2.13 Cone Dystrophy

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2.13 Cone Dystrophy 123

Patients with cone dystrophy belong clinically and genetically to a heterogeneous group of patients with inherited retinal dystrophies.

They are characterized by widespread degeneration of the cone photoreceptors, leading to impaired central vision, loss of color vision, and photophobia [1, 2]. The disease process is progressive. At the advanced stage, most patients with cone dystrophy also have abnormal sco- topic vision (cone–rod dystrophy) [2, 3].

Because impairment of the cones is widespread, the full-ﬁeld photopic ERG is always severely depressed, which is key to diagnosing cone dystrophy (Fig. 2.94). Localized macular problems, as with some types of macular dystrophy, do not lead to a signiﬁcant reduction of the photopic ERGs (see Section 1.2.2).

The fundus in patients with cone dystrophy may be within normal limits or may have subtle changes in the early stage [1, 2, 4]. These changes may progress to bull’s-eye maculopathy and diffuse atrophy of the RPE in the far-advanced stage (Fig. 2.95) [2]. It should be noted that the appearance of the fundus and ﬂuorescein angiograms may be essentially normal even when full-ﬁeld photopic ERGs are

absent [1, 3, 4]. In such cases, patients may be misdiagnosed as having optic nerve disease, central nerve system disease, amblyopia, or occult macular dystrophy [5] (see Section 2.19) unless the full-field ERGs are carefully evalu- ated. We have reported that the findings from vitreous fluorophotometry are normal in most patients with cone dystrophy, indicating that the barrier function of the RPE is well preserved until the advanced stage [6]. This is in marked contrast to patients with retinitis pigmentosa (rod–cone dystrophy), in whom vitreous fluorophotometry may reveal significant abnormalities even during the early stage.

Long-term follow-up of the full-field ERGs in two patients with autosomal dominant (A) and recessive (B) cone dystrophy is shown in Fig. 2.96 [2]. In 1981 the rod ERG was normal, but the cone and 30-Hz flicker ERGs were extremely reduced (B). Thereafter, the rod ERG gradually decreased (cone–rod dystrophy), and in 1998 it was essentially absent. The fundus in 1998 showed diffuse RPE degeneration with attenuation of the retinal vessels—similar to findings in patients with retinitis pigmentosa (rod–cone dystrophy).

2.13 Cone Dystrophy

2.13.1 General Concepts

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Fig. 2.94. Full-ﬁeld ERGs recorded from seven patients with typical cone dystrophy.

The rod and mixed rod–cone bright ﬂash ERGs are normal, but the cone-mediated ERGs (cone and 30-Hz ﬂicker) are selectively reduced. The column at the left indicates the age and sex of patients (Y, years; M, male; F, female)

Fig. 2.95. Fundi and ﬂuorescein angiograms of patients with cone dystrophy.

A Normal appearance. B Bull’s-eye maculopathy. C Diffuse RPE degeneration

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Fig. 2.96. Long-term follow-up of full-ﬁeld ERGs recorded from patients with autosomal dominant (A) and autosomal recessive (B) cone dystrophy. (From Miyake [2])

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To date, mutations in the peripherin/RDS [7], CRX 8 [7], GUCY2D [9], and GUCA1A [10]

genes have been reported to cause autosomal dominant cone dystrophy. Patients with cone dystrophy caused by GUCAIA mutations have relatively well preserved rod function until the late stage [10]. ABCR gene mutations have been reported to cause autosomal recessive cone dys- trophy [11], and RPGR gene mutations cause X- linked recessive cone dystrophy [12].

GUCY2D is the gene coding for retinal guany- late cyclase-1 (PETGC-1), which consists of a membrane guanylate cyclase with PETGC-2.

PETGC-1 is an important enzyme in the photo- transduction cascade and catalyzes the conver- sion of guanosine triphosphate (GTP) to cyclic 3¢,5¢-guanosine monophosphate (cGMP) [9].

Two Japanese families with RC38C and R838H mutations [13] are shown in Fig. 2.97. All of the affected members have high myopia and poor visual acuity (0.1–0.6) with central or paracentral scotoma and severe color vision defects.

The full-ﬁeld rod ERGs are relatively well preserved with nearly undetectable cone and 30-Hz ﬂicker ERGs (Fig. 2.98). The fundus has myopic changes, including chorioretinal atrophy around the optic disk, but minimal ophthalmoscopic abnormalities in the macula.

Fluorescein angiography showed mild hyper- ﬂuorescent pigmentary changes or small, round hyperﬂuorescent areas in the macula (Fig. 2.99).

2.13.2 Molecular Genetics

Fig. 2.97. Pedigrees of two families with autosomal dominant cone dystrophy, showing the affected (solid symbols) and unaffected (open symbols) members. Family and patient numbers correspond to those in Figs. 2.98 and 2.99Arrows point to probands. Individuals whose DNA was tested are indi- cated by an ¥.Squares,males;circles, females; slash through symbol, deceased. (From Ito et al. [13])

Fig. 2.98. Full-ﬁeld ERGs recorded from a normal subject and three patients in the two families shown in Figs. 2.96 and 2.97.The family and case numbers in parentheses corre- spond to those shown in Fig. 2.96.

(From Ito et al. [13])

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Fig. 2.99. Fundus photographs (A, C, E) and ﬂuorescein angiograms (B, D, F) of patients with muta- tions of the GUCY2D gene. Family and case numbers in parentheses correspond to those shown in Fig. 2.97. (From Ito et al. [13], with permission)

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2.13.3 Central or Peripheral Cone Dystrophy

The concept of regional cone dystrophy has been suggested by some clinicians [14], and these eyes were thought to have central or peripheral cone dystrophy. With central or peripheral cone dystrophy, the central or peripheral cone system is predominantly impaired and the rod system is completely preserved, even in the area where the cone system is impaired.

“Occult macular dystrophy” [5] is an example of a central cone dystrophy and is described later. We have reported that some patients with occult macular dystrophy show the pathophysiological properties of a central cone dystrophy, where only the macular cones are affected with preservation of the macular rods. These ﬁndings were detected by rod–cone sensitivity proﬁles in the macula area (see Section 2.19).

We have reported three patients from two pedigrees whose peripheral cone system was more affected than the central cone system and whose rod system was relatively normal [2, 15].

The fundi of these patients with peripheral cone dystrophy are essentially normal except

for mild temporal pallor of the optic disk in some of the patients (Fig. 2.100). The corrected visual acuity in the three patients ranged from 1.2 to 0.2, and the color vision was abnormal in two of the three. The full-ﬁeld cone ERGs were signiﬁcantly reduced, but the rod responses were normal, as in patients with typical cone dystrophy (Fig. 2.101).

However, the focal macular cone ERG were well preserved (Fig. 2.102), and the results of multifocal ERGs support the ﬁndings made by full-ﬁeld and focal macular ERGs (Fig. 2.103).

One of the patients (case 3) was examined 4 years after the initial examination using focal macular ERG because he had reported progres- sively increased blurring of his paracentral vision in the left eye. The responses clearly had become smaller during the 4 years (Fig. 2.101), suggesting that his retinopathy was progressive, even though his visual acuity was unchanged. Psychophysical rod–cone perimetry demonstrated that only the peripheral cone system was impaired, and the peripheral rod sensitivity was completely normal (Fig. 2.103).

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Fig. 2.100. Fundus photographs (top) and ﬂuorescein angiograms (bottom) of three patients with peripheral cone dystrophy. Cases 1 and 2 show slight temporal pallor of the optic disk, but otherwise their fundi appear normal. (From Kondo et al. [15], with permission)

Fig. 2.101. Full-ﬁeld ERGs recorded from three patients with peripheral cone dystrophy. Cone-mediated ERGs are selectively impaired. (From Kondo et al. [15], with permission)

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Fig. 2.102. Focal macular ERGs recorded with 5°, 10°, and 15° spots from the three patients with peripheral cone dystrophy shown in Fig. 2.101. Focal macular ERGs were recorded in 1993 and 1997 in case 3 (bottom) and show a progressive decrease in the responses. (From Kondo et al. [15], with permission)

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Fig. 2.104. Cone–rod perimetry (two-color perimetry) in the same three patients with peripheral cone dystrophy. Cone sensitivity proﬁles (upper trace) were determined with 31 red (600 nm) spots across a 60°horizontal meridian under a white background. For rod sensitivity (lower traces), two-color perime- try with blue-green (500- nm) and red (650- nm) stimuli being used after 45 min of dark adaptation.

Only the central cone was preserved. Rod sensitivity is normal over the entire retina. (From Kondo et al. [15], with permission)

Fig. 2.103. Top:Trace arrays of multifocal ERGs recorded from a normal subject and two patients with peripheral cone dystrophy (cases 1 and 2; see Figs. 2.100 and 2.101). Bottom: Three-dimensional (3D) topographic maps of the multi- focal ERGs shown in the trace arrays for the normal subject and the two patients with peripheral cone dystrophy.

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2.13.4 Unilateral Cone Dysfunction Syndrome

We reported a 20-year-old Japanese woman who had an acute onset of unilateral cone dysfunction associated with bull’s-eye maculopathy [16]. She complained of blurred central vision and abnormal color sensitivity of 3 days’

duration in her right eye. Her family history was negative, and her medical history revealed no previous or current systemic illnesses.

At her initial visit, visual acuity was 0.03 (OD) and 1.5 (OS) with a central scotoma in the right eye. The fundus and ﬂuorescein angiograms were normal at that time, but 3 months later bull’s-eye maculopathy appeared in the right eye;

her left fundus remained normal (Fig. 2.105).

The full-ﬁeld ERGs recorded from this patient are shown in Fig. 2.106. As shown in Fig.

2.106A, her rod responses and mixed rod–cone (bright white) responses were normal, and little

difference was observed between the right and left eyes. However, the cone-mediated responses (cone and 30-Hz ﬂicker) were severely reduced only in the right eye. The on and off components of the photopic ERGs (Fig. 2.106B) elicited by long-duration stimuli were undetectable in the right eye.

Kinetic visual ﬁeld showed a relative central scotoma within 10° of ﬁxation in the right eye, whereas the left eye was normal (Fig. 107A).

The cone and rod perimetry (two-color perimetry) showed normal sensitivity in both rod and cone in the right eye, but only the cone sensitivity was severely depressed in the left eye (Fig. 107B).

The pathogenesis of this disorder with severe impairment of the cone photoreceptors is unknown. However, a group of inherited

Fig. 2.105. Fundus photographs (top) and ﬂuorescein angiograms (bottom) of a patient with unilateral cone dysfunction in the affected right eye (left and middle); the normal left eye is shown as well (right). Three days after onset, the fundus of the right eye was essentially normal;

but 3 months after onset, bull’s-eye maculopathy appeared. (From Nomura et al. [17], with permission)

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retinal diseases should be ruled out. Further- more, the possibility of exposure to toxins, such as chloroquine [17] or digoxin [18], which can cause cone dysfunction, could be ruled out

because she had no history of taking such drugs. Because of her acute and severe clinical course, other factors such as inﬂammation should be considered.

Fig. 2.106. Full-ﬁeld ERGs (A) and photopic ERGs elicited by long stimuli (B) recorded from a patient with unilateral cone dysfunction. Cone-mediated responses are selectively depressed only in the right eye. (From Nomura et al.

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Fig. 2.107. Kinetic perimetry (A) and cone and rod perimetry (B) in a patient with unilateral cone dysfunction. (From Nomura et al. [17])

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