The Genetics of Hereditary Retinopathies and Optic Neuropathies

Alessandro Iannaccone, MD, MS

Disclosures

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

In This Article

Cone Dystrophies and Cone-Rod Dystrophies

Cone dystrophies and cone-rod dystrophies are a group of progressive diseases in which, opposite to rod-cone dystrophies, cone dysfunction (hence, light aversion, central scotomas, and loss of central vision) prevails compared to rod dysfunction. Accordingly, in cone dystrophies cone-driven electroretinograms are the only affected responses, whereas in cone-rod dystrophies rod electroretinogram compromise is present but typically less so than, or at least not more severely than, cone-driven electroretinograms. Specific patterns of retinal dysfunction that are useful for clinical classification and patient counseling have been identified.[39,40] Retinal damage (i.e., atrophy, pigmentary changes, or both) prevails at the posterior pole in both cone dystrophies and cone-rod dystrophies, and for this reason this group of diseases has also been broadly termed retinitis pigmentosa inversa. Both cone dystrophies and cone-rod dystrophies can be inherited as autosomal recessive, autosomal dominant, or X-linked traits. Cone-rod dystrophies, and even more so pure cone dystrophies, are substantially less common than rod-cone dystrophies. Based on a survey of 500 consecutive patients[15] and on personal experience, their overall prevalence can be estimated to be roughly between one per 10,000 to one per 25,000 people, with cone-rod dystrophies accounting for the majority of the cases. All known forms of cone dystrophy to date are allelic to other disorders, thereby simply representing phenotypic variants of other diseases ( Table 3 ). For example, both X-linked cone dystrophy and X-linked cone-rod dystrophy are due to mutations in the RPGR gene, which is responsible also for X-linked retinitis pigmentosa. Of note, the only gene known to cause autosomal recessive cone dystrophy, however rarely, is the CNGA3 gene, the same gene typically responsible for type II achromatopsia, a non-progressive retinal disorder (see section on congenital nonprogressive retinal diseases) ( www.sph.uth.tmc.edu/Retnet . Accessed October 4, 2004; www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM . Accessed October 4, 2004). In a continuum of phenotypic manifestations with Stargardt disease, the only established and common cause of autosomal recessive cone-rod dystrophy to date is the ABCA4 gene (Figure 1C),[41] whereas four distinct genes responsible for autosomal dominant-cone-rod dystrophy have been cloned to date ( Table 3 ) ( www.sph.uth.tmc.edu/Retnet . Accessed October 4, 2004; www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM . Accessed October 4, 2004). All autosomal dominant cone rod dystrophy genes are essential for photoreceptor function and/or development. One of these, RDS/peripherin, is also responsible for autosomal dominant macular pattern dystrophies[2] and forms of autosomal dominant retinitis pigmentosa, representing again an instance of remarkable allelic heterogeneity.

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