Search

Human X-linked blue-cone monochromacy (BCM), a disabling congenital visual disorder of cone photoreceptors, is a candidate disease for gene augmentation therapy. BCM is caused by either mutations in the red (OPN1LW) and green (OPN1MW) cone photoreceptor opsin gene array or large deletions encompassing portions of the gene array and upstream regulatory sequences that would predict a lack of red or green opsin expression. The fate of opsin-deficient cone cells is unknown. We know that rod opsin null mutant mice show rapid postnatal death of rod photoreceptors. Using in vivo histology with high-resolution retinal imaging, we studied a cohort of 20 BCM patients (age range 5-58) with large deletions in the red/green opsin gene array. Already in the first years of life, retinal structure was not normal: there was partial loss of photoreceptors across the central retina. Remaining cone cells had detectable outer segments that were abnormally shortened. Adaptive optics imaging confirmed the existence of inner segments at a spatial density greater than that expected for the residual blue cones. The evidence indicates that human cones in patients with deletions in the red/green opsin gene array can survive in reduced numbers with limited outer segment material, suggesting potential value of gene therapy for BCM.

X-linked megalocornea (MGC1) is an ocular anterior segment disorder characterized by an increased cornea diameter and deep anterior chamber evident at birth and later onset of mosaic corneal degeneration (shagreen), arcus juvenilis, and presenile cataracts. We identified copy-number variation, frameshift, missense, splice-site and nonsense mutations in the Chordin-like 1 gene (CHRDL1) on Xq23 as the cause of the condition in seven MGC1 families. CHRDL1 encodes ventroptin, a bone morphogenic protein antagonist with a proposed role in specification of topographic retinotectal projections. Electrophysiological evaluation revealed mild generalized cone system dysfunction and, in one patient, an interhemispheric asymmetry in visual evoked potentials. We show that CHRDL1 is expressed in the developing human cornea and anterior segment in addition to the retina. We explored the impact of loss of ventroptin function on brain function and morphology in vivo. CHRDL1 is differentially expressed in the human fetal brain, and there is high expression in cerebellum and neocortex. We show that MGC1 patients have a superior cognitive ability despite a striking focal loss of myelination of white matter. Our findings reveal an unexpected requirement for ventroptin during anterior segment development and the consequences of a lack of function in the retina and brain.

48,XXYY syndrome was first described in 1964 and approximately 100 cases have been reported in the literature. We report a case of 48,XXYY syndrome associated with high myopia and retinal dysfunction. Case report. A 28-year-old man was referred with progressive deterioration of visual acuity (VA) bilaterally during the previous 4–5 years. Physical examination revealed tall stature, large feet and irregular teeth. Refraction revealed high myopia with VA 6/60 bilaterally. Fundoscopy revealed a normal vitreous, lightly pigmented retinal pigment epithelium and choroid but no bone spicules or overt signs of retinal degeneration. His visual fields were constricted. Electrodiagnostic testing revealed bilateral generalised retinal dysfunction with severe macular involvement. During follow-up, his ophthalmic examination did not exhibit significant changes while VA was gradually deteriorating. Eight years after presentation, VA was 3/60 bilaterally; electrophysiological testing showed no further change. At that stage, his parents consented for DNA analysis in order to determine the cause of retinal dysfunction. Chromosomal analysis revealed an abnormal male karyotype with two X chromosomes and two Y chromosomes consistent with 48,XXYY syndrome. The present report is the first to describe retinal dysfunction and high myopia with 48,XXYY syndrome. The severe macular and generalised retinal dysfunction in this case are not those associated with myopia and are in keeping with a primary retinal dysfunction. A coincidental finding cannot be excluded, but ERGs have not previously been reported in 48,XXYY syndrome, and retinal dystrophy may be a previously undiagnosed component of this syndrome.