Ординатура / Офтальмология / Английские материалы / Electrodiagnosis of Retinal Disease_Miyake_2005

Recent molecular genetic studies have provided new insights into the mechanism involved in the retinal dysfunction of XLRS [15]. The gene causing XLRS encodes a retina-specific polypeptide, RS1, also called retinoschisim. RS1 is expressed on the cell surface of rod and cone photoreceptors and on bipolar cells but not on Mueller cells or ganglion cells. This protein is

thought to play an important role in cellular adhesion and the cell–cell interaction that maintains the integrity of retinal neurons. RS1deficient mice showed overall disorganization of the retinal cell layers, splitting of the inner nuclear layer, and reduction of the ERG b-wave amplitude.

In 1999 Sieving and coworkers reported on a 13-year-old boy with XLRS who had a preserved b-wave [16]. He was a member of a family affected by XLRS, with an Arg213Try mutation in the XLRS1 gene. His affected 54- year-old grandfather had negative-type ERGs. A similar patient from our clinic is shown in Fig. 2.45 [17]. This 26-year-old man was first examined at age 7 years because of reduced visual acuity of 0.7 in both eyes. Ophthalmoscopically, he had foveal cysts in both eyes but no other signs of retinoschisis; a golden tapetal reflex was not detected. During the 19-year follow-up, full-field ERGs were recorded six times, and the b-wave of the mixed rod–cone (single bright flash) ERGs were always normal,

as was the a-wave. However, the focal macular ERGs had a negative configuration (Fig. 2.46). Despite the normal full-field ERGs, he was diagnosed as having XLRS because a novel missense mutation, Pro193Ser (c.577C to T), in the XLRS gene was found in his blood DNA [17].

The findings in these patients indicate that we cannot exclude a diagnosis of XLRS in patients with foveal cysts even when the fullfield ERGs are normal. Although most patients with XLRS have widespread and diffuse dysfunction of the bipolar cell layer, including the fovea, as well as reduced b-waves in their fullfield ERGs, the pathology may be localized only in the fovea, as it was in this patient.

Fig. 2.45. Fundus of a patient with XLRS. There was a mutation, Pro193Ser, in the XLRS gene. Foveal schisis was present, but other parts of the retina appeared normal

Fig. 2.46. Full-field bright flash, mixed rod–cone ERGs (left) and focal macular ERGs elicited by a 15° spot (right) from a normal subject and the patient with XLRS whose fundus is shown in Fig. 2.44

As mentioned above, foveoschisis or nonspecific macular degeneration is always present in patients with XLRS. We have studied one patient who had a peripheral schisis with normal maculas. This 15-year-old boy had visual acuity of 1.0 in both eyes also visual field defects in both eyes. His maternal brother was reported to have poor visual acuity but was not available for examination. A peripheral schisis with inner retinal breaks in the inferior retina was present in both fundi, but ophthalmoscopy

and fluorescein angiography showed that the maculas were normal (Fig. 2.47). The full-field ERGs were the negative type, but the focal macular ERGs were normal (Fig. 2.48). Gene analysis has not been performed.

The ERGs of these patients suggest that, unlike most patients with XLRS, the functional abnormality is not widespread or homogeneous. It is limited to the area of the schisis that can be seen ophthalmoscopically.

White flecks in the retina may be associated with XLRS, as shown in Fig. 2.31I [18]. The visual functions, including ERG findings, are similar to those of typical XRLS patients. These flecks resemble to some degree those seen in patients with fundus albipunctatus with a mutation of the RDH5 gene, which is highly

References

1.Deutman AF (1971) Sex-linked juvenile retinoschisis. In: Deutman AF (ed) Hereditary dystrophies of the posterior pole of the eye. Charles C Thomas, Springfield, IL, pp 48–99

2.Miyake Y, Miyake S,Yamagida K, Kanda T (1981) X- chromosomal congenital retinoschisis: its fundus polymorphism and visual function. Acta Soc Ophthalmol Jpn 85:97–102

3.Hirose T, Wolf E, Hara A (1976) Electrophysiological and psychophysical studies in congenital retinoschisis of X-linked recessive inheritance. Doc Ophthalmol 13:178–184

4.Miyake Y (2003) Macular dystrophy (survey). Acta Soc Ophthalmol Jpn 107:229–241

5.Manschot WA (1972) Pathology of hereditary juvenile retinoschisis. Arch Ophthalmol 88:131–138

6.Kato K, Miyake Y, Kachi S, Suzuki T, Terasaki H, Kawase Y, et al (2001) Axial length and refractive error in X-linked retinoschisis. Am J Ophthalmol 131:812–814

7.Nakamura N, Miyake Y, Niwa M (1991) Diagnostic problems in a case of retinal detachment with juvenile retinoschisis. Jpn Rev Clin Ophthalmol 85:156– 160

8.Miyake Y, Yagasaki K, Horiguchi M, Kawase Y, Kanda T (1986) Congenital stationary night blindness with negative electroretinogram: a new classification. Arch Ophthalmol 104:1013–1020

9.Yagasaki K, Miyake Y (1983) Blue cone ERG in X- linked congenital retinoschisis. Folia Ophthalmol Jpn 34:1468–1475

10.Miyake Y, Shiroyama N, Ota I, Horiguchi M (1993) Focal macular electroretinogram in X-linked congenital retinoschisis. Invest Ophthalmol Vis Sci 34:512–515

expressed in the RPE and causes fundus albipunctatus. However, all of these patients with multiple white flecks have mutations only in the XLRS1 gene, and they do not have RDH gene mutations [19]. These results indicate that the association of multiple flecks in the retina is a phenotypic variation of XLRS.

11.Piao CH, Kondo M, Nakamura M, Terasaki H, Miyake Y (2003) Multifocal electroretinograms in X-linked retinoschisis. Invest Ophthalmol Vis Sci 44:4920–4930

12.Mizuo G (1913) A new discovery in the dark adaptation in Oguchi’s disease.Acta Soc Ophthalmol Jpn 17:1148–1150

13.De Jong PTVM, Zrenner E, van Meel GJ, Keunenn EE, van Norren D (1991) Mizuo phenomenon in X- linked juvenile retinoschisis: pathogenesis of the Mizuo phenomenon. Arch Ophthalmol 109:1104– 1108

14.Miyake Y, Terasaki H (1999) Golden tapetal-like fundus reflex and posterior hyaloid in a patient with X-linked juvenile retinoschisis. Retina 19:84– 86

15.The Retinoschisis Consortium (1998) Functional implication of the spectrum of mutations found in 234 cases with X-linked juvenile retinoschisis (XLRS). Hum Mol Genet 7:1185–1192

16.Sieving PA, Bingham EL, Kemp J, Richards J, Hiriyanna K (1999) Juvenile X-linked retinoschisis from XLRS1 Arg213Trp mutation with preservation of the electroretinogram scotopic b-wave. Am J Ophthalmol 128:179–184

17.Nakamura M, Ito S, Terasaki H, Miyake Y (2001) Japanese X-linked juvenile retinoschisis: conflict of phenotype and genotype with novel mutations in the XLRS1 gene. Arch Ophthalmol 119:1553–1554

18.van Schooneveld MJ, Miyake Y (1994) Fundus albipunctatus-like lesions in juvenile retinoschisis. Br J Ophthalmol 78:659–661

19.Hotta Y, Nakamura M, Okamoto Y, Nomura R, Terasaki H, Miyake Y (2001) Different mutation of the XLRS1 gene causes juvenile retinoschisis with retinal white flecks. Br J Ophthalmol 85:238– 239

Nettleship-Falls ocular albinism is an X-linked recessively inherited retinal disease characterized by reduced visual acuity,translucent irides, congenital nystagmus, photophobia, hypopigmentation of the fundi, and foveal dysplasia (Fig. 2.49) [1, 2]. Full-field ERGs and EOGs are normal (Fig. 2.50), and focal macular ERGs are moderately reduced because of the foveal dysplasia (Fig. 2.51).

Histopathological examination of the retina has revealed evidence of foveomacular dysplasia [3], including absence of a foveal pit, which can also be detected by OCT (Fig. 2.52). The ganglion cell layer is present throughout the macula and resembles that seen in the parafoveal area of normal subjects.

In a variant of X-linked ocular albinism in Black and Japanese men, the transillumination defect of the iris and the characteristic fundus hypopigmentation may not be present as shown in Fig. 2.49. Visual acuity may be better than that in typical X-linked ocular albinism. In such cases, the diagnosis may require skin biopsy. However, it should be noted that asymptomatic female carriers of these mutations always show streaky and mottled RPE ophthalmoscopically, which is of diagnostic value (Fig. 2.53) [2]. The full-field ERGs and the focal macular ERG and OCT are normal in the female carriers.

References

1.Nettleship E (1909) On some hereditary diseases of the eye. Trans Ophthalmol Soc UK 29:LVII– CXCVIII

2.Falls HF (1951) Sex-linked ocular albinism displaying typical fundus changes in the female heterozygote. Am J Ophthalmol 34(Pt 2):41–50

3.Garner A, Jay BS (1980) Macromelanosomes in X- linked ocular albinism. Histopathology 4:243–254

This section is one of the most important because of the time and energy we have spent studying the various types of congenital stationary night blindness (CSNB).

Patients with the Schubert-Bornschein type of CSNB [1] have normal fundi; and the mixed rod–cone ERGs, elicited by a single bright flash in the dark, has a negative configuration (negative-type ERG; amplitude of the a-wave > amplitude of the b-wave). Our phenotypic and molecular genetic analyses have proved that the Schubert-Bornschein type of CSNB is made up of two clinical entities: the complete type of CSNB (CSNB1) and the incomplete type of CSNB (CSNB2) [2].

The distinction between the complete and incomplete types of CSNB was based on rod function and was evaluated by routine darkadaptometry and rod-mediated ERGs. Patients with “complete” CSNB lack rod function, whereas those with “incomplete” CSNB have residual rod function.Although these two types of CSNB have common findings, such as normal fundi and negative ERGs with normal electrooculograms (EOGs), there are several important differences (described later).

This new classification of the CSNBs with normal fundi led us to identify a new clinical

entity, the incomplete type of CSNB [1]. Before then, patients with incomplete CSNB had been diagnosed as having a phenotypic subtype of the complete type of CSNB.

The hereditary mode of transmission of complete CSNB is either X-linked recessive or autosomal recessive, whereas that for incomplete CSNB is X-linked recessive only. In extensive studies, we have not been able to find any differences in the ocular findings in patients with X-linked versus those with autosomal recessive hereditary complete CSNB.

Our classification has been verified by molecular genetic analyses [3]. It has been reported that X-linked complete CSNB has a mutation of the leucine-rich repeat proteoglycan (NYX) gene [4, 5], whereas X-linked incomplete CSNB has a mutation in the calcium channel (CACNA1F) gene [6, 7]. In addition, dysfunction of either the on bipolar cells alone (complete CSNB) or of both the on and off bipolar cells (incomplete CSNB) has been demonstrated [7–9]. This difference has allowed us to investigate the function of the on and off bipolar cells individually in clinical patients.

The fundus photographs of patients with complete and incomplete CSNB, which was verified by molecular genetics [10, 11], are shown in Figs. 2.54 and 2.55. The fundus in both types of CSNB is essentially normal. However, because complete CSNB is often associated with high myopia, most patients with this disorder display the characteristics of a myopic fundus

and may show slight temporal pallor of the optic disk and/or a tilted disk.

Incomplete CSNB has been suggested to be the same clinical entity as the Forsius-Erickson type of ocular albinism (Åaland Island eye disease) [12] because of the similarities of the ERGs. However, none of our patients had hypopigmentation of the fundus.

Distribution of the corrected visual acuity of patients with both types of CSNB is shown in Fig. 2.56. The visual acuities ranged from 0.1 to 1.0 (mean 0.4–0.5). The visual acuities of the patients with complete CSNB do not differ significantly from those with incomplete CSNB [10].

The distribution of the refractive errors in the two groups is shown in Fig. 2.57. Many patients with complete CSNB have moderate to high myopic refractive errors, whereas those with incomplete CSNB have mild myopic to hyperopic refractive errors. The difference in the mean refractive errors is significant [10].