Hereditary Retinal Disease
Nystagmus is the most common presenting sign of hereditary retinal disease. The onset of nystagmus typically occurs between 8 and 12 weeks of age and indicates limited visual potential if the cause is retinal disease (see Chapter 13). In infantile nystagmus caused by certain forms of Leber congenital amaurosis, achromatopsia, or X-linked congenital stationary night blindness, the retinal appearance can be normal.
Nystagmus does not develop in all patients with hereditary retinal disease; for example, it may not develop in those with less severe retinal damage. Poor visual function or failed vision screening may be the presenting abnormality in older children with retinal disease. The paradoxical pupillary response (pupils that initially constrict in the dark rather than dilate) is common in hereditary retinal dystrophies (Table 25-6).
Tests utilized to evaluate a patient with a possible hereditary retinal disorder include electroretinography (ERG), electro-oculography (EOG), and optical coherence tomography (OCT), as well as color vision, visual field, and dark adaptation tests. Sedation or general anesthesia may be required in order to perform ERG or OCT in young children. Because significant retinal maturation occurs during the first few years of life, an ERG can appear subnormal in a healthy infant. To obtain more reliable results, ERG is performed after 6–10 months of age. Repeated ERG testing may be necessary to confirm abnormalities of phototransduction.
Table 25-6 Differential Diagnosis of Paradoxical Pupils
Hereditary retinal diseases with onset late in childhood are much like those in adulthood and are not covered here. See BCSC Section 12, Retina and Vitreous.
Leber congenital amaurosis
Leber congenital amaurosis (LCA) is a group of hereditary (usually autosomal recessive) retinal dystrophies 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 typically ranges from 20/200 to bare light perception, but in some patients is not very low.
Ophthalmoscopic appearance varies greatly, 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.
Additional ocular manifestations include the oculodigital reflex (rubbing or poking the eye), photoaversion, cataracts, keratoconus, and keratoglobus. High refractive errors, usually high hyperopia, are common.
LCA-like phenotypes can be found in a number of systemic diseases, including peroxisomal disorders (Zellweger [cerebrohepatorenal] syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease) and the ciliopathies (Alström syndrome, Joubert syndrome, Senior-Løken syndrome, and Bardet-Biedl syndrome). The ciliopathies are a group of genetic disorders in which the structure and/or function of the cilia is affected, manifesting in cerebral anomalies and renal and retinal disease. Retinal involvement is common because the junction between inner and outer segments of the photoreceptor cell is modified nonmotile cilium (see Chapter 28). Thus, ophthalmologists should be aware that an LCA-like phenotype may be the first sign of an undiagnosed systemic disease.
An ERG is typically used to diagnose LCA. However, in a child with an obvious phenotype (oculodigital reflex, severely decreased vision at birth, and pigmentary retinopathy), ERG is not always necessary. Genetic testing is important and can be used to confirm the diagnosis, distinguish LCA from other retinal diseases, predict prognosis, and help with family planning. Molecular diagnosis of LCA is hindered by the fact that the disease is heterogeneous. At least 20 different genetic mutations are known to cause LCA; the most frequent involve CEP290 (15%), GUCY2D (12%), and CRB1 (10%), as well as RPE65 (6%).
Figure 25-12 Leber congenital amaurosis with marbleized fundus.
Gene therapy is available for biallelic RPE65 disease. Studies have demonstrated improvement in subjective and objective vision after subretinal injections of the gene promoter attached to an adenovirus viral particle, but it is unclear whether these results will be sustainable. Results seem most promising in young children.
Alkharashi M, Fulton AB. Available evidence on Leber congenital amaurosis and gene therapy. Semin Ophthalmol. 2017;32(1):14–21.
Weleber RG, Pennesi ME, Wilson DJ, et al. Results at 2 years after gene therapy for RPE65-deficient Leber congenital amaurosis and severe early-childhood-onset retinal dystrophy. Ophthalmology. 2016;123(7):1606–1620.
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. 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, results of recent studies have shown deterioration of visual acuity, macular appearance, and cone function on ERG.
Results of color vision testing are markedly abnormal. The ERG is subnormal, showing extinguished cone or photopic responses but normal or nearly normal rod responses. Several recessive gene mutations have been identified as the cause of achromatopsia, including mutations in CNGA3, CNGB3 (most common), GNAT2, PDE6C, and PDE6H.
Other cone dystrophies causing early-onset visual impairment and nystagmus include incomplete achromatopsia, which is an autosomal recessive condition, and blue-cone monochromatism, which is an X-linked disorder. In both disorders, patients usually have better vision than do those with complete achromatopsia. In incomplete achromatopsia, some residual cone function is observed on ERG testing. In blue-cone monochromatism, the blue (short-wavelength) cones show normal function on specialized ERG testing, but the photopic response is usually extinguished.
Glasses with dark lenses or red lenses that exclude short wavelengths may help. Gene therapy has been used in animal models.
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.
Children with CSNB, especially the autosomal recessive and X-linked forms, usually present in early infancy with nystagmus and a normal fundus appearance. 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.
An ERG or genetic testing 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.
Bright illumination should be used for visual tasks and refractive errors corrected.
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.
Fundus examination showing foveal hypoplasia is diagnostic. OCT may be useful.
No treatment is currently available.
Aicardi syndrome is a presumed X-linked autosomal dominant disorder characterized by the clinical triad of widespread round or oval depigmented chorioretinal lacunae (Fig 25-13), infantile spasms, and agenesis of the corpus callosum. Chorioretinal lacunae have been shown to occur in 88% of patients; optic nerve abnormalities, in 81%. Colobomas, persistent pupillary membranes, and microphthalmia may also occur. Aicardi syndrome is typically lethal in males.
Figure 25-13 Aicardi syndrome. Fundus photograph showing optic disc coloboma and chorioretinal lacunae.
Fruhman G, Eble TN, Gambhir N, Sutton VR, Van den Veyver IB, Lewis RA. Ophthalmologic findings in Aicardi syndrome. J AAPOS. 2012;16(3):238–241.
The clinical picture provides the foundation for diagnosis.
No treatment is currently available.
Excerpted from BCSC 2020-2021 series: Section 10 - Glaucoma. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.