Cone-rod retinal dystrophy (CRD) characteristically leads to early impairment of vision. An initial loss of color vision and of visual acuity is followed by nyctalopia (night blindness) and loss of peripheral visual fields. In extreme cases, these progressive symptoms are accompanied by widespread, advancing retinal pigmentation and chorioretinal atrophy of the central and peripheral retina (Moore, 1992). Evans et al. (1995) found complete blindness (no light perception) in only 3 of the 34 patients studied, and these 3 were all over 65 years of age. Serious effects on visual acuity (light perception only) were present in 10 other patients; however, their mean age was 60.3 years. All other patients retained some visual acuity. In many families, perhaps a majority, atrophy of the central and peripheral choreoretinal atrophy is not found (Tzekov, 1998).
Hittner et al. (1975) described an extensively affected kindred with an autosomal dominant dystrophy of the retinal photoreceptors and pigment epithelium that is characterized by simultaneous abiotrophic degeneration of rods and cones. The onset of decreased central vision with concurrent progressive constriction of peripheral visual fields occurs prior to age 10. Unlike previously described cone dystrophies, there is an inexorable progression to no light perception. Ferrell et al. (1981) provided follow-up. In all, 25 persons had been identified as affected in the family. Linkage with 17 marker loci was tested, with negative results. Specifically, a large negative lod score with Rh argued against location of the CRD gene on 1p, a large negative lod score with acid phosphatase-1 argued against its location on 2p, and a large negative lod score with ABO and transcobalamin II argued against its location on 9q. Warburg et al. (1991) described a 20-year-old man with mental retardation and electrophysiologically demonstrated cone-rod dystrophy present since childhood. He had hypogonadism and a central postsynaptic hearing impairment. Particularly noteworthy was the finding of deletion of the 18q21.1-qter segment. Three patients with more distal deletions on chromosome 18 did not present retinal dystrophies. This led Warburg et al. (1991) to suggest that a locus for cone-rod dystrophy may be located in the segment 18q21.1-q21.3. The form of cone-rod dystrophy which may be determined by mutation in the gene on chromosome 18 has been designated here as CORD1; see 600624.
Kylstra and Aylsworth (1993) reported a case of cone-rod retinal dystrophy in association with neurofibromatosis type 1 (NF1; 162200), suggesting a localization for CRD close to NF1 on 17q. Although there may be genetic heterogeneity as well as the recognized phenotypic heterogeneity in the group called cone-rod retinal dystrophy, the most definitive mapping, using DNA markers, is that of Evans et al. (1994) to 19q13.1-q13.2.
In the large kindred with autosomal dominant cone-rod dystrophy studied by Evans et al. (1994), it appeared that inheritance was influenced by meiotic drive, resulting in segregation distortion. Affected fathers (N = 25) produced 71 children of whom 31 (44%) were affected, a value approximating the expected 1:1 ratio; however, 63 of 101 children (63%) born to 26 affected mothers inherited the CRD gene. The cumulative binomial distribution calculation for this finding in the progeny of affected mothers gave p = 0.008. Evans et al. (1995) reported on the clinical features of 34 affected members in 4 generations. Loss of visual acuity occurred in the first decade of life, onset of night blindness occurred after 20 years of age, and little visual function remained after the age of 50 years. Central and, later, peripheral retinal fundus changes were associated with central scotoma, pseudoaltitudinal field defects, and finally, global loss of function. Psychophysical and electrophysiologic testing before the age of 26 years showed more marked loss of cone than of rod function. Papaioannou et al. (1998) reported a 4-generation family of Greek origin with clinical features similar to those described in the British family by Evans et al. (1994). Linkage analysis gave a maximum lod score of 2.7 at theta = 0.0 with marker D19S412, confirming the data obtained in the British family.
Freund et al. (1997) cloned the CRX gene, an OTX-like homeo box gene, and found a missense and a frameshift mutation in 2 pedigrees with CORD2. The authors showed that the missense mutation (602225.0001) was not a polymorphic variant and concluded that mutation in the CRX gene is responsible for the CORD2 phenotype.