The Genetics of Hereditary Retinopathies and Optic Neuropathies

Alessandro Iannaccone, MD, MS


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

In This Article

Vitreoretinal Dystrophies

Hereditary vitreoretinal dystrophies are retinal disorders characterized by the concomitant presence of vitreal degeneration that share a predisposition to retinal breaks, tears, and detachment, a diathesis not present in any of the previously discussed hereditary retinal diseases. Vitreoretinal dystrophies are transmitted according to all Mendelian inheritance patterns and the known causal genes are summarized in Table 4 . The best known of these disorders is X-linked retinoschisis. As such, only males are affected by X-linked retinoschisis, representing one of the most common causes of macular disease in male children.[42] Sex-specific prevalence estimates of X-linked retinoschisis vary widely, ranging mainly between one per 12,500 and one per 30,000.[43,44] X-linked retinoschisis is particularly common among Finnish males, where a prevalence of one per 2,250 has been reported.[43] The clinical hallmarks of X-linked retinoschisis are macular and/or peripheral areas of retinoschisis (Figure 2A) and the functional hallmark is a selective reduction in the b-wave of the dark-adapted bright-flash electroretinogram (reduced b/a-wave ratio or electronegative electroretinogram). However, these features are not always present and instances of molecularly proven X-linked retinoschisis with normal b/a-wave ratio have been reported.[45] Other clinical features of X-linked retinoschisis have been reviewed elsewhere.[42] With rare exceptions, female X-linked retinoschisis carriers can be identified only by history (obligate carriers) or via molecular genetic testing. The only gene responsible for X-linked retinoschisis identified to date is RS1 .[46]

A : Posterior pole view of the right eye of a 11-year-old Caucasian male illustrating macrocystic macular changes in the characteristic spoke-wheel schisis pattern of X-linked retinoschisis, due in this case to an RS1 mutation leading to a glycine-to-serine amino acid change at codon 70 (G70S). Patchy retinal pigment epithelium drop-out is also visible at the arcades. This patient also had peripheral retinoschisis (not shown). B : This 72-year-old Italian-American female, homozygous for the highly prevalent IVS1-2A>C NR2E3 mutation, shows combined features of clumped pigmentary retinal degeneration, Goldmann-Favre vitreoretinal dystrophy, and enhanced S-cone syndrome, underscoring the allelic nature of these conditions. The confluent nummular pigmentary deposits surrounding the disk are typical of clumped pigmentary retinal degeneration, whereas the retinal flecks nasal to the disk (present also in other retinal quadrants, not shown) are more typical of Goldmann-Favre vitreoretinal dystrophy. This patient also had a band of peripheral retinoschisis and vitreoretinal strands (not shown), also typical of Goldmann-Favre vitreoretinal dystrophy, whereas macular schisis was no longer appreciated at this late stage of the disease. S-cone thresholds were preferentially preserved in the portions of intact visual field. C : Nasal left retinal mid-periphery in a congenitally night-blind 6-year-old Hispanic female, illustrating the diffuse white punctate deposits that are typical of fundus albipunctatus. This clinical and electroretinogramraphic diagnosis was corroborated by the identification of compound heterozygote mutations (D128N and G238W) in the RDH5 gene.

A rare group of disorders that can mimic X-linked retinoschisis is Goldmann-Favre vitreoretinal dystrophy, also known as enhanced S-cone syndrome because of a selective enhancement—or preferential preservation—of blue-light-sensitive S-cones in affected patients.[47] This peculiarity has been shown to be due to an abnormality of retinal cell development as a result of mutations in the nuclear transcription factor gene NR2E3 , leading to a development of rods into blue-light-sensitive cones.[48] The allelic nature of Goldmann-Favre vitreoretinal dystrophy, enhanced S-cone syndrome and another clinical entity known as clumped pigmentary retinal degeneration, has been recently confirmed (Figure 2B), although not all patients with clumped pigmentary retinal degeneration have mutations in NR2E3 , indicating that clumped pigmentary retinal degeneration itself is likely to be a genetically heterogeneous group of diseases.[49] As in X-linked retinoschisis, this group of diseases also usually displays an electronegative electroretinogram, although this unique feature is typically observed in response to bright flashes not only under dark-adapted but also under the light-adapted state.[47] Also, different from X-linked retinoschisis, these three diseases are all inherited as autosomal recessive traits, which can lead to the incorrect diagnosis of autosomal recessive retinitis pigmentosa. In addition, because of the congenital absence of rods, patients with this group of disorders typically complain of severe congenital night blindness, a complaint that is rarely reported by X-linked retinoschisis patients. Like in X-linked retinoschisis, vitreal abnormalities and peripheral retinoschisis are common and retinal detachment is a possible complication of this group of vitreoretinal dystrophies as well.

There are several autosomal dominant-transmitted vitreoretinal dystrophies that overlap in part both genetically and clinically. Of these, Stickler syndrome is the most common, affecting approximately one in every 10,000 people.[50] There are three known types of this syndromic disorder, types I (STL1) and II (STL2) being the only ones with vitreoretinal involvement. In both types of Stickler syndrome, myopia, multiple areas of lattice-like retinal degeneration, and marked predisposition to giant retinal tears and retinal detachment are obser ved, along with unique vitreal features[51] and systemic features, the most common of which are a progressive arthropathy and hearing loss.[52,53] Distinct yet related collagen genes are responsible for the various types of Stickler syndrome ( Table 4 ).[53] Stickler syndrome type I is allelic to type II Wagner disease, another more rare autosomal dominant vitreoretinal dystrophy in which no systemic findings are seen.[54] This brief update well underscores the complexity of this group of disorders and how molecular genetics is revolutionizing our understanding and classification of retinal diseases.

Lastly, one unique group of vitreoretinal dystrophies is that of the so-called exudative vitreoretinopathies. Exudative vitreoretinopathies are a rare group of vitreoretinal dystrophies that share vitreoretinal dystrophic features along with a unique predisposition to retinal exudates, leakage on angiography, and a predisposition to serous retinal detachments not seen in other vitreoretinal dystrophies. In recent years, there has been an explosion of new molecular knowledge in this specific subfield. Autosomal dominant, autosomal recessive, and X-linked exudative vitreoretinopathies genes have been cloned ( Table 4 ). One type of autosomal dominant exudative vitreoretinopathy, also known as familial exudative vitreoretinopathy or Criswick-Schepens syndrome, ( . Accessed October 4, 2004; . Accessed October 4, 2004) is the most common and has been recently shown to be caused by mutations either in the FZD4 (EVR1)[55] or the LRP5 (EVR4)[56] neighboring genes, whereas the x-linked variant of exudative vitreoretinopathy has long been known to be allelic to Norrie disease, a severe disorder of ocular development, being caused by distinct mutations of the NPD gene, encoding the norrin protein ( . Accessed October 4, 2004; . Accessed October 4, 2004). In addition, very recent evidence has shown that homozygous LRP5 mutations underlie also autosomal recessive forms of exudative vitreoretinopathy.[57] The understanding of this group of disorders has recently increased substantially with the discovery that the proteins encoded by these three genes, including norrin, all participate in the wnt pathway and play a key role in retinal vascular development,[58] thereby showing that these conditions share a common pathophysiology.


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