Ophthalmic Paediatrics and Genetics
ISSN: 0167-6784 (Print) (Online) Journal homepage: http://www.tandfonline.com/loi/iopg19
A Japanese pedigree of autosomal dominant congenital stationary night blindness with variable expressivity Mutsuko Hayakawa, Yoshie Imai, Mariko Wakita, Kazuo Kato, Kenji Yanashima, Yozo Miyake & Atsushi Kanai To cite this article: Mutsuko Hayakawa, Yoshie Imai, Mariko Wakita, Kazuo Kato, Kenji Yanashima, Yozo Miyake & Atsushi Kanai (1992) A Japanese pedigree of autosomal dominant congenital stationary night blindness with variable expressivity, Ophthalmic Paediatrics and Genetics, 13:4, 211-217, DOI: 10.3109/13816819209105169 To link to this article: http://dx.doi.org/10.3109/13816819209105169
Published online: 08 Jul 2009.
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Date: 31 March 2016, At: 21:06
0 Aeolus Press Ophthalmic Paediatrics and Genetics 0167-6784/92/US$3.50
(Accepted 20 August 1992)
A Japanese pedigree of autosomal dominant congenital stationary night blindness with variable expressivity
Downloaded by [New York University] at 21:06 31 March 2016
MUTSUKO HAYAKAWA', YOSHIE IMAI l, MARIKO WAKITA', KAZUO KATO', KENJI YANASHIMA2, YOZO MIYAKE3 and ATSUSHI KANAI'
'Department of Ophthalmology, Juntendo University School of Medicine, 3-1-3 Hongo, BunkyoKu, Tokyo; 2National Rehabilitation Center for the Disabled, 4-1, Namiki Tokorozawa, Saitama; 3Department of Ophthalmology, Nagoya University School of Medicine, 65 Tsurumai-cho, ShowaKu, Nagoya; Japan ABSTRACT. Three cases in three successive generations of one family with autosomal dominant congenital stationary night blindness are presented. Case 1, the proband, and Case 3, his grandfather had the same electroretinographic responses : nonrecordable scotopic electroretinogram (ERG), normal but slightly diminished flicker ERG, and negative-shaped single bright-flash ERG. Their dark adaptation curves were monophasic with no rod segment. However, Case 2, the proband's father, showed different ERG findings ; a moderately diminished scotopic ERG, a normal flicker ERG, and a biphasic dark adaptation curve with an elevated final rod threshold. The authors believe that these differences reflect variations in the expressivity of a single gene mutation with the Iowest expressivity being seen in Case 2. Key words: congenital stationary night blindness ; reduced penetrance ; variable expressivity ; electroretinography ; dark adaptation ; autosomal dominant inheritance
example of regular autosomal dominant inheritance, and one of the longest on record in Stationary nyctalopia is a group of disorders human genetics, is the Nougaret family which characterized by non-progressive night blind- includes 135 members with night blindness in ten ness with onset at birth. It is divided into night generations'?2. In Japan, information regarding blindness with abnormal ocular fundus (fundus the electrophysiological and psychophysical feaalbipunctatus and Oguchi's disease) and night tures of autosomal dominant CSNB is rare. blindness with normal fundus or congenital sta- There are detailed studies of autosomal recestionary night blindness (CSNB)'. CSNB is a sive and X-linked CSNB7.9, but, to our knowgenetically heterogeneous disease including ledge, autosomal dominant CSNB has not been autosomal dominant2-6, autosomal recessive7~* reported previously in Japan. We describe here and X-linked inheritance patterns7, lo. A famous electrophysiological and psychophysical findings in a family with autosomal dominant CSNB of variable expressivity. INTRODUCTION
*
Reprint requests to: Dr. Mutsuko Hayakawa, Department of Ophthalmology, Juntendo University School of Medicine, 3-1-3 Hongo, Bunkyo-Ku, Tokyo, 113, Jqpan
Ophthalmic Paediatrics and Genetics - 1992, Vol. 13, No. 4, pp. 211-217 Q Aeolus Press Buren (The Netherlands) 1992
21 1
M. Hayakawa et al.
N
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Propositus Congenital stationary night blindness 1
X : Examined
00:
Unaffected
Dyschrornatopsia
Fig. 1. Pedigree of K family.
Case 3
-
2
Fig. 2. Visual fields of Cases 1 (top), 2 (middle) and 3 (bottom).
~
212
Autosomal dominant congenital stationary night blindness
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CASE REPORT Case I, K . K . (IV-8, proband), a Japanese male, presented at age one year ten months with night blindness. He was the product of a normal gestation and delivery (birth weight, 3285 g); the past history was unremarkable except for atopic dermatitis. The family history included a paternal grandfather with night blindness and a maternal grandfather with deuteranopia; his parents were not consanguineous (Fig. 1). When he was 12 months old, his mother noticed that he had difficulty seeing in dimly lit areas. He used touch rather than vision to move under dim lighting.
Retinitis pigmentosa was diagnosed at another facility, and the patient was referred to our clinic. Visual acuity was difficult to assess at the initial visit because the patient was so young. When he was three years old, the visual acuity of his right eye was 0.1, correctable to 0.16, and that of his left was 0.2, correctable to 0.3. Exophoria with overaction of the right inferior oblique muscle without nystagmus was noted. The cornea, conjunctiva and sclera were normal, as were the media and intraocular pressure. Funduscopic examination revealed a tigroid fundus without remarkable abnormality except for a slightly increased retinal reflex in the periphery. When the patient was eight Galdmann-Weekers-Adaptometer
Case 1
Hioki-Adeptameter
ID
Case 2 10.' ID,
-.. ------_--
(Normal)
Case 3 3 Fig. 3. Dark adaptation curves of Cases 1 (top), 2 (middle) and 3 (bottom). Vertical and horizontal axes indicate threshold (log) and dark adaptation times, respectively.
213
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M. Hayakawa et al. years old, the visual acuity of his right eye was 0.1, correctable to I .O with a refraction of - 4.0 diopters sphere and - 1.5 diopters cylinder, and that of his left eye was 0.1, correctable to 1.0 with a refraction of - 6.0 diopters sphere and - 0.5 diopters cylinder. Goldmann perimetry revealed normal visual fields with V-4 and 1-4 targets, and slightly constricted fields with 1-3, 2 , 1 targets (Fig. 2). Goldmann-Weekers’ dark adaptometry showed a monophasic curve with an almost normal cone segment and absent rod segement (Fig. 3). Color vision tests (Ishihara, Ohkuma and Tokyo Medical College pseudoisochromatic plates) revealed low-grade deuteranopia, and Farnsworth dichromatous panel D-15test revealed minor disturbance without identifiable axis. After pupillary dilatation with 1 ‘To tropicamide and 20 minutes of dark adaptation, a scotopic ERG was recorded with a 0.3-Joule blue dim light stimulus and 50 responses were averaged (Neuropac-1, Nihonkoden Co. Ltd.). No scotopic b-wave was revealed. A singleflash ERG with a 20-Joule bright stimulus showed a negative shape (normal a-wave with a reduced
b-wave) ; oscillatory potential was nonrecordable. A flicker ERG was recorded with a 30-Hz whitelight stimulus and 100 responses were averaged. The flicker ERG revealed a slightly reduced response at the lower end of the normal range (Fig. 4). The Arden ratio of an EOG that was recorded in total darkness at one-minute intervals for I5 minutes, followed by recording under progressive light adaptation (1000 lux) for 15 minutes was 2.0 bilaterally, i.e., within normal range.
Case 2, Y.K. (111-7), is the 38-year-old father of Case 1. At his first clinic visit on April 11, 1985, he underwent detailed ophthalmological examination as part of his son’s assessment. His past medical history was unremarkable. He denied any symptoms of night blindness. Visual acuity was 0.3, correctable to 1.2 with a refraction of - 1.25 diopters sphere in his right eye, and 0.5, correctable to 1.2 with a refraction of - 1.O diopters sphere in his left eye. Ocular position, ocular motility, media, and intraocular pressure were normal. Funduscopic examination revealed a tigroid fundus with
ERG
scotopic
-
Case 3
Case 2
Case 1
Normal
1
IWPV -I
Pmuc
single bright flash
200p v
1p”
Z0m..c
w
l0OpV
J
20msec
flicker 4
w W
50p V
J
20msec
’”\nnnnj”p” -_I 20msec
Fig. 4. Scotopic ERG (top), single bright flash ERG (middle) and flicker ERG (bottom).
214
50p V 20msec
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Autosomal dominant congenital stationary night blindness two holes within an area of lattice degeneration at the periphery. The holes were treated with laser photocoagulation. Fluorescein angiography showed no remarkable abnormalities. Visual field and color vision (panel D-15 test, FarnsworthMunsell 100 hue test) were normal. Hioki's dark adaptometry test showed a biphasic curve with a 1.3 log elevation of final threshold and an almost normal cone segment (Fig. 3). The scotopic ERG revealed a diminished b-wave; the implicit time of the b-wave was within normal range. The singleflash ERG showed a negative shape with recordable oscillatory potentials. The flicker ERG was normal (Fig. 4). The Arden ratio of the EOG was 1.8 bilaterally, i.e., within normal limits.
Case 3, D.K. (11-2), the 72-year-old paternal grandfather of the proband, first visited our clinic on Dec. 25, 1985. He had severe night blindness and poor vision which had been stable since early childhood. His past medical history included gastric ulcer surgery at age 62. He had suffered from severe night blindness and squint since early childhood, and had worn corrective lenses for myopia since age six. Congenital night blindness was diagnosed by a military physician during World War 11. In his right eye visual acuity was 0.02, correctable to 0.2 with a refraction of - 14.0 diopters sphere and - 1.75 diopters cylinder, and in his left eye 0.02, correctable to 0.3 with a refraction of - 15.0 diopters sphere and - 2.50 diopters cylinder. He had 15" exotropia, without nystagmus. The cornea, sclera and conjunctiva were normal. Incipient cataracts were noted in both eyes. Intraocular pressure was normal bilaterally. Funduscopic examination revealed a tigroid fundus with atrophic changes of high myopia in the posterior pole and peripheral degeneration including a few old, pigmented, retinal holes. The outer right lower quadrant of both visual fields was absent homonymously (Fig. 2). C T scan revealed a lowdensity area in the left occipital lobe, apparently due to previous infarction. The dark adaptation pattern was monophasic, with a 4-log elevation of final threshold and a markedly elevated cone seg ment (Fig. 3). A panel D-15 test revealed normal color vision. The scotopic ERG, single-flash ERG, and flicker-ERG showed the same patterns as those of Case 1 (Fig. 4). The Arden ratio of the
EOG was 2.0, Le., normal bilaterally.
DISCUSSION Characteristic findings of CSNB include night blindness, abnormal ERG, abnormal vision, myopia, and squint, with considerable individual variation in each finding'. The fundus may be normal or have a myopic appearance. Indeed, many CSNB cases without discernible night blindness have been d i a g n o ~ e d ' , ~ In. this family, Cases 1 and 3 suffered from night blindness, while Case 2 was asymptomatic. The Riggs type of ERG, which is positive with a smaller b-wave than normal, has been observed in families affected by autosomal dominant night blindn e s ~ ~and . ~ the , Schubert-Bornchein type, a negative-shaped ERG, has been found in autosomal recessive and X-linked recessive pedigrees7,*, ' I . Recently, a family with the Schubert-Bornchein type, negative-shaped ERG and an autosomal dominant pattern of inheritance was reported4. Therefore, the negative-shaped ERG can be an important diagnostic sign, not only of autosoma1 recessive and X-linked recessive CSNB but of autosomal dominant CSNB as well. We can confidently diagnose autosomal dominant CSNB in this family, because a negative-shaped single-flash ERG was found in three successive generations, all males. The absence of subjective symptoms of night blindness in Case 2 is likely to be due to low penetrance, as individuals who appear to be normal are often found in pedigrees of autosomal dominant disordersI2. In this family, the dark adaptation curve was monophasic in Cases 1 and 3, but biphasic in Case 2. Scotopic b-wave was absent in Cases 1 and 3, but present in Case 2. Similarly, Case 2 as compared to Cases 1 and 3 (Table 1) showed preserved rod function, absence of squint, less severe myopia, and larger amplitude of flicker ERG. This most likely reflects the variable
215
M. Hayakawa et a/. TABLE 1. Summary of ophthalmological findings for CSNB proband (Case 1). his father (Case 2) and grandfather (Case 3)
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Case Age (Y.o.) Visual acuity
OD
Refractive error*
OD
Strabismus Night blindness (subjective) Dark adaptation ERG single flash Op** scotopic b flicker Color vision Panel D-15test 100 hue test Pseudoisochromatic plates+ Nystagmus EOG Fundus
0s
0s
+
1
2
3
8 0.1 (1.0)' 0.1 (1.0)' - 4.75 - 6.25 exophoria present monophasic
38 0.3 (1.2)' 0.5 (1.2)' - 1.25 - 1.0 orthophoria absent biphasic
72
negative not recordable absent diminished (w.n.1. +)
negative recordable diminished normal
negative not recordable absent diminished (w.n.1. + )
minor error unreliable low-grade deuteranopia absent 2.0 tigroid peripheral reflex
normal normal
normal not examined
absent 1.8 tigroid
absent 2.0 tigroid myopic atrophy holes
holes ( ):
0.02 (0.2)' 0.02 (0.3)' - 14.88 - 16.25 exotropia present monophasic
corrected visual acuity
* Refractive error : spherical equivalence * * Op : oscillatory potential +
+
w.n.1. : within normal limits Pseudoisochromatic plates: Ishihara, Ohkuma, and Tokyo Medical College +
expressivity of a dominant gene mutation. It has been reported that most patients with CSNB have mild to moderate cone system abnormalities', with marked elevation of the cone segment of the dark adaptation c u r ~ e l - ~ In, this ~ ~ fami. ly, the dark adaptation test showed marked elevation of the cone segment in Case 3, whereas cone adaptation segments were almost normal in Cases 1 and 2. Visual acuity was abnormal only in Case 3 . These same differences have been reported among cases of X-linked CSNB7,lo. The different clinical features in Xlinked CSNB may be due to a different pathogenesis' rather than to a variable expressivity. Two forms of X-linked CSNB, complete and incomplete, have been classified based on differ-
216
ences in ERG and dark adaptation7#14. Our family had some ERG features of X-linked CSNB. The monophasic dark adaptation curve and nonrecordable scotopic b-wave in our Cases 1 and 3 are consistent with the complete type. The biphasic dark adaptation curve and reduced scotopic b-wave in Case 2 are consistent with the incomplete type, but the normal amplitude of the flicker ERG and normal visual acuity are not. Moderately impaired visual acuities and diminished flicker ERG are common in incomplete CSNB7. 14. Similarly, the autosomal dominant CSNB cases described by Noble ef a/.4 had ERG patterns consistent with the complete type and dark adaptation curves consistent with the incomplete type. We feel that the different levels
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Autosomal dominant congenital stationary night blindness of expression among related individuals in our family are consistent with autosomal dominant CSNB. In CSNB, color vision is normal or only mildly abnormal’, and visual fields are normal or constricted in the lower mesopic luminant range’. The abnormal color vision (low grade deuteranopia) in Case 1 appears not to be associated with CSNB, but to be X-linked, since the patient’s maternal grandfather had the same disorder. The visual field defect in Case 3 appears to reflect an old cerebral infarction diagnosed by a neurologist. We have detected phenotypic variation due to variable expressivity in a family with autosomal dominant CSNB. Recently, a tight genetic linkage between X-linked CSNB and the Xp 11.3
DNA marker, DXS7, was reportedI5. However, no clear linkage has yet been identified in autosoma1 dominant CSNB. Future molecular biological investigation, designed to elucidate the locus of the autosomal dominant CSNB gene and the role of variable gene expressivity, must include examination of all family members, even those who are asymptomatic, in order to confirm the inheritance pattern and to identify all clinical features of autosomal dominant CSNB. ACKNOWLEDGEMENT This work was supported by a grant for the study of chorioretinal degenerations from the Japanese Ministry of Health and Welfare. The authors are grateful to Professor emeritus Akira Nakajima for valuable comments on the manuscript.
REFERENCES 1 . Krill AE. Congenital stationary night blindness. In : Krill’s Hereditary Retinal and Choroidal Diseases, vol. 2. Clinical Characteristics. Hagerstown : Harper & Row 1977 ; 391-404. 2. Franqois J , Verriest G, De Rouck A. Les fonctions visuelles dans I’himeralopie essentielle nougarienne. Ophthalmologica 1956; 132:244-255. 3. FranCois J, Verriest G, De Rouck A . A new pedigree of idiopathic congenital night blindness. Am J Ophthalmol 1965; 59 :621-625. 4. Noble KG, Carr RE, Siege1 1M. Autosomal dominant congenital stationary night blindness and normal fundus with an electronegative electroretinogram. Am J Ophthalmol 1990; 109:44-48. 5 . Carr RE. Congenital stationary night blindness. Trans Am Ophthalmol SOC1974; 72:448-487. 6. Carrol FD, Haig G. Congenital stationary night blindness without ophthalmoscopic or other abnormalities. Arch Ophthalmol 1953; 50:35-44. 7. Miyake Y, Yagasaki K, Horiguchi M, Kawase Y, Kanda T. Congenital stationary night blindness with negative electroretinogram, a new classification. Arch Ophthalmol 1986; 104: 1013-1020. 8. Kubota Y. Seven cases of congenital hemeralopia. Acta SOCOphthalmol Jpn 1972; 76: 179-183. 9. Nettleship E. A pedigree of congenital night blindness with myopia. Trans Ophthalmol SOCUK 1912; 32:21-45. 10. Pearce WB, Reedyk M, Coupland SG. Variable expressivity in X-linked congenital stationary night blindness. Can J Ophthalmol 1990; 25 : 3-10. 1 1 . Auerbach E, Godel V, Rowe H . An electrophysiological and psychophysical study of two forms of congenital night blindness. Invest Ophthalmol 1969; 8 : 332-345. 12. Vogel F, Motulsky AG. Human Genetics. 2nd edn. Berlin: Springer Verlag 1986; 112-1 16. 13. Weleber RG, Eisner A. Retinal function and physiological studies. In: Newsome DA, editor. Retinal Dystrophies and Degenerations. New York: Raven Press 1988; 39-42. 14. Miyake Y, Horiguchi M, Ota I, Shiroyama N. Characteristic flicker anomaly in incomplete congenital stationary night blindness. Invest Ophthalmol Vis Sci 1987; 28: 1816-1823. 15. Gal A, Scheinzel A, Orth U, Fraser NA, Mollica F, Craig IW et al. Gene of X-chromosomal congenital stationary night blindness is closely linked to DXS 7 on Xp. Hum Genet 1989; 81 :315-318.
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ISSN: 0167-6784 (Print) (Online) Journal homepage: http://www.tandfonline.com/loi/iopg19
A Japanese pedigree of autosomal dominant congenital stationary night blindness with variable expressivity Mutsuko Hayakawa, Yoshie Imai, Mariko Wakita, Kazuo Kato, Kenji Yanashima, Yozo Miyake & Atsushi Kanai To cite this article: Mutsuko Hayakawa, Yoshie Imai, Mariko Wakita, Kazuo Kato, Kenji Yanashima, Yozo Miyake & Atsushi Kanai (1992) A Japanese pedigree of autosomal dominant congenital stationary night blindness with variable expressivity, Ophthalmic Paediatrics and Genetics, 13:4, 211-217, DOI: 10.3109/13816819209105169 To link to this article: http://dx.doi.org/10.3109/13816819209105169
Published online: 08 Jul 2009.
Submit your article to this journal
Article views: 2
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=iopg19 Download by: [New York University]
Date: 31 March 2016, At: 21:06
0 Aeolus Press Ophthalmic Paediatrics and Genetics 0167-6784/92/US$3.50
(Accepted 20 August 1992)
A Japanese pedigree of autosomal dominant congenital stationary night blindness with variable expressivity
Downloaded by [New York University] at 21:06 31 March 2016
MUTSUKO HAYAKAWA', YOSHIE IMAI l, MARIKO WAKITA', KAZUO KATO', KENJI YANASHIMA2, YOZO MIYAKE3 and ATSUSHI KANAI'
'Department of Ophthalmology, Juntendo University School of Medicine, 3-1-3 Hongo, BunkyoKu, Tokyo; 2National Rehabilitation Center for the Disabled, 4-1, Namiki Tokorozawa, Saitama; 3Department of Ophthalmology, Nagoya University School of Medicine, 65 Tsurumai-cho, ShowaKu, Nagoya; Japan ABSTRACT. Three cases in three successive generations of one family with autosomal dominant congenital stationary night blindness are presented. Case 1, the proband, and Case 3, his grandfather had the same electroretinographic responses : nonrecordable scotopic electroretinogram (ERG), normal but slightly diminished flicker ERG, and negative-shaped single bright-flash ERG. Their dark adaptation curves were monophasic with no rod segment. However, Case 2, the proband's father, showed different ERG findings ; a moderately diminished scotopic ERG, a normal flicker ERG, and a biphasic dark adaptation curve with an elevated final rod threshold. The authors believe that these differences reflect variations in the expressivity of a single gene mutation with the Iowest expressivity being seen in Case 2. Key words: congenital stationary night blindness ; reduced penetrance ; variable expressivity ; electroretinography ; dark adaptation ; autosomal dominant inheritance
example of regular autosomal dominant inheritance, and one of the longest on record in Stationary nyctalopia is a group of disorders human genetics, is the Nougaret family which characterized by non-progressive night blind- includes 135 members with night blindness in ten ness with onset at birth. It is divided into night generations'?2. In Japan, information regarding blindness with abnormal ocular fundus (fundus the electrophysiological and psychophysical feaalbipunctatus and Oguchi's disease) and night tures of autosomal dominant CSNB is rare. blindness with normal fundus or congenital sta- There are detailed studies of autosomal recestionary night blindness (CSNB)'. CSNB is a sive and X-linked CSNB7.9, but, to our knowgenetically heterogeneous disease including ledge, autosomal dominant CSNB has not been autosomal dominant2-6, autosomal recessive7~* reported previously in Japan. We describe here and X-linked inheritance patterns7, lo. A famous electrophysiological and psychophysical findings in a family with autosomal dominant CSNB of variable expressivity. INTRODUCTION
*
Reprint requests to: Dr. Mutsuko Hayakawa, Department of Ophthalmology, Juntendo University School of Medicine, 3-1-3 Hongo, Bunkyo-Ku, Tokyo, 113, Jqpan
Ophthalmic Paediatrics and Genetics - 1992, Vol. 13, No. 4, pp. 211-217 Q Aeolus Press Buren (The Netherlands) 1992
21 1
M. Hayakawa et al.
N
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Propositus Congenital stationary night blindness 1
X : Examined
00:
Unaffected
Dyschrornatopsia
Fig. 1. Pedigree of K family.
Case 3
-
2
Fig. 2. Visual fields of Cases 1 (top), 2 (middle) and 3 (bottom).
~
212
Autosomal dominant congenital stationary night blindness
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CASE REPORT Case I, K . K . (IV-8, proband), a Japanese male, presented at age one year ten months with night blindness. He was the product of a normal gestation and delivery (birth weight, 3285 g); the past history was unremarkable except for atopic dermatitis. The family history included a paternal grandfather with night blindness and a maternal grandfather with deuteranopia; his parents were not consanguineous (Fig. 1). When he was 12 months old, his mother noticed that he had difficulty seeing in dimly lit areas. He used touch rather than vision to move under dim lighting.
Retinitis pigmentosa was diagnosed at another facility, and the patient was referred to our clinic. Visual acuity was difficult to assess at the initial visit because the patient was so young. When he was three years old, the visual acuity of his right eye was 0.1, correctable to 0.16, and that of his left was 0.2, correctable to 0.3. Exophoria with overaction of the right inferior oblique muscle without nystagmus was noted. The cornea, conjunctiva and sclera were normal, as were the media and intraocular pressure. Funduscopic examination revealed a tigroid fundus without remarkable abnormality except for a slightly increased retinal reflex in the periphery. When the patient was eight Galdmann-Weekers-Adaptometer
Case 1
Hioki-Adeptameter
ID
Case 2 10.' ID,
-.. ------_--
(Normal)
Case 3 3 Fig. 3. Dark adaptation curves of Cases 1 (top), 2 (middle) and 3 (bottom). Vertical and horizontal axes indicate threshold (log) and dark adaptation times, respectively.
213
Downloaded by [New York University] at 21:06 31 March 2016
M. Hayakawa et al. years old, the visual acuity of his right eye was 0.1, correctable to I .O with a refraction of - 4.0 diopters sphere and - 1.5 diopters cylinder, and that of his left eye was 0.1, correctable to 1.0 with a refraction of - 6.0 diopters sphere and - 0.5 diopters cylinder. Goldmann perimetry revealed normal visual fields with V-4 and 1-4 targets, and slightly constricted fields with 1-3, 2 , 1 targets (Fig. 2). Goldmann-Weekers’ dark adaptometry showed a monophasic curve with an almost normal cone segment and absent rod segement (Fig. 3). Color vision tests (Ishihara, Ohkuma and Tokyo Medical College pseudoisochromatic plates) revealed low-grade deuteranopia, and Farnsworth dichromatous panel D-15test revealed minor disturbance without identifiable axis. After pupillary dilatation with 1 ‘To tropicamide and 20 minutes of dark adaptation, a scotopic ERG was recorded with a 0.3-Joule blue dim light stimulus and 50 responses were averaged (Neuropac-1, Nihonkoden Co. Ltd.). No scotopic b-wave was revealed. A singleflash ERG with a 20-Joule bright stimulus showed a negative shape (normal a-wave with a reduced
b-wave) ; oscillatory potential was nonrecordable. A flicker ERG was recorded with a 30-Hz whitelight stimulus and 100 responses were averaged. The flicker ERG revealed a slightly reduced response at the lower end of the normal range (Fig. 4). The Arden ratio of an EOG that was recorded in total darkness at one-minute intervals for I5 minutes, followed by recording under progressive light adaptation (1000 lux) for 15 minutes was 2.0 bilaterally, i.e., within normal range.
Case 2, Y.K. (111-7), is the 38-year-old father of Case 1. At his first clinic visit on April 11, 1985, he underwent detailed ophthalmological examination as part of his son’s assessment. His past medical history was unremarkable. He denied any symptoms of night blindness. Visual acuity was 0.3, correctable to 1.2 with a refraction of - 1.25 diopters sphere in his right eye, and 0.5, correctable to 1.2 with a refraction of - 1.O diopters sphere in his left eye. Ocular position, ocular motility, media, and intraocular pressure were normal. Funduscopic examination revealed a tigroid fundus with
ERG
scotopic
-
Case 3
Case 2
Case 1
Normal
1
IWPV -I
Pmuc
single bright flash
200p v
1p”
Z0m..c
w
l0OpV
J
20msec
flicker 4
w W
50p V
J
20msec
’”\nnnnj”p” -_I 20msec
Fig. 4. Scotopic ERG (top), single bright flash ERG (middle) and flicker ERG (bottom).
214
50p V 20msec
Downloaded by [New York University] at 21:06 31 March 2016
Autosomal dominant congenital stationary night blindness two holes within an area of lattice degeneration at the periphery. The holes were treated with laser photocoagulation. Fluorescein angiography showed no remarkable abnormalities. Visual field and color vision (panel D-15 test, FarnsworthMunsell 100 hue test) were normal. Hioki's dark adaptometry test showed a biphasic curve with a 1.3 log elevation of final threshold and an almost normal cone segment (Fig. 3). The scotopic ERG revealed a diminished b-wave; the implicit time of the b-wave was within normal range. The singleflash ERG showed a negative shape with recordable oscillatory potentials. The flicker ERG was normal (Fig. 4). The Arden ratio of the EOG was 1.8 bilaterally, i.e., within normal limits.
Case 3, D.K. (11-2), the 72-year-old paternal grandfather of the proband, first visited our clinic on Dec. 25, 1985. He had severe night blindness and poor vision which had been stable since early childhood. His past medical history included gastric ulcer surgery at age 62. He had suffered from severe night blindness and squint since early childhood, and had worn corrective lenses for myopia since age six. Congenital night blindness was diagnosed by a military physician during World War 11. In his right eye visual acuity was 0.02, correctable to 0.2 with a refraction of - 14.0 diopters sphere and - 1.75 diopters cylinder, and in his left eye 0.02, correctable to 0.3 with a refraction of - 15.0 diopters sphere and - 2.50 diopters cylinder. He had 15" exotropia, without nystagmus. The cornea, sclera and conjunctiva were normal. Incipient cataracts were noted in both eyes. Intraocular pressure was normal bilaterally. Funduscopic examination revealed a tigroid fundus with atrophic changes of high myopia in the posterior pole and peripheral degeneration including a few old, pigmented, retinal holes. The outer right lower quadrant of both visual fields was absent homonymously (Fig. 2). C T scan revealed a lowdensity area in the left occipital lobe, apparently due to previous infarction. The dark adaptation pattern was monophasic, with a 4-log elevation of final threshold and a markedly elevated cone seg ment (Fig. 3). A panel D-15 test revealed normal color vision. The scotopic ERG, single-flash ERG, and flicker-ERG showed the same patterns as those of Case 1 (Fig. 4). The Arden ratio of the
EOG was 2.0, Le., normal bilaterally.
DISCUSSION Characteristic findings of CSNB include night blindness, abnormal ERG, abnormal vision, myopia, and squint, with considerable individual variation in each finding'. The fundus may be normal or have a myopic appearance. Indeed, many CSNB cases without discernible night blindness have been d i a g n o ~ e d ' , ~ In. this family, Cases 1 and 3 suffered from night blindness, while Case 2 was asymptomatic. The Riggs type of ERG, which is positive with a smaller b-wave than normal, has been observed in families affected by autosomal dominant night blindn e s ~ ~and . ~ the , Schubert-Bornchein type, a negative-shaped ERG, has been found in autosomal recessive and X-linked recessive pedigrees7,*, ' I . Recently, a family with the Schubert-Bornchein type, negative-shaped ERG and an autosomal dominant pattern of inheritance was reported4. Therefore, the negative-shaped ERG can be an important diagnostic sign, not only of autosoma1 recessive and X-linked recessive CSNB but of autosomal dominant CSNB as well. We can confidently diagnose autosomal dominant CSNB in this family, because a negative-shaped single-flash ERG was found in three successive generations, all males. The absence of subjective symptoms of night blindness in Case 2 is likely to be due to low penetrance, as individuals who appear to be normal are often found in pedigrees of autosomal dominant disordersI2. In this family, the dark adaptation curve was monophasic in Cases 1 and 3, but biphasic in Case 2. Scotopic b-wave was absent in Cases 1 and 3, but present in Case 2. Similarly, Case 2 as compared to Cases 1 and 3 (Table 1) showed preserved rod function, absence of squint, less severe myopia, and larger amplitude of flicker ERG. This most likely reflects the variable
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M. Hayakawa et a/. TABLE 1. Summary of ophthalmological findings for CSNB proband (Case 1). his father (Case 2) and grandfather (Case 3)
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Case Age (Y.o.) Visual acuity
OD
Refractive error*
OD
Strabismus Night blindness (subjective) Dark adaptation ERG single flash Op** scotopic b flicker Color vision Panel D-15test 100 hue test Pseudoisochromatic plates+ Nystagmus EOG Fundus
0s
0s
+
1
2
3
8 0.1 (1.0)' 0.1 (1.0)' - 4.75 - 6.25 exophoria present monophasic
38 0.3 (1.2)' 0.5 (1.2)' - 1.25 - 1.0 orthophoria absent biphasic
72
negative not recordable absent diminished (w.n.1. +)
negative recordable diminished normal
negative not recordable absent diminished (w.n.1. + )
minor error unreliable low-grade deuteranopia absent 2.0 tigroid peripheral reflex
normal normal
normal not examined
absent 1.8 tigroid
absent 2.0 tigroid myopic atrophy holes
holes ( ):
0.02 (0.2)' 0.02 (0.3)' - 14.88 - 16.25 exotropia present monophasic
corrected visual acuity
* Refractive error : spherical equivalence * * Op : oscillatory potential +
+
w.n.1. : within normal limits Pseudoisochromatic plates: Ishihara, Ohkuma, and Tokyo Medical College +
expressivity of a dominant gene mutation. It has been reported that most patients with CSNB have mild to moderate cone system abnormalities', with marked elevation of the cone segment of the dark adaptation c u r ~ e l - ~ In, this ~ ~ fami. ly, the dark adaptation test showed marked elevation of the cone segment in Case 3, whereas cone adaptation segments were almost normal in Cases 1 and 2. Visual acuity was abnormal only in Case 3 . These same differences have been reported among cases of X-linked CSNB7,lo. The different clinical features in Xlinked CSNB may be due to a different pathogenesis' rather than to a variable expressivity. Two forms of X-linked CSNB, complete and incomplete, have been classified based on differ-
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ences in ERG and dark adaptation7#14. Our family had some ERG features of X-linked CSNB. The monophasic dark adaptation curve and nonrecordable scotopic b-wave in our Cases 1 and 3 are consistent with the complete type. The biphasic dark adaptation curve and reduced scotopic b-wave in Case 2 are consistent with the incomplete type, but the normal amplitude of the flicker ERG and normal visual acuity are not. Moderately impaired visual acuities and diminished flicker ERG are common in incomplete CSNB7. 14. Similarly, the autosomal dominant CSNB cases described by Noble ef a/.4 had ERG patterns consistent with the complete type and dark adaptation curves consistent with the incomplete type. We feel that the different levels
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Autosomal dominant congenital stationary night blindness of expression among related individuals in our family are consistent with autosomal dominant CSNB. In CSNB, color vision is normal or only mildly abnormal’, and visual fields are normal or constricted in the lower mesopic luminant range’. The abnormal color vision (low grade deuteranopia) in Case 1 appears not to be associated with CSNB, but to be X-linked, since the patient’s maternal grandfather had the same disorder. The visual field defect in Case 3 appears to reflect an old cerebral infarction diagnosed by a neurologist. We have detected phenotypic variation due to variable expressivity in a family with autosomal dominant CSNB. Recently, a tight genetic linkage between X-linked CSNB and the Xp 11.3
DNA marker, DXS7, was reportedI5. However, no clear linkage has yet been identified in autosoma1 dominant CSNB. Future molecular biological investigation, designed to elucidate the locus of the autosomal dominant CSNB gene and the role of variable gene expressivity, must include examination of all family members, even those who are asymptomatic, in order to confirm the inheritance pattern and to identify all clinical features of autosomal dominant CSNB. ACKNOWLEDGEMENT This work was supported by a grant for the study of chorioretinal degenerations from the Japanese Ministry of Health and Welfare. The authors are grateful to Professor emeritus Akira Nakajima for valuable comments on the manuscript.
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