Cone-Rod Dystrophy 11
A number sign (#) is used with this entry because of evidence that cone-rod dystrophy-11 (CORD11) is caused by heterozygous mutation in the RAXL1 gene (RAX2, 610362) on chromosome 19p13.
For a phenotypic description and a discussion of genetic heterogeneity of cone-rod dystrophy, see 120970.
Clinical FeaturesYang et al. (2015) studied a 4-generation family in which 6 members had retinal dystrophy. All affected individuals presented with declining visual acuity, although the age at onset of symptoms varied widely, with vision loss reported as early as age 15 years and as late as age 60. Examination of all 4 living patients revealed relative central scotoma on kinetic visual fields and obvious macular changes consistent with cone or cone-rod dystrophy, including small yellow macular deposits and/or macular pigment mottling, as well as waxy disc pallor and attenuated vasculature indicating diffuse dystrophy. Central scotomas worsened as macular atrophy progressed. In older patients, mid- and far-peripheral scotomas were detected that correlated with retinal pigment epithelium changes and atrophy of the mid- and far-peripheral retina. Spectral-domain optical coherence tomography of the macula revealed subfoveal hyperreflective deposits and severe diffuse attenuation of the outer retina. In addition, all patients had abnormal electroretinograms (ERGs) demonstrating variable patterns of both cone- and rod-system dysfunction. Scotopic responses to bright flashes were attenuated and prolonged for both the a- and b-waves, but the b-wave was predominantly affected, producing electronegative waveforms as well as b-wave to a-wave amplitude ratios of less than 1.0 in all patients. No other cause of an electronegative ERG was identified in any of the affected patients.
Molecular GeneticsTo test the hypothesis that defects in the RAXL1 gene could result in retinal disease, Wang et al. (2004) screened a cohort of patients with retinopathies, including 322 with a diagnosis of CORD, 107 with Leber congenital amaurosis, 92 with age-related macular degeneration, 14 with autosomal recessive retinitis pigmentosa, and 14 with autosomal dominant retinitis pigmentosa, as well as 94 normal individuals, for mutations in RAXL1. In 2 unrelated patients with CORD, one of whom was described as having macular degeneration with ERG evidence of peripheral retinal involvement, Wang et al. (2004) identified heterozygous mutations (610362.0002 and 610362.0003). In coimmunoprecipitation analyses and transient transfection assays, these mutations resulted in decreased interaction of the protein with CRX (602225) and altered transactivation activity.
In a 4-generation family exhibiting retinal dystrophy with an electronegative scotopic response to bright stimuli, Yang et al. (2015) screened 3 affected and 2 unaffected individuals for mutation in 26 genes associated with cone or cone-rod dystrophy, including CRX, GUCY2D (600179), and PRPH2 (179605), and identified a heterozygous 11-bp deletion in the RAX2 gene (610362.0004) that segregated with disease. Yang et al. (2015) noted that the ERG results in this family showed both inner-retinal and photoreceptor dysfunction, consistent with expression of the RAX2 gene in both the inner and outer layers of the retina (Wang et al., 2004).