STARGARDT DISEASE 1; STGD1

One patient with a diagnosis of juvenile macular degeneration was found to be compound heterozygous for mutations in the CNGB3 gene (605080) on chromosome 8q.

Fundus flavimaculatus (FFM) is an allelic subtype of Stargardt disease that has been associated with mutation in the ABCA4 gene and the PRPH2 gene (179605). FFM has a later age of onset. If loss of visual acuity begins in the first 2 decades, the designation Stargardt disease is preferred; if it begins later in life and has a more progressive course, the term FFM is preferred (Weleber, 1994).

An early-onset severe form of retinal dystrophy (CORD3; 604116) is caused by homozygous null mutations in the ABCA4 gene.

Pearce (1975) reported 4 families with 9 affected persons. In 1 instance, 2 affected persons married and both of their children were affected. Carpel and Kalina (1975)described 3 affected sisters.

Isashiki and Ohba (1985) remarked on variable expression. Among the 3 children of normal first-cousin parents were a 12-year-old boy with bull’s eye macular change and sparse fundus flavimaculatus type flecks, and an 11-year-old girl with numerous fleck lesions of FFM throughout the posterior fundus and virtually no macular change.

As pointed out by Weleber (1994), Rosehr (1954) found that 2 of the original patients described by Stargardt (1909), when seen almost 50 years later, still did not complain of night blindness and their visual fields were, at most, only mildly constricted. The macular regions showed marked atrophy in each patient, and 1 patient had peripheral pigment clumping and drusen.

Stargardt disease is the most common hereditary recessive macular dystrophy, with an estimated incidence of 1 in 10,000 (Blacharski, 1988). Whereas Stargardt disease shows juvenile to young adult age of onset, the clinically similar retinal disorder fundus flavimaculatus often displays later age of onset and slower progression. Histologically the disorder is characterized by subretinal deposition of lipofuscin-like material. As pointed out by Meitinger (1997), Stargardt disease had always been considered to be a retinal degeneration originating in the retinal pigment epithelium, which underlies the photoreceptors, predominantly cones, of the macula. Thus, the findings of Allikmets et al. (1997) that it is a disease of the rods and that the particular mutant ABC transporter is expressed in rod photoreceptors but not in blue cones came as a surprise.

To understand better the shared characteristics of Stargardt macular dystrophy and fundus flavimaculatus, Armstrong et al. (1998) surveyed 52 patients with STGD and 48 patients with FFM over a period ranging from 1 to 22 years. They found that morphologic changes and retinal function degeneration were more severe in patients with FFM than in patients with STGD. The duration of the disease had a greater effect on patients with FFM than on patients with STGD.

Rotenstreich et al. (2003) reviewed the clinical findings in 361 patients with Stargardt disease. Eighty-two (23%) had visual acuity of 20/40 or better, whereas only 16 (4%) had acuity of worse than 20/400. The presence of foveal sparing on ophthalmoscopy was associated with a higher prevalence of 20/40 acuity or better. Survival analysis showed that the prognosis of patients who were seen initially with visual acuity of 20/40 or better was related to age at initial visit: the earlier the patient presented, the more rapidly the acuity was likely to decrease below 20/40.

Chen et al. (2011) studied the relationship between macular cone structure, fundus autofluorescence (AF), and visual function in 12 patients with Stargardt disease and 27 age-matched healthy individuals. Patients were 15 to 55 years old, and visual acuities ranged from 20/25 to 20/320. At least 1 disease-causing mutation in the ABCA4 gene was found in 11 of the patients. High-resolution images of the macula were obtained with adaptive optics scanning laser ophthalmoscopy (AOSLO) and spectral domain optical coherence tomography (SD-OCT). Central scotomas were present in all patients, although the fovea was spared in 3. The earliest cone spacing abnormalities were observed in regions of homogeneous AF, normal visual function, and normal outer retinal structure. Outer retinal structure and AF were most normal near the optic disc. Longitudinal studies showed progressive increases in AF followed by reduced AF associated with losses of visual sensitivity, outer retinal layers, and cones. Chen et al. (2011) concluded that their findings support a model of STGD disease progression in which lipofuscin accumulation results in homogeneously increased AF with cone spacing abnormalities, followed by heterogeneously increased AF with cone loss, and then reduced AF with cone and RPE cell death.

Hoyng et al. (1996) carried out linkage analysis in 7 families with recessive Stargardt disease and confirmed the location of a major recessive STGD gene on chromosome 1p22-p21. The maximum 2-point lod score for all families combined was 5.35 at theta = 0.04 for the marker D1S188 and the disease locus. Hoyng et al. (1996) genotyped 9 markers in 7 families to construct haplotypes, and this enabled them to reduce the STGD critical region to 2 cM, flanked by D1S406 and D1S236. In 1 family they encountered an affected female who, on the basis of haplotype analysis, carried only 1 disease allele. Hoyng et al. (1996)proposed several possible explanations for this finding, including the occurrence of genetic heterogeneity and the possibility that dominant and recessive mutations may be observed at 1 gene locus. They reported apparent nonpenetrance in a 45-year-old male.

Bernstein et al. (2002) examined 19 of 33 sibs from 15 Stargardt families who carried their respective proband’s variant ABCA4 allele. Some families exhibited concordance of ABCA4 alleles with the macular degeneration phenotype, but others did not. Exudative ARMD was uncommon among both probands and sibs.

Weleber et al. (1993) reported the occurrence of 3 separate phenotypes within a single family with a 3-bp deletion of codon 153 or 154 of the RDS gene (179605.0017). The mother presented at age 63 with adult-onset retinitis pigmentosa (608133) that progressed dramatically over 12 years, with marked loss of peripheral visual field. One daughter developed pattern macular dystrophy (169150) at age 31 years. At age 44 years, her ERG was moderately abnormal, but her clinical disease was limited to the macula. Another daughter presented at age 42 years with macular degeneration; over 10 years, she developed a clinical picture of fundus flavimaculatus. Her peripheral visual field was preserved but her ERG was moderately abnormal. A son had onset of macular degeneration at age 44 years. Pericentral scotomas were present and ERG was markedly abnormal.

Fingert et al. (2006) reported a case of Stargardt disease in a patient homozygous for a mutation in the ABCA4 gene (601691.0026) as a result of uniparental isodisomy of chromosome 1. The patient’s father was heterozygous for the mutation.

In a patient with juvenile macular degeneration in whom mutation in the ABCA4 gene was excluded (Briggs et al., 2001),Nishiguchi et al. (2005) identified mutations in the CNGB3 gene (605080.0002 and 605080.0006). Stargardt disease had not previously been associated with mutations in the cone channel subunits.

Pal Singh et al. (2006) identified homozygous null ABCA4 mutations (601691.0028–601691.0029) causing autosomal recessive nonsyndromic retinal dystrophy in 2 Indian families. Affected individuals in both families had early-onset visual loss, diminished rod and cone electroretinographic responses, and widespread atrophy of the retinal pigment epithelium.