1. Foveal sparing in patients with
Stargardt disease
Ramon van Huet
OOG/ZOG
Hotel Val Monte
December 1st, 2012

2. Introduction | Foveal sparing
• Macular atrophy that spares the fovea
• Atrophy surrounds the fovea for at least 180

3. Introduction | Foveal sparing in Stargardt patients
Foveal sparing is observed in:
• Stargardt disease
• Maternally Inherited Diabetes & Deafness (MIDD)
• Age-related macular degeneration (AMD)
• Some PRPH2 (RDS) related diseases (e.g.
pseudostargardt phenotype)

4. Introduction | Purpose
• To give a clinical description of foveal sparing in
Stargardt patients
• Provide some possible pathogenic pathways
• Knowledge about the origin of the foveal sparing may be
beneficial for the development of new therapeutic
options

5. Methods | Patients
13 STGD1
patients with
149 patients foveal sparing
who are
genetically
Database: analysed 136 patients
without foveal
316 patients sparing
167 patients
without genetic
analyses

6. Methods | Parameters
History
• Age of onset
• Initial symptom
• Family history
Ophthalmic examinations
• Visual acuity
• Perimetry
Imaging
• Fundus photographs
• Autofluorescence
• OCT scans

7. Results | Genetics
• 3 patients (23%) carried two mutations
• 10 patients (77%) carried one mutation
Mutation 1 (DNA) Mutation 1(Peptide) Mutation 2 (DNA) Mutation 2(Peptide)
Patient 10 c.5461-10T>C - - -
Patient 14 c.3113C>T p.Ala1038Val c.3874C>T p.Gln1292X
Patient 17 c.5461-10T>C - - -
Patient 24 c.4363T>C p.Cys1455Arg - -
Patient 26 c.1822T>A p.Phe608Ile - -
Patient 55 c.768G>T p.Val256Val c.3113C>T p.Ala1038Val
Patient 84 c.768G>T p.Val256Val - -
Patient 96 c.3874C>T p.Gln1292X - -
Patient 102 c.4771G>A p.Gly1591Arg - -
Patient 117 c.5461-10T>C - - -
Patient 118 c.2588G>C p.Gly863Ala - -
Patient 244 c.3874C>T p.Gln1292X c.1928T>G p.Val643Gly
Patient 311 c.5196+1G>T - - -

8. Results | History
Age of onset
• Mean onset: 51,8 years (range: 39 - 81 years)
Symptoms
• Initial symptom:
 Progressive visual acuity loss (92%)
 Metamorphopsia (8%)
Family history
• 54% affected family members

9. Results | Ophthalmic examination
Leeftijd
BCVA ≤ 0.8 59.7
BCVA ≤ 0.4 74.6
BCVA ≤ 0.1 78.6
BCVA ≤ 1/60 80.7
BCVA = Best corrected visual acuity

10. Results | Imaging
Visual acuity 0.8-

11. Results | Perimetry

12. Results | Imaging
4.5 year
Visual acuity 0.8+ Visual acuity 0.8-

13. Results | Imaging
Normal
Visual acuity 0.8-

14. Results | Imaging
Visual acuity 0.1-

15. Results | Perimetry

16. Results | Imaging
Visual acuity 0.1-

17. Results | Imaging
Normal
Visual acuity 0.1-

18. But what causes this preservation of
the foveal area??

19. Discussion | Possible causes of foveal sparing
Late-onset Stargardt is on the mild side of the spectrum of
retinal dystrophies caused by mutations in ABCA4
Fovea spared because of:
• Only one ABCA4 mutation
• Mild mutations in ABCA4
Late-onset Stargardt

20. Discussion | Possible causes of foveal sparing
Influence of other genes:
• Protective variants in modifier genes
• Digenic phenotype
On which cells/structures do these additional genes act?
RPE? Photoreceptors? Müller cells? The ABCA4 gene? The
ABCR channel?
(Modifier)
ABCA4
Gene X
ABCR

21. Discussion | Possible causes of foveal sparing
• Inhomogeneity in distribution of spectrally different cones
Sparing of L- and M- cones which are more centrally
located1
• Inhomogeneity in distribution of RPE cells
 In the macula, RPE cells are thicker and narrowly
spaced.1
1. D. Besch et al, Vision research 43 (2003) p. 3095-3108

22. Discussion | Possible causes of foveal sparing
• Inhomogeneity in distribution of the Müller cells
Differences in Müller cell density in fovea and
periphery1
Various types of Müller cells2
1. Chao et al, (1997) Journal of Neurocytology 26(7), p.439-454
2. Schnitzer et al (1987) Cell Tissue Research 248(1), 55-61

23. Acknowledgements
Ophthalmology
Muhamad Muhamad
Carla Westeneng
Jeroen Klevering
Carel Hoyng
Human genetics
Frans Cremers
Anneke den Hollander