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Brief Report |

Phenotypic Variation in a Family With Pseudodominant Stargardt Disease

Rachel M. Huckfeldt, MD, PhD1,2; Jade S. East, MS1,2; Edwin M. Stone, MD, PhD1,3; Elliott H. Sohn, MD1,2
[+] Author Affiliations
1Stephen A. Wynn Institute for Vision Research, Iowa City, Iowa
2Department of Ophthalmology and Visual Sciences, University of Iowa Carver College of Medicine, Iowa City
3Howard Hughes Medical Institute, Iowa City, Iowa
JAMA Ophthalmol. 2016;134(5):580-583. doi:10.1001/jamaophthalmol.2015.5471.
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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.

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Figure 1.
Pedigree With Genetic Results

Filled circles indicate clinical diagnosis of Stargardt disease. ABCA4 sequence changes are indicated adjacent to family members who had genetic testing performed. Numbers in the circles correspond to patient cases.

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Figure 2.
Clinical Progression and Manifestations of Stargardt Disease in 3 Members of a Family

Color fundus photographs from 2 examinations (A and B, F and G, K and L) are compared with Goldmann perimetry (C, H, M), reduced-illuminance autofluorescence imaging (D, I, N), and optical coherence tomography (E, J, O) at the follow-up examination.

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Figure 3.
Choroidal Neovascularization in Patient 1 With Stargardt Disease

A small subretinal hemorrhage was present (A; black arrowhead) and associated with a fibrovascular pigment epithelium detachment on optical coherence tomography (B; asterisk) and overlying cystoid macular edema (B; white arrowhead). Edema was resolved after 7 bevacizumab injections (C). Dashed line indicates position of optical coherence tomographic image (A).

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