The Genetics of Hereditary Retinopathies and Optic Neuropathies

Alessandro Iannaccone, MD, MS


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

In This Article

Rod-Cone Dystrophies

Rod-cone dystrophies are a family of progressive diseases in which rod dysfunction, which leads to night blindness and loss of peripheral visual field expanses, is either the prevailing problem or occurring at least as severely as cone dysfunction. Retinitis pigmentosa, characterized by the development of intraretinal pigmentary deposits (most often of the bone spicule-like type), is the main group of diseases included under this definition and, as a whole, is estimated to affect approximately one in every 3,500 people.[14] Depending on the classification criteria used, about 60-80% of all retinitis pigmentosa patients have a clear-cut rod-cone dystrophy pattern of retinal disease and once other syndromic forms are taken into account, about 50-60% of all retinitis pigmentosas fall in the rod-cone dystrophy nonsyndromic category.[15]

For mere clinical classification purposes, rod-cone dystrophies can be broadly divided into early onset forms (i.e., which are either consistently severe from birth with little progression thereafter or that consistently develop in childhood and evolve rapidly toward severe loss of vision) and delayed-onset forms (i.e., those in which, regardless of eventual severity of the visual loss, symptoms develop more often later [second to sixth decade of life] and/or progress relatively more slowly than the former group). The genes responsible for these forms of retinal disease are summarized in Table 1 and Table 2 , respectively. In all of these conditions, rod-driven electroretinogram responses are always more or at least as severely compromised as cone-driven electroretinograms.

Early onset retinitis pigmentosa and Leber congenital amaurosis, once considered distinct entities by virtue of age of onset, at birth and within early childhood, respectively, represent the main group among the early onset rod-cone dystrophies ( Table 1 ). Early onset retinitis pigmentosa and Leber congenital amaurosis are estimated to affect about three per 100,000 neonates and to account for approximately 5% of all forms of retinitis pigmentosa and about 20% of children in schools for the blind worldwide.[16] This autosomal recessive group of diseases represents the spectrum of disease associated to date with different mutations in nine distinct genes, which is an excellent example of both genetic and allelic heterogeneity.[17] The majority of patients with early onset retinitis pigmentosa and Leber congenital amaurosis have had very poor vision since birth, with roving nystagmus either present at birth or developing later. While the retinal tissue may even appear completely normal in childhood, at times fundus abnormalities can be overt at a young age. For example, 80% of patients harboring mutations in the AIPL1 gene show macular atrophy,[18] including colobomatous lesions like that of the case illustrated in Figure 1A, but this presentation has been observed also in patients with CRB1 mutations.[19] Regardless of fundus appearance, electroretinogram testing is invariably abnormal in these children since infancy.

A : Left fundus of a 5-year-old Caucasian male with Leber congenital amaurosis obtained under anesthesia. The disk appears severely pale, retinal vessels are extremely attenuated, the retinal tissue is thinned and has a salt-and-pepper appearance, and the macular region is remarkable for a coloboma-like lesion surrounded by pigmentary deposits. Electroretinograms, also performed under anesthesia, showed no detectable response from this patient under any testing condition. The genetic cause for Leber congenital amaurosis in this patient is presently under investigation, AIPL1 being the strongest candidate. B : The nasal quadrant of the left eye of this African-American male with autosomal dominant retinitis pigmentosa, harboring a mutation leading to a rhodopsin proline-to-alanine amino acid change at codon 180 (P180A), illustrates well the altitudinal nature of the disease that can be observed in association with certain mutations in the RHO gene. At 23 years of age, the superior retina of this patient retained near-normal thresholds for both rods and cones and all electroretinogram responses were attenuated but still very well preserved. C : View of the right macula of a 10-year-old Jordanian male with autosomal recessive cone-rod dystrophy. There are atrophic changes, a beaten-bronze appearance, and abnormal vitreoretinal interface reflexes. The central lesion is surrounded by a halo of coarse deep mottling and there were pigmentary deposits in the retinal midperiphery (not shown). Electroretinogram testing revealed a cone-rod pattern of severe retinal dysfunction. This patient was homozygous for a previously reported ABCA4 mutation resulting in a glycine-to-glutamate amino acid substitution at codon 1961 (G1961E), as well as a previously unreported change at codon 1838, predicting a histidine-to-aspartate amino acid change (H1838D) and seven additional polymorphisms.

Rarely, Leber congenital amaurosis can be inherited also as an autosomal dominant condition.[17] To date, this possibility has been associated only with mutations in the CRX gene, the product of which has a key developmental role in photoreceptors.

The other most common form of early onset rod-cone dystrophy is the X-linked type of retinitis pigmentosa.[20] In this case, males are usually fully affected by the disease, whereas females commonly have only mild, late-onset, asymmetric signs of retinal dysfunction, although they can express a spectrum of disease manifestations ranging from normal to nearly fully affected. The most common form of X-linked retinitis pigmentosa is due to mutations in the RPGR gene.[20] It has also been recently recognized that RPGR -linked X-linked retinitis pigmentosa can also be associated with predisposition to respiratory tract infections and sensorineural hearing loss.[21,22] Other genes responsible for x-linked retinitis pigmentosa are yet to be cloned. Although disease severity in X-linked retinitis pigmentosa varies and it is different from the other forms of early onset retinitis pigmentosa and Leber congenital amaurosis, most children with X-linked retinitis pigmentosa are born with fairly good vision but tend to lose both peripheral and central vision more rapidly than the average retinitis pigmentosa patient.[23,24]

For the most part, the delayed-onset forms of rod-cone dystrophies differentiate themselves from early onset retinitis pigmentosa only by the later age of onset and/or the relatively slower progression of retinal disease, resulting only rarely in nystagmus or near complete visual loss. Within this group of disorders, the autosomal recessive forms are typically at the more severe end of the spectrum, resulting from abnormalities in no less than 12 distinct genes ( Table 2 ) ( . Accessed January 7, 2005). Noteworthy forms of autosomal recessive retinitis pigmentosa in this group result from mutations in the ABCA4 gene, which also causes Stargardt disease and cone-rod dystrophies (see also Oh[3] and Chung[4] for additional reviews on Stargardt disease and associated phenotypes); the RLBP1 gene, which initially causes a retinal phenotype clinically indistinguishable from the nonprogressive disease fundus albipunctatus (see section on congenital nonprogressive retinal disease)[25,26] and then progresses to a special form of retinitis pigmentosa known as retinitis punctata albescens;[27] and the CRB1 gene, which causes not only forms of Leber congenital amaurosis and severe autosomal recessive retinitis pigmentosa[28] but also a unique form of autosomal recessive retinitis pigmentosa with preservation of the para-arteriolar retinal pigment epithelium.[29] For the other genes, the clinical and functional features of this group of rod-cone dystrophies remain essentially those of classical retinitis pigmentosa. It must also be noted that recent evidence shows that retinitis punctata albescens itself is genetically heterogeneous,[26] and that mutations in the RLBP1 gene do not account for all patients presenting with a retinitis punctata albescens-like phenotype.

Autosomal dominant forms of rod-cone dystrophies vary widely in severity depending on the type of abnormal function gained (e.g., rhodopsin mutations) or the severity of the haploinsufficiency (e.g., RDS/peripherin mutations) caused by the disease-causing alleles. As a result, a great deal of allelic heterogeneity is observed within the dominant diseases in this group, ranging from rather mild forms to rather aggressive forms, such as those associated with distinct rhodopsin mutations.[30,31,32] Marked variability in the age of onset is also often observed within families in this group of disorders (e.g., RP1 mutations),[33] as well as instances of true nonpenetrance of the disease trait (e.g., mutations in the premRNA splicing factor PRPF31 ),[34] which can significantly complicate the diagnostic and genetic counseling process. Phenotypic variability within a family is also possible, especially in association with RDS/peripherin mutations.[35] Except for the latter instance and the occurrence of sectoral retinitis pigmentosa affecting only the inferior hemi-retina in rhodopsin-linked forms of autosomal dominant retinitis pigmentosa (Figure 1B),[30,31,32] there is hardly any clinical uniqueness associated with any other form of autosomal dominant retinitis pigmentosa, making it in most instances extremely difficult to predict the causal gene from the observed phenotype. Ten distinct autosomal dominant retinitis pigmentosa genes have been cloned to date ( Table 2 ).

An 11th gene for a specific form of autosomal dominant late-onset retinal degeneration has also been recently cloned. Late-onset retinal degeneration was only very recently recognized as a clinical entity[36,37] and is characterized by onset of retinal degenerative changes after 50 years of age associated with subretinal pigment epithelium lipid-rich deposits[36] and visual field and electroretinogram changes similar to early stage retinitis pigmentosa. The functional hallmark of late-onset retinal degeneration is delayed dark adaptation, which is present at least 10 years prior to development of any sign of disease.[37] The same mutation in the CTRP5 gene (S163R) has been found to cause this disorder in seven of 14 late-onset retinal degeneration families thus far identified (founder effect).[38]


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