Stargardt disease (STGD) has a juvenile to young–adult onset, a rapid decrease of central vision and a progressive bilateral atrophy of the sensory retina and retinal pigment epithelium (RPE) in the macula. Yellow-orange flecks are often detected around the macula, the midretina and or both (Rotenstreich et al. 2003). Mutations in the gene encoding the ATP-binding cassette transporter gene (ABCA4) are responsible for autosomal recessive STGD (Allikmets 1997; Webster et al. 2001). We examined a patient who had the characteristic signs of STGD but had good visual acuity.

A 66-year-old man complained of photophobia and a paracentral scotoma which was present since his teens and had not worsened. None of his family members had similar symptoms. His visual acuity was 20/15 OU, and ophthalmoscopy identified a dark brown, well-demarcated area at the fovea surrounded by RPE atrophy and flecks (Fig. 1A). Fluorescein angiography showed window defects at the flecks and a dark choroid (Fig. 1B). The optical coherence tomographic (OCT) images showed a well-preserved sensory retina and normal thickness RPE at the fovea (Fig. 1C, D). The foveal area was surrounded by atrophic sensory retina and RPE. Static perimetry showed ring-shaped paracentral relative scotoma which surrounded the normal area seeing area of 5° (Fig. 1E). Focal macular electroretinograms (FMERGs) also demonstrated a well-preserved retinal function at the fovea (Fig. 1F). Compared to age-matched controls, the FMERGs had normal responses elicited by a 5-degree stimulus spot and severely reduced responses elicited by 10-degree and 15-degree spots (Fig. 1F, G). Genetic analysis with direct DNA sequencing of amplified products revealed four reported polymorphisms (Allikmets 1997; Briggs et al. 2001; Webster et al. 2001; Fukui et al. 2002) and one novel mutation, Met280Thr, in exon 7 of the ABCA4 gene (Table 1).


Figure 1.  Fundus photograph (A), fluorescein angiogram (FA) (B), optical coherence tomography (OCT) (C, D), Humphrey static perimetry (E), and focal macular electroretinograms (FMERGs) (F) of an eye of a patient with Stargardt disease. (A) Fundus photograph showing dark brown, well demarcated area in the fovea surrounded by orange-yellow flecks in the macula. (B) FA showing blockage in the foveal area, ring-shaped mottled hyperfluorescence in the macula, and dark choroid. (C, D) OCT images (C; horizontal, D; vertical) showing well-preserved sensory retina and retinal pigment epithelium (RPE) layer in the fovea. In the juxta-foveal region, an atrophy of both sensory retina and RPE can be seen. The enlarged images within the red lines are attached. (E) Humphrey static perimetry showing ring-shaped paracentral relative scotoma (10-2 strategy). (F, G) FMERGs showing normal responses elicited by a 5-degree stimulus spot and severely reduced responses elicited by 10-degree and 15-degree spots, when compared with the age-matched control.

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Table 1.   ABCA4 GENE MUTATION AND Polymorphisms.
ExonNucleotide ChangeEffect ChangesHet/HomReferences
  1. The translational start codon ATG/methionine is numbered as +1. One novel disease-associated mutation [c.839T>C (p.Met280Thr)] was found. References of previously reported polymorphisms are indicated.

  2. Het, heterozygote; Hom, homozygote.

 7c.839T>Cp.Met280ThrHetPresent study
 10c.1269C>Tp.His424HisHomWebster AR et al.
 45c.6249C>Tp.Ile2083IleHetAllikmets R et al.
 46c.6285T>Cp.Asp2095AspHetBriggs CE et al.
 49c.6764G>Tp.Ser2255IleHetAllikmets R et al.

Our patient had clinical findings that were pathognomonic of typical STGD, except that the clinical course was stationary and he had 20/15 vision because of well-preserved foveal function. The preserved foveal area was small and well demarcated. Visual acuity, fundus appearance, OCT images, static perimetry and FMERGs supported the well-preserved foveal function. We report our case because the patient had a unique phenotype with a novel putative mutation in the ABCA4 gene, not yet shown to segregate with the disease.

The well-demarcated dark brown foveal RPE appeared to be hyperpigmented although the thickness measured by OCT was 29 μm which was within normal limits. The findings in our case could indicate that the non-atrophic foveal RPE had an effect in preserving the foveal morphology and function.

The inheritance of STGD is autosomal recessive; however, our patient had four polymorphisms and one heterozygous gene mutation c.839T>C in exon 7 in the ABCA4 gene. A second mutation was not found, but it may well exist outside of the coding sequence of the ABCA4 gene. The new mutation in our patient was located outside the known functional domains of ATP-binding or transmembrane site (Lewis et al. 1999), which may explain the mild effect of the missense mutation. We should also consider a modifier gene effect in our patient.

Although the relationship between the new mutation of the ABCA4 gene and the well-preserved foveal structure is unresolved, the unique phenotype and genotype of our patient may give additional information on the mechanism of photoreceptor degeneration in eyes with STGD.


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  2. References
  • Allikmets R (1997): A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat Genet 17: 122.
  • Briggs CE, Rucinski D, Rosenfeld PJ, Hirose T, Berson EL & Dryja TP (2001): Mutations in ABCR (ABCA4) in patients with Stargardt macular degeneration or cone-rod degeneration. Invest Ophthalmol Vis Sci 42: 22292236.
  • Fukui T, Yamamoto S, Nakano K et al. (2002): ABCA4 gene mutations in Japanese patients with Stargardt disease and retinitis pigmentosa. Invest Ophthalmol Vis Sci 43: 28192824.
  • Lewis RA, Shroyer NF, Singh N et al. (1999): Genotype/Phenotype analysis of a photoreceptor-specific ATP-binding cassette transporter gene, ABCR, in Stargardt disease. Am J Hum Genet 64: 422434.
  • Rotenstreich Y, Fishman GA & Anderson RJ (2003): Visual acuity loss and clinical observations in a large series of patients with Stargardt disease. Ophthalmology 110: 11511158.
  • Webster AR, Heon E, Lotery AJ et al. (2001): An analysis of allelic variation in the ABCA4 gene. Invest Ophthalmol Vis Sci 42: 11791189.