Stargardt Disease

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Retrieved

2021-01-23

Source

Orphanet

Trials

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Genes

ABCA4, ELOVL4, CNGB3, PRPH2, PROM1, ITIH2, ABCG2, PLXNA2, GNAT2, TST, RPGR, ERG, CRB1, AKR1A1, NR2E3, RPE, USP9X, PNPLA6, ZAP70, BEST1, CILK1, SULT2A1, RDH8, SENP7, NYX, AAVS1, RBP4, RHO, PRPH, AMD1

ABCA4, ELOVL4, CNGB3, PRPH2, PROM1, ITIH2, ABCG2, PLXNA2, GNAT2, TST, RPGR, ERG, CRB1, AKR1A1, NR2E3, RPE, USP9X, PNPLA6, ZAP70, BEST1, CILK1, SULT2A1, RDH8, SENP7, NYX, AAVS1, RBP4, RHO, PRPH, AMD1, AMD1P2, CFTR, CLN3, CRX, DPYD, DPYS, FANCF, GNAZ, GRM6, GUCY2D, CFH, MPO, PDE6B, PPT1, PCARE

Drugs

1-(3-{4-[3,4-difluoro-2-(trifluoromethyl)phenyl]piperidine-1-carbonyl}-1H,4H,5H,6H,7H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one, 3-(3-(3,5-bis(trifluoromethyl)phenyl)-1h-pyrazol-1-yl)propanoic acid, Adeno-associated viral vector serotype 5 containing the human ABCA4 gene, Adeno-associated virus serotype 8 containing the human RdCVF sequence and the human RdCVFL sequence, Combination of three adeno-associated viral vectors of serotype 8 containing the 5'-, the body- and the 3'- coding sequences of human CEP290 fused to inteins, Combination of two adeno-associated viral vectors of serotype 8 containing the 5'- and the 3'- half coding sequences of human ABCA4 fused to inteins, Echothiophate iodide, Ecothiopate iodide, Emixustat hydrochloride, Human embryonic stem-cell-derived retinal pigment epithelial cells, Lentiviral vector containing the human ABCA4 gene, Ma09-Hrpe Cells, Mixture of two adeno-associated viral vectors of serotye 8 containing the 5'-half sequence of human ABCA4 gene and the 3'-half sequence of human ABCA4 gene, Ramiprilat, Soraprazan

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A rare ophthalmic disorder that is usually characterized by a progressive loss of central vision associated with irregular macular and perimacular yellow-white fundus flecks, and a so-called ''beaten bronze'' atrophic central macular lesion.

Epidemiology

The prevalence is estimated at 1/8,000 - 1/10,000. Both sexes are equally affected.

Clinical description

The disease typically presents within the first two decades of life, even though symptoms can also appear during adulthood and as late as the seventh decade. Although disease progression and severity varies widely, Stargardt disease (STGD1) is usually characterized by a progressive loss of central vision causing blurry vision and, occasionally, an increasing difficulty to adapt in the dark. Peripheral vision is usually normal. Most affected individuals also have impaired color vision. Photophobia may be present.

Etiology

The disorder has been linked to mutations in the ABCA4 gene, which encodes an adenosine triphosphate (ATP)-binding cassette transporter (ABCR) expressed specifically in the cones and rods of the retina. Defects in ABCR function cause the accumulation of all-trans-retinal and its cytotoxic derivatives, mainly lipofuscin pigments (e.g., diretinoid-pyridinium-ethanolamine) in photoreceptors and retinal pigment epithelial (RPE) cells, ultimately causing RPE cell death and the subsequent loss of photoreceptors. Mutations in ABCA4 have been linked to a spectrum of phenotypes ranging from STGD1 to cone rod dystrophy and severe early-onset retinal dystrophy.

Diagnostic methods

The clinical diagnosis is based on ophthalmological examinations consisting of visual acuity and visual field testing, ophthalmoscopy, electroretinography (ERG), fluorescein angiography (FA), fundus autofluorescence (FAF), and optical coherence tomography (OCT), revealing macular anomalies (progressive atrophy often in a 'beaten bronze pattern') and yellow-white fishtail flecks that may present only in the central macula but may also extend beyond the vascular arcades. These flecks are hyper autofluorescent on FAF images. Fluorescein angiography reveals the characteristic dark choroid (''silence choroidien'') in aproximately 85% of the patients. Diagnosis can be confirmed by genetic testing of the ABCA4 gene.

Differential diagnosis

Differential diagnosis includes multifocal pattern dystrophy simulating STGD1 and retinal and/ or macular dystrophies such as central areolar choroidal dystrophy (CACD), achromatopsia, cone dystrophy (CD) and cone rod dystrophy (CRD). In addition, two autosomal dominant types of macular dystrophy exist that resemble STGD1: STGD3 caused by mutations in the ELOVL4 gene and STGD4 associated with mutations in PROM1.

Antenatal diagnosis

Prenatal diagnosis is technically possible by means of genetic testing of the ABCA4 gene, but is not used in clinical practice.

Genetic counseling

The disorder is transmitted in an autosomal recessive or an autosomal dominant mode of inheritance. Genetic counseling should be offered to at-risk couples informing them that there is 25% or 50% risk, respectively, of transmitting the disease to offspring.

Management and treatment

Preventive measures for slowing down the progression of the disease include avoidance of overexposure to visible light with sunglasses and no intake of vitamin A supplements. Regular ophthalmologic evaluations are recommended. Currently, various treatment options are being developed. Different oral medical treatments that prevent the accumulation of lipofuscin in Stargardt disease are being tested in phase II/III clinical trials. These medical treatments inhibit the visual cycle by blocking the action of certain enzymes in the retina (RPE65/RBP4/LRAT/RDH5), replace vitamin A with a deuterated form of vitamin A (ALK001) or aid in the removal of lipofuscine by breaking down the lipofuscin (Soraprazan).

Prognosis

Due to the high clinical variability, prognosis depends on certain parameters (notably age of onset and electroretinographic findings) that may help the clinician provide the patient with an indication of the course of the disease. STGD1 may progress rapidly over a few months or gradually over several years leading to a severe decrease in visual acuity. Typically, peripheral vision is not affected, although certain patients may progress to a cone-rod phenotype that does affect the peripheral retinal function.