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A Retrospective Natural History Study

Di Iorio, Valentina PhD, MD*; Orrico, Ada MD*; Esposito, Gabriella PhD; Melillo, Paolo PhD*; Rossi, Settimio MD*; Sbordone, Sandro MD*; Auricchio, Alberto MD‡,§; Testa, Francesco PhD, MD*; Simonelli, Francesca MD*

doi: 10.1097/IAE.0000000000002151
Original Study

Purpose: To investigate the natural history of Stargardt disease over a multiyear follow-up.

Methods: We reviewed medical records of Stargardt disease patients, with clinical diagnosis of Stargardt disease at a single institution, which was also supported by molecular diagnosis. All patients underwent best-corrected visual acuity, fundus photography, optical coherence tomography, and full-field electroretinography.

Results: The study cohort consisted of 157 Stargardt disease patients aged 30.4 ± 1.1 years. Longitudinal analysis (mean follow-up: 3 years) showed a significant worsening of best-corrected visual acuity at an average rate of 1.5 Early Treatment Diabetic Retinopathy Study letters/year (P < 0.001), an enlargement of retinal pigment epithelium lesion area by optical coherence tomography at an average linear rate of 0.10 mm2/year (P < 0.001), and a thinning of central macular thickness at a mean rate of −1.42 μm/year (P < 0.001). Survival analysis showed that patients with 2 alleles harboring likely-null variants, on average, reached most severe disease stage, i.e., legal blindness, alteration in both dark-adapted and light-adapted electroretinographic responses, and retinal pigment epithelium lesion area larger than 2.5 mm2 significantly earlier than patients with at least one allele harboring a missense variant.

Conclusion: The current longitudinal study showed a significant genotype–phenotype correlation characterization, because patients harboring 2 likely-null alleles reach a severe disease stage about 10 years earlier than patients with at least one missense allele.

The current longitudinal study investigates natural history of Stargardt disease in a large Italian cohort in relationship with the genotype, showing a faster progression of visual function loss and of retinal atrophy in patients that harbor two likely null mutations.

*Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania Luigi Vanvitelli, Naples, Italy;

Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy and CEINGE - Advanced Biotechnologies, Naples, Italy;

Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy; and

§Medical Genetics, Department of Advanced Biomedicine, University of Naples Federico II, Naples, Italy.

Reprint requests: Paolo Melillo, PhD, Via S. Pansini, 5, Naples 80131, Italy; e-mail:

Supported by Fondazione Telethon.

P. Melillo has been consultant of Sanofi and of Shire. F. Testa has been consultant of Sanofi and of Shire. F. Simonelli has been consultant of Sanofi and of Spark Therapeutics. The remaining authors have no any financial/conflicting interests to disclose.

V. Di Iorio and A. Orrico contributed equally to the current study.

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© 2019 by Ophthalmic Communications Society, Inc.