Figure 1. The phenotype of a 63-year-old woman showing unilateral right-sided retinal dystrophy (A) and patchy hypofluorescence in the periphery (B). There is unilateral right-sided absence of the photoreceptor–pigment epithelium complex in the peripheral retina on optical coherence tomography (C), a narrowed Goldmann visual field (D), and a severely affected rod and cone system on electroretinography (E). DA indicates dark adapted; LA, light adapted; PERG, pattern electroretinography; RE, right eye; and LE, left eye.
Figure 2. Pedigree and electropherogram. A, Pedigree showing dominant inheritance. Squares indicate males; circles, females; diamond, unknown sex; diagonal lines, deceased; open symbols, unaffected; solid symbols, affected; and arrow, proband. B, Electropherogram displaying the heterozygous c.2029C>T change in forward and reverse strands as compared with the reference sequence (top line).
Mukhopadhyay R, Holder GE, Moore AT, Webster AR. Unilateral Retinitis Pigmentosa Occurring in an Individual With a Germline Mutation in the RP1 Gene. Arch Ophthalmol. 2011;129(7):954-956. doi:10.1001/archophthalmol.2011.171
Author Affiliations: Moorfields Eye Hospital NHS Foundation Trust and University College London Institute of Ophthalmology, London, England.
Retinitis pigmentosa (RP) is a heterogeneous group of monogenic retinal disorders characterized by progressive rod and then cone photoreceptor degeneration. Although female carriers of mutations in the X-linked genes RP2 and RP3 show asymmetry, cases due to mutations of autosomal genes show a high degree of symmetry between eyes. Patients with unilateral RP have been described,1- 3 but none of these cases have been reported to be familial or associated with a gene mutation and the cause of these cases remains unclear. We describe the phenotype of a patient with entirely unilateral disease despite the inheritance of a germline mutation.
The study adhered to the tenets of the Declaration of Helsinki and was approved by the local ethics committee.
A 63-year-old woman was visually asymptomatic but was found to have retinal signs as an incidental observation. Subsequent review showed best-corrected visual acuity of 20/30 OU. Anterior segment examination of both eyes revealed posterior subcapsular cataracts. Dilated funduscopy revealed narrow arterioles, retinal pigment epithelial atrophy, and bone-spicule intraretinal pigment deposition in all quadrants of the peripheral retina in the right eye with sparing of the macular region (Figure 1). The left fundus was completely normal. There was no abnormality of color vision (Hardy-Rand-Rittler and Ishihara pseudoisochromatic charts) in either eye.
Goldmann peripheral fields were normal in the right eye but showed generalized constriction to 10° transversely with a III4e target in the left. Fundus autofluorescence of the right eye showed patchy hypofluorescence in the midperipheral retina and a hyperfluorescent ring in the macular region; the left eye was normal. Optical coherence tomographic findings of the left eye were normal. The right eye showed preservation of the outer retinal architecture in the foveal and parafoveal regions with loss in the more peripheral macula (Figure 1).
The full-field electroretinogram (ERG) of the left eye was normal. The ERGs in the right eye showed undetectable rod-specific findings; a delayed and markedly subnormal bright-flash ERG a-wave and proportional b-wave; and markedly subnormal but not delayed results on 30-Hz flicker and single-flash photopic ERGs. Pattern ERG results were bilaterally normal. Electro-oculogram light rise was undetectable on the right and normal on the left.
The patient is part of a family showing dominantly segregating RP (Figure 2). Sequencing exon 4 of the RP1 gene revealed a p.R677X mutation, which segregated with the disease in the family.
We describe the clinical findings in the first case, to our knowledge, of unilateral RP in a person carrying a germline mutation. Detailed evaluation confirmed the dysfunction to be confined to one eye.
The heterozygous nonsense mutation p.R677X, detected in RP1 from the leukocyte DNA of the patient, is one of the most common causes of autosomal dominant RP.4 Although all of the mutations in RP1 causing dominant RP result in truncation of the protein, in human cultured lymphoblasts the p.R677X allele is shown to be expressed.5 Therefore, haploinsufficiency is unlikely and a toxic or dominant negative effect of the truncated protein is possible. It is difficult to propose that the complete unilaterality of the disease in this patient is due to differences in environmental or genetic exposures between the two eyes. One possibility might be a somatic mutation in a progenitor cell during the development of the unaffected retinal tissue that ameliorates the effect of the mutation.
To conclude, this represents the first report to our knowledge of unilateral disease occurring in a patient with a germline mutation for a known RP-associated variant. The phenotype, even when investigated carefully, is entirely normal in the unaffected eye. A somatic, embryonic mutation causing mosaicism at this locus is proposed.
Correspondence: Dr Mukhopadhyay, University College London Institute of Ophthalmology, 11-43 Bath St, London EC1V 9EL, England (firstname.lastname@example.org).
Financial Disclosure: None reported.
Funding/Support: This work was supported by grants from the British Retinitis Pigmentosa Society, Foundation Fighting Blindness USA, Fight for Sight, and the National Institute for Health Research UK to the Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital and University College London Institute of Ophthalmology.