Hereditary Retinal Disease

Many important tests necessary for diagnosis of hereditary retinal disorders (eg, electroretinogram [ERG], electro-oculogram [EOG], color vision testing, visual field testing, dark adaptation tests) are difficult to perform in young children. Sedation or general anesthesia may be required for an ERG. The ERG response matures in the first year of life. Thus, an ERG can appear highly abnormal in an infant who will later develop a normal response. It is often advisable to either delay the ERG until age 6 months or repeat the ERG after 6 months of age.

Hereditary retinal diseases with onset late in childhood are much like adult hereditary retinal diseases and are not covered here.

Leber congenital amaurosis

Leber congenital amaurosis (LCA) is a group of hereditary (usually autosomal recessive) retinal diseases that affect both rod and cone photoreceptors. LCA is characterized by severe vision loss in infancy, nystagmus, poorly reactive pupils, and an extinguished ERG. Visual acuity ranges from 20/200 to bare light perception in most patients. Funduscopic appearance varies highly, depending on the genotype. It ranges from a normal appearance, particularly in infancy; to pigment clumping in the retinal pigment epithelium (RPE); to resemblance of classic retinitis pigmentosa, with bone spicules, attenuation of arterioles, and disc pallor. Other reported but less common fundus findings include extensive chorioretinal atrophy, macular coloboma, white dots (similar to those seen in retinitis punctata albescens), and marbleized retinal appearance (Fig 25-12). Histologic examination shows diffuse absence of photoreceptors.

Figure 25-12 Leber congenital amaurosis with marbleized fundus.

Additional ocular manifestations include the oculodigital reflex (eye poking), photoaversion, cataracts, keratoconus, and keratoglobus. High refractive errors, usually high hyperopia, are common.

LCA-like phenotypes can also be found in a number of systemic diseases, including peroxisomal diseases (Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease) and the ciliopathies (Alström syndrome, Joubert syndrome, Senior-Loken syndrome, and Bardet-Biedl syndrome). The ciliopathies are a group of disorders that affect the function and/or structure of the cilia, manifesting in brain, renal, and eye disease.

Diagnosis An ERG is usually required to diagnose LCA. Genetic testing is important and can be used to counsel the patient’s family, confirm the diagnosis, distinguish LCA from other retinal diseases, and predict prognosis. Molecular diagnosis of LCA is hindered by the fact that the disease is heterogeneous. Currently, there are 15 genetic mutations known to cause LCA; the most frequent involve CEP290 (15%), GUCY2D (12%), and CRB1 (10%). Mutations cannot be identified in approximately 30% of cases.

Treatment Currently, gene therapy is available in human clinical trials only for the RPE65 gene. These studies have demonstrated improvement in subjective and objective vision after subretinal injections of the gene promoter attached to an adeno-associated viral particle.

Jacobson SG, Cideciyan AV, Ratnakaram R, et al. Gene therapy for Leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years. Arch Ophthalmol. 2012;130(1):9–24.

Achromatopsia

Complete achromatopsia, also known as rod monochromatism, is an autosomal recessive congenital disorder of the cone photoreceptors in which patients have no color vision, poor central vision, nystagmus, and photophobia. These patients see the world in shades of gray. The photophobia actually represents a desire to avoid bright light rather than true pain or discomfort; it may be manifested by squinting or fluttering of the eyelids in normal indoor illumination. Hemeralopia, the inability to see clearly in bright light, occurs in these patients.

Findings on retinal examination are usually normal, with the possible exception of a poor or absent foveal reflex. Although achromatopsia was initially thought to be a stationary disorder, recent studies have shown deterioration of visual acuity, macular appearance, and cone function on ERG.

Diagnosis Results of color vision testing are markedly abnormal, as is the ERG, which shows extinguished cone or photopic responses but normal rod responses. To date, 3 autosomal recessive genes have been linked to achromatopsia: CNGA3, CNGB3, and GNAT2; the CNGB3 mutation is the most common.

Other cone dystrophies causing early-onset visual impairment and nystagmus include incomplete achromatopsia and blue-cone monochromatism. In both disorders, patients usually have better vision than do those with complete achromatopsia. Incomplete achromatopsia is an autosomal recessive disorder that shows some residual cone function on ERG testing. Blue-cone monochromatism is an X-linked disorder; on ERG testing, the blue (short-wavelength) cones show normal function but the photopic response is usually extinguished.

Treatment Dark glasses or red glasses that exclude short wavelengths may help. Gene therapy has been used in animal models.

Thiadens AA, Slingerland NW, Roosing S, et al. Genetic etiology and clinical consequences of complete and incomplete achromatopsia. Ophthalmology. 2009;116(10):1984–1989.

Congenital stationary night blindness

Congenital stationary night blindness (CSNB) refers to a group of nonprogressive retinal disorders characterized predominantly by abnormal function of the rod system. The condition may be X-linked (the most common form), autosomal recessive, or autosomal dominant. The X-linked form has been mapped to the locus Xp11.

CSNB, especially the autosomal recessive and X-linked forms, usually presents in early infancy with nystagmus and normal fundi. These forms are often also associated with myopia and decreased visual acuity of roughly 20/200. However, the range of vision in these patients is wide, and occasionally, patients have normal vision. The retina usually appears normal, but the optic nerve may show myopic tilt and temporal pallor.

Diagnosis An ERG is necessary for diagnosis. The most common ERG pattern seen in CSNB is the “negative” dark-adapted ERG: a large a-wave and a reduced-amplitude (negative) b-wave. Dark adaptation is abnormal in all patients with CSNB. Infants with CSNB may have a flat ERG until approximately 6 months of age, when it converts to the classic negative configuration.

Treatment Bright illumination should be used for visual tasks and refractive errors corrected.

Foveal hypoplasia

Foveal hypoplasia, or incomplete development of the fovea, is another cause of nystagmus in early infancy. Although this condition is most often associated with albinism or aniridia, it may also be isolated or familial and may be related to a defect in the PAX6 gene. On ophthalmoscopic examination, the foveal reflex is poor or absent and the macula exhibits hypoplasia to varying degrees, which can also be seen in patients with complete achromatopsia.

Diagnosis Fundus examination showing foveal hypoplasia is diagnostic. Optical coherence tomography may be useful.

Treatment No treatment is currently available.

Al-Saleh AA, Hellani A, Abu-Amero KK. Isolated foveal hypoplasia: report of a new case and detailed genetic investigation. Int Ophthalmol. 2011;31(2):117–120.

Aicardi syndrome

Aicardi syndrome is an X-linked autosomal dominant disorder characterized by the clinical triad of widespread round or oval depigmented chorioretinal lacunae, infantile spasms, and agenesis of the corpus callosum (Fig 25-13). Chorioretinal lacunae occur in 88% of patients, and optic nerve abnormalities occur in 81%. Colobomas, persistent pupillary membranes, and microphthalmos may also occur. Aicardi syndrome is typically lethal in males.