Original article
A Longitudinal Study of Stargardt Disease: Clinical and Electrophysiologic Assessment, Progression, and Genotype Correlations

https://doi.org/10.1016/j.ajo.2013.01.018Get rights and content

Purpose

To investigate the clinical and electrophysiologic natural history of Stargardt disease and correlate with the genotype.

Design

Cohort study of 59 patients.

Methods

Clinical history, examination, and electrophysiologic assessment were undertaken in a longitudinal survey. Patients were classified into 3 groups based on electrophysiologic findings, as previously published: Group 1 had dysfunction confined to the macula; Group 2 had macular and generalized cone system dysfunction; and Group 3 had macular and both generalized cone and rod system dysfunction. At baseline, there were 27 patients in Group 1, 17 in Group 2, and 15 in Group 3. Amplitude reduction of >50% in the relevant electroretinogram (ERG) component or a peak time shift of >3 ms for the 30 Hz flicker ERG or bright flash a-wave was considered clinically significant ERG deterioration. Molecular screening of ABCA4 was undertaken.

Results

The mean age at baseline was 31.7 years, with the mean follow-up interval being 10.5 years. A total of 22% of patients from Group 1 showed ERG group transition during follow-up, with 11% progressing to Group 2 and 11% to Group 3. Forty-seven percent of patients in Group 2 progressed to Group 3. There was clinically significant ERG deterioration in 54% of all subjects: 22% of Group 1, 65% of Group 2, and 100% of Group 3. At least 1 disease-causing ABCA4 variant was identified in 47 patients.

Conclusions

All patients with initial rod ERG involvement demonstrated clinically significant electrophysiologic deterioration; only 20% of patients with normal full-field ERGs at baseline showed clinically significant progression. Such data assist counseling by providing more accurate prognostic information and are also highly relevant in the design, patient selection, and monitoring of potential therapeutic interventions.

Section snippets

Patients and Methods

A cohort of 59 patients with a clinical diagnosis of Stargardt disease and a minimum of 7 years of follow-up were ascertained at Moorfields Eye Hospital. All patients were first diagnosed between 1997 and 2000, with the latest examinations performed between 2009 and 2011. The baseline clinical and electrophysiologic characteristics of 33 of these 59 patients have been previously reported.31 The panel included 5 sibships (4 sibling pairs and 1 set of 3 siblings). Informed consent was obtained

Clinical Findings

Fifty-nine patients, 31 female (52%, 31/59) and 28 male (48%, 28/59), were included in the study. All complained of central visual loss with a median age of onset of 20.8 years (range, 5-48 years) and a median duration of disease of 10.9 years (range, 0-31 years). The median ages at baseline and at follow-up were 31.7 and 42.2 years (range, 8-64 and 20-73 years), respectively. The mean follow-up interval was 10.5 years (range, 7-13 years). Seven patients (12%, 7/59) presented before 16 years of

Discussion

This report addresses longitudinal changes in clinical and electrophysiologic features of Stargardt disease in a large, well-characterized cohort of patients, with 1 or both likely disease-causing ABCA4 alleles identified in 80% of subjects (47/59). The findings confirm the prognostic value of ERG suggested by earlier cross-sectional data and are relevant to the design of future clinical trials.

Approximately one-fifth of Group 1 patients (dysfunction confined to the macula) progressed to either

Kaoru Fujinami, MD, is a clinical research fellow in the Departments of Inherited Eye Disease at Moorfields Eye Hospital and Genetics at University College London, Institute of Ophthalmology, United Kingdom. He graduated from Nagoya University and completed ophthalmology clinical training under Professor Miyake at the National Institute of Sensory Organs, Tokyo, Japan. His research interests include clinical electrophysiology and ophthalmic genetics, with his current projects relating to

References (45)

  • T. Jayasundera et al.

    Peripapillary dark choroid ring as a helpful diagnostic sign in advanced stargardt disease

    Am J Ophthalmol

    (2010)
  • A. von Ruckmann et al.

    In vivo fundus autofluorescence in macular dystrophies

    Arch Ophthalmol

    (1997)
  • S. Walia et al.

    Natural history of phenotypic changes in Stargardt macular dystrophy

    Ophthalmic Genet

    (2009)
  • R. Allikmets et al.

    A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy

    Nat Genet

    (1997)
  • R. Allikmets et al.

    Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration

    Science

    (1997)
  • T.R. Burke et al.

    Allelic and phenotypic heterogeneity in ABCA4 mutations

    Ophthalmic Genet

    (2011)
  • F.P. Cremers et al.

    Autosomal recessive retinitis pigmentosa and cone-rod dystrophy caused by splice site mutations in the Stargardt's disease gene ABCR

    Hum Mol Genet

    (1998)
  • G.A. Fishman et al.

    ABCA4 gene sequence variations in patients with autosomal recessive cone-rod dystrophy

    Arch Ophthalmol

    (2003)
  • B.J. Klevering et al.

    The spectrum of retinal phenotypes caused by mutations in the ABCA4 gene

    Graefes Arch Clin Exp Ophthalmol

    (2005)
  • N. Lois et al.

    Intrafamilial variation of phenotype in Stargardt macular dystrophy-Fundus flavimaculatus

    Invest Ophthalmol Vis Sci

    (1999)
  • M. Michaelides et al.

    ABCA4 mutations and discordant ABCA4 alleles in patients and siblings with bull's-eye maculopathy

    Br J Ophthalmol

    (2007)
  • M.A. van Driel et al.

    ABCR unites what ophthalmologists divide(s)

    Ophthalmic Genet

    (1998)
  • Cited by (0)

    Kaoru Fujinami, MD, is a clinical research fellow in the Departments of Inherited Eye Disease at Moorfields Eye Hospital and Genetics at University College London, Institute of Ophthalmology, United Kingdom. He graduated from Nagoya University and completed ophthalmology clinical training under Professor Miyake at the National Institute of Sensory Organs, Tokyo, Japan. His research interests include clinical electrophysiology and ophthalmic genetics, with his current projects relating to genotype-phenotype correlations in inherited retinal disease.

    Supplemental Material available at AJO.com.

    View full text