Recommended panel testing at Breda Genetics for this condition:
Stargardt disease is the most common form of inherited juvenile macular degeneration. Decreased central vision with decreased color perception is a hallmark of Stargardt disease, whereas side vision is usually preserved. The condition can be caused by mutations in one of 4 different genes, but significant overlap exists with some other genetically determined conditions.
Detailed clinical description
Stargardt disease (also known as Stargardt macular dystrophy or fundus flavimaculatus) is the most common form of inherited juvenile macular degeneration. Decreased central vision with decreased color perception is a hallmark of Stargardt disease, whereas side vision is usually preserved (this also differentiates Stargardt disease from retinitis pigmentosa, where peripheral vision is firstly affected, only eventually developing in central vision loss). The progressive vision loss associated with Stargardt disease is caused by the death of photoreceptor cells in the central portion of the retina called the macula. The macula is responsible for sharp central vision — for tasks like reading, watching television, and looking at faces.
The onset of Stargardt disease is typically in childhood or adolescence and the progression rate is quite variable. Eventually, almost everyone with Stargardt disease has a visual acuity in the range of 20/200 to 20/400. The vision loss is not correctable with prescription eyeglasses, contact lenses, or refractive surgery. Patients may exhibit color vision deficiencies. The degree and type of colour vision deficiency correlate better with best-corrected visual acuity (BCVA) than with full-field electroretinography (ffERG) results.
Yellowish flecks in and under the macula are typically observed at first ophthalmologic examination. Flecks are deposits of lipofuscin, a fatty byproduct of normal cell activity, which accumulates abnormally in Stargardt disease. A “beaten-metal” appearance in the fovea or parafoveal region is typical. The “dark choroid” sign on fundus fluorescein angiography in seen most cases.
In addition to genetic heterogeneity, Stargardt’s disease is characterized by a high degree of phenotypic heterogeneity even among individuals of the same family and/or with the same mutation. To explain the great phenotypic variability associated with ABCA4, a genotype-phenotype correlation model has been proposed, according to which the phenotypic severity is inversely correlated to the residual activity of the protein.
Clinical trials currently ongoing all over the world on Stargardt disease patients are listed at clinicaltrials.gov.
The incidence of Stargardt disease is estimated in 1 on 8000–10,000 individuals. However, the healthy carrier frequency in the general population is estimated to be higher than expected from the incidence (ABCA4 mutation carriers are about 1:20).
Stargardt disease is most commonly inherited as an autosomal recessive trait. However, Stargardt disease-3 (ELOVL4 gene mutations) and Stargardt disease-4 (PROM1 gene mutations) are inherited in an autosomal dominant fashion. Furthermore, in families in which three or more pathogenic alleles for Stargardt disease-1 segregate, numerous cases of pseudodominance have been described mainly due to the high frequency of carriers in the general population.
Stargardt disease-1 (STGD1) is caused by homozygous or compound heterozygous mutation in the ABCA4 gene on chromosome 1p22. Over 1000 mutations in ABCA4 are now known to cause Stargardt disease. Most of the mutations are missense, which change the amino acid encoded by the protein. Nonsense, frameshift, splice and small insertions/deletions have also been identified. Large multi-exon deletions/duplications are reported in the literature, but are generally rare (old studies indicate a frequency between 0.3% and 2.2% of the chromosomes analyzed). The mutational spectrum of the ABCA4 gene differs consistently between different ethnic groups.
To date, only one pathogenic variant in ABCA4 is identified in a still significant number of patients (about 15-20%). There are several explanations for this possibility:
- The second pathogenic mutation is not found in the coding parts of the ABCA4 gene. Some variants may be found in the gene promoter or in regulatory regions such as enhancers, altering the transcription efficiency of the gene (such as some variants identified by Bauwens et al., 2019, PMID: 30670881). Recently, 35 deep intronic mutations have also been identified, some of which alter canonical splicing.
- There is a structural variant (deletions, duplications, inversions…), which cannot be identified by NGS sequencing, although this type of mutation is very rare. In one case uniparental disomy was also reported.
- There is a second allele that does not follow classical Mendelian genetics. Zernant et al. (2018) identified the first “extremely hypomorphic allele”, which is an intronic variant that is pathogenic only when it is in trans to another loss-of-function mutation. The same authors also identified the presence of recurrent hypomorphic alleles, such as c.5603A> T (p.A Asn1868Ile), which have a high frequency in the general population (>1%) and which cause a late-onset phenotype when in trans to an allele that causes the complete loss of protein function. Complex alleles, consisting of two pathogenic variants in cis (on the same allele), have also been reported in the literature (such as p. [(L541P; A1038V)] in central Europe), which contribute to increasing phenotypic variability.
- Dominant, di- or polygenic forms of ABCA4-related retinopathy may exist, although to date this hypothesis has to be confirmed. In fact, on the basis of several studies, the mutations mainly act through a loss-of-function or haploinsufficiency mechanism, while a negative dominant effect has never been hypothesized. For this reason, it seems more likely that the cases that appear to be dominant to date are actually due to a second allele not yet identified. In addition, in families in which three or more pathogenic alleles segregate, numerous cases of pseudodominance have been described, mainly due to the high frequency of carriers in the general population (ranging from 1.6% to 10%, depending on ethnicity).
ABCA4 was first characterized in 1997 as the causal gene for Stargardt disease. Shortly thereafter several other phenotypes were associated with mutations in ABCA4, which now have collectively emerged as the most frequent cause of retinal degeneration phenotypes of Mendelian inheritance. Other ABCA4-associated phenotypes include: cone-rod dystrophy 3, retinitis pigmentosa 19 and age-related macular degeneration 2. Overall, ABCA4 mutations are estimated to account for 80% of all Stargardt disease cases (and for about 30% of all cone-rod dystrophy cases).
A clinical subtype of Stargardt disease-1, called juvenile macular degeneration, is caused by mutations in the CNGB3 gene. The term Stargardt disease 2 (STGD2) has been withdrawn because the genetic locus originally identified was found in error and later on remapped on the STGD3 locus.
In two families, ABCA4 disease-causing mutations have been found in addition to GPR143 pathogenic mutations (ocular albinism type 1). Patients variably expressed a complex phenotype, overlapping with both Stargardt disease and X-linked ocular albinism (OA1).
A clinical prenatal diagnosis based on US examination is not possible. Molecular testing is possible only if the familial disease-causing mutation is known. Identification of ABCA4 retinopathies provides a specific molecular diagnosis and justifies a prompt introduction of simple precautions that may slow disease progression.
Best vitelliform macular dystrophy (BEST1 gene mutations) is a slowly progressive macular dystrophy with onset generally in childhood or teenage years. Decreased central visual acuity and metamorphopsia are typical, whereas patients retain normal peripheral vision and dark adaptation. In one patient with BEST1 mutations, a bull’s-eye maculopathy (which can be usually seen in cone-rod dystrophy, Stargardt disease and other maculopathies) was found.
Late-onset retinal degeneration (LORD, C1QTNF5 gene mutations) is an autosomal dominant disorder characterized by night blindness and punctate yellow-white deposits in the retinal fundus. However, the peripheral vision is also compromised in LORD and the onset is typically in the fifth to sixth decade.
Hypotrichosis with juvenile macular dystrophy (HJMD) is caused by homozygous mutation in the CDH3 gene. Patients do not show any other manifestations of ectodermal dysplasia. Cone-mediated as well as rod-mediated vision loss with slight peripheral retinal dystrophy can be seen.
Some patients with vitelliform macular dystrophy 3 (PRPH2 gene mutations) may be originally given a diagnosis of Stargardt disease. Vitelliform macular dystrophy 3 is characterized by a solitary, oval, slightly elevated yellowish subretinal lesion of the fovea. However, the onset is usually later than in Stargardt disease, as it mainly occurs in the fourth or fifth decade of life with a protracted decrease of visual acuity and mild metamorphopsia.
Occult macular dystrophy can be easily differentiated from Stargardt disease by fundus examination, since the macula appears to be completely normal. However, age of onset, clinical symptoms and progression may vaguely recall Stargardt disease, especially because of reduced visual acuity and possible mild disturbances of color vision. Patients have severely reduced focal macular ERGs (whereas full-field ERGs are normal). Occult macular dystrophy patients are believed to have localized retinal dysfunction distal to the ganglion cells in the central retina. The disease shows autosomal dominant transmission and is caused by mutation in the RPIL1 gene.
X-linked atrophic macular degeneration (RPGR gene mutations) is characterized by primarily macular atrophy causing progressive loss of visual acuity with minimal peripheral visual impairment. It usually presents in males. Full-field electroretinograms (ERGs) may show normal cone and rod responses in some affected males.
Sorsby fundus dystrophy is an autosomal dominant retinal dystrophy characterized by the loss of central vision as a result of macular disease by the fourth to fifth decade and peripheral vision loss in late life. Sorsby fundus dystrophy is autosomal dominant and it is caused by heterozygous mutation in the TIMP3 gene.
In some patients with cone-rod dystrophy 7 (RIMS1 gene mutations, autosomal dominant inheritance), features highly suggestive of a Stargardt-like disease can be found. Cone-rod dystrophy (CORD) characteristically leads to early impairment of vision. An initial loss of color vision and of visual acuity is followed by nyctalopia (night blindness) and loss of peripheral visual fields.
Genetic testing strategy
In the past, it was highly recommended to perform a genetic test based on panels, given the high genetic heterogeneity and the presence of some overlapping traits with other ophthalmopathies of Stargardt’s disease. Panels based on clinical exome sequencing (6,000 genes; EXOME PANEL) open the possibility to explore mutations in any additional gene if the first panel is negative. Although this indication remains the gold standard, with the identification of more and more mutations that lie outside the coding regions of the ABCA4 gene (i.e., deep intronic, in the UTR, or in the promoter), it is becoming increasingly more necessary to perform sequencing based on the whole genome (GENOME PANEL). Large deletions/duplications may be initially inferred by appropriate calculations on sequencing data and later on confirmed by dedicated methods such as MLPA or qPCR.
Recommended panel testing at Breda Genetics for this condition:
Progress and prospects of next-generation sequencing testing for inherited retinal dystrophy. Chiang JP, Lamey T, McLaren T, Thompson JA, Montgomery H, De Roach J. Expert Rev Mol Diagn. 2015;15(10):1269-75. PMID: 26394700
Fixation Improvement through Biofeedback Rehabilitation in Stargardt Disease. Scuderi G, Verboschi F, Domanico D, Spadea L. Case Rep Med. 2016;2016:4264829. PMID: 27212950
Phenotypic Variation in a Family With Pseudodominant Stargardt Disease. Huckfeldt RM, East JS, Stone EM, Sohn EH. JAMA Ophthalmol. 2016 Mar 31. PMID 27030965
Screening of ABCA4 Gene in a Chinese Cohort With Stargardt Disease or Cone-Rod Dystrophy With a Report on 85 Novel Mutations. Jiang F, Pan Z, Xu K, Tian L, Xie Y, Zhang X, Chen J, Dong B, Li Y. Invest Ophthalmol Vis Sci. 2016 Jan 1;57(1):145-52. PMID: 26780318
Next-generation sequencing of ABCA4: High frequency of complex alleles and novel mutations in patients with retinal dystrophies from Central Europe. Ścieżyńska A, Oziębło D, Ambroziak AM, Korwin M, Szulborski K, Krawczyński M, Stawiński P, Szaflik J, Szaflik JP, Płoski R, Ołdak M. Exp Eye Res. 2016 Apr;145:93-99. PMID: 26593885
Cerebral Involvement in Stargardt’s Disease: A VBM and TBSS Study. Olivo G, Melillo P, Cocozza S, D’Alterio FM, Prinster A, Testa F, Brunetti A, Simonelli F, Quarantelli M. Invest Ophthalmol Vis Sci. 2015 Nov;56(12):7388-97. PMID: 26574798
Complex inheritance of ABCA4 disease: four mutations in a family with multiple macular phenotypes. Lee W, Xie Y, Zernant J, Yuan B, Bearelly S, Tsang SH, Lupski JR, Allikmets R. Hum Genet. 2016 Jan;135(1):9-19. PMID: 26527198
Colour Vision in Stargardt Disease. Vandenbroucke T, Buyl R, De Zaeytijd J, Bauwens M, Uvijls A, De Baere E, Leroy BP. Ophthalmic Res. 2015;54(4):181-94. PMID: 26492201
Expanding the Mutation Spectrum in ABCA4: Sixty Novel Disease Causing Variants and Their Associated Phenotype in a Large French Stargardt Cohort. Nassisi M, Mohand-Saïd S, Dhaenens CM, Boyard F, Démontant V, Andrieu C, Antonio A, Condroyer C, Foussard M, Méjécase C, Eandi CM, Sahel JA, Zeitz C, Audo I. Int J Mol Sci. 2018 Jul 27;19(8):2196. doi: 10.3390/ijms19082196. PMID: 30060493
Mutation Spectrum of the ABCA4 Gene in 335 Stargardt Disease Patients From a Multicenter German Cohort-Impact of Selected Deep Intronic Variants and Common SNPs. Schulz HL, Grassmann F, Kellner U, Spital G, Rüther K, Jägle H, Hufendiek K, Rating P, Huchzermeyer C, Baier MJ, Weber BH, Stöhr H. Invest Ophthalmol Vis Sci. 2017 Jan 1;58(1):394-403. doi: 10.1167/iovs.16-19936. PMID: 28118664
Extremely hypomorphic and severe deep intronic variants in the ABCA4 locus result in varying Stargardt disease phenotypes. Zernant J, Lee W, Nagasaki T, Collison FT, Fishman GA, Bertelsen M, Rosenberg T, Gouras P, Tsang SH, Allikmets R. Cold Spring Harb Mol Case Stud. 2018 Aug 1;4(4):a002733. doi: 10.1101/mcs.a002733. PMID: 29848554
Clinical spectrum, genetic complexity and therapeutic approaches for retinal disease caused by ABCA4 mutations. Cremers FPM, Lee W, Collin RWJ, Allikmets R. Prog Retin Eye Res. 2020 Nov;79:100861. doi: 10.1016/j.preteyeres.2020.100861. Epub 2020 Apr 9. PMID: 32278709
Frequent hypomorphic alleles account for a significant fraction of ABCA4 disease and distinguish it from age-related macular degeneration. Zernant J, Lee W, Collison FT, Fishman GA, Sergeev YV, Schuerch K, Sparrow JR, Tsang SH, Allikmets R. J Med Genet. 2017 Jun;54(6):404-412. doi: 10.1136/jmedgenet-2017-104540. Epub 2017 Apr 26. PMID: 28446513;
Correlating the Expression and Functional Activity of ABCA4 Disease Variants With the Phenotype of Patients With Stargardt Disease. Garces F, Jiang K, Molday LL, Stöhr H, Weber BH, Lyons CJ, Maberley D, Molday RS. Invest Ophthalmol Vis Sci. 2018 May 1;59(6):2305-2315. doi: 10.1167/iovs.17-23364. PMID: 29847635
ABCA4-associated disease as a model for missing heritability in autosomal recessive disorders: novel noncoding splice, cis-regulatory, structural, and recurrent hypomorphic variants. Bauwens M, Garanto A, Sangermano R, Naessens S, Weisschuh N, De Zaeytijd J, Khan M, Sadler F, Balikova I, Van Cauwenbergh C, Rosseel T, Bauwens J, De Leeneer K, De Jaegere S, Van Laethem T, De Vries M, Carss K, Arno G, Fakin A, Webster AR, de Ravel de l’Argentière TJL, Sznajer Y, Vuylsteke M, Kohl S, Wissinger B, Cherry T, Collin RWJ, Cremers FPM, Leroy BP, De Baere E. Genet Med. 2019 Aug;21(8):1761-1771. doi: 10.1038/s41436-018-0420-y. Epub 2019 Jan 23. PMID: 30670881