Inherited Macular Dystrophies

Stargardt Disease

Stargardt disease is the most common inherited juvenile macular dystrophy, caused by autosomal recessive mutations in ABCA4. The gene normally clears visual-cycle byproducts from photoreceptor outer segments. When it fails, toxic lipofuscin builds up in the RPE and damages the macula.

The signature finding is the "dark choroid" (or "silent choroid") sign on fundus autofluorescence and fluorescein angiography. Lipofuscin accumulation in the RPE masks the normal background choroidal fluorescence, so the choroid appears abnormally dark on angiography. This is the hallmark feature that separates Stargardt from the other macular dystrophies below.

Best Vitelliform Macular Dystrophy

Best disease is an autosomal dominant macular dystrophy caused by mutations in BEST1, which encodes bestrophin-1, a chloride channel expressed in the retinal pigment epithelium. Its dysfunction is detected electrophysiologically rather than by fundus appearance alone: the electro-oculogram shows a reduced Arden ratio, reflecting abnormal RPE function even when the macula still shows only a mild "egg-yolk" (vitelliform) lesion. That EOG finding is what separates Best disease from other maculopathies that can mimic its fundus appearance.

Pattern Dystrophy

Pattern dystrophy is caused by mutations in PRPH2 (also called RDS), which encodes peripherin-2, a structural protein in the photoreceptor outer segment discs. The same gene can cause isolated pattern dystrophy in one family and autosomal dominant retinitis pigmentosa in another, depending on other genetic and modifying factors. One mutated structural protein, several possible phenotypes.

Leber Congenital Amaurosis

Leber congenital amaurosis (LCA) is the inherited retinal dystrophy with the earliest and most severe onset. It typically presents within the first year of life with profound vision loss, nystagmus, and often a nonrecordable electroretinogram. The dysfunction is near-total from infancy, not a later degenerative course superimposed on previously normal vision.

CEP290 is the most common cause of autosomal recessive LCA in many populations. It disrupts connecting-cilium function shared by photoreceptors and other ciliated cells, which in some patients produces a systemic ciliopathy phenotype related to the mechanism seen in Bardet-Biedl syndrome. RPE65 mutations are a separate cause: they disrupt the visual cycle in the RPE and are the target of voretigene neparvovec (Luxturna), the first FDA-approved gene therapy for an inherited retinal disease. This subretinal treatment delivers a functional RPE65 gene copy and can improve functional vision in patients with confirmed biallelic RPE65-mediated disease.

Achromatopsia

Achromatopsia is a disorder of cone photoreceptor function. The most common cause is mutation in CNGB3, which encodes a subunit of the cone cyclic nucleotide-gated channel used in phototransduction; CNGA3 mutations are next most common. Inheritance is autosomal recessive, and the phenotype is congenital absence or near-absence of color vision with photophobia and reduced visual acuity. The dysfunction is cone-specific, the opposite pattern from rod-first RP.

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