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(Investigative Ophthalmology and Visual Science. 2005;46:4402-4408.)
© 2005 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.05-0504
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Correlation of Clinical and Genetic Findings in Hungarian Patients with Stargardt Disease

Janos Hargitai,1 Jana Zernant,2 Gabor M. Somfai,1 Rita Vamos,1 Agnes Farkas,1 Gyorgy Salacz,1 and Rando Allikmets2,3

1From the 2nd Department of Ophthalmology, Semmelweis University, Budapest, Hungary; and the 2Departments of Ophthalmology and 3Pathology and Cell Biology, Columbia University, New York, New York.


   Abstract
Top
 Abstract
Subjects and Methods
 Results
 Discussion
 References
 
PURPOSE. Autosomal recessive Stargardt disease (arSTGD) presents with substantial clinical and genetic heterogeneity. This study was conducted to correlate foveolar thickness (FT) and total macular volume (TMV), measured by optical coherence tomography (OCT), with other clinical characteristics and with specific genetic variation in Hungarian patients with arSTGD.

METHODS. After a standard ophthalmic workup, both eyes of 35 patients with STGD from Hungary and of 25 age-matched healthy control subjects were tested with OCT. FT and TMV were measured automatically with the OCT mapping software in the nine Early Treatment Diabetic Retinopathy Study areas of 3500 µm in diameter. All patients were screened for mutations by a combination of the ABCR400 microarray and direct sequencing.

RESULTS. The patients with STGD presented with markedly thinned retina in the foveola and decreased macular volume, 72 µm and 1.69 mm3, respectively, compared with 169 µm and 2.48 mm3 in the normal subjects, respectively. Statistically significant correlation was observed between visual acuity (VA) and TMV and between VA and FT. Disease-associated mutations were detected in 23 (65.7%) of 35 patients, including 48.5% with both alleles and 17.2% with one allele. The most frequent ABCA4 alleles in Hungarian patients with STGD were L541P/A1038V (in 28% of all patients), G1961E (20%) and IVS40+5G->A (17%). Specific genotypes correlated with some phenotypic features and allowed for predictions of the disease progression.

CONCLUSIONS. Hungarian patients with STGD presented with extensive foveolar thinning and macular volume loss. Genetic analysis detected several ABCA4 alleles at high frequency in the cohort of patients, suggesting founder effect(s). Unusually homogeneous distribution of disease-associated mutations aided genotype–phenotype correlation analyses in this population.

Stargardt macular dystrophy (STGD), the most common juvenile-onset, inherited macular disorder, was first described by Karl Stargardt in 1909.1 2 The disease is characterized by a severe reduction of central vision, often occurring before the age of 20 years. At the end-stage of the disease, the distance visual acuity (VA) is stabilized at approximately 20/200.3 Near vision is even more markedly reduced, but is not accompanied by the loss of color vision in all cases. Loss of photopic function is dominant; however, delayed dark adaptation has been described in some cases. The fundus photograph is characterized by "beaten bronze" or "snail slime" macular lesions and yellowish-white flecks around the macula and/or throughout the posterior pole.

STGD (also designated as arSTGD or STGD1) is inherited as an autosomal recessive trait caused by mutations in the ABCA4 gene, located on human chromosome 1, region p13-p21.4 5 The ABCA4 gene encodes a transmembrane protein belonging to the adenosine triphosphate (ATP)-binding cassette (ABC) transporter superfamily, which plays a major role in the ATP-dependent membrane transport in both rod and cone photoreceptors. Most of the protein is localized to the photoreceptor outer segment disc rims, where it is suggested to clear all-trans retinal phosphatidylethanolamine (RAL-PE) conjugates from the disc membranes.6 7 8 9 This hypothesis is supported by the fact that lipofuscin accumulation, consisting mainly of the adduct of two RAL-PE molecules, A2E, is detected as the earliest sign of the disease in patients with STGD and also in the Abca4 knockout mouse model.10 11 12

The genetic heterogeneity underlying STGD is exceptionally high, complicating genotype–phenotype correlation studies designed to facilitate precise molecular and clinical diagnosis of patients with STGD. Mutational analyses of patients with STGD, consisting of screening of the ABCA4 gene by various methods, reveal an average mutation detection rate between 30% and 70% across various studies, whereas the total number of potentially disease-associated variants is reaching 500.13 14 15 16 17 18

Progressively more is known about the pathologic course of STGD; however, the prognosis, including the pace of visual loss, is still unpredictable in most cases. At early stages of the disease, the reduction of VA is not concomitant with the severity of the fundus lesion.19 20 21 Therefore, a quantitative method that correlates the fundus status with exact functional values would be useful in determining the disease prognosis. To date, the clinical diagnosis has usually been established by biomicroscopy, fluorescein angiography (FA), and multifocal electroretinography (mfERG). None of these methods can examine and determine morphologic changes of the retina, to observe and to quantify the photoreceptor degeneration. Optical coherence tomography (OCT) was first described by Hee and Puliafito as a method that is capable of examining the retinal layers with micrometer-scale resolution.22 23 24

One way to overcome this complexity is to define precise, quantifiable phenotypic features that can be correlated to disease-associated genotypes in large, ethnically homogeneous patient cohorts.25 In this study, we sought to correlate the clinical data, such as foveolar thickness (FT) and total macular volume (TMV) measured by OCT, with the genetic data acquired by the ABCR400 microarray screening and direct sequencing, in patients with STGD from Hungary.


   Subjects and Methods
Top
 Abstract
 Subjects and Methods
Results
 Discussion
 References
 
Study Subjects
We examined 70 eyes of 35 patients with diagnosed STGD (ages, 15–55; mean age, 28.3 ± 7.6 years) and 50 eyes of 25 age-matched healthy individuals of Hungarian origin (ages, 14–51 years; mean age, 27.6 ± 8.7 years), ascertained at the 2nd Department of Ophthalmology, Semmelweis University, Budapest, Hungary. All research procedures were performed in accordance with institutional guidelines and the Declaration of Helsinki. Informed consent was obtained from all study subjects after the nature of the procedures was fully explained. Inclusion and exclusion criteria for patients with STGD were as described previously.5 13 The control group was free of any ocular disease.

The disease group consisted of 19 females and 16 males, the control group of 13 females and 12 males. Demographics, age of onset, and duration of the disease were recorded for all study subjects. The age of onset was defined as either the patient’s age at which visual loss was first noted or the age documented in an ophthalmic record of the first diagnosis. The duration of the disease was defined as the difference between the age at the time of the examination and the age of onset of initial symptoms. In all cases, a general ophthalmic examination was performed, including documentation of the best corrected visual acuity (BCVA) using a standard Snellen chart and a slit lamp biomicroscope. In addition, fundus photographs were obtained (by JH) and OCT (model 2000; Carl Zeiss Meditec, Jena, Germany) was performed on all study subjects in a masked fashion (by GMS). Six 6-mm long radial scans, manually centered on the fovea, were obtained in all eyes. FT and TMV were measured automatically using the mapping software of OCT (ver. A-2) in areas 3500 µm in diameter. To eliminate false scans resulting from eye movements caused by altered fixation due to bad VA, all scans were positioned manually.

For genotype–phenotype correlation studies, patients were classified in the subgroups according to Fishman et al.25 as follows. Phenotype I included patients with a small atrophic-appearing foveal lesion with mild pigment mottling and localized perifoveal yellowish-white flecks; phenotype II was defined by numerous yellowish-white fundus lesions throughout the posterior pole; and phenotype III included subjects with extensive atrophic-appearing RPE changes. Linear regression analysis was performed to examine the correlation between BCVA and TMV/FT. Statistical analyses were performed on computer (Statistica 6.0 software; Statsoft Inc., Tulsa, OK), and P < 0.05 was considered a statistically significant difference.

Molecular Analysis
All patients were screened for genetic variation in the ABCA4 gene with the ABCR400 microarray,26 which includes all currently known (>450) disease-associated variants, followed by validation by direct sequencing. The ABCA4 genotyping microarray enables simultaneous detection of all known ABCA4 variants in one reaction. The array utilizes the arrayed primer extension (APEX) technology and is constructed by synthesis and application of sequence-specific oligonucleotides for every known ABCA4 allele. For template preparation, all exons of the ABCA4 gene were PCR amplified, as described previously.27 In the amplification mixture, 20% of the dTTP was replaced with dUTP.27 The amplification products were concentrated and purified with a PCR kit (MIPSpin PCR kit; Genotein, Inc., Seoul, Korea). Fragmentation of amplification products was achieved by adding thermolabile uracil N-glycosylase (Epicentre Biotechnologies, Madison, WI) and the following heat treatment.27 For the APEX-based genotyping, one third of every amplification product was used in the primer extension reaction on the ABCR400 microarray. Each APEX reaction consisted of a fragmented and denatured PCR product, 4 units of DNA polymerase (ThermoSequenase; GE Healthcare, Amersham, UK), 1x reaction buffer, and a 1.4-µM final concentration of each fluorescently labeled ddNTP: Texas red-ddATP, fluorescein-ddGTP (GE Healthcare), Cy3-ddCTP, and Cy5-ddUTP (NEN, Boston, MA). The reaction mixture was applied to the ABCR400 microarray slide for 15 minutes at 58°C, and the reaction was stopped by washing the slide at 95°C in distilled water28 (Milli-Q; Millipore, Bedford, MA). The slides were imaged (Genorama QuattroImager; Asper Biotech, Ltd., Tartu, Estonia), and the ABCA4 sequence variants were identified by the accompanying software28 (Genorama Genotyping Software; Asper Biotech, Ltd.). Array-identified variants were confirmed by direct sequencing with a dye-termination cycle sequencing kit (Taq Dyedeoxy Terminator Cycle Sequencing; Applied Biosystems, Foster City, CA), according to the manufacturer’s instructions. Sequencing reactions were resolved on an automated sequencer (model 377; Applied Biosystems, Inc.). Segregation analysis was performed in all families, to determine the phase for all mutations.


   Results
Top
 Abstract
 Subjects and Methods
 Results
Discussion
 References
 
The summary of clinical and genetic findings is presented in Table 1 . The mean VA was 20/100 (ranging from 20/1000 to 20/20) in the STGD group and 20/20 in the control group. No significant pathology of the anterior segment was detected in any of the study subjects. Fundus examination classified three patients as phenotype I, 21 as phenotype II, and 11 as phenotype III, according to Fishman et al.25 Consistent with the earlier studies, patients in the phenotype III group showed the most markedly reduced VA.


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  		TABLE 1. Summarized Clinical and Genetic Data of Patients with STGD

 
Patients with STGD presented with a markedly thinned retina in the foveola (mean ± SE, 71.78 ± 32.85 µm), compared with healthy control subjects (mean ± SE, 161.26 ± 15.90 µm; P < 0.001). The macular volume was also significantly decreased in patients with STGD compared with control subjects (mean ± SE, 1.69 ± 0.32 mm3 vs. 2.45 ± 0.13 mm3; P < 0.001, respectively; Table 1 ). Figure 1 shows the OCT result of a 25-year-old healthy individual with no pathologic signs in the retina or in the retinal pigment epithelium. FT was 168 µm, whereas TMV measured 2.66 mm3. For comparison, the macula of a 25-year-old female patient with Stargardt is shown in Figure 2 . Her BCVA was 20/35 in the presented eye, with an 8-µm FT and 1.94 mm3 TMV. Figure 3 shows the macula of a 28-year-old male patient with a BCVA of 25/100, FT of 49 µm, and TMV of 1.83 mm3. Finally, Figure 4 presents the macula of a 15-year-old male patient. In this eye, the BCVA were 20/200, FT was 38 µm, and TMV was 1.3 mm3. Multiple regression analysis determined a significant correlation between BCVA and both FT and TMV in our patients with Stargardt macular dystrophy (P < 0.05; Figs. 5 6 ). In addition, in this study we found significant correlation between the duration of the disease and BCVA (P = 0.0019), however, the onset of STGD did not correlate with the BCVA in this cohort (P = 0.884).



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  		FIGURE 1. Optical coherence tomography (OCT) image of a 25-year-old healthy control subject.

 


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  		FIGURE 2. OCT image of a 25-year-old patient with STGD (21).

 


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  		FIGURE 3. OCT image of a 28-year-old patient with STGD (18).

 


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  		FIGURE 4. OCT image of a 15-year-old patient with STGD (28).

 


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  		FIGURE 5. Correlation between BCVA and FT in the entire STGD group.

 


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  		FIGURE 6. Correlation between BCVA and TMV in the entire STGD group.

 
Genetic variation, defined as disease-associated mutations, was detected in 23 (65.7%) of 35 patients, including 48.5% of patients with both alleles and 17% with one allele (Table 1) . The most frequent ABCA4 allele in the Hungarian STGD population was the complex allele L541P/A1038V at 14.3% (i.e., 28% of all screened patients carried at least one allele). Other frequent alleles included the G1961E mutation (10%), the IVS40+5G->A splice site variant (8.6%) and the 5917delG nonsense allele at 7%. Several unrelated STGD subjects were compound heterozygous for the IVS40+5G->A and 5917delG variants. Most of these patients originated from the Hungarian Romany population. This, and the high frequency of specific ABCA4 alleles in the cohort of Hungarian patients with STGD, suggests founder effect(s).

All five patients with a homozygous or a compound heterozygous IVS40+5G->A allele belonged to the phenotype III group (Table 1) . They presented with severe macular changes and significantly decreased VA compared with the average in STGD group (0.12–0.21, respectively). This observation is not fully supported by some earlier studies; however, those studies incorporated other morphologic and functional values (e.g., autofluorescence, ERG) when making genotype–phenotype correlation.20 21 Rivera et al.15 suggested a residual ABCA4 activity for the IVS40+5G->A allele. However, when coupled with a deleterious variant such as the 5917delG mutation, it seems to result in a more severe phenotype.21

Patients with the L541P/A1038V complex allele were classified as phenotype II in 70% (7/10) of cases, the rest (3/10) as belonging to the phenotype III group (Table 1) . The higher frequency of the milder phenotype in this group is probably associated with a severely reduced but not abolished ATPase activity.8 In cases classified as phenotype III (patients 2, 18, 25), we were unable to relate this difference to a compound mutation, to the age of onset or to the duration of the disease. Of the 10 patients, BCVA, FT, and TMV were more severely reduced in the phenotype III group than in the phenotype II group. In patients compound heterozygous for the L541P/A1038V and G863A alleles (patients 11, 21, 32), a decrease in vision with the duration of the disease was observed.

Subjects compound heterozygous for the G1961E mutation (n = 7) were classified into phenotype groups II and III based on their fundus appearance. This result does not agree with previous studies20 25 in which patients with the G1961E allele mainly presented with the Fishman I fundi. A possible explanation for this disagreement is that, in the present study, these subjects were clinically evaluated at a more advanced age (second and third decade) and at a substantially longer duration of the disease. Other possible reasons include different genetic background and variation in the second allele.


   Discussion
Top
 Abstract
 Subjects and Methods
 Results
 Discussion
References
 
We compared the BCVA, a functional measure, with two morphologic features of the retina (FT and TMV) in Hungarian patients with STGD. In all STGD cases, a severe reduction of VA was observed in relation with the duration of the disease. FT and TMV were decreased in all patients with STGD compared with healthy individuals. According to our results, fundus disease in STGD is accompanied by foveolar thinning and a marked reduction of the macular volume. These results correlate well with those from other studies (Sodi AC, et al. IOVS 2003;44:ARVO E-Abstract 526).29 30 We found a linear correlation between BCVA and FT, and BCVA and TMV. Degeneration of the foveal (and the foveolar) photoreceptors, where the density of cones is the highest in the retina, explains the loss of detailed vision. As the destructive process involves more and more of the fovea, the point of fixation shifts to the periphery, where the retinal structure, the decrease of cone density, will not support detailed vision. The detected decrease of the TMV is caused by the thinning of all retinal layers according to the OCT measurements. We hypothesize that the decrease in BCVA is associated with the increasing cone loss as determined by the decreased macular volume. However, in some cases, patients with the same TMV showed different VAs. To explain this phenomenon, we suggest the following hypotheses: (1) In cases of equal macular volume, the VA is worse if the central fovea is more affected, and (2) the volume measurement includes nonfunctioning, but still morphologically present, photoreceptor cells. In some cases of extensive atrophy, we detected a better VA than in patients with mild pigmentary changes of the retina. This finding could be explained as follows. In the severe, early-onset cases of the disease the eccentric fixation can be obtained easier because of the enhanced (retained) plasticity of the central visual pathways; whereas in cases of later onset, the plasticity of the central nervous system is substantially reduced.

The retinal degeneration observed in STGD is caused by the accumulation of lipofuscin (A2E) in the retinal pigment epithelium, resulting in RPE death followed by the degeneration of the photoreceptor layer. These disorders lead to the atrophic macula in the end stage of the disease, which is accompanied by a severe reduction in VA. Patients with phenotype III showed worse VA than subjects in phenotype groups I and II. Our observation supports the hypothesis that VA is reduced with time during the disease progression.

Correlation of some phenotypic features (e.g., the loss of TMV and the duration of the disease; Supplementary Figures, http://www.iovs.org/cgi/content/full/46/12/4402/DC1) with specific genotypes resulted in the following conclusions.

First, patients with the G1961E mutation, although classified in phenotype groups II and III, show the slowest progression of the TMV loss. Therefore, patients with STGD with the G1961E variant have, in general, a better than average disease prognosis. This observation is supported by two earlier reports20 25 and could be explained by the fact that although the G1961E variant had a drastic effect on ATPase activity, it was comparable to the wild-type protein in yield.8

Second, patients with the L541P/A1038V complex allele have, near the average in all patients with STGD, a moderate rate of disease progression. In in vitro studies, the L541P/A1038V variant demonstrated a reduced, but not completely abolished, ATPase activity.20 The subgroup of patients, compound heterozygous for the L541P/A1038V and G863A alleles, show a better prognosis (i.e., a slower progression of the disease). This conclusion is also supported by other studies.8 13

Third, patients heterozygous for the IVS40+5G->A allele progress faster than the average STGD group, although this variant has been shown not to alter the splicing completely and, therefore, should result in a partially functional ABCA4 protein.15 21 Our findings are not fully supported by previous studies that estimated the disease progression rate by other criteria (e.g., fundus autofluorescence, ERG).20 21 The rapid loss of macular volume in patients with STGD included in this study (consisting mainly of persons of the Hungarian Romany population) may be, in addition, associated with the relatively frequent IVS40+5G->A and 5917delC compound heterozygosity and/or other yet unknown genetic factors.

Fourth and finally, carriers of the 5917delC protein-truncating variant have the worst prognosis. Because this variant results in a frameshift and consequently in a nonfunctional protein, it also explains why patients homozygous for this mutation have a worse prognosis than those compound heterozygous with another allele.

Particularly interesting is the observation of no disease-associated variants in patients belonging to the Fishman I group. Although the number of analyzed cases is certainly small (n = 3), this observation correlates with previous data from both our laboratory (Allikmets R, unpublished observation, 2005) and from others,20 25 in that the screening of patients with STGD with late-onset and/or a slow-progressing phenotype results in less than the average of identified disease-associated alleles. Excluding misdiagnosis (phenocopies) and considering the fact that no other gene has been linked to arSTGD, this phenomenon may be due to yet unknown mutations outside of the coding regions of the ABCA4 gene.

In conclusion, we suggest that a careful and thorough workup of patients with STGD, both clinically and genetically, would help in defining factors that would predict the prognosis of the disease. However, even in a population with unusually homogeneous distribution of disease-associated mutations (e.g., Hungarian, as presented in this study), the size of the examined cohort would greatly influence any genotype–phenotype correlation analyses. Therefore, establishing uniform standards for clinical evaluation and genetic screening would allow direct comparison or even a combination of studies from different centers, which would directly benefit patients by substantially advancing our knowledge of STGD’s etiology.


   Acknowledgements
 
The authors thank the study subjects and their families for their willing and continued cooperation in these investigations, Zsuzsa Pámer for assistance with the clinical evaluation of patients, and Jószef Gyory, Zsolt Öri, and János Nemes for expert technical assistance.


   Footnotes
 
Supported in part by National Eye Institute EY13435 (RA), Foundation Fighting Blindness (RA), and Research to Prevent Blindness (RA).

Submitted for publication April 24, 2005; revised July 31 and September 8, 2005; accepted October 19, 2005.

Disclosure: J. Hargitai, None; J. Zernant, None; G.M. Somfai, None; R. Vamos, None; A. Farkas, None; G. Salacz, None; R. Allikmets, None

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Corresponding author: Rando Allikmets, Department of Ophthalmology, Columbia University, Eye Institute Research, Rm. 715, 630 West 168th Street, New York, NY 10032; rla22{at}columbia.edu.


   References
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 Abstract
 Subjects and Methods
 Results
 Discussion
 References
 

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