Monitoring and Management of the Patient with Stargardt Disease

Figures & data

Figure 1 Multimodal imaging of a patient with STGD1 and macular involvement. Color fundus photograph (A), near-infrared-autofluorescence (B) and short wavelength fundus autofluorescence (C). Absence of RPE is visible as an area of irregular hyopoautofluorescence on fundus autofluorescence. Several hyperautofluorescence lesions at the macula correspond to the flecks. The OCT scan (D) centered on the fovea shows atrophy of RPE and ellipsoid zone and backscattering.

Figure 2 Ultra-widefield fundus photograph and autofluorescence of an advanced form of STGD1. The area of RPE mottling is comprised between the vascular arcades and broadens nasally to the optic disc (A, B). The macular area shows a marked hypofluorescence, with a little amount of foveal sparing (C). The OCT scan (C) demonstrates irregularity in the subfoveal RPE-photoreceptors complex and extensive atrophy in RPE and external retinal layers in the peri- and para-foveal areas. Foveal sparing is better seen on near-infrared autofluorescence (D) rather than short wavelength autofluorescence (E).

Table 1 Classifications of Stargardt Disease. The Groups Proposed Do Not Always Correspond to Different Progressive Stages of the Disease but Have Important Implications in the Clinical and Functional Assessment of the Patients

Fishman Classification^Citation43	Lois Classification^Citation44	FAF^Citation45	Early Onset STGD Fundus Grading System^Citation46	Genotype^Citation45
1. Flecks confined to the fovea, with pigmentary changes; “beaten-metal” or “snail-slime” appearance. EOG and both scotopic and fotopic ERG) normal (Figure 1)	1. PERG abnormality with normal full-field ERG	1. Localized low foveal FAF signal surrounded by a homogeneous background with or without perifoveal foci of high or low signal	1. Normal fundus	A. Patients with ≥2 severe/null variants
2. Flecks, extending anterior to the vascular arcades and/or nasally to the optic disc. Flecks might be partially or totally resorbed. Subnormal cone and rod responses on EOG and ERG, delayed dark adaptation (Figure 2)	2. PERG abnormality with cone ERG abnormality	2. Focal low FAF signal at the macula encircled by heterogeneous background and foci of high or low FAF signal anteriorly to the vascular arcades	2. Macular and/or peripheral flecks without central atrophy	B. Patients with 1 severe/null variant and ≥1 variant that are missense or in-frame insertion/deletion.
3. Flecks reabsorbed, atrophy of RPE and CC. EOG testing subnormal; ERG severely altered	3. Pattern ERG abnormality with generalized cone and rod dysfunction	3. Multiple areas of low FAF signal in macular area with heterogeneous background and/or foci of high or low signal	3a. Central atrophy without flecks 3b. Central atrophy with macular and/or peripheral flecks 3c. Paracentral atrophy with macular and/or peripheral flecks, without central atrophy	C. Patients with no severe/null variant, but ≥2 variants that are missense or in-frame insertion/deletion.
4. Further worsening of stage 3, complete reabsorption of flecks, extensive CC and RPE loss. ERG responses extinguished			4. Multiple extensive atrophic changes of the RPE, extending beyond the vascular arcades	D. Patients with 1 missense or in-frame insertion/deletion variant or with only variants predicted as less likely pathogenic or uncertain.

Abbreviations: CC, choriocapillaris; FAF, fundus autofluorescence; EOG, electrooculogram; ERG, electroretinogram; PERG, pattern electroretinogram; RPE, retinal pigment epithelium.

Figure 3 Progression of STGD1. First row: Short wavelength autofluorescence, Multicolor imaging, and OCT at baseline. Second row: Short wavelength autofluorescence, Multicolor imaging, and OCT after 12 months, showing enlargement of the area of RPE and photoreceptor loss on autofluorescence and central retinal thinning the foveal area.

Figure 4 Comparison between short wavelength autofluorescence and near-infrared autofluorescence. Preservation of RPE in the foveal region is clearer on multicolor (A, B) and near-infrared autofluorescence (C, D) than on short wavelength autofluorescence (E–F), as the dark signal in the fovea in the latter due to blockage of normal choroidal fluorescence might be misinterpreted as RPE atrophy in the macular region.

Figure 5 Foveal cavitation in STGD1. Short wavelength autofluorescence (A) and near-infrared autofluorescence (B) show macular mottling of RPE. In OCT (C), foveal cavitation appears as a hollow subfoveal space due to focal loss of RPE and photoreceptors with backscattering effect. External limiting membrane is preserved.

Figure 6 Choroidal neovascularization in STGD1. Fundus autofluorescence (A) shows hyperautofluorescent flecks s and irregular macular hypoautofluorescence. Early (B) and late (C) fluorescein angiography frames demonstrate a parafoveal focal dye leakage, corresponding to a type 1 choroidal neovascularization (CNV). OCT scan (D) reveals growth of the CNV above the RPE with mild exudation, along with focal irregularity/atrophy of RPE/ellipsoid zone layers.

Figure 7 Optical coherence tomography angiography of STGD1. OCT angiography (left) shows foveal avascular zone enlargement and reduced vessel density on superficial capillary plexus (A) and deep capillary plexus (B), as well as damaged choriocapillaris (C). (D) Shows the corresponding autofluorescence.

Table 2 Treatment Currently Under Investigation for Stargardt Disease

Treatment	Class	Mechanism	Company	Phase
ACU-4429 (Emixustat)	Visual Cycle Modulator	Inhibition of retinoid isomerohydrolase	Acucela Inc	Phase 3 (SeaSTAR)
ALK-001	Visual Cycle Modulator	Chemically modified Vitamin A preventing Vitamin A dimerization	Alkeus Pharmaceuticals	Phase 2 (TEASE)
VM200	Visual Cycle Modulator	Primary ammine which reacts with all-trans retinal forming a non-toxic Schiff base	Vision Medicine	Preclinical Trials
Isotretinoin	Visual Cycle Modulator	Inhibition of 11-cis-retinol dehydrogenase	Patent expired	Preclinical Trials
Fenretinide	Visual Cycle Modulator	Synthetic retinoid which binds to retinol-binding protein 4	Sirion Therapeutics	Preclinical Trials
A1120	Visual Cycle Modulator	Non retinoid RBP4 antagonist	iCura Vision	Preclinical Trials
Avacincaptad pegol (Zimura^®)	Complement inhibition	Complement C5 inhibitor	Ophthotech Corporation	Phase 2b
SAR422459	Gene therapy	Recombinant lentiviral vector containing a functioning ABCA4	Sanofi, Oxford Biomedica	Phase I/II
Human embryonic stem cell-derived RPE	Stem cells therapy	Replacement of RPE cells restoring the function of overlying retina	Advanced Cell Technology	Phase I/II

Fishman GA. Fundus flavimaculatus. A clinical classification. Arch Ophthalmol. 1976;94(12):2061–2067. doi:10.1001/archopht.1976.03910040721003999551

 PubMedGoogle Scholar

Lois N, Holder GE, Bunce C, Fitzke FW, Bird AC. Phenotypic subtypes of Stargardt macular dystrophy-fundus flavimaculatus. Arch Ophthalmol. 2001;119(3):359–369. doi:10.1001/archopht.119.3.35911231769

 PubMedGoogle Scholar

Fujinami K, Lois N, Mukherjee R, et al. A longitudinal study of Stargardt disease: quantitative assessment of fundus autofluorescence, progression, and genotype correlations. Invest Ophthalmol Vis Sci. 2013;54(13):8181–8190. doi:10.1167/iovs.13-1210424265018

 PubMed Web of Science ®Google Scholar

Fujinami K, Zernant J, Chana RK, et al. Clinical and molecular characteristics of childhood-onset Stargardt disease. Ophthalmology. 2015;122(2):326–334. doi:10.1016/j.ophtha.2014.08.01225312043

 PubMed Web of Science ®Google Scholar