Fundus flavimaculatus

Although it had been strongly stated that Stargardt's disease [1] and fundus flavimaculatus [2] are the same entity based on clinical findings [3], it was proven conclusively only by molecular genetic analysis [4]. Stargart's disease, a frequent cause of autosomal recessive macular dystrophy, is characterized by onset during juvenile to young adult years, decreased central vision, progressive bilateral atrophy of the RPE, and the presence of orange-yellow flecks in the macula and/or mid-periphery of the retina (Fig. 2.138). In most cases, the onset of visual symptoms occurs between the first to third decades of life.

Fluorescein angiography has proved to be helpful in a number of ways with this disease. There is an absence or decrease in the normal background choroidal fluorescence, called a "dark choroid" or a "silent choroid," in Stargardt's patients [5] (Fig. 2.138). Histopatholog-ical and histochemical studies have provided evidence that these patients have a diffuse lipo-

Retinal Disease Clinic

Fig. 2.138. Fundus photograph and fluorescein angiogram from a patient with Stargardt's disease (fundus flavimaculatus). The dark choroid is shown in the fluorescein angiogram fuscin storage disease affecting the RPE, which is the cause of the "dark" or "silent" choroid [6].

Patients with Stargardt's disease can be subdivided into four groups based on the fundus and fluorescein angiographic findings: group 1, vermillion fundi and hidden choroidal fluorescence; group 2, atrophic maculopathy with or without flecks; group 3, atrophic maculopathy with late signs and symptoms of retinitis pigmentosa; and group 4, flecks not associated with macular atrophy [7].

Stargardt's disease has been thought to be a representative example of macular dystrophy (a localized retinal dystrophy), in contrast to retinitis pigmentosa and cone dystrophy (which are considered generalized retinal dystrophy) [8]. This is because the results of general retinal function tests, such as full-field ERGs and EOGs, are normal and only the focal macular ERG is abnormal or undetectable in Stargardt's disease. Indeed, early in the course of the disease, the ERG is usually normal (groups 1 and 2), and only in the more advanced stages do the photopic and scotopic ERGs become abnormal. Full-field ERGs and focal macular ERGs recorded from a 16-year-old male patient with Stargardt's disease in group 2 are shown in Fig. 2.139. The full-field ERG is normal, but the focal macular ERGs are undetectable.

The causative gene for Stargardt's disease (fundus flavimaculatus) was identified as the retina-specific adenosine triphosphate (ATP)-binding cassette transporter, ABCR, a gene renamed the ABCA4 gene [4]. It was subsequently found that mutations of the ABCA4 gene also cause autosomal recessive retinitis pigmentosa [9]. Most patients with Stargardt's disease are compound heterozygotes, but patients with autosomal recessive retinitis pigmentosa are homozygous with null mutations in the ABCA4 gene.

A severe type of Stargardt's disease (group 3) was found in a Japanese patient with homozygous mutations in the ABCA4 gene [10]. This severe type was progressive with diffuse retinal dysfunction, as in retinitis pigmentosa. It has been suggested that there is an association between the null mutations in the ABCA4 gene and panretinal degeneration [11]. Full-field ERGs recorded from a patient with Stargardt's disease and two patients with autosomal recessive retinitis pigmentosa are shown in Fig. 2.140. Both diseases were caused by null ABCA4 gene mutations, and the two patients with autosomal recessive retinitis pigmentosa were diagnosed with Stargardt's disease when they were younger. The disease was progressive, and the full-field ERGs became nearly unde-tectable, as shown in Fig. 2.140. The patient with Stargardt's disease also showed reduced sco-topic and photopic responses during the second decade of life.

Patients in group 4 are relatively rare. A 36-year-old woman was found to have multiple flecks in both fundi, and fluorescein angiography revealed multiple flecks of hyperfluores-cence associated with a dark choroid, indicating group 4 Stargardt's disease (Fig. 2.141). She had no subjective complaint, and her visual acuity was 0.9 in both eyes. The full-field ERG, the focal macular ERG, and the multifocal ERGs were normal (Fig. 2.142). The multifocal ERGs recorded from the sites of the flecks were also normal, indicating that the flecks do not affect retinal function.

Fig.2.139. Full-field ERGs and focal macular ERGs recorded from a patient with Stargardt's disease
Normale Erg

Fig. 2.140. Full-field ERGs recorded from a normal subject, a patient with Stargardt's disease (case 1), and two patients with autosomal recessive retinitis pigmentosa (cases 2 and 3). Patients with Stargardt's disease and retinitis pigmentosa had null ABCA gene mutations.Case 1 was a 15-year-old boy who had reduced scotopic and photopic functions during his second decade of life.Case 2 was a 28-year-old man, and case 3 was a 41-year-old man, both of whom were diagnosed with Stargardt's disease when they were young. Their ERGs were severely deteriorated when they were tested recently. (From Fukui et al. [10])

Fig. 2.140. Full-field ERGs recorded from a normal subject, a patient with Stargardt's disease (case 1), and two patients with autosomal recessive retinitis pigmentosa (cases 2 and 3). Patients with Stargardt's disease and retinitis pigmentosa had null ABCA gene mutations.Case 1 was a 15-year-old boy who had reduced scotopic and photopic functions during his second decade of life.Case 2 was a 28-year-old man, and case 3 was a 41-year-old man, both of whom were diagnosed with Stargardt's disease when they were young. Their ERGs were severely deteriorated when they were tested recently. (From Fukui et al. [10])

Fig. 2.141. Fundus photograph (top) and fluorescein angiogram (bottom) from a 36-year-old woman with group 4 Stargardt's disease. Multiple flecks in the posterior pole and dark choroid of fluorescein angiography are observed. The macula appears normal, and the visual acuity was 0.9 in both eyes

Fig. 2.141. Fundus photograph (top) and fluorescein angiogram (bottom) from a 36-year-old woman with group 4 Stargardt's disease. Multiple flecks in the posterior pole and dark choroid of fluorescein angiography are observed. The macula appears normal, and the visual acuity was 0.9 in both eyes

Renal Oncocytoma Fundus Images

Fig. 2.142. Focal macular ERGs recorded with three spots and multifocal ERGs recorded from the patient whose fundus and fluorescein angiogram are shown in Fig. 2.141. Regardless of the retinal area, all ERG responses are normal

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