Phenotypic Variation in a Family With Pseudodominant Stargardt Disease

Importance  Stargardt disease is a phenotypically diverse macular dystrophy caused by the autosomal recessive inheritance of mutations in ABCA4. Pseudodominant transmission occurs more often than might be expected because of the relatively high carrier frequency of pathogenic ABCA4 variants. Genetic characterization of affected individuals permits a more precise understanding of these genotype-phenotype associations.

Observations  In this case series, we explore the clinical courses and genotypes of a woman and her 2 daughters with pseudodominant transmission of Stargardt disease. The mother had choroidal neovascularization that was treated with bevacizumab. Both daughters exhibited worse vision than their mother, despite lacking choroidal neovascularization, because of the extent of photoreceptor and retinal pigment epithelium atrophy in the macula. Genetic testing confirmed pseudodominant inheritance and the presence of 3 ABCA4 alleles within the family.

Conclusions and Relevance  These cases emphasize the clinical relevance of recognizing pseudodominant transmission and the resultant phenotypic variability. Differing degrees of visual impairment in these patients emphasize the need to continue refining our understanding of how individual ABCA4 mutations contribute to phenotype.

Stargardt disease is a macular dystrophy caused by the autosomal recessive inheritance of mutations in ABCA4 (OMIM 601691), which encodes an adenosine triphosphate–binding cassette transporter.¹ In the absence of normal ABCA4 function, photoreceptor metabolism is compromised and A2E, a component of lipofuscin, accumulates in photoreceptors and the retinal pigment epithelium (RPE), causing injury to both. Although considerable phenotypic variability exists, the resulting disease is classically characterized by early-onset central vision loss accompanied by macular lesions and small yellow subretinal flecks scattered throughout the posterior pole. We describe a family with both intrafamilial variation arising from pseudodominant inheritance (in which a disease associated with autosomal recessive transmission appears in 2 successive generations simulating autosomal dominant inheritance) and the rare occurrence of choroidal neovascularization (CNV) in Stargardt disease.

A 51-year-old woman presented to establish care at the University of Iowa but was diagnosed as having Stargardt disease at 26 years of age by an outside ophthalmologist. Her 2 daughters had decreased vision, but her sons were asymptomatic (examined by a local ophthalmologist), and there was no additional contributory family history (Figure 1). Best-corrected visual acuity (VA) was 20/20 OD and 20/25 OS. Ophthalmoscopic examination revealed extensive RPE atrophy with foveal and peripapillary sparing in both eyes (Figure 2A) and corresponding paracentral scotomas apparent on Goldmann perimetry.

Three years later, the patient experienced an acute decrease in vision in the right eye and was diagnosed by an outside physician as having CNV. An intravitreal injection of bevacizumab was administered by her local retina specialist, and she presented to our clinic 1 week later with a VA of 20/125 OD. Fundus examination revealed a parafoveal subretinal hemorrhage (Figure 3A), and optical coherence tomography (OCT) revealed a subfoveal fibrovascular pigment epithelium detachment with associated cystoid edema (Figure 3B). Diffuse atrophy of the parafoveal outer retina was also noted. The patient received 5 additional bevacizumab injections during 7 months. Within a year, her VA returned to 20/20 OD, and the edema improved (Figure 3C).

The patient returned to our clinic at the age of 57 years with a VA of 20/20 OU and mildly worsened RPE atrophy without active CNV (Figure 2B). Goldmann perimetry revealed a dense paracentral scotoma–sparing fixation in the right eye and a centrocecal scotoma–abutting fixation in the left eye (Figure 2C). Reduced-illuminance autofluorescence imaging² revealed extensive hypofluorescence in both eyes with foveal and peripapillary sparing (Figure 2D). Optical coherence tomography revealed fovea-sparing atrophy similar to her previous presentation without subretinal or intraretinal fluid (Figure 2E). Molecular analysis identified 2 previously described ABCA4 variations (IVS42 + 1 G>A and Gly1507Arg GGG>AGG) (Figure 1).^3,4

A daughter of patient 1 was evaluated at the age of 16 years after a subjective decrease in vision. Her VA was 20/125 OD and 20/80 OS. Fundus examination revealed a deeply pigmented fovea with numerous small pisciform flecks throughout the macula and midperiphery in both eyes (Figure 2F). Bilateral central scotomas were present on Goldmann perimetry. At the age of 22 years, the patient’s VA had decreased to 20/160 OU. Increased foveal atrophy was present (Figure 2G) with enlargement of the central scotomas in both eyes on Goldmann perimetry (Figure 2H). Abnormal granular foveal hypofluorescence was present on reduced-illuminance autofluorescence imaging with hypofluorescent and hyperfluorescent flecks scattered throughout the macula and midperiphery in both eyes (Figure 2I). Widespread photoreceptor and RPE atrophy was visualized with OCT (Figure 2J). Genetic testing revealed 2 previously described ABCA4 variations (IVS42 + 1 G>A and Pro1380Leu CCG>CTG) (Figure 1).^3,5 Testing of her father confirmed that he carried the Pro1380Leu variant.

The sister of patient 2 was noted to have retinal changes at the age of 12 years. She was first evaluated in our clinic at the age of 13 years and had a VA of 20/50 OD and 20/125 OS. Her fundus examination findings, which were similar to those of her sister, included increased foveal pigmentation and scattered flecks (Figure 2K) and corresponding central scotomas in both eyes on Goldmann perimetry. At the age of 17 years, the patient’s VA was 20/160 OD and 20/200 OS, with granular-appearing macular lesions (Figure 2L) and enlarged scotomas (Figure 2M). Reduced-illuminance autofluorescence imaging revealed a central region of coarse granular hypofluorescence larger than that present in patient 2 (Figure 2N). Optical coherence tomography revealed diffuse central photoreceptor and RPE loss (Figure 2O). Genetic testing identified the same ABCA4 genotype as that of patient 2 (Figure 1).

Molecular analysis was performed at the Carver Laboratory using previously described methods⁶ after written informed consent was obtained. The University of Iowa Institutional Review Board approved this study.

These cases emphasize important aspects of the inheritance and phenotypic expression of Stargardt disease. First, pseudodominant transmission occurs more often than might be expected for a rare disease and is not infrequently encountered in clinical practice. The frequency with which Stargardt disease appears in 2 successive generations is related to the carrier rate of pathogenic alleles, which have previously been estimated to occur in 5% to 10% of the population.^7,8 This range of frequencies would seem to be at odds with the estimated frequency of Stargardt disease of 1 in 10 000 individuals. The discrepancy may be explained by several characteristics of ABCA4. The unusually large number of benign polymorphisms⁹ in ABCA4 may have resulted in rare and ethnic group–specific variants being incorrectly labeled as pathogenic in early studies.^7,8 Our review of the Exome Variant Server¹⁰ and Exome Aggregation Consortium¹¹ databases reveals 150 variants that we consider to cause disease to have a cumulative frequency of 1.6% in unaffected individuals. The contributions of rare and noncoding variants¹² would make the total carrier frequency even higher than this.

It has been recognized for more than a decade that some disease-causing mutations in ABCA4 are associated with more severe phenotypes than others^6,13 and that some disease-causing mutations will cause clinically detectable disease when paired with a more severe allele but not when paired with a milder allele or with itself.¹³ The absence of the latter cases from the pool of clinically affected individuals may at least in part explain the discrepancy between the cumulative carrier frequency of disease-causing ABCA4 alleles seen in population databases of genetic variants and the observed frequencies of ABCA4-associated retinal disease.

A second point illustrated by these cases is that intrafamilial phenotypic variability is a predictable consequence of the introduction of a third ABCA4 allele into a family by a parent of the pseudodominant individuals. In our cases, patients 2 and 3 exhibited substantially more vision loss than their mother. Indeed, the Pro1380Leu substitution inherited from their father has been associated with age at onset of 6 years.⁵ Minimal clinical data are available for the Gly1507Arg substitution⁴ carried by patient 1 and the shared IVS42 + 1 G>A mutation.³ These variants may be less deleterious, or patient 1 may alternatively possess a genetic or environmental factor that protects the fovea from atrophy.⁶

The excellent VA of patient 1 is particularly notable given her history of CNV, which is a rare complication of Stargardt disease. Previous reports of anti–vascular endothelial growth factor therapy for Stargardt disease–associated CNV, including those from Koh et al¹⁴ and Cohen et al,¹⁵ reveal variable efficacy, but the improvement observed in our case supports its use. Future analysis of additional patients with Stargardt disease and CNV may indicate whether specific ABCA4 variants, such as the Gly1507Arg substitution carried by the mother, or other genetic interactions influence the risk of CNV or the response to treatment.

Due to the relatively high carrier rate of pathogenic ABCA4 alleles, the appearance of genetically confirmed Stargardt disease in successive generations of a family can be encountered in clinical practice. The phenotypic variability resulting from this pseudo-dominant transmission emphasizes the varying pathogenicity of individual disease-causing ABCA4 mutations. Further evaluation of genotype-phenotype relationships and associated genetic modifiers should provide greater insight into factors that modulate the severity of visual impairment in Stargardt disease.

Submitted for Publication: April 8, 2015; final revision received October 27, 2015; accepted November 18, 2015.

Corresponding Author: Elliott H. Sohn, MD, Department of Ophthalmology and Visual Sciences, University of Iowa Carver College of Medicine, 200 Hawkins Dr, Iowa City, IA 52242 (elliott.sohn@gmail.com).

Published Online: March 31, 2016. doi:10.1001/jamaophthalmol.2015.5471.

Author Contributions: Drs Huckfeldt and Sohn had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Huckfeldt, Stone, Sohn.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Huckfeldt, East, Sohn.

Critical revision of the manuscript for important intellectual content: Huckfeldt, Stone, Sohn.

Statistical analysis: East.

Obtained funding: Stone.

Administrative, technical, or material support: All authors.

Study supervision: Stone, Sohn.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Funding/Support: This study was supported in part by grant EY-024605 from the National Institutes of Health. Dr Huckfeldt was supported by the Heed Ophthalmic Foundation.

Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: A full list of contributing research groups to the genomic data for references 10 and 11 can be found at http://evs.gs.washington.edu/EVS/ and http://exac.broadinstitute.org/about. We thank the patient for granting permission to publish this information.