The Molecular Genetic and Clinical Findings in two Probands with Stargardt Disease

Authors: B. Kousal 1,5;  J. Záhlava 2;  Š. Vejvalková 3;  M. Hejtmánková 4;  P. Lišková 1,5
Authors‘ workplace: Oãní klinika, 1. lékafiská fakulta, Univerzita Karlova v Praze a V‰eobecná fakultní nemocnice v Praze, pfiednostka doc. MUDr. Bohdana Kalvodová, CSc. 1;  Oãní klinika JL, s. r. o., primáfi MUDr. Ján Le‰ták, CSc., FEBO, MBA, LL. A FAOG 2;  Ústav biologie a lékafiské genetiky, 2. lékafiská fakulta, Univerzita Karlova v Praze a Fakultní nemocnice v Motole pfiednosta prof. MUDr. Milan Macek jr. DrSc. 3;  GENNET, Praha, vedoucí MUDr. David Stejskal 4;  Laboratofi biologie a patologie oka Ústav dûdiãn˘ch metabolick˘ch poruch 1. lékafiská fakulta, Univerzita Karlova v Praze a V‰eobecná fakultní nemocnice v Praze, pfiednosta prof. MUDr. Viktor KoÏich, CSc. 5
Published in: Čes. a slov. Oftal., 70, 2014, No. 6, p. 228-233
Category: Original Article


The aim of our study was to describe the phenotype and to perform molecular genetic investigation in two probands of Czech origin diagnosed with Stargardt disease (STGD).

Both males underwent ocular examination including assessment by high-resolution spectral domain optical coherence tomography (SD-OCT). DNA was isolated from venous blood. Mutation detection was performed using the ABCA4 genotyping microarray (Asper Ophthalmics, Estonia).

The best corrected visual acuity in proband 1 (aged 39 years) was 0.1 bilaterally, and 0.05 in proband 2 (aged 26 years). Fundus examination showed typical multiple yellow-white lesions and macular atrophy. Alterations of retinal pigment epithelium, retinal thinning and disruption of the photoreceptor inner segment ellipsoid band were detected with an SD-OCT. Two known disease-causing mutations in ABCA4 were identified in proband 1; c.4234C>T, p.(Gln1412*) in exon 28; and c.5882G>A, p.(Gly1961Glu) in exon 42. Only one pathogenic change was detected in proband 2; c.1988G>A, p.(Trp663*) in exon 14. A second change, anticipated because of the recessive status of the disease, was not identified.

The frequency and full spectrum of ABCA4 mutations in Czech patients with inherited retinal disorders is yet to be established. The inability to detect a second pathogenic change in ABCA4 coding sequences in proband 2 warrants further investigation.

Key words:
Stargardt disease, ABCA4, mutation, SD-OCT


1. Aguirre-Lamban, J., Riveiro-Alvarez, R., Maia-Lopes, S., et al.: Molecular analysis of the ABCA4 gene for reliable detection of allelic variations in Spanish patients: identification of 21 novel variants. Br J Ophthalmol, 2009; 93(5): 614–21.

2. Aleman, TS., Cideciyan, AV., Windsor, EA., et al.: Macular pigment and lutein supplementation in ABCA4-associated retinal degenerations. Invest Ophthalmol Vis Sci, 2007; 48(3): 1319–29.

3. Allikmets, R.: Further evidence for an association of ABCR alleles with age-related macular degeneration. The International ABCR Screening Consortium. Am J Hum Genet, 2000; 67(2): 487–91.

4. Allikmets, R.: Simple and complex ABCR: genetic predisposition to retinal disease. Am J Hum Genet, 2000; 67(4): 793–9.

5. Allikmets, R., Shroyer, NF., Singh, N., et al.: Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration. Science, 1997; 277(5333): 1805–7.

6. Allikmets, R., Singh, N., Sun, H., et al.: A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat Genet, 1997; 15(3): 236–46.

7. Bellmann, C., Holz, FG., Schapp, O., et al.: Topography of fundus autofluorescence with a new confocal scanning laser ophthalmoscope. Ophthalmologe, 1997; 94(6): 385–91.

8. Braun, TA., Mullins, RF., Wagner, AH., et al.: Non-exomic and synonymous variants in ABCA4 are an important cause of Stargardt disease. Hum Mol Genet, 2013; 22(25): 5136–45.

9. Briggs, CE., Rucinski, D., Rosenfeld, PJ., et al.: Mutations in ABCR (ABCA4) in patients with Stargardt macular degeneration or cone-rod degeneration. Invest Ophthalmol Vis Sci, 2001; 42(10): 2229–36.

10. Burke, TR., Tsang, SH., Zernant, J., et al.: Familial discordance in Stargardt disease. Mol Vis, 2012; 18: 227–33.

11. Cella, W., Greenstein, VC., Zernant-Rajang, J., et al.: G1961E mutant allele in the Stargardt disease gene ABCA4 causes bull’s eye maculopathy. Exp Eye Res, 2009; 89(1): 16–24.

12. Cremers, FP., Van de Pol, DJ., Van Driel, M., et al.: Autosomal recessive retinitis pigmentosa and cone-rod dystrophy caused by splice site mutations in the Stargardt’s disease gene ABCR. Hum Mol Genet, 1998; 7(3): 355–62.

13. Downs, K., Zacks, DN., Caruso, R., et al.: Molecular testing for hereditary retinal disease as part of clinical care. Arch Ophthalmol, 2007; 125(2): 252–8.

14. Edwards, AO., Donoso, LA., Ritter, R., 3rd. A novel gene for autosomal dominant Stargardt-like macular dystrophy with homology to the SUR4 protein family. Invest Ophthalmol Vis Sci, 2001; 42(11): 2652–63.

15. Ergun, E., Hermann, B., Wirtitsch, M., et al.: Assessment of central visual function in Stargardt’s disease/fundus flavimaculatus with ultrahigh-resolution optical coherence tomography. Invest Ophthalmol Vis Sci, 2005; 46(1): 310–6.

16. Fishman, GA.: Historical evolution in the understanding of Stargardt macular dystrophy. Ophthalmic Genet, 2010; 31(4): 183–9.

17. Fishman, GA., Stone, EM., Eliason, DA., et al.: ABCA4 gene sequence variations in patients with autosomal recessive cone-rod dystrophy. Arch Ophthalmol, 2003; 121(6): 851–5.

18. Fishman, GA., Stone, EM., Grover, S., et al.: Variation of clinical expression in patients with Stargardt dystrophy and sequence variations in the ABCR gene. Arch Ophthalmol, 1999; 117(4): 504-10.

19. Fujinami, K., Zernant, J., Chana, RK., et al.: ABCA4 gene screening by next-generation sequencing in a British cohort. Invest Ophthalmol Vis Sci, 2013; 54(10): 6662–74.

20. Hargitai, J., Zernant, J., Somfai, GM., et al.: Correlation of clinical and genetic findings in Hungarian patients with Stargardt disease. Invest Ophthalmol Vis Sci. 2005; 46(12): 4402–8.

21. Hentze, MW., Kulozik, AE.: A perfect message: RNA surveillance and nonsense-mediated decay. Cell, 1999; 96(3): 307–10.

22. Holz, FG.: Autofluorescence imaging of the macula. Ophthalmologe, 2001; 98(1): 10-8.

23. Itabashi, R., Katsumi, O., Mehta, MC., et al.: Stargardt’s disease/fundus flavimaculatus: psychophysical and electrophysiologic results. Graefes Arch Clin Exp Ophthalmol, 1993; 231(10): 555–62.

24. Jaakson, K., Zernant, J., Kulm, M., et al.: Genotyping microarray (gene chip) for the ABCR (ABCA4) gene. Hum Mutat, 2003; 22(5): 395–403.

25. Lachapelle, P., Little, JM., and Roy, MS.: The electroretinogram in Stargardt’s disease and fundus flavimaculatus. Doc Ophthalmol, 1989; 73(4): 395–404.

26. Martinez-Mir, A., Paloma, E., Allikmets, R., et al.: Retinitis pigmentosa caused by a homozygous mutation in the Stargardt disease gene ABCR. Nat Genet, 1998; 18(1): 11–2.

27. Mata, NL., Weng, J., Travis, GH.: Biosynthesis of a major lipofuscin fluorophore in mice and humans with ABCR-mediated retinal and macular degeneration. Proc Natl Acad Sci U S A, 2000; 97(13): 7154–9.

28. Maugeri, A., van Driel, MA., Van de Pol, DJ., et al.: The 2588G—>C mutation in the ABCR gene is a mild frequent founder mutation in the Western European population and allows the classification of ABCR mutations in patients with Stargardt disease. Am J Hum Genet, 1999; 64(4): 1024–35.

29. Molday, RS., Zhang, K.: Defective lipid transport and biosynthesis in recessive and dominant Stargardt macular degeneration. Prog Lipid Res, 2010; 49(4): 476–92.

30. Radu, RA., Han, Y., Bui, TV., et al.: Reductions in serum vitamin A arrest accumulation of toxic retinal fluorophores: a potential therapy for treatment of lipofuscin-based retinal diseases. Invest Ophthalmol Vis Sci, 2005; 46(12): 4393–401.

31. Radu, RA., Yuan, Q., Hu, J., et al.: Accelerated accumulation of lipofuscin pigments in the RPE of a mouse model for ABCA4-mediated retinal dystrophies following Vitamin A supplementation. Invest Ophthalmol Vis Sci, 2008; 49(9): 3821–9.

32. Rencová, E., Studnička, J., Marák, J., et al.: Koincidence lokalizace defektů vrstvy junkce IS/OS fotoreceptorů na SD OCT s funkčními poruchami v případě Stargardtovy choroby. Čes a slov Oftal, 2012; 68(2): 84–88.

33. Rivera, A., White, K., Stohr, H., et al.: A comprehensive survey of sequence variation in the ABCA4 (ABCR) gene in Stargardt disease and age-related macular degeneration. Am J Hum Genet, 2000; 67(4): 800–13.

34. Roberts, LJ., Ramesar, RS., Greenberg, J.: Clinical utility of the ABCR400 microarray: basing a genetic service on a commercial gene chip. Arch Ophthalmol, 2009; 127(4): 549–54.

35. Rosenberg, T., Klie, F., Garred, P., et al.: N965S is a common ABCA4 variant in Stargardt-related retinopathies in the Danish population. Mol Vis, 2007; 13: 1962–9.

36. Shroyer, NF., Lewis, RA., Lupski, JR.: Complex inheritance of ABCR mutations in Stargardt disease: linkage disequilibrium, complex alleles, and pseudodominance. Hum Genet, 2000; 106(2): 244–8.

37. Schindler, EI., Nylen, EL., Ko, AC., et al.: Deducing the pathogenic contribution of recessive ABCA4 alleles in an outbred population. Hum Mol Genet. 2010; 19(19): 3693–701.

38. Simonelli, F., Testa, F., Zernant, J., et al.: Genotype-phenotype correlation in Italian families with Stargardt disease. Ophthalmic Res, 2005; 37(3): 159–67.

39. Sohrab, MA., Allikmets, R., Guarnaccia, MM., et al.: Preimplantation genetic diagnosis for stargardt disease. Am J Ophthalmol, 2010; 149(4): 651–655 e2.

40. Stanga, PE., Downes, SM., Ahuja, RM., et al.: Comparison of optical coherence tomography and fluorescein angiography in assessing macular edema in retinal dystrophies: preliminary results. Int Ophthalmol, 2001; 23(4-6): 321-5.

41. Stavrou, P., Good, PA., Misson, GP., et al.: Electrophysiological findings in Stargardt’s-fundus flavimaculatus disease. Eye (Lond), 1998; 12 ( Pt 6): 953–8.

42. Stone, EM., Webster, AR., Vandenburgh, K., et al.: Allelic variation in ABCR associated with Stargardt disease but not age-related macular degeneration. Nat Genet, 1998; 20(4): 328–9.

43. Sun, H., Nathans, J.: ABCR: rod photoreceptor-specific ABC transporter responsible for Stargardt disease. Methods Enzymol, 2000; 315: 879–97.

44. Valverde, D., Riveiro-Alvarez, R., Aguirre-Lamban, J., et al.: Spectrum of the ABCA4 gene mutations implicated in severe retinopathies in Spanish patients. Invest Ophthalmol Vis Sci, 2007; 48(3): 985–90.

45. Vasireddy, V., Wong, P., Ayyagari, R.: Genetics and molecular pathology of Stargardt-like macular degeneration. Prog Retin Eye Res, 2010; 29(3): 191–207.

46. Voigt, M., Querques, G., Atmani, K., et al.: Analysis of retinal flecks in fundus flavimaculatus using high-definition spectral-domain optical coherence tomography. Am J Ophthalmol, 2010; 150(3): 330–7.

47. Von Ruckmann, A., Fitzke, FW., Bird, AC.: In vivo fundus autofluorescence in macular dystrophies. Arch Ophthalmol, 1997; 115(5): 609–15.

48. Webster, AR., Heon, E., Lotery, AJ., et al.: An analysis of allelic variation in the ABCA4 gene. Invest Ophthalmol Vis Sci, 2001; 42(6): 1179–89.

49. Yang, Z., Chen, Y., Lillo, C., et al.: Mutant prominin 1 found in patients with macular degeneration disrupts photoreceptor disk morphogenesis in mice. J Clin Invest, 2008; 118(8): 2908–16.

50. Yatsenko, AN., Shroyer, NF., Lewis, RA., et al.: Late-onset Stargardt disease is associated with missense mutations that map outside known functional regions of ABCR (ABCA4). Hum Genet, 2001; 108(4): 346–55.

51. Zernant, J., Schubert, C., Im, KM., et al.: Analysis of the ABCA4 gene by next-generation sequencing. Invest Ophthalmol Vis Sci. 2011; 52(11): 8479–87.

52. Zhang, K., Kniazeva, M., Han, M., et al.: A 5-bp deletion in ELOVL4 is associated with two related forms of autosomal dominant macular dystrophy. Nat Genet, 2001; 27(1): 89–93.

Forgotten password

Don‘t have an account?  Create new account

Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.


Don‘t have an account?  Create new account