X-linked cone-rod dystrophy is a rare, progressive visual disorder primarily affecting cone photoreceptors (Demirci et al., 2002). Affected individuals, essentially all of whom are males, present with decreased visual acuity, myopia, photophobia, abnormal color vision, full peripheral visual ... X-linked cone-rod dystrophy is a rare, progressive visual disorder primarily affecting cone photoreceptors (Demirci et al., 2002). Affected individuals, essentially all of whom are males, present with decreased visual acuity, myopia, photophobia, abnormal color vision, full peripheral visual fields, decreased photopic electroretinographic responses, and granularity of the macular retinal pigment epithelium. The degree of rod photoreceptor involvement is variable, with increasing degeneration. Although penetrance appears to be nearly 100%, there is variable expressivity with respect to age at onset, severity of symptoms, and findings (Hong et al., 1994). - Genetic Heterogeneity of X-linked Cone-Rod Dystrophy Additional forms of X-linked cone-rod dystrophy include CORDX2 (300085), which has been mapped to chromosome Xq27.2-q28, and CORDX3 (300476), which is caused by mutation in the CACNA1F gene (300110) on chromosome Xp11.23. For a discussion of autosomal forms of cone-rod dystrophy, see CORD2 (120970).
Cone dysfunction may be suspected if there is photophobia, fine nystagmus, reduced visual acuity, and abnormal color vision. (Patients with predominantly rod disease complain of difficulty with night vision and in the early stage of the disease may ... Cone dysfunction may be suspected if there is photophobia, fine nystagmus, reduced visual acuity, and abnormal color vision. (Patients with predominantly rod disease complain of difficulty with night vision and in the early stage of the disease may have normal visual acuity and color vision.) Although in some cases the diagnosis can be made on the basis of history and clinical examination, further tests of rod and cone function by special electrodiagnostic methods are often needed. These are important not only for diagnosis but also for recognition of the carrier state in X-linked dystrophies. Pinckers et al. (1981) and Pinckers and Timmerman (1981) reported 2 families with X-linked cone dystrophy. According to Pinckers (1982), the disorder begins as a peripheral cone disease and progresses to a diffuse cone disease. Affected males present with diminished visual acuity, myopia, disturbed cone ERG, and a type I color vision defect. Heterozygous females have diminished visual acuity and myopia, but a normal cone ERG and normal color vision. In a Dutch family with X-linked cone dystrophy in 5 generations, routine ophthalmologic examination showed no abnormalities in carriers, but detailed color vision testing detected 87% of obligate heterozygotes. Onset of visual deterioration in affected males occurred after age 20, with only one exception. It was preceded by marked pseudoprotanomaly in the patients who still had normal visual acuity. Pseudoprotanomaly was the label attached also to the functional derangement detected in carrier females (van Everdingen et al., 1992). Fleischman and O'Donnell (1981) reported another family as incomplete achromatopsia. Pinckers and Deutman (1987) suggested that this was the same disorder as that reported by Pinckers et al. (1981). The X-linked recessive cone dystrophy reported by Heckenlively and Weleber (1986) differed in its symptomatology and may be a distinct entity; see 304030. Pinckers and Deutman (1987) suggested that X-linked cone dystrophy may be much more frequent than generally realized. Among 25 patients with diffuse cone disease, 22 were males. Fleischman and O'Donnell (1981) studied a black kindred with 9 affected males and 7 carrier females. They concluded that this disorder is a slowly progressive abiotrophy, with progressive macular scarring and cone dysfunction, rather than a stationary anomaly. Some carrier females have ophthalmoscopic and fluorescein angiographic abnormalities in the macula. The extent of rod and cone involvement among affected males was quite variable in the family described by Hong et al. (1994). Although all the affected demonstrated some of the symptoms and features generally associated with primary cone abnormalities, such as photophobia, color-vision deficits, and central scotomas, significant rod dysfunction was also observed. The scotopic electroretinography of the proband was more impaired than the photopic responses, while the other affected males continued to show some rod function even when cone responses were nearly extinguished. All but 1 of the affected males examined had moderate to high myopia. Most of the affected males lost central vision in their late teens or early twenties, although 1 reported normal vision until the age of 35 years. Funduscopic examination ranged from normal to severe macular atrophy to widespread retinal degeneration (as illustrated in their Figure 2). One example of a 'bull's eye' macula was illustrated. The most common symptom among carrier women was photophobia under normal daylight conditions. Many noted difficulties with light adaptation and/or night vision. Holopigian et al. (2002) compared the patterns of local cone and rod system impairment in patients with progressive cone dystrophy using psychophysical and electrophysiologic techniques. The authors found poor correspondence among local measures of cone and rod system losses in their patients with progressive cone dystrophy. The results suggested that the spatial pattern of cone system losses in progressive cone dystrophy differed from the spatial pattern of rod system losses. Because of the disturbance of color vision, the cone dystrophies are sometimes labeled as incomplete achromatopsia; such is a symptom, not a primary diagnosis. The term incomplete achromatopsia is also used at times for blue cone monochromatism (303700). Jalkanen et al. (2003) tabulated the genetic and clinical features of X-linked recessive cone-rod dystrophies.
Demirci et al. (2002) performed mutation analysis of the entire RPGR coding region in the families studied by Seymour et al. (1998) and identified 2 different 2-nucleotide deletions in open reading frame 15 (ORF15), in family 2 (delAG; ... Demirci et al. (2002) performed mutation analysis of the entire RPGR coding region in the families studied by Seymour et al. (1998) and identified 2 different 2-nucleotide deletions in open reading frame 15 (ORF15), in family 2 (delAG; 312610.0015) and in families 1 and 3 (delGG; 312610.0014), both of which resulted in a frameshift leading to altered amino acid structure and early termination. In addition, an unrelated individual with X-linked cone-rod dystrophy demonstrated a 1-nucleotide insertion (insA) in ORF15. The presence of 3 distinct mutations associated with the same disease phenotype provided strong evidence that mutations in RPGR exon ORF15 are responsible for CORDX1. Genetic heterogeneity exists, however, because of findings in 3 other families. Yang et al. (2002) mapped 2 Caucasian families of Northern European ancestry with X-linked cone dystrophy to the CORDX1 locus on Xp, and identified mutations in ORF15 of the RPGR gene in each: ORF15+1343-1344delGG (312610.0014) and ORF15+694-708del15 (312610.0017). The latter mutation was predicted to delete 5 amino acids from the C-terminal region of the protein. Ebenezer et al. (2005) identified novel RPGR ORF15 protein truncation mutations in 2 of 6 families with CORDX1. In family A, a 2-bp mutation predicted to result in a truncated protein was identified (312610.0021). In family B, a G-to-T transversion resulted in a nonsense mutation (312610.0022). Phenotypic characteristics in both families included progressive deterioration of central vision and subsequently night vision, mild photophobia, and moderate to high myopia. Ophthalmoscopic abnormalities were generally confined to the macula: a parafoveal ring of increased autofluorescence was observed and electrophysiologic evidence of greater generalized abnormality in cone than rod responses were consistent with a cone-rod dystrophy phenotype.