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