Foveal sparing in patients with Stargardt disease OOG/ZOG Hotel Val Monte December 1 st , 2012 Ramon van Huet
Foveal sparing in patients with
Stargardt disease
OOG/ZOG
Hotel Val Monte
December 1st, 2012
Ramon van Huet
Introduction | Foveal sparing
• Macular atrophy that spares the fovea
• Atrophy surrounds the fovea for at least 180
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)
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
Methods | Patients
Database:
316 patients
149 patients who are
genetically analysed
13 STGD1 patients with
foveal sparing
136 patients without foveal
sparing 167 patients
without genetic analyses
Methods | Parameters
History
• Age of onset
• Initial symptom
• Family history
Ophthalmic examinations
• Visual acuity
• Perimetry
Imaging
• Fundus photographs
• Autofluorescence
• OCT scans
Results | Genetics
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 - - -
• 3 patients (23%) carried two mutations
• 10 patients (77%) carried one mutation
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
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
Results | Imaging
Visual acuity 0.8-
Results | Perimetry
Results | Imaging
4.5 year
Visual acuity 0.8- Visual acuity 0.8+
Results | Imaging
Normal
Visual acuity 0.8-
Results | Imaging
Visual acuity 0.1-
Results | Perimetry
Results | Imaging
Visual acuity 0.1-
Results | Imaging
Normal Normal
Visual acuity 0.1-
But what causes this preservation of
the foveal area??
Late-onset Stargardt
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
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?
ABCA4 (Modifier)
Gene X
ABCR
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
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
Acknowledgements
Ophthalmology
Muhamad Muhamad
Carla Westeneng
Jeroen Klevering
Carel Hoyng
Human genetics
Frans Cremers
Anneke den Hollander