MACULAR DEGENERATION, JUVENILE
FFM, INCLUDED
RETINAL DYSTROPHY, EARLY-ONSET SEVERE, INCLUDED
MACULAR DYSTROPHY WITH FLECKS, TYPE 1 FUNDUS FLAVIMACULATUS, INCLUDED
STGD
STGD1
Stargardt disease is one of the most frequent causes of macular degeneration in childhood. It has onset between 7 and 12 years, a rapidly progressive course, and a poor final visual outcome. Although visual acuity is severely reduced, ... Stargardt disease is one of the most frequent causes of macular degeneration in childhood. It has onset between 7 and 12 years, a rapidly progressive course, and a poor final visual outcome. Although visual acuity is severely reduced, peripheral visual fields remain normal throughout life. Degeneration limited to the macular area of the retina was described in multiple sibs by Ford (1961) and by Walsh (1957). Fundus flavimaculatus, which is a form of fleck fundus disease (see 228980), derives its name from the occurrence of many yellow spots rather uniformly distributed over the fundus. In some older patients the flecks fade with time as atrophy of the retinal pigment epithelium (RPE) increases. Round, linear, or pisciform lesions are distributed in the posterior pole, sometimes with extension to the equator, and with macular involvement. Network atrophy of the retinal pigment epithelium, and choroidal vascular atrophy are features. Central visual loss, loss of color vision, photophobia, paracentral scotoma, and slow dark adaptation are features. This is probably an autosomal recessive disorder. Klien and Krill (1967) observed a 'familial incidence...in 10 of 27 patients.' The 10 familial cases included 4 pairs of affected sibs with ostensibly normal parents who were, however, not examined in most instances. No parental consanguinity was described. In 1 instance the father and 2 daughters were affected. In the instance of an affected brother and sister, the father was black and the mother white. Krill and Deutman (1972) concluded that recessive macular dystrophy was the disorder described and beautifully illustrated by Stargardt (1909), and also was the disorder that Franceschetti (1963) renamed fundus flavimaculatus. Krill and Deutman (1972) suggested the possibility of a rarer, phenotypically indistinguishable, autosomal dominant form. Hadden and Gass (1976) presented evidence that fundus flavimaculatus is the same as the Stargardt form of macular dystrophy. 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.
Rozet et al. (1998) reported a genotype/phenotype correlation in ABCA4 gene mutations. They found that nonsense mutations truncating the ABCA4 protein consistently led to Stargardt disease, whereas all mutations they identified in the ABCA4 gene in fundus flavimaculatus ... Rozet et al. (1998) reported a genotype/phenotype correlation in ABCA4 gene mutations. They found that nonsense mutations truncating the ABCA4 protein consistently led to Stargardt disease, whereas all mutations they identified in the ABCA4 gene in fundus flavimaculatus were missense mutations affecting uncharged amino acids. In a family segregating retinitis pigmentosa-19 (RP19; 601718) and STGD1 in 2 first cousins, Rozet et al. (1999) found that heterozygosity for a splice acceptor site mutation in the ABCA4 gene (601691.0017) resulted in STGD1, whereas hemizygosity for this mutation resulted in RP19. In the patient with RP19, a partial deletion of the maternal ABCA4 gene was presumed to be the source of a null allele, although this was not conclusively proven.
Allikmets et al. (1997) performed mutation analysis of the ABCA4 gene in STGD families and identified a total of 19 different mutations, including homozygous mutations in 2 families with consanguineous parentage (see, e.g., 601691.0002).
Shroyer et ... Allikmets et al. (1997) performed mutation analysis of the ABCA4 gene in STGD families and identified a total of 19 different mutations, including homozygous mutations in 2 families with consanguineous parentage (see, e.g., 601691.0002). Shroyer et al. (1999) analyzed the ABCA4 gene in a 3-generation family manifesting both Stargardt disease and age-related macular degeneration (ARMD; see 153800), and identified heterozygosity for a missense mutation (P1380L; 601691.0026) in the paternal grandmother with ARMD, whereas the proband and his 2 paternal cousins with Stargardt disease were compound heterozygous for the P1380L mutation and another missense mutation in the ABCA4 gene (601691.0036 and 601691.0037, respectively). Shroyer et al. (1999) suggested that carrier relatives of STGD patients may have an increased risk of developing ARMD. Single-copy variants of the ABCA4 gene have been shown to confer enhanced susceptibility to ARMD. By mutation analysis in a cohort of families that manifested both STGD and ARMD, Shroyer et al. (2001) found that ARMD-affected relatives of STGD patients are more likely to be carriers of pathogenic STGD alleles than predicted based on chance alone. Shroyer et al. (2001) used an in vitro biochemical assay to test for protein expression and ATP-binding defects, and found that mutations associated with ARMD have a range of assayable defects ranging from no detectable defect to apparent null alleles. Of the 21 missense ABCA4 mutations reported in patients with ARMD, 16 (76%) showed abnormalities in protein expression, ATP-binding, or ATPase activity. They inferred that carrier relatives of STGD patients are predisposed to develop ARMD. 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.