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Ophthalmology. 2019 Jul 16. pii: S0161-6420(19)30657-8. doi: 10.1016/j.ophtha.2019.07.010. [Epub ahead of print]

Highly Variable Disease Courses in Siblings with Stargardt Disease.

Author information

1
Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
2
Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Radiology, Radboud University Medical Center, Nijmegen, The Netherlands.
3
Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
4
Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: carel.hoyng@radboudumc.nl.

Abstract

PURPOSE:

To investigate intersibling phenotypic concordance in Stargardt disease (STGD1).

DESIGN:

Retrospective cohort study.

PARTICIPANTS:

Siblings with genetically confirmed STGD1 and at least 1 available fundus autofluorescence (FAF) image of both eyes.

METHODS:

We compared age at onset within families. Disease duration was matched to investigate differences in best-corrected visual acuity (BCVA) and compared the survival time for reaching severe visual impairment (<20/200 Snellen or >1.0 logarithm of the minimum angle of resolution [logMAR]). Central retinal atrophy area was quantified independently by 2 experienced graders using semiautomated software and compared between siblings. Both graders performed qualitative assessment of FAF and spectral-domain (SD) OCT images to identify phenotypic differences.

MAIN OUTCOME MEASURES:

Differences in age at onset, disease duration-matched BCVA, time to severe visual impairment development, FAF atrophy area, FAF patterns, and genotypes.

RESULTS:

Substantial differences in age at onset were present in 5 of 17 families, ranging from 13 to 39 years. Median BCVA at baseline was 0.60 logMAR (range, -0.20 to 2.30 logMAR; Snellen equivalent, 20/80 [range, 20/12-hand movements]) in the right eye and 0.50 logMAR (range, -0.20 to 2.30 logMAR; Snellen equivalent, 20/63 [range, 20/12-hand movements]) in the left eye. Disease duration-matched BCVA was investigated in 12 of 17 families, and the median difference was 0.41 logMAR (range, 0.00-1.10 logMAR) for the right eye and 0.41 logMAR (range, 0.00-1.08 logMAR) for the left eye. We observed notable differences in time to severe visual impairment development in 7 families, ranging from 1 to 29 years. Median central retinal atrophy area was 11.38 mm2 in the right eye (range, 1.98-44.78 mm2) and 10.59 mm2 in the left eye (range, 1.61-40.59 mm2) and highly comparable between siblings. Similarly, qualitative FAF and SD OCT phenotypes were highly comparable between siblings.

CONCLUSIONS:

Phenotypic discordance between siblings with STGD1 carrying the same ABCA4 variants is a prevalent phenomenon. Although the FAF phenotypes are highly comparable between siblings, functional outcomes differ substantially. This complicates both sibling-based prognosis and genotype-phenotype correlations and has important implications for patient care and management.

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