ABCMdb

ABCA4 p.Asn96Asp

ClinVar:	c.286A>C , p.Asn96His ? , not provided c.286A>G , p.Asn96Asp ? , not provided
Predicted by SNAP2:	A: D (63%), C: D (63%), D: D (80%), E: D (53%), F: D (71%), G: D (53%), H: D (75%), I: D (66%), K: N (57%), L: D (66%), M: D (66%), P: D (63%), Q: N (53%), R: N (57%), S: N (66%), T: N (61%), V: D (63%), W: D (85%), Y: D (71%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D,

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[hide] Correlation between photoreceptor layer integrity ... Invest Ophthalmol Vis Sci. 2012 Jul 3;53(8):4409-15. doi: 10.1167/iovs.11-8201. Print 2012 Jul. Testa F, Rossi S, Sodi A, Passerini I, Di Iorio V, Della Corte M, Banfi S, Surace EM, Menchini U, Auricchio A, Simonelli F
Correlation between photoreceptor layer integrity and visual function in patients with Stargardt disease: implications for gene therapy.
Invest Ophthalmol Vis Sci. 2012 Jul 3;53(8):4409-15. doi: 10.1167/iovs.11-8201. Print 2012 Jul., [PMID:22661472]

Abstract [show]
PURPOSE: To perform a clinical characterization of Stargardt patients with ABCA4 gene mutation, and to investigate the correlation between the inner and outer segment (IS/OS) junction morphology and visual acuity, fundus lesions, electroretinogram abnormalities, and macular sensitivity. METHODS: Sixty-one patients with Stargardt disease (STGD) were given a comprehensive ophthalmic examination. Inner-outer photoreceptor junction morphology evaluated by spectral-domain optical coherence tomography was correlated with visual acuity, fundus lesions, fundus autofluorescence, full-field and multifocal electroretinography responses, and microperimetric macular sensitivities. We classified STGD patients into three groups: (1) IS/OS junction disorganization in the fovea, (2) IS/OS junction loss in the fovea, and (3) extensive loss of IS/OS junction. Mutation analysis of the ABCA4 gene was carried out by sequencing the complete coding region. RESULTS: A significant difference in visual acuity was observed between IS/OS groups 1 and 2 and between IS/OS groups 2 and 3 (P < 0.0001). A significant difference in microperimetry sensitivity was observed between IS/OS groups 2 and 3, and between IS/OS groups 1 and 3 (P < 0.0001). There was also a statistically significant correlation between IS/OS abnormalities and the extent of fundus lesions (Spearman P </= 0.01), as well as with the type of ERG and multifocal ERG results (Spearman P </= 0.01). Finally, the degree of IS/OS junction preservation showed a statistically significant correlation with the extension of foveal abnormalities assessed by fundus autofluorescence imaging (Spearman P </= 0.01). The G1961E mutation was more frequent in the patients without extensive loss of IS/OS junction (P = 0.01) confirming its association with a milder STGD phenotype. CONCLUSIONS: The results of this study suggest that a comprehensive approach in the examination of Stargardt patients has the potential to improve the understanding of vision loss and may provide a sensitive measure to evaluate the efficacy of future experimental therapies in patients with STGD.

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66 Clinical and Molecular Data of STGD Patients Patient ID/Fam Age (y) Visual Acuity OCT ft (lm) MP (dB) IS/OS* Fundus† FAF‡ ERG§ mfERGjj Mutation 1 Mutation 2 4/2 50 0.0715 134 5.25 - 1 - 2 4 G1961E 250InsCAAA 5/2 47 0.1 127 14.2 2 1 1 1 3 G1961E 250InsCAAA 6/3 33 0.05 125 9.8 2 2 2 1 3 G1961E R2149X 7/4 18 0.085 135 0 - 2 - 3 4 5917del G 5917del G 8/5 16 0.095 104 0.9 3 2 3 3 4 L541P; A1038V L541P; A1038V 9/6 71 0.03 109 0 3 3 3 2 4 IVS35þ2t > c G1961E 11/7 46 0.2 137 9.35 2 1 2 1 1 Y850K A1598D 13/8 35 0.017 163 0 - 3 - 3 4 L541P R1098C 15/10 20 0.1 135.5 11.05 2 1 1 1 4 IVS35þ2t > c G1961E 16/11 20 0.47 96 16.7 2 1 2 1 2 L541P; A1038V L541P; A1038V 17/11 34 0.1 114.5 7.55 2 1 2 1 3 L541P; A1038V L541P; A1038V 18/11 18 1 134 16.15 1 1 1 1 3 L541P; A1038V L541P; A1038V 19/12 12 0.12 242 6.5 3 1 2 1 2 L541P; A1038V L541P; A1038V 20/13 28 0.1 111 14.2 2 2 2 1 3 R1443H IVS35þ2t > c 21/14 34 0.2 152 14.15 2 1 2 2 4 R653C G1961E 22/15 69 0.079 122 0 3 3 3 3 4 I1562T R2149X 23/15 46 0.55 162 1.05 3 3 3 3 4 I1562T IVS45þ1g > c 25/16 28 0.11 105.5 3.1 3 2 2 3 4 R212C R212C 26/17 13 0.084 138.5 0.2 3 2 3 1 3 R18W C1490Y 27/4 20 0.0775 131 0 - 3 - 3 4 5917del G 5917del G 28/4 23 0.042 159.5 0 - 3 - 3 4 5917del G 5917del G 30/18 29 0.0375 103 0 3 3 3 3 4 N965S G1961E 31/19 17 0.1 102 9 3 2 2 3 4 L541P F655C 38/20 20 0.225 95 16 2 1 1 3 4 L541P G1961E 39/21 20 0.17 146 16.7 2 1 1 1 3 G1961E R2030X 42/22 43 0.575 127 7.05 2 1 2 1 2 250insCAAA G1961E 43/23 12 0.1 117.5 11.55 2 2 2 1 3 IVS40þ5g > a IVS15-8g > a 44/24 29 0.1 149 18.5 2 1 2 1 3 G1961E 4736del6bpins2bp 46/25 38 0.0075 182.5 0 - 3 - 3 4 G618R G1972R 48/26 35 0.46 133.5 12.25 2 1 - 1 3 4538insC G1961E 50/27 13 0.2 122.5 17.35 2 1 2 1 3 IVS35þ2t > c G1961E 51/28 24 0.065 123 0 3 3 3 3 4 250InsCAAA V767D 52/29 14 1 147 6.15 1 1 1 3 4 L2027F A1881V 53/30 45 0.1 120 6.05 3 2 2 1 3 G1961E R2030X 54/30 24 0.09 159 2.65 3 3 3 3 4 V767D R2030X 55/31 34 0.085 150 5.15 3 3 3 3 4 N96H IVS40þ5g > a 56/32 48 0.0335 118.5 4.4 - 3 - 2 4 IVS35þ2t > c G1961E 58/32 52 0.05 124 5.8 3 2 2 2 4 IVS35þ2t > c G1961E 60/33 43 0.065 163 15.95 2 1 - 1 2 250InsCAAA G1961E 61/34 45 0.03 187.5 4.5 1 1 1 2 1 R1640Q G1961E 64/35 33 0.0665 158 0 3 3 3 3 4 C2150R 2626InsTTT 65/35 38 0.008 172 0.05 3 3 3 3 4 C2150R 2626InsTTT 66/36 42 0.4 137 0.95 3 2 2 1 3 N96D IVS40þ5g > a 67/37 14 0.235 132 0.15 3 2 3 3 4 IVS6-2a > t IVS6-2a > t 69/38 19 0.09 120 0 3 1 2 1 3 R511H N529S 70/39 42 0.515 140 0.4 3 3 3 3 4 IVS40þ5g > a N965S 72/40 33 0.096 116.5 5.1 3 2 2 1 3 N96D L2140Q 73/41 17 0.1 160 14.35 2 2 2 3 4 G690D A1598D 74/42 36 0.0125 142.5 0 3 3 3 3 4 N96H N96H 75/43 45 0.2 214.5 11.7 2 1 2 1 3 IVS35þ2t > c G1961E 77/44 19 0.34 137.5 11.75 2 1 - 1 3 G1961E G618R 81/45 66 0.335 163 2 - 3 - 2 4 N96D G1961E 82/46 41 0.1 116.5 0.15 3 3 3 3 4 4538insC IVS40þ5g > a 83/47 17 0.395 165 19.25 1 1 1 1 2 G1961E IVS45þ1g > c 84/47 26 0.135 120 16.2 2 1 2 1 3 G1961E IVS45þ1g > c 85/48 10 0.16 149.5 12.4 2 2 2 1 3 IVS35þ2t > c IVS40þ5g > a 87/40 25 0.9 155 15 2 1 2 1 2 N96D L2140Q 88/49 32 0.0715 144 0.1 - 3 - 3 4 IVS45þ1g > c R2149X 89/50 14 0.1185 147 1.85 3 1 - 3 4 P402A 250insCAAA 90/51 35 0.07 116.5 0 - 3 - 3 4 A1598D R2030X 94/52 30 0.1 144 12.85 2 1 - 1 1 A1598D G1961E Fam, family; OCT ft, optical coherence tomography foveal thickness; MP, microperimetry; IS/OS, inner-outer segment junction; FAF, fundus autofluorescence; ERG, electroretinogram; mfERG, multifocal-electroretinogram. Login to comment
67 Clinical and Molecular Data of STGD Patients Patient ID/Fam Age (y) Visual Acuity OCT ft (lm) MP (dB) IS/OS* Fundusߤ FAFߥ ERG&#a7; mfERGjj Mutation 1 Mutation 2 4/2 50 0.0715 134 5.25 - 1 - 2 4 G1961E 250InsCAAA 5/2 47 0.1 127 14.2 2 1 1 1 3 G1961E 250InsCAAA 6/3 33 0.05 125 9.8 2 2 2 1 3 G1961E R2149X 7/4 18 0.085 135 0 - 2 - 3 4 5917del G 5917del G 8/5 16 0.095 104 0.9 3 2 3 3 4 L541P; A1038V L541P; A1038V 9/6 71 0.03 109 0 3 3 3 2 4 IVS35&#fe;2t > c G1961E 11/7 46 0.2 137 9.35 2 1 2 1 1 Y850K A1598D 13/8 35 0.017 163 0 - 3 - 3 4 L541P R1098C 15/10 20 0.1 135.5 11.05 2 1 1 1 4 IVS35&#fe;2t > c G1961E 16/11 20 0.47 96 16.7 2 1 2 1 2 L541P; A1038V L541P; A1038V 17/11 34 0.1 114.5 7.55 2 1 2 1 3 L541P; A1038V L541P; A1038V 18/11 18 1 134 16.15 1 1 1 1 3 L541P; A1038V L541P; A1038V 19/12 12 0.12 242 6.5 3 1 2 1 2 L541P; A1038V L541P; A1038V 20/13 28 0.1 111 14.2 2 2 2 1 3 R1443H IVS35&#fe;2t > c 21/14 34 0.2 152 14.15 2 1 2 2 4 R653C G1961E 22/15 69 0.079 122 0 3 3 3 3 4 I1562T R2149X 23/15 46 0.55 162 1.05 3 3 3 3 4 I1562T IVS45&#fe;1g > c 25/16 28 0.11 105.5 3.1 3 2 2 3 4 R212C R212C 26/17 13 0.084 138.5 0.2 3 2 3 1 3 R18W C1490Y 27/4 20 0.0775 131 0 - 3 - 3 4 5917del G 5917del G 28/4 23 0.042 159.5 0 - 3 - 3 4 5917del G 5917del G 30/18 29 0.0375 103 0 3 3 3 3 4 N965S G1961E 31/19 17 0.1 102 9 3 2 2 3 4 L541P F655C 38/20 20 0.225 95 16 2 1 1 3 4 L541P G1961E 39/21 20 0.17 146 16.7 2 1 1 1 3 G1961E R2030X 42/22 43 0.575 127 7.05 2 1 2 1 2 250insCAAA G1961E 43/23 12 0.1 117.5 11.55 2 2 2 1 3 IVS40&#fe;5g > a IVS15-8g > a 44/24 29 0.1 149 18.5 2 1 2 1 3 G1961E 4736del6bpins2bp 46/25 38 0.0075 182.5 0 - 3 - 3 4 G618R G1972R 48/26 35 0.46 133.5 12.25 2 1 - 1 3 4538insC G1961E 50/27 13 0.2 122.5 17.35 2 1 2 1 3 IVS35&#fe;2t > c G1961E 51/28 24 0.065 123 0 3 3 3 3 4 250InsCAAA V767D 52/29 14 1 147 6.15 1 1 1 3 4 L2027F A1881V 53/30 45 0.1 120 6.05 3 2 2 1 3 G1961E R2030X 54/30 24 0.09 159 2.65 3 3 3 3 4 V767D R2030X 55/31 34 0.085 150 5.15 3 3 3 3 4 N96H IVS40&#fe;5g > a 56/32 48 0.0335 118.5 4.4 - 3 - 2 4 IVS35&#fe;2t > c G1961E 58/32 52 0.05 124 5.8 3 2 2 2 4 IVS35&#fe;2t > c G1961E 60/33 43 0.065 163 15.95 2 1 - 1 2 250InsCAAA G1961E 61/34 45 0.03 187.5 4.5 1 1 1 2 1 R1640Q G1961E 64/35 33 0.0665 158 0 3 3 3 3 4 C2150R 2626InsTTT 65/35 38 0.008 172 0.05 3 3 3 3 4 C2150R 2626InsTTT 66/36 42 0.4 137 0.95 3 2 2 1 3 N96D IVS40&#fe;5g > a 67/37 14 0.235 132 0.15 3 2 3 3 4 IVS6-2a > t IVS6-2a > t 69/38 19 0.09 120 0 3 1 2 1 3 R511H N529S 70/39 42 0.515 140 0.4 3 3 3 3 4 IVS40&#fe;5g > a N965S 72/40 33 0.096 116.5 5.1 3 2 2 1 3 N96D L2140Q 73/41 17 0.1 160 14.35 2 2 2 3 4 G690D A1598D 74/42 36 0.0125 142.5 0 3 3 3 3 4 N96H N96H 75/43 45 0.2 214.5 11.7 2 1 2 1 3 IVS35&#fe;2t > c G1961E 77/44 19 0.34 137.5 11.75 2 1 - 1 3 G1961E G618R 81/45 66 0.335 163 2 - 3 - 2 4 N96D G1961E 82/46 41 0.1 116.5 0.15 3 3 3 3 4 4538insC IVS40&#fe;5g > a 83/47 17 0.395 165 19.25 1 1 1 1 2 G1961E IVS45&#fe;1g > c 84/47 26 0.135 120 16.2 2 1 2 1 3 G1961E IVS45&#fe;1g > c 85/48 10 0.16 149.5 12.4 2 2 2 1 3 IVS35&#fe;2t > c IVS40&#fe;5g > a 87/40 25 0.9 155 15 2 1 2 1 2 N96D L2140Q 88/49 32 0.0715 144 0.1 - 3 - 3 4 IVS45&#fe;1g > c R2149X 89/50 14 0.1185 147 1.85 3 1 - 3 4 P402A 250insCAAA 90/51 35 0.07 116.5 0 - 3 - 3 4 A1598D R2030X 94/52 30 0.1 144 12.85 2 1 - 1 1 A1598D G1961E Fam, family; OCT ft, optical coherence tomography foveal thickness; MP, microperimetry; IS/OS, inner-outer segment junction; FAF, fundus autofluorescence; ERG, electroretinogram; mfERG, multifocal-electroretinogram. Statistics Our set of data is described by continuous (BCVA, OCT foveal thickness, and macular sensitivities) and categorical (fundus, FAF, IS/ OS, ERG, and mfERG groups) variables. Login to comment

[hide] Outcome of ABCA4 microarray screening in routine c... Mol Vis. 2009 Dec 20;15:2841-7. Ernest PJ, Boon CJ, Klevering BJ, Hoefsloot LH, Hoyng CB
Outcome of ABCA4 microarray screening in routine clinical practice.
Mol Vis. 2009 Dec 20;15:2841-7., [PMID:20029649]

Abstract [show]
PURPOSE: To retrospectively analyze the clinical characteristics of patients who were screened for mutations with the ATP-binding cassette transporter gene ABCA4 (ABCA4) microarray in a routine clinical DNA diagnostics setting. METHODS: We performed a retrospective analysis of the medical charts of 65 patients who underwent an ABCA4 microarray screening between the years 2002 and 2006. An additional denaturing gradient gel electrophoresis (DGGE) was performed in these patients if less than two mutations were found with the microarray. We included all patients who were suspected of autosomal recessive Stargardt disease (STGD1), autosomal recessive cone-rod dystrophy (arCRD), or autosomal recessive retinitis pigmentosa at the time of microarray request. After a retrospective analysis of the clinical characteristics, the patients who were suspected of STGD1 were categorized as having either a typical or atypical form of STGD1, according to the age at onset, fundus appearance, fluorescein angiography, and electroretinography. The occurrence of typical clinical features for STGD1 was compared between patients with different numbers of discovered mutations. RESULTS: Of the 44 patients who were suspected of STGD1, 26 patients (59%) had sufficient data available for a classification in either typical (six patients; 23%) or atypical (20 patients; 77%) STGD1. In the suspected STGD1 group, 59% of all expected pathogenic alleles were found with the ABCA4 microarray. DGGE led to the finding of 12 more mutations, resulting in an overall detection rate of 73%. Thirty-one percent of patients with two or three discovered ABCA4 mutations met all typical STGD1 criteria. An age at onset younger than 25 years and a dark choroid on fluorescein angiography were the most predictive clinical features to find ABCA4 mutations in patients suspected of STGD1. In 18 patients suspected of arCRD, microarray screening detected 22% of the possible pathogenic alleles. CONCLUSIONS: In addition to confirmation of the diagnosis in typical STGD1, ABCA4 microarray screening is usually requested in daily clinical practice to strengthen the diagnosis when the disease is atypical. This study supports the view that the efficiency and accuracy of ABCA4 microarray screening are directly dependent upon the clinical features of the patients who are screened.

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143 DISCOVERED MUTATIONS IN THE ABCA4 GENE IN THE PATIENTS INCLUDED IN THIS STUDY Nucleotide change Effect Alleles References Mutations already included in the ABCA4 microarray c.286A>G p.Asn96Asp 2 [25] c.656G>C p.Arg219Thr 1 [10] c.740A>T p.Asn247Ile 1 This study* c.768G>T splice site 7 [13] c.899C>A p.Thr300Asn 1 [14] c.1805G>A p.Arg602Gln 1 [9] c.1822T>A p.Phe608Ile 2 [13] c.1853G>A p.Gly618Glu 1 [19] c.1938-1G>A splice site 1 [26] c.2588G>C p.DelGly863/Gly863Ala 8 [13] c.2919del exons20-22 deletion/frameshift 2 [13] c.3335C>A p.Thr1112Asn 1 [13] c.3874C>T p.Gln1292X 1 This study* c.3899G>A p.Arg1300Gln 1 [27] c.4297G>A p.Val1433Ile 1 [17] c.4462T>C p.Cys1488Arg 1 [17] c.4506C>A p.Cys1502X 1 This study* c.4539+1G>T splice site 1 [28] c.4774+1G>A splice site 1 [1] c.5161-5162delAC p.Thr1721fs 1 [27] c.5337C>A p.Tyr1779X 1 This study* c.5461-10T>C unknown 9 [9] c.5537T>C p.Ile1846Thr 1 [13] c.5693G>A p.Arg1898His 1 [1] c.5715+5G>A splice site 2 [28] c.5882G>A p.Gly1961Glu 10 [1] c.6088C>T p.Arg2030X 1 [14] c.6089G>A p.Arg2030Gln 1 [9] c.6238-6239delTC p.Ser2080fs 1 [29] c.6529G>A p.Asp2177Asn 1 [1] New mutations found with DGGE analysis c.303+4A>C splice site 1 c.872C>T p.Pro291Leu 1 c.2906A>G p.Lys969Arg 1 c.2947A>G p.Thr983Ala 1 c.3233G>A p.Gly1078Glu 1 c.3305A>T p.Asp1102Val 1 c.4353+1G>A splice site 1 c.5113C>T p.Arg1705Trp 1 c.5762_5763dup p.Ala1922fs 1 c.6411T>A p.Cys2137X 1 Total 74 Mutations are designated by their nucleotide change, followed by their effect on the protein and the number of alleles that were found with the mutation. Login to comment

[hide] ABCA4 mutations in Portuguese Stargardt patients: ... Mol Vis. 2009;15:584-91. Epub 2009 Mar 25. Maia-Lopes S, Aguirre-Lamban J, Castelo-Branco M, Riveiro-Alvarez R, Ayuso C, Silva ED
ABCA4 mutations in Portuguese Stargardt patients: identification of new mutations and their phenotypic analysis.
Mol Vis. 2009;15:584-91. Epub 2009 Mar 25., [PMID:19365591]

Abstract [show]
PURPOSE: To resolve the spectrum of causative retina-specific ATP-binding cassette transporter gene (ABCA4) gene mutations in Portuguese Stargardt (STGD) patients and compare allele frequencies obtained in this cohort with those of previous population surveys. METHODS: Using a microarray technique (ABCR400 gene chip), we screened all previously reported ABCA4 gene mutations in the genomic DNA of 27 patients from 21 unrelated Stargardt families whose phenotypes had been clinically evaluated using psychophysics and electrophysiological measurements. Furthermore, we performed denaturing high performance liquid chromatography whenever one or both mutant alleles failed to be detected using the ABCR gene chip. RESULTS: A total of 36 mutant alleles (out of the 54 tested) were identified in STGD patients, resulting in a detection rate of 67%. Two mutant alleles were present in 12 out of 21 STGD families (57%), whereas in four out of 21 (19%) of the families, only one mutant allele was found. We report the presence of 22 putative pathogenic alterations, including two sequence changes not found in other populations, c.2T>C (p.Met1Thr) and c.4036_4037delAC (p.Thr1346fs), and two novel disease-associated variants, c.400C>T (p.Gln134X) and c.4720G>T (p.Glu1574X). The great majority of the mutations were missense (72.7%). Seven frameshift variants (19.4%), three nonsense mutations (8.3%), and one splicing sequence change (2.7%) were also found in STGD chromosomes. The most prevalent pathologic variant was the missense mutation p.Leu11Pro. Present in 19% of the families, this mutation represents a quite high prevalence in comparison to other European populations. In addition, 23 polymorphisms were also identified, including four novel intronic sequence variants. CONCLUSIONS: To our knowledge, this study represents the first report of ABCA4 mutations in Portuguese STGD patients and provides further evidence of different mutation frequency across populations. Phenotypic characterization of novel putative mutations was addressed.

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63 [Met1Val]+ [Arg2030Gln], found in 4.8% of the families (for details, see Table 1). Login to comment
64 Most of the mutations detected have been reported as STGD-associated variants: p.Met1Val, p.Asn96Asp, p.Arg290Trp, p.Val931Met, p.Gly1961Glu, p.Leu2027Phe, p.Arg2030Gln, p.Asp1048fs, and IVS40+5G>A. Login to comment
68 Family Patient CFC Onset (age) VA (OD/OS) Nucleotide changes (exons) Effect changes [references] 1 4427 S 7 1/10 / 1/10 c.286A>G(3) / c.4139C>T(28) p.Asn96Asp [30]/p.Pro1380Leu [13] 4413 S 14 1/10 / 0.5/10 c.286A>G(3) / c.4139C>T(28) p.Asn96Asp [30]/p.Pro1380Leu [13] 4454 S 11 1/10 / 1/10 c.286A>G(3) / c. Login to comment
69 4139C>T(28) p.Asn96Asp [30]/p.Pro1380Leu [13] 2 4458 Mi 5 8/10 / 6/10 ND / ND ND/ND 4455 S 8 1/10 / 8/10 ND / ND ND/ND 3 4431 Mo 6 1,6/10 / 1,6/10 c.1804C>T(13) / c.IVS+5G>A(40) p.Arg602Trp [30]/SPLICE [11] 4 4626 S 6 FC / FC c.3211_3212insGT(22) / c.3211_3212insGT(22) p.Asp1048fs [5]/p.Asp1048fs [5] 5 4514 S 12 1/10 / 1/10 c.32T>C(1) / c. Login to comment
67 Family Patient CFC Onset (age) VA (OD/OS) Nucleotide changes (exons) Effect changes [references] 1 4427 S 7 1/10 / 1/10 c.286A>G(3) / c.4139C>T(28) p.Asn96Asp [30]/p.Pro1380Leu [13] 4413 S 14 1/10 / 0.5/10 c.286A>G(3) / c.4139C>T(28) p.Asn96Asp [30]/p.Pro1380Leu [13] 4454 S 11 1/10 / 1/10 c.286A>G(3) / c. Login to comment

[hide] Evidence of widespread retinal dysfunction in pati... Invest Ophthalmol Vis Sci. 2008 Mar;49(3):1191-9. Maia-Lopes S, Silva ED, Silva MF, Reis A, Faria P, Castelo-Branco M
Evidence of widespread retinal dysfunction in patients with stargardt disease and morphologically unaffected carrier relatives.
Invest Ophthalmol Vis Sci. 2008 Mar;49(3):1191-9., [PMID:18326749]

Abstract [show]
PURPOSE: To characterize contrast sensitivity (CS) across the visual field for two achromatic spatial-temporal frequencies in 21 families with Stargardt disease (STGD) and to correlate psychophysical impairment with patterns of change in multifocal electroretinography (mfERG). METHODS: Twenty-seven eyes from patients with STGD, 16 eyes from asymptomatic relatives, and 44 age-matched control eyes were included. Chromatic CS function was assessed by comparing protan, deutan, and tritan (Cambridge Color Test; Cambridge Research Systems Ltd., Rochester, UK) and anomaloscope measures (IF-2; Roland Consult, Wiesbaden, Germany). Achromatic CS measures were obtained with custom-made software in nine locations by using randomly interleaved staircases. The first task-low spatial frequency (LSF)-matched the known frequency-doubling method that is believed to activate the magnocellular pathway preferentially. The second included an intermediate spatial frequency (ISF, 3.5 cyc/deg). mfERGs (RETIscan; Roland Consult) were also obtained. Relatives were screened for ABCA4 mutations by ABCR400 microarray and direct sequencing. RESULTS: Central impairment of achromatic and chromatic CS (along the three isolation axes) was observed in STGD. LSF and ISF tasks revealed significant and widespread dysfunction in patients and their morphologically unaffected relatives, 80% of whom were found to be ABCA4 mutation carriers. Significant reduction of P1 amplitudes was also observed in both groups. CONCLUSIONS: CS function is impaired in patients with STGD at distinct spatial-temporal frequencies, which, in addition to the color vision deficits, suggests dual impairment of the magno- parvocellular pathways. STGD morphologically unaffected carriers may show patterns of psychophysical dysfunction that are mirrored by abnormal mfERG responses.

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150 Several other sequence changes that have been significantly correlated to the STGD phenotype (M1V, N96D, R290W, L2027F, R2030Q, V2050L, 3211insGT, and IVS40ϩ5GϾA) were also identified. Login to comment
134 Several other sequence changes that have been significantly correlated to the STGD phenotype (M1V, N96D, R290W, L2027F, R2030Q, V2050L, 3211insGT, and IVS40af9;5Gb0e;A) were also identified. Login to comment

[hide] The ABCA4 gene in autosomal recessive cone-rod dys... Am J Hum Genet. 2002 Dec;71(6):1480-2. Ducroq D, Rozet JM, Gerber S, Perrault I, Barbet D, Hanein S, Hakiki S, Dufier JL, Munnich A, Hamel C, Kaplan J
The ABCA4 gene in autosomal recessive cone-rod dystrophies.
Am J Hum Genet. 2002 Dec;71(6):1480-2., [PMID:12515255]

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30 Among these 13 patients, 2 were homozygotes (from two consanguineous families), 4 were compound heterozygotes, and 7 were Letters to the Editor 1481 Table 1 ABCA4 Mutations in Patients with CRD Patient ABCA4 ALLELE 1 ABCA4 ALLELE 2 OriginNucleotide Change Effect Nucleotide Change Effect 16 AAC 286 GAC N96D - - France 52 ATC 466 GTC I156V - - North Africa 57 ATC 466 GTC I156V GGG 1819 AGG G607R North Africa 51 CGA 455 CAA 5084ϩ1G/A R152Q Frameshift CGC 3323 TGC AGT 6764 ATT R1108C S2256I France 11 CGT 764 TGT R255C - - France 41 GCC 3113 GTC A1038V - - France 60 CTG 3602 CGG L1201R AGT 6764 ATT S2256I South Africa 21 CTC 5908 TTC L1970F - - France 30 AGT 6764 ATT S2256I - - Africa 48 GAA 3259 TAA E1087X - - France 2 2617 del CT Frameshift 2617 del CT Frameshift Portugal 5 571-2A/G Frameshift 571-2A/G Frameshift Morocco 61 CGG 4918 TGG R1602W GGC 5929 AGC G1977S England single heterozygotes (see table 1). Login to comment
31 Among these 13 patients, 2 were homozygotes (from two consanguineous families), 4 were compound heterozygotes, and 7 were Letters to the Editor 1481 Table 1 ABCA4 Mutations in Patients with CRD Patient ABCA4 ALLELE 1 ABCA4 ALLELE 2 Origin Nucleotide Change Effect Nucleotide Change Effect 16 AAC 286 GAC N96D - - France 52 ATC 466 GTC I156V - - North Africa 57 ATC 466 GTC I156V GGG 1819 AGG G607R North Africa 51 CGA 455 CAA 5084af9;1G/A R152Q Frameshift CGC 3323 TGC AGT 6764 ATT R1108C S2256I France 11 CGT 764 TGT R255C - - France 41 GCC 3113 GTC A1038V - - France 60 CTG 3602 CGG L1201R AGT 6764 ATT S2256I South Africa 21 CTC 5908 TTC L1970F - - France 30 AGT 6764 ATT S2256I - - Africa 48 GAA 3259 TAA E1087X - - France 2 2617 del CT Frameshift 2617 del CT Frameshift Portugal 5 571-2A/G Frameshift 571-2A/G Frameshift Morocco 61 CGG 4918 TGG R1602W GGC 5929 AGC G1977S England single heterozygotes (see table 1). Login to comment

[hide] An analysis of ABCR mutations in British patients ... Invest Ophthalmol Vis Sci. 2000 Jan;41(1):16-9. Papaioannou M, Ocaka L, Bessant D, Lois N, Bird A, Payne A, Bhattacharya S
An analysis of ABCR mutations in British patients with recessive retinal dystrophies.
Invest Ophthalmol Vis Sci. 2000 Jan;41(1):16-9., [PMID:10634594]

Abstract [show]
PURPOSE: Several reports have shown that mutations in the ABCR gene can lead to Stargardt disease (STGD)/fundus flavimaculatus (FFM), autosomal recessive retinitis pigmentosa (arRP), and autosomal recessive cone-rod dystrophy (arCRD). To assess the involvement of ABCR in these retinal dystrophies, the gene was screened in a panel of 70 patients of British origin. METHODS: Fifty-six patients exhibiting the STGD/FFM phenotype, 6 with arRP, and 8 with arCRD, were screened for mutations in the 50 exons of the ABCR gene by heteroduplex analysis and direct sequencing. Microsatellite marker haplotyping was used to determine ancestry. RESULTS: In the 70 patients analyzed, 31 sequence changes were identified, of which 20 were considered to be novel mutations, in a variety of phenotypes. An identical haplotype was associated with the same pair of in-cis alterations in 5 seemingly unrelated patients and their affected siblings with STGD/FFM. Four of the aforementioned patients were found to carry three alterations in the coding sequence of the ABCR gene, with two of them being in-cis. CONCLUSIONS: These results suggest that ABCR is a relatively polymorphic gene. Because putative mutations have been identified thus far only in 25 of 70 patients, of whom only 8 are compound heterozygotes, a large number of mutations have yet to be ascertained. The disease haplotype seen in the 5 patients carrying the same "complex" allele is consistent with the presence of a common ancestor.

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45 Neither of these putative TABLE 1. List of Mutations Found in 70 Patients of British Origin Nucleotide Change Amino Acid Change No. of Patients (/70) Phenotype No. of Controls (/96) G161A Cys-54-Tyr 1 STG/FFM NF A286G Asn-96-Asp 1 STG/FFM NF A286C Asn-96-His 1 STG/FFM NF A466G Ile-156-Val 1 STG/FFM NF C1220T Ala-407-Val 6 STG/FFM, arCRD NF T1271C Val-424-Ala 2 STG/FFM, arRP NF C1335G Ser-445-Arg 1 STG/FFM NF C1804T Arg-602-Trp 1 STG/FFM NF C2337A Cys-779-Ter 1 STG/FFM NF *G2588C Gly-863-Ala 5 STG/FFM 2/176 3392delC 1147 Ter 1 STG/FFM NF T4286C Val-1429-Ala 1 STG/FFM NF 4774-2A3C Splice acceptor 2 STG/FFM NF †C4918T Arg-1640-Trp 1 STG/FFM NF C5107G Gln-1703-Lys 1 STG/FFM NF 5161delAC Frameshift 1 STG/FFM NF C5337G Tyr-1779-Ter 1 STG/FFM NF C6088T Arg-2030-Ter 1 arCRD NF 6282ϩ7G3A Splice donor 1 STG/FFM NF G6449A Cys-2150-Tyr 2 arCRD NF A6479G Lys-2160-Arg 1 STG/FFM NF * Independently reported by Allikmets et al.6 † Independently reported by Rozet et al.8 NF, not found in 96 ethnically matched control individuals. Login to comment

[hide] Quantitative fundus autofluorescence distinguishes... Ophthalmology. 2015 Feb;122(2):345-55. doi: 10.1016/j.ophtha.2014.08.017. Epub 2014 Oct 3. Duncker T, Tsang SH, Lee W, Zernant J, Allikmets R, Delori FC, Sparrow JR
Quantitative fundus autofluorescence distinguishes ABCA4-associated and non-ABCA4-associated bull's-eye maculopathy.
Ophthalmology. 2015 Feb;122(2):345-55. doi: 10.1016/j.ophtha.2014.08.017. Epub 2014 Oct 3., [PMID:25283059]

Abstract [show]
PURPOSE: Quantitative fundus autofluorescence (qAF) and spectral-domain optical coherence tomography (SD OCT) were performed in patients with bull's-eye maculopathy (BEM) to identify phenotypic markers that can aid in the differentiation of ABCA4-associated and non-ABCA4-associated disease. DESIGN: Prospective cross-sectional study at an academic referral center. SUBJECTS: Thirty-seven BEM patients (age range, 8-60 years) were studied. All patients exhibited a localized macular lesion exhibiting a smooth contour and qualitatively normal-appearing surrounding retina without flecks. Control values consisted of previously published data from 277 healthy subjects (374 eyes; age range, 5-60 years) without a family history of retinal dystrophy. METHODS: Autofluorescence (AF) images (30 degrees , 488-nm excitation) were acquired with a confocal scanning laser ophthalmoscope equipped with an internal fluorescent reference to account for variable laser power and detector sensitivity. The grey levels (GLs) from 8 circularly arranged segments positioned at an eccentricity of approximately 7 degrees to 9 degrees in each image were calibrated to the reference (0 GL), magnification, and normative optical media density to yield qAF. In addition, horizontal SD OCT images through the fovea were obtained. All patients were screened for ABCA4 mutations using the ABCR600 microarray, next-generation sequencing, or both. MAIN OUTCOME MEASURES: Quantitative AF, correlations between AF and SD OCT, and genotyping for ABCA4 variants. RESULTS: ABCA4 mutations were identified in 22 patients, who tended to be younger (mean age, 21.9+/-8.3 years) than patients without ABCA4 mutations (mean age, 42.1+/-14.9 years). Whereas phenotypic differences were not obvious on the basis of qualitative fundus AF and SD OCT imaging, with qAF, the 2 groups of patients were clearly distinguishable. In the ABCA4-positive group, 37 of 41 eyes (19 of 22 patients) had qAF8 of more than the 95% confidence interval for age. Conversely, in the ABCA4-negative group, 22 of 26 eyes (13 of 15 patients) had qAF8 within the normal range. CONCLUSIONS: The qAF method can differentiate between ABCA4-associated and non-ABCA4-associated BEM and may guide clinical diagnosis and genetic testing.

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65 Sex Age (yrs) Race or Ethnicity Best-Corrected Visual Acuity (Logarithm of the Minimum Angle of Resolution Units) Genetic Data Average of Quantitative Fundus Autofluorescence Values of the 8 Segments ABCA4 Mutations Right Eye Left Eye Allele 1 Allele 2 Right Eye Left Eye 1 M 36 White 0.70 0.70 p.G1961E p.G1961E 282 279 2 F 46 White 0.40 0.40y p.G1961E p.R1129C 391 3 M 17 Asian Indian 0.70 0.88 p.G1961E c.6729&#fe;4_&#fe;18del 340 363 4 M 17 White 0.88 0.88 p.G1961E p.A1773V 340 366 5 M 21 White 0.88 0.88 p.G1961E p.W15* 341 325 6 F 22 White 0.70 0.48 p.G1961E p.G863A 361 351 7 F 20 White 0.70z 0.88z p.G1961E p.L541P 317 8 M 12 White 0.80 0.70 p.G1961E p.P1380L 251 242 9 F 21 White 0.88 0.88 p.G1961E p.R212C 407 439 10 F 26 White 0.40z 0.70z p.G1961E c.5196&#fe;1056A/G 379 344 11 F 24 White 0.88z 0.88z p.G1961E p.C2150R 405 396 12 F 24 White 0.30z 0.18z p.G1961E p.N96D 513 549 13 F 20 White 0.30 0.40 p.G1961E p.N96D 397 355 14 M 25 White 0.00y 0.30 p.G1961E p.Q1003* 322 328 15 M 8.2 White 0.88 0.88 p. Login to comment

[hide] Structural and genetic assessment of the ABCA4-ass... Invest Ophthalmol Vis Sci. 2014 Oct 9;55(11):7217-26. doi: 10.1167/iovs.14-14674. Noupuu K, Lee W, Zernant J, Tsang SH, Allikmets R
Structural and genetic assessment of the ABCA4-associated optical gap phenotype.
Invest Ophthalmol Vis Sci. 2014 Oct 9;55(11):7217-26. doi: 10.1167/iovs.14-14674., [PMID:25301883]

Abstract [show]
PURPOSE: To investigate the developmental stages and genetic etiology of the optical gap phenotype in recessive Stargardt disease (STGD1). METHODS: Single and longitudinal data points from 15 patients, including four sibling pairs, exhibiting an optical gap phenotype on spectral-domain optical coherence tomography (SD-OCT) with confirmed disease-causing ABCA4 alleles were retrospectively analyzed. Fundus images with corresponding SD-OCT scans were collected with a confocal scanning laser ophthalmoscope. Structural phenotypes were assigned to three developmental stages according to SD-OCT. The ABCA4 gene was screened in all patients. RESULTS: At least two disease-causing ABCA4 variants where identified in each patient; all except one (91%) were compound heterozygous for the p.G1961E mutation. All patients exhibited structural findings on SD-OCT that grouped into three progressive developmental stages over several years. Stage 1 was characterized by mild disruptions of the ellipsoid zone (EZ) band over the fovea. Stage 2 was a progressive expansion of the EZ band loss resulting in an empty lesion devoid of photoreceptors. Stage 3 observed a structural collapse of the inner retinal layers into the optical gap space leading to involvement and atrophy of the RPE thereafter. CONCLUSIONS: The optical gap phenotype in STGD1 can be structurally divided into three progressive stages spanning several years. This particular phenotype also appears to be highly associated with the p.G1961E mutation of ABCA4. Taken together, it appears that a focal loss of photoreceptors sequentially precedes RPE dysfunction in the early development of ABCA4-associated optical gap lesions.

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79 [286A > G];[5882G > A] p.[(N96D)];[(G1961E)] P2, F*ߤ c. Login to comment
80 [286A > G];[5882G > A] p.[(N96D)];[(G1961E)] P3, M* c. Login to comment

[hide] Foveal sparing in Stargardt disease. Invest Ophthalmol Vis Sci. 2014 Oct 16;55(11):7467-78. doi: 10.1167/iovs.13-13825. van Huet RA, Bax NM, Westeneng-Van Haaften SC, Muhamad M, Zonneveld-Vrieling MN, Hoefsloot LH, Cremers FP, Boon CJ, Klevering BJ, Hoyng CB
Foveal sparing in Stargardt disease.
Invest Ophthalmol Vis Sci. 2014 Oct 16;55(11):7467-78. doi: 10.1167/iovs.13-13825., [PMID:25324290]

Abstract [show]
PURPOSE: To provide a clinical and genetic description of a patient cohort with Stargardt disease (STGD1) with identifiable foveal sparing. METHODS: Patients with retinal atrophy (defined as an absence of autofluorescence) that surrounded the fovea by at least 180 degrees and did not include the fovea were defined as having foveal sparing; eyes with visual acuity (VA) worse than 20/200 were excluded. We reviewed the medical files and extracted data regarding medical history, VA, ophthalmoscopy, static perimetry, fundus photography, spectral-domain optical coherence tomography (SD-OCT), fluorescein angiography (FA), fundus autofluorescence (FAF), and electroretinography (ERG). We screened each patient's ABCA4 gene for mutations. RESULTS: Seventeen eyes with foveal sparing were identified in 13 unrelated patients. In 4 eyes, the fovea gradually became atrophic after the initial foveal sparing. The mean age at onset was 51 years (range, 32-67 years). Visual acuity was 20/40 or better in all foveal sparing eyes and was 20/25 or better in 41%. Fundus autofluorescence imaging revealed hyperautofluorescent flecks and parafoveal retinal atrophy; SD-OCT revealed sharply delineated atrophy; and perimetry revealed parafoveal scotomas with intact foveal sensitivity. Finally, genetic screening identified mutations in 19 of the 26 ABCA4 gene alleles. CONCLUSIONS: Foveal sparing occurs mainly in patients with late-onset STGD1 and represents the milder end of the clinical spectrum in STGD1. The anatomy, metabolism, and biochemistry of the retina, as well as genetic variations in genes other than ABCA4, can influence the etiology of foveal sparing. Identifying these fovea-protecting factors will facilitate the future development of strategies designed to treat STGD1.

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114 ABCA4 Mutations in STGD1 Patients With Foveal Sparing Allele 1 Allele 2 References DNA Variant Effect DNA Variant Effect P1 c.5461-10TC Unknown NI NA 35, 36 P2 c.3113CT p.Ala1038Val c.3874CT p.Gln1292* 16, 37, 38, 58 P3 c.5461-10TC Unknown c.5537TC p.Ile1846Thr 23, 35, 39, 58 P4 c.4363TC p.Cys1455Arg NI NA 40 P5 c.1822TA p.Phe608Ile c.4685TC p.Ile1562Thr 23, 40, 41, 59 P6 c.768GT Splice defect c.3113CT p.Ala1038Val 16, 23, 37 P7 c.5196&#fe;1GT Splice defect NI NA 45, 58 P8 c.3874CT p.Gln1292* NI NA 38 P9 c.5461-10TC Unknown NI NA 35, 58 P10 c.1822TA p.Phe608Ile NI NA 23, 41 P11 c.286AG p.Asn96Asp NI NA 43 P12 c.1805GA p.Arg602Gln c.4462TC p.Cys1488Arg 37, 39, 42-44 P13 c.3874CT p.Gln1292* c.1928TG p.Val643Gly 38, 45 NI, not identified; NA, not applicable. Login to comment
151 ABCA4 Mutations in STGD1 Patients With Foveal Sparing Allele 1 Allele 2 References DNA Variant Effect DNA Variant Effect P1 c.5461-10TC Unknown NI NA 35, 36 P2 c.3113CT p.Ala1038Val c.3874CT p.Gln1292* 16, 37, 38, 58 P3 c.5461-10TC Unknown c.5537TC p.Ile1846Thr 23, 35, 39, 58 P4 c.4363TC p.Cys1455Arg NI NA 40 P5 c.1822TA p.Phe608Ile c.4685TC p.Ile1562Thr 23, 40, 41, 59 P6 c.768GT Splice defect c.3113CT p.Ala1038Val 16, 23, 37 P7 c.5196&#fe;1GT Splice defect NI NA 45, 58 P8 c.3874CT p.Gln1292* NI NA 38 P9 c.5461-10TC Unknown NI NA 35, 58 P10 c.1822TA p.Phe608Ile NI NA 23, 41 P11 c.286AG p.Asn96Asp NI NA 43 P12 c.1805GA p.Arg602Gln c.4462TC p.Cys1488Arg 37, 39, 42-44 P13 c.3874CT p.Gln1292* c.1928TG p.Val643Gly 38, 45 NI, not identified; NA, not applicable. Login to comment

[hide] Correlations among near-infrared and short-wavelen... Invest Ophthalmol Vis Sci. 2014 Oct 23;55(12):8134-43. doi: 10.1167/iovs.14-14848. Duncker T, Marsiglia M, Lee W, Zernant J, Tsang SH, Allikmets R, Greenstein VC, Sparrow JR
Correlations among near-infrared and short-wavelength autofluorescence and spectral-domain optical coherence tomography in recessive Stargardt disease.
Invest Ophthalmol Vis Sci. 2014 Oct 23;55(12):8134-43. doi: 10.1167/iovs.14-14848., [PMID:25342616]

Abstract [show]
PURPOSE: Short-wavelength (SW) fundus autofluorescence (AF) is considered to originate from lipofuscin in retinal pigment epithelium (RPE) and near-infrared (NIR) AF from melanin. In patients with recessive Stargardt disease (STGD1), we correlated SW-AF and NIR-AF with structural information obtained by spectral-domain optical coherence tomography (SD-OCT). METHODS: Twenty-four STGD1 patients (45 eyes; age 8 to 61 years) carrying confirmed disease-associated ABCA4 mutations were studied prospectively. Short-wavelength AF, NIR-AF, and SD-OCT images were acquired. RESULTS: Five phenotypes were identified according to features of the central lesion and extent of fundus change. Central zones of reduced NIR-AF were typically larger than areas of diminished SW-AF and reduced NIR-AF usually approximated areas of ellipsoid zone (EZ) loss identified by SD-OCT (group 1; r, 0.93, P < 0.0001). In patients having a central lesion with overlapping parafoveal rings of increased NIR-AF and SW-AF (group 3), the extent of EZ loss was strongly correlated with the inner diameter of the NIR-AF ring (r, 0.89, P < 0.0001) and the eccentricity of the outer border of the NIR-AF ring was greater than that of the SW-AF ring. CONCLUSIONS: Lesion areas were more completely delineated in NIR-AF images than with SW-AF. In most cases, EZ loss was observed only at locations where NIR-AF was reduced or absent, indicating that RPE cell atrophy occurs in advance of photoreceptor cell degeneration. Because SW-AF was often increased within the central area of EZ disruption, degenerating photoreceptor cells may produce lipofuscin at accelerated levels. Consideration is given to mechanisms underlying hyper-NIR-AF in conjunction with increased SW-AF.

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89 [L541P;A1038V] 2 8 42.8 M White Blue 0.9 0.4 c.571-1G>T 1 9 24.6 F White Hazel 0.3 0.2 p.G1961E p.N96D 5 10 21.9 F White Brown 0.3 0.4 p.G1961E p.N96D 5 11 25.3 M White Brown 0.0 0.3 p.G1961E p.Q1003* 3 12 8.5 M White Green n/a (n/a) p. Login to comment

[hide] Early-onset stargardt disease: phenotypic and geno... Ophthalmology. 2015 Feb;122(2):335-44. doi: 10.1016/j.ophtha.2014.08.032. Epub 2014 Oct 17. Lambertus S, van Huet RA, Bax NM, Hoefsloot LH, Cremers FP, Boon CJ, Klevering BJ, Hoyng CB
Early-onset stargardt disease: phenotypic and genotypic characteristics.
Ophthalmology. 2015 Feb;122(2):335-44. doi: 10.1016/j.ophtha.2014.08.032. Epub 2014 Oct 17., [PMID:25444351]

Abstract [show]
OBJECTIVE: To describe the phenotype and genotype of patients with early-onset Stargardt disease. DESIGN: Retrospective cohort study. PARTICIPANTS: Fifty-one Stargardt patients with age at onset </=10 years. METHODS: We reviewed patient medical records for age at onset, medical history, initial symptoms, best-corrected visual acuity (BCVA), ophthalmoscopy, fundus photography, fundus autofluorescence (FAF), fluorescein angiography (FA), spectral-domain optical coherence tomography (SD-OCT), and full-field electroretinography (ffERG). The ABCA4 gene was screened for mutations. MAIN OUTCOME MEASURES: Age at onset, BCVA, fundus appearance, FAF, FA, SD-OCT, ffERG, and presence of ABCA4 mutations. RESULTS: The mean age at onset was 7.2 years (range, 1-10). The median times to develop BCVA of 20/32, 20/80, 20/200, and 20/500 were 3, 5, 12, and 23 years, respectively. Initial ophthalmoscopy in 41 patients revealed either no abnormalities or foveal retinal pigment epithelium (RPE) changes in 10 and 9 patients, respectively; the other 22 patients had foveal atrophy, atrophic RPE lesions, and/or irregular yellow-white fundus flecks. On FA, there was a "dark choroid" in 21 out of 29 patients. In 14 out of 50 patients, foveal atrophy occurred before flecks developed. On FAF, there was centrifugal expansion of disseminated atrophic spots, which progressed to the eventual profound chorioretinal atrophy. Spectral-domain OCT revealed early photoreceptor damage followed by atrophy of the outer retina, RPE, and choroid. On ffERG in 26 patients, 15 had normal amplitudes, and 11 had reduced photopic and/or scotopic amplitudes at their first visit. We found no correlation between ffERG abnormalities and the rate of vision loss. Thirteen out of 25 patients had progressive ffERG abnormalities. Finally, genetic screening of 44 patients revealed >/=2 ABCA4 mutations in 37 patients and single heterozygous mutations in 7. CONCLUSIONS: In early-onset Stargardt, initial ophthalmoscopy can reveal no abnormalities or minor retinal abnormalities. Yellow-white flecks can be preceded by foveal atrophy and may be visible only on FAF. Although ffERG is insufficient for predicting the rate of vision loss, abnormalities can develop. Over time, visual acuity declines rapidly in parallel with progressive retinal degeneration, resulting in profound chorioretinal atrophy. Thus, early-onset Stargardt lies at the severe end of the spectrum of ABCA4-associated retinal phenotypes.

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136 ABCA4 Mutations in Early-Onset Stargardt Patients Mutation Effect Allele References Frequency Percentage c.122G>A p.Trp41* 1 1 35 c.214G>A p.Gly72Arg 1 1 32 c.286A>G p.Asn96Asp 4 5 36 c.443-?_570&#fe;?del p.Arg149fs 1 1 This study c.455G>A p.Arg152Gln 1 1 32, 37 c.656G>C p.Arg219Thr 1 1 38 c.768G>T p.Val256Val/p.? Login to comment

[hide] Quantitative Fundus Autofluorescence and Optical C... Invest Ophthalmol Vis Sci. 2015 Nov 1;56(12):7274-85. doi: 10.1167/iovs.15-17371. Duncker T, Stein GE, Lee W, Tsang SH, Zernant J, Bearelly S, Hood DC, Greenstein VC, Delori FC, Allikmets R, Sparrow JR
Quantitative Fundus Autofluorescence and Optical Coherence Tomography in ABCA4 Carriers.
Invest Ophthalmol Vis Sci. 2015 Nov 1;56(12):7274-85. doi: 10.1167/iovs.15-17371., [PMID:26551331]

Abstract [show]
PURPOSE: To assess whether carriers of ABCA4 mutations have increased RPE lipofuscin levels based on quantitative fundus autofluorescence (qAF) and whether spectral-domain optical coherence tomography (SD-OCT) reveals structural abnormalities in this cohort. METHODS: Seventy-five individuals who are heterozygous for ABCA4 mutations (mean age, 47.3 years; range, 9-82 years) were recruited as family members of affected patients from 46 unrelated families. For comparison, 57 affected family members with biallelic ABCA4 mutations (mean age, 23.4 years; range, 6-67 years) and two noncarrier siblings were also enrolled. Autofluorescence images (30 degrees , 488-nm excitation) were acquired with a confocal scanning laser ophthalmoscope equipped with an internal fluorescent reference. The gray levels (GLs) of each image were calibrated to the reference, zero GL, magnification, and normative optical media density to yield qAF. Horizontal SD-OCT scans through the fovea were obtained and the thicknesses of the outer retinal layers were measured. RESULTS: In 60 of 65 carriers of ABCA4 mutations (age range, 9-60), qAF levels were within normal limits (95% confidence level) observed for healthy noncarrier subjects, while qAF levels of affected family members were significantly increased. Perifoveal fleck-like abnormalities were observed in fundus AF images in four carriers, and corresponding changes were detected in the outer retinal layers in SD-OCT scans. Thicknesses of the outer retinal layers were within the normal range. CONCLUSIONS: With few exceptions, individuals heterozygous for ABCA4 mutations and between the ages of 9 and 60 years do not present with elevated qAF. In a small number of carriers, perifoveal fleck-like changes were visible.

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68 [66G>A;859-9T>C] p.Q2220* CF 1.30 n/a n/a P 11.1 M 15.0 Asian p.R408* c.5935del 1.10 1.30 n/a n/a P 12.1&#a7; M 15.1 White p.L2027F p.R2077W 0.80 0.80 728 697 P 13.1&#a7; F 23.8 White p.R1161S 0.60 0.40 571 647 P 14.1&#a7; F 27.3 White p.P1380L p.P1380L 1.30 1.00 n/a 577 P 15.1 M 17.0 White p.G1961E c.3050&#fe;5G>A 0.88 0.88 n/a n/a P 15.2 F 22.0 White p.G1961E c.3050&#fe;5G>A 0.88 0.88 n/a n/a P 16.1 F 19.1 Black p.V989A c.4253&#fe;5G>T 0.30 0.40 97 n/a P 17.1 F 21.8 Hispanic p.A1038V p.G1441D 0.70 0.88 551 528 P 18.1 M 22.0 Indian c.859-9T>C c.5917del 0.88 0.88 527 n/a P 19.1&#a7; F 27.2 White p.G851D p.L2027F 0.88 0.88 448 459 P 19.2&#a7; F 29.2 White p.G851D p.L2027F 1.30 1.18 538 569 P 19.3 F 34.2 White p.G851D p.L2027F 1.00 1.30 442 n/a P 20.1 F 9.5 White c.5312&#fe;1G>A p.R2030* 0.88 0.70 998 929 P 21.1ߤ F 24.6 White p.N96D p.G1961E 0.30 0.18 513 549 P 21.2ߤ F 20.9 White p.N96D p.G1961E 0.30 0.40 397 355 P 22.1 M 8.0 White p. Login to comment

[hide] Cerebral Involvement in Stargardt's Disease: A VBM... Invest Ophthalmol Vis Sci. 2015 Nov 1;56(12):7388-97. doi: 10.1167/iovs.15-16899. Gaia O, Melillo P, Sirio C, D'Alterio FM, Prinster A, Testa F, Brunetti A, Simonelli F, Quarantelli M
Cerebral Involvement in Stargardt's Disease: A VBM and TBSS Study.
Invest Ophthalmol Vis Sci. 2015 Nov 1;56(12):7388-97. doi: 10.1167/iovs.15-16899., [PMID:26574798]

Abstract [show]
PURPOSE: To assess whether and to what extent macro- and/or microstructural modifications are present in the brain of patients with selective central visual loss due to a juvenile macular degeneration, Stargardt's disease (STGD), taking advantage of the complementary information provided by voxel-based morphometry (VBM) and diffusion tensor imaging (DTI). METHODS: Eighteen patients with clinical and molecular diagnosis of STGD related to ABCA4 mutations and 23 normally sighted volunteers of comparable age and sex were enrolled. Structural T1-weighted (T1w) volumes, for brain tissue volume assessment by segmentation, and DTI, for the investigation of diffusivity parameters via a tract-based spatial statistics (TBSS) procedure, were acquired at 3 Tesla in all subjects. All patients underwent a complete ophthalmologic examination, including best-corrected visual acuity (BCVA), biomicroscopy, ophthalmoscopy, electroretinography (ERG), microperimetry, and optical coherence tomography (OCT). Correlations between imaging data and clinical measures were tested. RESULTS: Stargardt's disease patients showed a significant gray matter (GM) loss bilaterally in the occipital cortices, extending into the right precuneus, and in the fronto-orbital cortices. At TBSS, significant reductions in fractional anisotropy were detected throughout large regions in the supratentorial white matter (WM), more pronounced in the posterior areas. Gray matter volume correlated directly with mean visual sensitivity in the right middle frontal and left calcarine gyri, and inversely with retinal thickness in the left supramarginal gyrus. CONCLUSIONS: In STGD, widespread microstructural WM alterations are present, suggestive of minor fiber loss coupled with GM loss, also in cortical regions not traditionally linked to visual pathways, at least partly related to the retinal damage.

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81 Demographic and Genetic Data of STGD Patients Age Sex ABCR Mutations Age of Onset 19 F 250insCAAA G1961E D498N 4017ins24bp 11 18 M L541P/A1038V IVS40&#fe;5g->a 14 25 M L541P/A1038V G1961E 17 15 F G1961E R2149X 13 48 M N96D IVS40&#fe;5G>A 38 29 M G1961E L1938L L1894L S1689P 25 23 F L541P/A1038V F655C 14 33 M R152Q G1961E 402ins24bp 18 21 M A60V G1961E 15 23 M G690V A1598D 11 27 M G1961E R2149X 11 51 F V615A G1961E 25 54 M N96D N1436I 28 21 M 250insCAAA P402A 13 25 F R1448K c.5018&#fe;2T>C 21 49 M 4538insC IVS40&#fe;5G>A 18 23 F G1961E c.6282&#fe;1G>C 18 46 M N96D N1436I 30 T ABLE 4. Login to comment