Barrie Jay

Autosomal dominant retinitis pigmentosa: four new mutations in rhodopsin, one of them in the retinal attachment site

Several mutations in the rhodopsin gene in patients affected by autosomal dominant retinitis pigmentosa (ADRP) have recently been described. We report four new rhodopsin mutations in ADRP families, initially identified as hetero-duplexed PCR fragments on hydrolink gels. One is an in-frame 12-bp deletion of codons 68 to 71. The other three are point mutations involving codons 190, 211, and 296. Each alters the amino acid encoded. The codon 190 mutation has been detected in 2 from a panel of 34 ADRP families, while the remaining mutations were seen in single families. This suggests that, consistent with a dominant condition, no single mutation will account for a large fraction of ADRP cases. The base substitution in codon 296 alters the lysine residue that functions as the attachment site for 11-cis-retinal, mutating it to glutamic acid. This mutation occurs in a family with an unusually severe phenotype, resulting in early onset of disease and cataracts in the third or fourth decade of life. This result demonstrates a correlation between the location of the mutation and the severity of phenotype in rhodopsin RP.

Relapse following goniotomy for congenital glaucoma due to trabecular dysgenesis

Three hundred and thirty-five eyes of 210 patients with congenital glaucoma due to trabecular dysgenesis were treated by goniotomy as the primary procedure in infancy. In 313 eyes (93.5%) glaucoma was controlled at one year following surgery. Using Kaplan Meier actuarial survival analysis we found that eyes controlled in infancy by one or more goniotomies are at risk of relapse of glaucoma for at least 15 years although 93% of eyes are still controlled five years after the initial surgery. Patients whose symptoms of congenital glaucoma presented at birth were more likely to relapse than those whose symptoms developed in the first few months of life. Eyes requiring multiple goniotomies in infancy were more likely to relapse than those controlled by a single procedure.

Prenatal diagnosis of X-linked choroideremia with mental retardation, associated with a cytologically detectable X-chromosome deletion

SummaryWe describe a family in which an X-chromosome deletion is segregating with choroideremia, an X-linked recessive condition. The DNA sequences DXYS1 and DXS3, defined by the probes pDP34 and 19.2 respectively, are absent in the affected male (who is also mentally retarded), and hemizygous in his mother and in his carrier sister, who presented early in pregnancy. Analysis of chorionic villus DNA formed the basis of prenatal exclusion of choroideremia in her male fetus. In three female relatives, studied with late-labelling techniques, the deleted X was preferentially inactivated in 86–100% of cells studied. This family confirms the localisation of the choroideremia locus to within Xq13→21, and places the loci for anhidrotic ectodermal dysplasia and the X-linked immunodeficiencies outside this region.

No evidence for linkage between late onset autosomal dominant retinitis pigmentosa and chromosome 3 locus d3s47 c17 evidence for genetic heterogeneity

Retinitis pigmentosa is an inherited form of blindness caused by progressive retinal degeneration. P. McWilliam et al. (1989, Genomics 5: 619-622) demonstrated close genetic linkage between autosomal dominant retinitis pigmentosa (ADRP) and locus D3S47 (C17) in a single early onset pedigree. The marker C17 maps to the long arm of chromosome 3. Clinically, the disease phenotype has been subdivided into at least two forms on the basis of age of onset, as well as electrodiagnostic criteria. We demonstrate that C17 is unlinked in a late onset pedigree, indicating that the phenotypic variation seen reflects underlying genetic heterogeneity.

Pigmented Lesions of the Retinal Pigment Epithelium and Familial Adenomatous Polyposis.

Bilateral pigmented fundus lesions were found in 65 out of 72 patients with familial adenomatous polyposis, an additional five patients having unilateral lesions. With a family history of familial adenomatous polyposis, the occurrence of multiple bilateral fundus lesions indicates the presence of the abnormal gene, as does the occurrence of oval pigmented lesions with surrounding pale haloes. The absence of pigmented fundus lesions does not exclude the abnormal genotype, while the presence of occasional pigmented spots can be found in an appreciable percentage of the population. Ocular examination would, however, appear to be valuable in screening those at risk, with a positive yield in most carriers of the gene for familial adenomatous polyposis.

Linkage analysis in X-linked congenital stationary night blindness

X-linked congenital stationary night blindness (XL-CSNB) is a nonprogressive disorder of the retina, characterized by night blindness, reduced visual acuity, and myopia. Previous studies have localized the CSNB1 locus to the region between OTC and TIMP on the short arm of the X chromosome. We have carried out linkage studies in three XL-CSNB families that could not be classified as either complete or incomplete CSNB on the criteria suggested by Miyake et al. (1986. Arch. Ophthalmol. 104: 1013-1020). We used markers for the DXS538, DMD, OTC, MAOA, DXS426, and TIMP loci. Two-point analyses show that there is close linkage between CSNB and MAOA (theta max = 0.05, Zmax = 3.39), DXS426 (theta max = 0.06, Zmax = 2.42), and TIMP (theta max = 0.07, Zmax = 2.04). Two multiply informative crossovers are consistent with CSNB lying proximal to MAOA and distal to DXS426, respectively. Multipoint analysis supports this localization, giving the most likely order as DMD-17 cM-MAOA-7.5 cM-CSNB-7.5 cM-DXS426/TIMP-cen, and thus refines the localization of CSNB.

Genetic linkage between X-linked retinitis pigmentosa and DNA probe DXS7 {L1.28}: further linkage data, heterogeneity testing, and risk estimation

SummaryFurther linkage data relating X-linked retinitis pigmentosa and DNA probe DXS7 {L1.28} is presented in this paper. The current mean estimate of the recombination fraction (θ) including this and all published data, is 0.09, with confidence limits 0.04 to 0.17 (maximum Lod score of 14.01 at a θ of 0.08). There is no evidence for heterogeneity of recombination fraction between the 13 families for which data are available. However, it is argued that heterogeneity should be assumed to exist for the purposes of risk estimation. Mean estimates and variances of risk are calculated for hypothetical families each with different linkage data. In families in which no recombination has been observed, the mean and variance of risk are sufficiently small for the clinical use of this probe to be acceptable to many.

Aortic compliance in connective tissue disorders affecting the eye

Several connective tissue diseases are characterized by specific ocular changes. When these diseases affect the aortic wall as in Marfan syndrome, Ehlers-Danlos syndrome and homocystinuria, abnormal aortic compliance measurements enable us to make a diagnosis, even in a mildly affected individual, which allows for early and frequent ophthalmological assessment to minimize the effect of ocular manifestations.

X-linked ocular albinism

SummaryA pedigree of X-linked ocular albinism is presented containing nine affected males and 10 heterozygous females. One carrier female showed ocular changes similar to those of affected males. She is considered to be a manifesting heterozygote, a situation explained by the Lyon hypothesis. One affected male married a female with autosomal recessive ocular albinism and produced one daugher with the fundus changes of the carrier state of X-linked ocular albinism, and one son with normal eyes. The daughter did not show any evidence of the additive effect of the two different genes for X-linked and autosomal recessive ocular albinism.

In-Utero Diagnosis of Norrie Disease by Ultrasonography

Obstetric ultrasonography of an obligate Norrie disease carrier revealed bilateral retinal detachments in a third trimester male fetus. Postnatal examination confirmed the diagnosis of Norrie disease. DNA linkage analysis with the markers L1.28 and MAO had been uninformative for this family. This report suggests that retinal detachment occurs late in the gestation of the affected fetus.