Ординатура / Офтальмология / Английские материалы / Electrophysiology of Vision_Lam_2005

indicate not only that the number of S cones is increased in affected patients but also that these S cones have replaced some of the normal red, long-wavelength sensitive cones (L cones), green, medium-wavelength sensitive cones (M- cones), and many of the rods. This hypothesis was subsequently supported by further testing with measurements of cone system sensitivities, S-cone acuity, and other psychophysical measurements of the S-cone system (160).

Subsequently, Haider et al. (161) found mutations of a nuclear receptor gene, NR2E3, in 94% of patients with enhanced S-cone syndrome. The NR2E3 protein is a part of a large family of nuclear receptor transcription factors. Nuclear receptors are involved in the regulation of embryonic development, and expression of NR2E3 is thought to be limited to the outer nuclear layer of the human retina. This finding of NR2E3 mutations in affected patients suggests that enhanced S-cone syndrome is a disorder of differentiation of the photoreceptors and that NR2E3 plays a role in determining photoreceptor phenotype during human retinal development. Subsequently, NR2E3 mutations are found also to produce Goldmann–Favre syndrome and clumped pigmentary retinal degeneration (162).

GOLDMANN–FAVRE SYNDROME

Goldmann–Favre syndrome described in 1958 is an autosomal recessive disorder characterized by progressive pigmentary retinal degeneration, peripheral retinoschisis, vitreous strands, macular cystoid changes, and posterior subcapsular cataract (163). Affected persons have night blindness and variably decreased visual acuity and peripheral vision.

In patients with Goldmann–Favre syndrome, both rod and cone ERGs are markedly diminished and may be nondetectable (164). When standard full-field ERG is detectable, the entire light-adapted ERG flash cone response is reduced and prolonged and quite similar to the dark-adapted brightflash rod–cone maximal response. By using dark-adapted perimetry and spectral ERG, Jacobson et al. (158) showed

that the predominant ERG signal was from the short-wave- length sensitive cones. This relative hypersensitivity of the short-wavelength sensitive cones (S-cone, blue-sensitive cones) is similar to ERG features of the enhanced S-cone syndrome which is associated with mutations of the NR2E3 gene. At least some cases of Goldmann–Favre syndrome are also associated with NR2E3 mutations (162).

DOMINANT LATE-ONSET RETINAL

DEGENERATION

In 1996, Kuntz et al. (165) reported an autosomal dominant late-onset retinal degeneration characterized by night vision impairment developing in the sixth decade of life with subsequent progressive pigmentary retinopathy. Patchy puncatate yellow–white lesions may be visible in the early stages, and with time, islands of pigmentary disturbance and chorioretinal atrophy develop in the midperipheral regions of the retina with sparing of the macula and the far peripheral retina (165,166). With further progression, diffuse pigmentary retinal atrophy occurs. The most consistent early manifestation of the condition is abnormal dark adaptation which occurs even in affected but asymptomatic persons. Full-field ERG responses are usually normal early in the disease or may demonstrate mild impairment of the rod response (165,166). As the disease progresses, the ERG responses becomes non-detectable.

CONE–ROD DYSTROPHY

Cone–rod dystrophy refers to a large group of genetically heterogeneous disorders characterized by early cone photoreceptor dysfunction and progressive cone and rod dysfunction. In contrast to RP (rod–cone dystrophy), patients with cone–rod dystrophy generally have decreased central vision rather than night vision impairment, macular pigmentary changes usually with some peripheral retinopathy, and full-field ERG cone responses that are more or equally reduced than

cassette transporter protein ABCA4 (recessive). Mutations of some of these genes are also associated with other phenotypes such as RP, Leber congenital amaurosis, and Stargardt macular dystrophy.

The clinical features of cone–rod dystrophy are diverse, and the degree of cone as well as rod dysfunction may be variable even among family members with the same genotype (167). Several studies have classified cone–rod dystrophy into subtypes based on clinical and ERG findings. In a study of 14 patients with recessive or sporadic cone–rod dystrophy using full-field ERG and dark-adapted static threshold perimetry, Yagasaki and Jacobson (168) described three patterns of visual dysfunction. The first pattern shows slowly progressive central scotoma with mild peripheral retinal dysfunction equally affecting rod and cone systems. The second pattern is more progressive and characterized by central scotoma, greater cone than rod retinal dysfunction, and earlier peripheral than midperipheral visual field loss. The third pattern is the most progressive with marked central scotoma, no measurable cone function, and patches of rod function retained in the central and inferotemporal regions of the visual field. In another study, Szlyk et al. (169) prospectively examined 33 patients and reviewed clinical records of 150 patients with isolated, autosomal dominant, and autosomal recessive cone– rod dystrophy. Based on the full-field ERG results, two major types of cone–rod dystrophy were differentiated. In type 1, cone amplitudes were reduced more than rod amplitudes, and in type 2, cone and rod amplitudes were decreased to the same extent. These two types were further subdivided based on visual field loss and threshold elevation. In types 1a and 2a, central scotomas were accompanied by more elevated cone thresholds centrally than peripherally, and in types 1b and 2b, central scotoma is absent (1b) or a ring scotoma is present (2b) accompanied by more elevated cone thresholds peripherally than centrally.

In general, the likelihood of progressive ERG amplitude loss is similar among cone–rod dystrophy patients and RP patients. In a 4-year study of 29 cone–rod dystrophy patients and 67 RP patients with detectable rod and cone full-field

ERG responses by Birch and Fish (170), the percentage of patients with RP showing rod amplitude progression (64%) was not significantly different from the percentage of patients with cone–rod dystrophy (45%) (p ¼ 0.14). Likewise, the percentage of patients demonstrating cone amplitude progression was similar between RP patients (60%) and cone– rod dystrophy patients (62%) (p ¼ 0.97). However, when rod sensitivity as measured by retinal illumination necessary to elicit half of the maximal response (log k, Naka–Rushton function) during the scotopic intensity response series, the rod sensitivity is normal or near normal in cone–rod dystrophy and significantly elevated in RP. Further, patients with advanced cone–rod dystrophy with diffuse pigmentary retinopathy and non-detectable full-field ERG are clinically virtually indistinguishable from patients with advanced RP. On the other end of the spectrum, it may be difficult to distinguish cone dystrophy from cone–rod dystrophy in patients with maculopathy, minimal peripheral retinopathy, and reduced cone but borderline rod ERG responses.

Several reports have studied the clinical features of cone–rod dystrophy associated with specific disease-causing genotypes (167,171–178). The degree of intrafamilial and interfamilial variability associated with a specific genotype ranges from differences only in severity to wide differences in clinical features among affected persons.

Female carriers of X-linked cone–rod dystrophy may appear clinically normal (179). However, some carriers may demonstrate subtle color vision defects, various degree of retinal degeneration, and prolonged 30-Hz cone flicker fullfield ERG responses with interocular asymmetry (180).

Rarely in cone–rod dystrophy, one finds a negative ERG pattern where a selective reduction of the b-wave produces a b-wave to a-wave amplitude ratio of less than 1 in the scotopic bright-flash combined rod–cone full-field ERG response (174,181). A negative ERG pattern may be a prominent feature in a kindred or occur in an isolated affected family member.

In 1974, Deutman (182) reported four affected members of a family with a bull’s-eye-like maculopathy consisting a ring of depigmentation surrounding a normal central macular area

and called this autosomal dominant condition ‘‘benign concentric annular macular dystrophy’’ (182). In a follow-up examination of this kindred 10 years later, van den Biesen et al. (183) noted deterioration of vision and progression of the macular lesions. Some family members were also found to have peripheral pigmentary retinopathy with bone-spicule- like pigmentation. Full-field ERG responses showed equally impaired rod and cone responses. Subsequently, Miyake et al. (184) described four unrelated patients with bull’s eye maculopathy and full-field ERG with maculopathy similar to patients with benign concentric annular macular dystrophy. However, the full-field ERG responses demonstrated a negative pattern of the scotopic bright-flash combined rod–cone full-field ERG response as well as markedly reduced oscillatory potentials and elevated dark adaptation rod thresholds. The cone responses were normal or mildly reduced. Whether the patients reported by Deutman and Miyake represent a variant of cone–rod dystrophy or RP is unclear.

¨

ALSTROM SYNDROME

Alstro¨m syndrome, first described in 1959, is a rare autosomal recessive disorder characterized by obesity, pigmentary retinopathy, sensorineural hearing loss, cardiomyopathy, and diabetes mellitus (185,186). Alstro¨m syndrome is associated with mutations of the ALMS1 gene on chromosome 2p13 (187,188). Although the disorder shares some similar features to Bardet–Biedl syndrome, Alstro¨m syndrome is not associated with mental retardation and polydactyly and in contrast to Bardet–Biedl syndrome, Alstro¨m syndrome is associated with nystagmus, early loss of central vision, and generalized cone– rod rather than rod–cone dysfunction. The predominant ocular feature is the early development of retinal vascular attenuation with progressive diffuse pigmentary retinopathy involving the macula and optic nerve atrophy (185,189). Both cone and rod full-field ERG responses are severely reduced early in the disease and in many patients, the responses are nondetectable on presentation even in infancy (185,186,190). In

those with detectable ERG responses, severe early cone dysfunction occurs with the cone response diminishing rapidly to become non-detectable (190). The ERG rod response is affected to a less lesser degree initially but deteriorates rapidly as well.

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