carriers, which turned out to be the case.The samewas true for the tympanometric and acoustic reflex examinations. In the literature, very few articles are available on possible clinical abnormalities in carriers of the Usher syndrome [4,17,25]. In other studies, one single family was described [ 1,2,6,12,13,18]or the carriers were only mentioned indirectly [3,14,16,26].
170
A. van Aarem et al. /Int. J. Pediatr. Otorhinolaryngol.
31 (1995) 159-174
The lack of clinical data and the lack of gene linkage results on affected persons meansthat it is not always clear which type of the Usher syndrome was studied c.q. or in which type of carrier the abnormalities were diagnosed (Table 9). Therefore, no direct comparison can be made between our results in obligate type 2A carriers and previously reported results. Only three earlier studies present the audiograms of obligate (0) c.q. possible carriers (P) [ 1,2,13]. Two additional studies mention either the mean hearing lossesfor the various frequencies [ 171or the mean hearing loss is presented in figures [18]. An overview of the hearing lossesin the various studies is given in Table 10. No technical data on audiometry were reported in the majority of studies, therefore we cannot make any meaningful direct comparisons with our findings. We have already mentioned our reservations about some of the vestibular findings, for example, the responseswhich showed hyporeflexia (low V and G values) in carrier No 6, who might have developed vestibulo-ocular reflex (VOR) suppresTable 9 Overview of clinical studies on carriers in the literature Author
No. + type AudioType Usher of carriersb metry syndrome,
Hal&en [5]
I
Holland [6]
I+IMll
Davenport
II
90 40 28 0 22 P 20 3P 140 SP 80 1P 80 2P 20
?
14 0
Kloepfer [17] I Goode [2]
IMII
de Haas [4]
I+Iulll
McL.eod 1181 XVIII
Vestibular test
III
10 6P Grmdahl [3] I + II + III 35 0 Rimberling I + II 23 0 1141 Kimberling I + II 20 0
ERG/DA
EOG
ERG
-
DA
-
-
-
? ? +
+
+
+
+
+
+
+
-
+
+
ERG+DA
+
+
+
ERG
+
+
-
DA
+ +
-
+
+
+
111 Sondheimer 1251 Karjalainen
Fundus- PeriscOPY metry
?
+
+
?
?
?
?
+ (4) +
? +
?
+
DA ERG
? -
+
+
+
ERG
-
?
ERG
-
Ml31
1161 Tamayo [26] ?
80
t
Abbreviations: +, mentioned in methods, -, not performed; ?, unclear; %ype Usher syndrome: author’s classification is shown in bold italics; bcarrier type: 0, obligate; P, possible.
I
typeb
Usher Syndrome
1I/Mf?d
11/w?d
I/M/adult
I/F/adult
l/F/6
l/F/8
l/M/IO
P
P
0
0
P
P
P
lJFJ49s
1 /M/81
lJM/+’
1/Mf?dJ
0
0
P
P
l/M/54’
18/F/> 14
0
0
10/M/> 14
No&x/age
0
Carrier tYpeC
ADe AS ADe AS= ADe ASe ADe ASe AD AS AD AS AD AS AD AS AD AS AD AS AD AS AD AS AD AS AD AS 10
5
15 10
35
3s
0.125 kHz
dRHL:
5q45
5 IO
IO 5
55wo
+ IS)
+ 5)
+ ABG)~
12.0 13.5 10.5 10.8 15.3 15.0 0.0 2.7 25 15 20 25 20 25 45 40 35 30 10 10 15 10
0.25 kHz
AC(BC
+ 5)
65wl
qMl+
8.0 10.5 5.5 3.1 6.3 4.0 0.5 6.8 15 20 5 IO 5 IO 70 65 50 55 IO 5 10 5 0) + 5)
I kHz
5 5
5
10
IS(l5 + 0) *000 + IO) 20(20+ 0)
;;r++O;o)
50(45
9.0 11.0 6.1 5.2 1.7 9.0 2.2 9.5 20 15 I5 20 15 15 50 45 45 40 5 5 10 0
0.5 kHz
+ 0) + 0)
5
5
25(lS + 10) 2000 + 0)
q,
q60
9.5 14.0 4.4 3.6 6.8 0.4 1.8 8.6 15 IO I5 IO 5 0 75 70 80 70 I5 15 20 5
2 kHz
20 20 40 5
22.0 34.5 12.5 13.6 17.2 IO.4 5.4 4.0
3 kHz
+ 20)
+ IO) + 0)
6s,5
+ 10) 7s(65
75f65
6SVlo+ 5) 7005 + 20)
75C55
30.5 39.0 16.3 16.6 20.4 12.2 5.0 5.0 IO 20 20 10 -5 5 70 65 60 55 55 15 45 10
4 kHz
25 55 15
5s
25
28.5 37.0 18.8 20.8 17.7 10.4 7.2 6.3
8 kHz
75 55
0 5 65 75 65 60 35 5 3s 5 90 85
30.5 32.5 15.0 16.3 12.7 8.6 6.3 0.4 5 IO IS
Abbreviations: ahearing loss, air conduction threshold (bone conduction threshold + air-bone gap); btype Usher syndrome, author’s classification is shown in bold italics; ‘carrier type: 0, obligate; P, possible; d?, age unknown; emean values; ‘noise exposure +; hoise exposure -.
Karjalainen III H31
[ll
Davenport II
Khrepfer I171
Author
Table 10 Results of pure tone audiometry in carriers in the literature
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sion in responseto his professional activities. Hyperreflexia was found in 4 other carriers, of whom at least 2 (Nos 1 and 5) were suspectedof being susceptible to motion sickness.If we exclude these 2 carriers and the above-mentioned carrier No 6 from the present evaluation, hyperreflexia occurred in 3 casesout of the 7, which may have been due to false positivity [27]. It is possible that in carrier Nos 1 and 5, motion sicknesswas secondary to their abnormal VOR behavior. Be this as it may, for the moment it seemsthat the odds are against the type 2A carriers having specific vestibular abnormalities. In the literature, 10 obligate carriers of a presumed type II Usher syndrome were tested by other authors and only 2 of them were found to have reduced caloric responses.If we include the report by Karjalainen et al. [12] the score for hypoexcitability in type II/III carriers is 2 out of 12 and, including the present report, it is 2 out of 22 carriers. This can certainly be reconciliated with false positivity at a presumed level of significance of 5%. Although several authors mentioned employing SP [14], and OKN tests [14,18], no results pertaining to carriers were mentioned in their reports. We could not find any reports about rotatory tests on carriers. Our ophthalmological investigations did not show any RP-specific fundus changes in the carriers; the media were normal for their age. Sondheimer et al. [25] did not find any fundus abnormalities either, in 14 obligate carriers (type unknown). Fundus and media abnormalities in carriers were reported by Kloepfer et al. [ 171in 4 out of the 13 carriers (type unknown); they displayed a fundus picture typical of RP. During re-evaluation, 3 out of the 4 did not have RP, but gyrate atrophy-like fundus abnormalities, with abnormal ERG, the fourth did not have any fundus abnormalities [6]. Thesegyrate atrophy-like findings were later criticized by Sondheimer et al. [251. Conflicting results have been published in the literature on dark adaption (DA) measurements[3,4,25]. In view of these findings and the fact that DA measurement is a subjective method, we chose objective test methods: EOG and ERG. Table 8 shows that the EOG and ERG results of some of the carriers were abnormal: 5 out of the 10carriers had an EOG value of below the 5% lower confidence limit; 1 carrier also had an abnormal ERG result. The literature also mentioned abnormal EOG and ERG results in carriers. The two parents (type II) examined by Davenport et al. [l] underwent general ophthalmologic tests, fundoscopy, perimetry and ERG tests and no abnormalities were found. One of the two carriers displayed subnormal EOG values. Tamayo [26] found subnormal ERG values in 2 out of the 8 obligate carriers (type unknown). Hallgren [5] did not find any abnormal ERG values in 4 obligate carriers tYPe 1. Summarizing, no clear ophthalmologic abnormalities were found in carriers in this study, which supports the lack of abnormalities reported in carriers in the literature. Although EOG and ERG abnormalities were found, these methods do not appear to be sufficient sensitive and specific for the identification of heterozygotes. The fact that the affected persons were found to have vestibular abnormalities (hyporeflexia or hyperreflexia) might suggestthe possibility that the obligate carriers
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also had (some)similar symptoms. As shown above, similar findings (i.e. hyporeflexia or hyperreflexia) were indeed encountered in the present study, but not beyond the level of false positivity. It seemsjustified to attribute the abnormal rotatory responsesin the affected persons to functional impairment of the afferent visual system, causedby abnormalities in the peripheral retina. These features were generally lacking in the obligate carriers. The results of our study on 10 obligate Usher type 2A syndrome carriers and the review of the literature, indicate that it is not (yet) possible to identify carriers using extensive audiovestibular and ophthalmologic tests. Acknowledgements The authors would like to thank the patients and their family members for their help and cooperation. The authors are indebted to Professor E.M. BleekerWagemakers,MD, International Ophthalmic ResearchInstitute, Ophthalmogenetic Department, Amsterdam, The Netherlands, for providing genealogic data. They wish to thank Mrs. P. Folman, Mr. M.G.M. Nicolasen, Mr. J.F.P. Noten, Mrs. E.M. Hoeks and Mr. A.A.I. van ‘t Pad Bosch for their technical assistance.This researchproject was supported in The Netherlands by grants from the following Foundations and Societies: ‘De Drie Lichten’, ‘Heinsius Houbolt’, ‘Voor de Blinden en Slechtzienden’, and ‘De Gelderse Blindenvereniging’. References [I] Davenport, S.L., O’Nuallain, S, Omenn, G.S. and Wilkus, R.J. (1978)Usher syndrome in four hard of hearing siblings. Pediatrics 62, 578-583. [2] Goode, R.L., Rafaty, F.M. and Simmons, F.B. (1967) Hearing loss in retinitis pigmentosa. Pediatrics 40, 875-880. [3] Grottdahl, J. and Mj@n, S. (1986) Usher syndrome in four Norwegian counties. Chn. Genet. 30, 14-28. [4] Haas, E.B., de Lith, G.H., van Rijnders, J., Rumke, A.M., Volmer, C. (1970) Usher’s syndrome, with special reference to heterozygous manifestations. Dot. Ophthalmol. 28, 166-190. [5] Hallgren, B. (1959) Retinitis pigmentosa combined with congenital deafness;with vestibulocerebellar ataxia and mental abnormality in a proportion of cases: a clinical and geneticostatistical study. Acta Psychiatr. Neural. Stand. 34 (Suppl. 138), l-99. [6] Holland, M.G., Cambie, E. and Kloepfer, W. (1972) An evaluation of genetic carriers of Usher’s syndrome. Am. J. Ophthalmol. 74, 940-947. [7] Huygen, P.L.M., van Rijn, P.M., Cremers, C.W.R.J. and Theunissen, E.J.J.M. (1993) The vestibulo-ocular reflex in pupils at a Dutch school for the hearing impaired; findings relating to acquired causes.Int. J. Pediatr. Otorhinolaryngol. 25, 39-47. [8] IS0 7029(1984)Acoustics - Threshold of hearing by air conduction as a function of age and sex for otologically normal persons. Geneva, International Organization for Standardization. [9] IS0 8253-l (1989) Acoustics - Audiometric test methods - Part I: Basic pure tone air and bone conduction threshold audiometry. Geneva, International Organization for Standardization. [IO] Kaplan, J., Gerber, S., Bonneau, D., Rozet, J.M., Dufier, J.L., Munnich, A. and Frezal, J. (1991) Probable location of Usher type I gene on chromosome 14q by linkage with D14S13 (MLJl4 probe). Cytogenet. Cell Genet. 58, A27446, 1991/l Ith International Workshop on Human Gene Mapping, London, 18-22 August.
174
A. van Aarem et al. /Int. J. Pediatr. Otorhinolaryngol.
31 (1995) 159-174
[I 1) Kaplan, J,. Gerber, S., Bonneau, D., Roxct, J.M., Dehieu, 0.. Briard, M.L., Dolfus, H., Ghazi, I., Dutier, J.L., F&al, I. and Munnich, A. (1992)A genefor Usher syndrome type I (USHIA) maps to chromosome 14q. Genomics 14, 979-987. [12] Karjalainen, S., Tergsvirta, M., Karja, J. and Kiilriainen, H. (1985) Usher’s syndrome type III: ENG findings in four affected and six unaffected siblings. J. Laryngol. Otol. 99, 43-48. 1131 Karjalainen, S., Teriisvirta, M., Kiirjl, J. and KLiiriHinen, H. (1983) An unusual otological manifestation of Usher’s syndrome in four siblings. Clin. Genet. 24, 273-279. [14] Kimberhng, W.J., Mtiller, C.G., Davenport, S.L. et al. (1989)Usher syndrome:clinical findings and gene localization studies. Laryngoscope 99, 66-72. [IS] Kimberhng, W.J., Miiller, C.G., Davenport, S., Priluck, I.A., Beighton, P.H., Greenberg, J., Reardon, W., Weston, M.D., Kenyon, J.B., Grunkemeyer, J.A., Pieke Dahl S., Overbeck, L.D., Blackwood, D.J., Brower, A.M., Hoover, D.M., Rowland, P. and Smith, R.J.H. (1992) Linkage of Usher syndrome type I gene (USHlB) to the long arm of chromosome 11. Genomics 14, 988-994. [16] Kimberling, W.J., Weston, M.D., Pieke Dahl, S., Kenyon, J.B., Shugart, Y.Y., MBller, C., Davenport, S.L.H., Martini, A., Milani, M. and Smith, R.J.H. (1991)Genetic studies of Usher syndrome. Ann. N.Y. Acad. Sci. 630, 167-175. [17] Kloepfer, H.W. and Laguite, J.K. (1966) The hereditary syndrome of congenital deafness and retinitis pigmentosa. (Usher’s syndrome). Laryngoscope 76, 850-862. 1181 McLeod, AC., McConnell, F.E., Sweeney,A., Cooper, M.C. and Nance, W.E. (1971)Clinical variation in Usher’s syndrome. Arch. Otolaryngol. 94, 321-334. [IS] Nijhuis, B.G. and Huygen, P.L.M. (1980)Single-responsevariability of air and water caloric reactions. Otorhinolaryngol. 42, 196-205. [20] Pieke Dahl, S.A., Kimberling, W.J., Gorin, M.B. et al., (1993) Genetic heterogenicity of Usher Syndrome type II. J. Med. Genet. 30, 843-848. [21] Pinckers, A., Hardus, P. and Nabbe, B. (1983)The EOG in unilateral eye disease:injuries. Graefe’s Arch. Clin. Exp. Ophthalmol. 220, 87-91. [22] Regenbogen, L.S. and Coscas, G.J. (1985) Oculo-auditory Syndromes. Masson, New York. [23] Robinson, D.W. and Sutton, G.J. (1979) Age effect in Hearing - A comparative analysis of published threshold data. Audiology 18, 320-334. [24] Smith, R.J.H., Lee, E.C., Kimberling, W.J., Daiger, S.P., Pelias, M.Z., Keats, B.J.B., Jay, M., Bird, A., Reardon, W., Guest, M., Ayyagari, R. and Hejtmancik, J.F. (1992) Localization of two genes for Usher syndrome type I to chromosome 11. Genomics 14, 995-1002. [25] Sondheimer, S., Fishman, G.A., Young, R.S. and Vasquez, V.A. (1979) Dark adaptation testing in heterozygotes of Usher’s syndrome. Am. J. Ophthalmol. 63, 547-550. [26] Tamayo, M.L., Bemal, J.E., Tamayo, G.E. et al. (1991)Usher syndrome: results of a screeningprogram in Colombia. Clin. Genet. 40, 304-311. [27] Theunissen, E.J.J.M., Huygen, P.L.M. and Folgering, H.T. (1986) Vestibular hyperreactivity and hyperventilation. Clin. Otolaryngol. 11, 161-169. [28] Thijssen, J.M., Pinckers, A. and Otto, A.J. (1974) A multipurpose optical system for ophthalmic diagnosis. Ophthalmologica 168, 308-314. [29] Usher, C.H. (1914) On the inheritance of retinitis pigmentosa, with notes of cases. R. Lond. Ophthalmol. Hosp. Rep. 19, 130-236. [30] Verhagen, W.I.M., Ter Bruggen, J.P. and Huygen, P.L.M. (1992) Oculomotor, auditory and vestibular responsesin myotonic dystrophy. Arch. Neurol. 49, 954-960. [31] Vernon, M. (1969)Usher’s syndrome - deafnessand progressive blindness: clinical cases,prevention, theory and literature survey. J. Chronic Dis. 22, 133-151.