The Genetics of Hereditary Retinopathies and Optic Neuropathies

Alessandro Iannaccone, MD, MS


Compr Ophthalmol Update. 2005;6(1):39-62. 

In This Article

Congenital Nonprogressive Retinal Diseases

Next to the aforementioned retinal diseases—which by virtue of degenerative, rhegmatogenous, exudative complications, or a combination thereof, worsen over time leading to progressive deterioration of vision—there is another large group of disorders in which retinal function is compromised, with or without overt ophthalmoscopically appreciable retinal changes, but in which little or no deterioration in vision occurs over time. Although these conditions are substantially more rare than progressive retinal disorders, they must be taken into account in the differential diagnostic process of several of them.

Congenital stationary night blindness is the first of this group of disorders.[59] Congenital stationary night blindness can be inherited according to all Mendelian inheritance patterns. Two X-linked and two autosomal dominant genes have been cloned ( Table 5 ). In all types of congenital stationary night blindness, night vision is congenitally but nonprogressively impaired and the retinal examination is normal. Most congenital stationary night blindness patients also have congenital nystagmus as the presenting sign, which can create a differential diagnostic challenge with Leber congenital amaurosis. Typically, patients with complete X-linked congenital stationary night blindness are also moderate-to-high myopes. The X-linked congenital stationary night blindness forms, which are the most common ones, all share an electronegative electroretinogram response similar to that seen in X-linked retinoschisis, and are distinguished in congenital stationary night blindness type 1 (also known as complete congenital stationary night blindness) and congenital stationary night blindness type 2 (incomplete congenital stationary night blindness) based on additional electroretinogram features,[60] a distinction that has been confirmed at the genetic level ( . Accessed October 4, 2004; . Accessed October 4, 2004).[59]

In the autosomal dominant forms of congenital stationary night blindness the electroretinogram is also diminished but typically not electronegative like in X-linked congenital stationary night blindness, although exceptions to this pattern of electroretinogram abnormalities in autosomal dominant families have been reported.[61,62,63] Two genetic causes for autosomal dominant congenital stationary night blindness have been identified to date (the GNAT1 and the PDE6B genes for the Nougaret type and the Rambusch type autosomal dominant congenital stationary night blindness, respectively, see Table 5 ).[59] In addition, three specific mutations of the rhodopsin ( RHO ) gene, which typically causes autosomal dominant-retinitis pigmentosa (see section on rod-cone dystrophies), have been associated with autosomal dominant congenital and essentially non-progressive night blindness ( . Accessed October 4, 2004; . Accessed October 4, 2004).[59] These RHO mutations share the unique feature of causing congenital loss of rod sensitivity to light via constitutive activation of rhodopsin (i.e., it is as if rods were exposed to constant light from within) without leading to clear-cut rod structural damage and progressive retinal degeneration like other RHO mutations do, and one of them is associated with the aforementioned electronegative electroretinogram pattern.[62] However, a very mild and late-onset form of retinitis pigmentosa can eventually develop in some of these RHO mutation-positive patients,[59] a manifestation that is never observed in genuine congenital stationary night blindness. A rarer autosomal recessive complete congenital stationary night blindness also exists,[60] but its cause remains unknown.

In addition to congenital stationary night blindness, in which the retinal examination is normal, there are other nonprogressive, night-blinding disorders associated with retinal changes.[59] One of these is Oguchi disease, an autosomal recessive condition in which a midperipheral patchy metallic sheen can be observed but disappears after prolonged dark adaptation (Mizuo-Nakamura phenomenon).[64] Mutations in two distinct genes have been identified in this disorder, which is particularly common in patients of Japanese descent. Mutations in one of the causal genes, encoding for the phototransduction protein arrestin, has also been implicated in causing autosomal recessive retinitis pigmentosa in Japanese patients ( . Accessed October 4, 2004; . Accessed October 4, 2004). Another autosomal recessive night blinding disorder of which the cause has become known in recent years is fundus albipunctatus. Fundus albipunctatus patients have characteristic disseminated punctate white dots across the retina (Figure 2C).[59] These fundus abnormalities and the ability of fundus albipunctatus patients to overcome their night blindness if allowed to adapt to darkness for a sufficiently long time (typically, at least 2-3 hours) differentiate them from congenital stationary night blindness patients. Fundus albipunctatus is caused by mutations in the RDH5 gene ( Table 5 ).[59,65] Although fundus albipunctatus is rare, in childhood, the clinical picture of fundus albipunctatus may be indistinguishable from that of its nonstationary phenocopy known as retinitis punctata albescens. This condition will ultimately lead to diffuse retinal degeneration (see section on rod-cone dystrophies), thereby posing a considerable differential diagnostic challenge. In addition, recent evidence for compromised cone function and macular dystrophy in some fundus albipunctatus patients has challenged the classical notion that fundus albipunctatus itself is a completely benign night-blinding disorder.[66]

The next group of congenital nonprogressive diseases is that affecting cone function (i.e., daytime vision) ( Table 6 ). The most common of these rare disorders is complete achromatopsia—also ter med rod monochromatism—in which the development of all cone subpopulations is compromised. Complete achromatopsia is estimated to affect approximately one in every 30,000 individuals.[67] Although the phenotype of light aversion, poor visual acuity, absent color vision, congenital nystagmus, and an essentially normal fundus examination, except for blunted foveal reflexes and some degree of retinal pigment epithelium foveal mottling is virtually indistinguishable across patients, there are four distinct genes that can cause achromatopsia ( . Accessed October 4, 2004; . Accessed October 4, 2004). Complete achromatopsia is inherited as an autosomal recessive trait, whereas an even rarer (less than one instance per 100,000 individuals) form of partial achromatopsia called blue cone monochromatism is due to genetic changes that affect the function of the red-green cone photopigment genes and, as such, is inherited as an X-linked trait ( . Accessed October 4, 2004; . Accessed October 4, 2004).[67] Clinically, blue cone monochromatism patients are virtually indistinguishable from rod monochromats. However, the X-linked pattern of inheritance, overall milder symptoms, including a rudimentary ability to distinguish colors in mesopic but not in bright lighting conditions, preserved spectral sensitivity at short (blue-violet) but not middle (green) or long (red) wavelengths, and partial preservation of cone-driven electroretinogram responses, allows for differentiation of these two entities in most cases.[67,68,69]

In the clinical setting, the preserved function of blue cones can be appreciated with both the Panel D15 and the Hardy-Rand-Rittler color vision tests.[68] Also, mildly abnormal electroretinogram responses—mainly cone-mediated ones[70]—defective fixation and subtle ocular motility abnormalities[71] have been reported in blue cone monochromatism female carriers, features that are not present in carriers of the autosomal recessive-inherited rod monochromatism. Traditionally, lack of progression over time in both diseases is considered the rule. However, there have been reports of late development of atrophic macular lesions in patients with blue cone monochromatism, leading to further reduction in visual acuity.[72,73,74] Both complete achromatopsia and blue monochromatism can be clinically difficult to distinguish in childhood from Leber congenital amaurosis, but electroretinogram and, when possible, molecular testing make the differential diagnosis possible.

The last disorder pertaining to this group is ocular albinism. There are three recognized types of pure ocular albinism, the most common of which, type I or Nettleship-Falls variant, is inherited as a X-linked trait and is due to mutations in the OA1 gene ( . Accessed October 4, 2004; . Accessed October 4, 2004). X-linked ocular albinism has been estimated to affect about one of every 150,000 males.[75] Autosomal recessive inheritance is also possible and rare syndromic associations have also been reported, the latter form being due to simultaneously occurring mutations in two distinct genes ( Table 6 ) ( . Accessed October 4, 2004; . Accessed October 4, 2004). In all forms of ocular albinism, symptoms are very similar to those experienced by patients with achromatopsia and blue cone monochromatism. However, in ocular albinism color vision and all electroretinogram responses are typically normal, the retinal tissue is hypopigmented, and iris transillumination defects can be seen. Often, female carriers of OA1 mutations also have coarse patchy irregularities in the retinal pigment epithelium layer that confer a mud-splattered appearance to the retina that, when present, aid the differential diagnostic process.[76] In three of the four ocular albinism variants, mutations in the causal genes disrupt melanin biogenesis, which in turn adversely affects retinal development and the segregation of nerve fibers in the optic pathways.[77,78,79,80,81] This melanogenesis defect also accounts for the giant melanosomes that can be found in skin biopsies of both affected males and female carriers.[78]


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