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Biomedical subjects

A T Moore

Publications and source records attributed to A T Moore.

At least 73 records · Page 4Linked to original sources
PubMed1998

The cone dystrophies.

The cone dystrophies are a heterogeneous group of inherited disorders that result in dysfunction of the cone photoreceptors and sometimes their post-receptoral pathways. The major clinical features of cone dystrophy are photophobia, reduced visual acuity and abnormal colour vision. Ganzfeld electroretinography shows reduced or absent cone responses. On the basis of their natural history, the cone dystrophies may be broadly divided into two groups: stationary and progressive cone dystrophies. The stationary cone dystrophies have received more attention, and subsequently our knowledge of their molecular genetic, psychophysical and clinical characteristics is better developed. Various methods of classification have been proposed for the progressive cone dystrophies, but none is entirely satisfactory, largely because the underlying disease mechanisms are poorly understood. Multidisciplinary studies involving clinical assessment, molecular genetics, electrophysiology and psychophysics should lead to an improved understanding of the pathogenesis of these disorders.

Color Vision Defects↗
PubMed1998

An analysis of phenotypic variation in the familial cancer syndrome von Hippel-Lindau disease: evidence for modifier effects.

von Hippel-Lindau disease (VHL) is a dominantly inherited familial cancer syndrome predisposing to ocular and CNS hemangioblastomas, renal-cell carcinoma (RCC), and pheochromocytoma. Both interfamilial and intrafamilial variability in expression is well recognized. Interfamilial differences in pheochromocytoma susceptibility have been attributed to allelic heterogeneity such that specific missense germ-line mutations confer a high risk for this complication. However, in most cases, tumor susceptibility does not appear to be influenced by the type of underlying VHL mutation. To probe the causes of phenotypic variation, we examined 183 individuals with germ-line VHL gene mutations, for the presence and number of ocular tumors. The prevalence of ocular angiomatosis did not increase with age, and the distribution of these tumors in gene carriers was significantly different than the expected stochastic distributions. Individuals with ocular hemangioblastomas had a significantly increased incidence of cerebellar hemangioblastoma and RCC (hazard ratios 2.3 and 4.0, respectively). The number of ocular tumors was significantly correlated in individuals of 12 degree relatedness but not in more distantly related individuals. These findings suggest that the development of VHL ocular tumors is determined at an early age and is influenced by genetic and/or environmental modifier effects that act at multiple sites. Functional polymorphisms in the glutathione-S-transferase M1 gene (GSTM1) or the cytochrome P450 2D6 gene (CYP2D6) did not show a significant association with the severity of ocular or renal involvement.

Adolescent↗
PubMed1998

Mutations in the retinal guanylate cyclase (RETGC-1) gene in dominant cone-rod dystrophy.

The dominant cone-rod dystrophy gene CORD6 has previously been mapped to within an 8 cM interval on chromosome 17p12-p13. The retinal-specific guanylate cyclase gene (RETGC-1), which maps to within this genetic interval and previously was implicated in Leber's congenital amaurosis, was screened for mutations within this family and in a panel of small families and individuals with various cone and cone- rod dystrophy phenotypes. A missense mutation (E837D) was identified in affected members of the CORD6 family, as well as a second missense mutation (R838C) in three other families with dominant cone-rod dystrophy. RETGC-1 is only the fourth gene to be implicated in cone-rod dystrophy and this is the first report of dominant mutations in this gene.

Adolescent↗
PubMed1998

Phenotype of a British North Carolina macular dystrophy family linked to chromosome 6q.

AIMS: To document the phenotype of an autosomal dominant macular dystrophy diagnosed as having North Carolina macular dystrophy (NCMD) in this British family, and to verify that the disease locus corresponds with that of MCDR1 on chromosome 6q. METHODS: 37 family members were examined and the phenotype characterised. DNA samples from the affected members, 19 unaffected and five spouses, were used to perform linkage analysis with six microsatellite marker loci situated within the MCDR1 region of chromosome 6q. RESULTS: Every affected family member had lesions characteristic of NCMD, which developed early in life and usually remain stable thereafter. Although fundus changes are evident in the periphery, all tests revealed that functional loss is restricted to the macula. Some patients with large macular lesions had good visual acuity with fixation at the edge of the lesion at 5 degrees eccentricity. Significant linkage to the MCDR1 locus on chromosome 6q was obtained with three marker loci, with a maximum lod score of 5.9 (q = 0.00) obtained with D6S249. CONCLUSION: This family has the typical phenotype NCMD, and the causative gene was linked to the disease locus (MCDR1) on chromosome 6q. Early onset and localisation of the disease to the central macula allow specialisation of eccentric retina in some eyes with resultant good visual acuity.

Adolescent↗
PubMed1998

Clinical features, molecular genetics, and pathophysiology of dominant optic atrophy.

Inherited optic neuropathies are a significant cause of childhood and adult blindness and dominant optic atrophy (DOA) is the most common form of autosomally inherited (non-glaucomatous) optic neuropathy. Patients with DOA present with an insidious onset of bilateral visual loss and they characteristically have temporal optic nerve pallor, centrocaecal visual field scotoma, and a colour vision deficit, which is frequently blue-yellow. Evidence from histological and electrophysiological studies suggests that the pathology is confined to the retinal ganglion cell. A gene for dominant optic atrophy (OPA1) has been mapped to chromosome 3q28-qter, and studies are under way to refine the genetic interval in which the gene lies, to map the region physically, and hence to clone the gene. A second locus for dominant optic atrophy has recently been shown to map to chromosome 18q12.2-12.3 near the Kidd blood group locus. The cloning of genes for dominant optic atrophy will provide important insights into the pathophysiology of the retinal ganglion cell in health and disease. These insights may prove to be of great value in the understanding of other primary ganglion cell diseases, such as the mitochondrially inherited Leber's hereditary optic neuropathy and other diseases associated with ganglion cell loss, such as glaucoma.

Chromosome Mapping↗
PubMed1997

Linkage mapping in 29 Bardet-Biedl syndrome families confirms loci in chromosomal regions 11q13, 15q22.3-q23, and 16q21.

Bardet-Biedl syndrome (BBS) is a clinically and genetically heterogeneous autosomal recessive disorder characterized by retinitis pigmentosa, polydactyly, obesity, hypogenitalism, mental retardation, and renal anomalies. To detect linkage to BBS loci, 29 BBS families, of mixed but predominantly European ethnic origin, were typed with 37 microsatellite markers on chromosomes 2, 3, 11, 15, 16, and 17. The results show that an estimated 36-56% of the families are linked to the 11q13 chromosomal site (BBS1) previously described by M. Leppert et al. (1994, Nature Genet. 7, 108-112), with the gene order cen-D11S480-5 cM-BBS1-3 cM-D11S913/D11S987-qter. A further 32-35% of the families are linked to the BBS4 locus, reported by R. Carmi et al. (1995, Hum. Mol. Genet. 4, 9-13) in chromosomal region 15q22.3-q23, with the gene order cen-D15S125-5 cM-BBS4-2 cM-D15S131/D15S204-qter. Three consanguineous BBS families are homozygous for three adjacent chromosome 15 markers, consistent with identity by descent for this region. In one of these families haplotype analysis supports a localization for BBS4 between D15S131 and D15S114, a distance of about 2 cM. Weak evidence of linkage to the 16q21 (BBS2) region reported by A. E. Kwitek-Black et al. (1993, Nature Genet. 5, 392-396) was observed in 24-27% of families with the gene order cen-D16S408-2 cM-BBS2-5 cM-D16S400. A fourth group of families, estimated at 8%, are unlinked to all three of the above loci, showing that at least one other BBS locus remains to be found. No evidence of linkage was found to markers on chromosome 3, corresponding to the BBS3 locus, reported by V. C. Sheffield et al. (1994, Hum. Mol. Genet. 3, 1331-1335), or on chromosome 2 or 17, arguing against the involvement of a BBS locus in a patient with a t(2;17) translocation.

Abnormalities, Multiple↗
PubMed1997

A locus for autosomal dominant posterior polar cataract on chromosome 1p.

Autosomal dominant congenital cataract is a clinically and genetically heterogeneous lens disease. Here we report the linkage of a locus for autosomal dominant posterior polar cataract (CPP) to the distal short arm of chromosome 1. To map the CPP locus we performed molecular genetic linkage analysis using microsatellite markers in a three-generation pedigree. After exclusion of 13 known loci and candidate lens genes for autosomal dominant cataract, we obtained significantly positive LOD scores for markers D1S508 (Z = 3.14, theta = 0) and D1S468 (Z = 2.71, theta = 0). Multipoint analysis gave a maximum LOD score of 3.48 (theta = 0.07) between markers D1S508 and D1S468. From haplotype data, however, CPP probably lies in the telomeric interval D1S2845-1pter, which includes the locus for the clinically distinct Volkman congenital cataract (CCV). This study provides the first evidence for genetic heterogeneity of autosomal dominant posterior polar cataract for which a locus had been linked previously to chromosome 16q.

Cataract↗
PubMed1997

Localisation of a gene for dominant cone-rod dystrophy (CORD6) to chromosome 17p.

We have performed genetic linkage analysis on a four generation British family with cone-rod dystrophy. Significant linkage to the disease gene was obtained with eight marker loci situated on chromosome 17p12-p13. A maximum two-point lod score of 5.93 with no recombination was obtained with marker locus D17S1844. Critical recombinants identified with flanking marker loci placed the disease gene between D17S796/D17S938 and D17S954, an interval estimated to be 8 cM in size. This new localisation for autosomal dominant cone-rod dystrophy (CORD6) overlaps with regions attributed previously to Leber's congenital amaurosis, central areolar choroidal dystrophy and dominant cone dystrophy. Given their differences in phenotype, the most plausible explanation would be that these different retinal disorders are caused by mutations in different genes mapping close together within the genome.

Chromosome Mapping↗
PubMed1997

Genetic refinement of dominant optic atrophy (OPA1) locus to within a 2 cM interval of chromosome 3q.

Autosomal dominant optic atrophy (OPA, MIM 165500) is an eye disease characterised by variable optic atrophy and reduction in visual acuity. It has an insidious onset in the first decade of life and is clinically highly heterogeneous. It is associated with a centrocecal scotoma of varying size and density and an acquired blue-yellow dyschromatopsia. Recent studies of three large Danish pedigrees have mapped a gene for dominant optic atrophy (OPA1) to a 10 cM region on chromosome 3q, between markers D3S1314 and D3S1265 (3q28-qter). Genetic linkage analysis in five British pedigrees confirms mapping to chromosome 3q28-qter. Haplotype analysis of a seven generation pedigree positions the disease causing gene between loci D3S3590 and D3S1305, corresponding to a genetic distance of 2 cM. This represents a significant linkage refinement and should facilitate positional cloning of the disease gene.

Adolescent↗
PubMed1996

Clinical features in affected males with X-linked retinoschisis.

OBJECTIVES: To assess the phenotypic variation and visual prognosis of affected males with X-linked retinoschisis. DESIGN: Patients were ascertained from clinical geneticists and ophthalmologists in the United Kingdom. Genetic linkage analysis was carried out using polymorphic microsatellite markers from the Xp22 region of the X chromosome. PATIENTS: Fifty-six males from 16 British families with X-linked retinoschisis. RESULTS: Best-corrected visual acuity ranged from 20/20 to 20/600; 14 (25%) of the patients saw 20/40 or better, and 27 (55%) read N6 or better. Visual acuity was poorer in older patients (chi 2 =30.4, df=4, P<.001). Macular abnormalities were seen in all eyes. Foveal schisis was the most common abnormality seen in patients younger than 40 years (73 eyes [83%]), but in older patients a blunted foveal reflex or pigmentary atrophy was more common (17 eyes [85%]). Peripheral retinoschisis was seen in 40 (71%) of the patients. Vitreous hemorrhage occurred in 12 (21%) and retinal detachment in nine (16%) of the patients. Four eyes were blind as a result of retinal detachment. CONCLUSIONS: Although no evidence exists for genetic heterogeneity in X- linked retinoschisis, there is wide phenotypic variation. The most serious sight-threatening complications are vitreous hemorrhage and retinal detachment. In uncomplicated cases, the prognosis for vision is good, although deterioration of vision occurs in the fourth and fifth decades of life because of macular atrophy.

Adolescent↗
PubMed1996

A locus for autosomal dominant anterior polar cataract on chromosome 17p.

Inherited cataract is a clinically and genetically heterogeneous disease. Here we report the identification of a new locus for an autosomal dominant anterior polar cataract on the short arm of chromosome 17. To map this new locus we performed genetic linkage analysis with microsatellite markers in a four-generation pedigree. After exclusion of seven candidate loci for cataract, we obtained significant positive LOD scores for markers D17S849 (Z = 4.01 / theta = 0.05) and D17S796 (Z = 4.17 / theta = 0.05). Multipoint analysis gave a maximum LOD score of 5.2 (theta max = 0.06) between these two markers. From haplotype analysis, the cataract locus lies in the 13 cM interval between markers D17S849 and D17S796. This study provides the first genetic mapping of an autosomal dominant anterior polar cataract.

Cataract↗
PubMed1996

Molecular genetics of central retinal dystrophies.

A range of chorioretinal dystrophies that principally affect the central retina have recently been associated with either specific genetic mutations or mapped to refined genomic loci. Mutations of two genes, peripherin/RDS (chromosome 6p) and TIMP3 (chromosome 22q) have been shown to be of particular importance to this group of disorders. Other conditions such as Stargardt's disease, Best's disease, pattern dystrophy, cone dystrophy and cone-rod dystrophy have been mapped to different regions of the genome, however the underlying genetic mutations await identification. Molecular genetic diagnostic techniques are now available for a number of central choroidoretinal dystrophies allowing for earlier, accurate diagnosis and laying the groundwork for future studies of potential therapeutic protocols.

Eye Proteins↗
PubMed1996

Preschool vision screening: outcome of children referred to the hospital eye service.

AIMS: To assess the outcome of children referred to the hospital eye service (HES) from an orthoptist based preschool vision screening programme. METHODS: A retrospective study was conducted of children referred from screening during a 2 year period. Children were screened by community orthoptists at 3 1/2 years of age. The main outcome measures were (1) HES findings for children referred from screening, and (2) visual outcome for amblyopic children after completion of treatment. RESULTS: The attendance rate at screening was 79.3% (6794 children): 348 children (5.1% of those screened) were referred to the HES. The HES findings were refractive error (32.9%), amblyopia (29.9%), false positive referral (20.1%), strabismus (13.2%), and other ocular disorders (3.9%). The positive predictive value of screening was 79.9%. Screening detected 48 children with straight eyed amblyopia and 43 children with strabismic amblyopia. A visual acuity of 6/9 or better in the amblyopic eye was achieved by 87.2% of straight eyed amblyopes and 64.3% of strabismic amblyopes (chi 2 = 5.27, p = 0.02). Residual amblyopia of 6/24 or worse occurred in only 5.6% of amblyopic children. CONCLUSION: Most amblyopic children detected by preschool vision screening achieve a good visual outcome with treatment. While treatment earlier in the sensitive period might be expected to give improved results, it remains to be demonstrated that preschool screening results in a better outcome than screening at school entry. Preschool vision screening also detects a significant number of children without amblyopia who have reduced vision due to refractive errors. This group of children must be included in any analysis of the cost effectiveness of preschool vision screening.

Amblyopia↗
PubMed1996

Improved genetic mapping of X linked retinoschisis.

X linked retinoschisis (RS) causes poor vision in affected males owing to radial cystic changes at the macula. Genetic linkage analysis was carried out in 16 British families with X linked retinoschisis using markers from the Xp22 region. Linkage was confirmed between the RS locus and the markers DXS207 (lod score, Zmax = 17.9 at recombination fraction theta = 0.03; confidence interval for theta = 0.007-0.09), DXS1053 (Zmax = 18.0 at theta = 0.01, CI = 0.001-0.06), DXS43 (Zmax = 12.9 at theta = 0.03, CI = 0.004-0.09), DXS1195 (Zmax = 6.4 at theta = 0.00), DXS418 (Zmax = 8.2 at theta = 0.00), DXS999 (Zmax = 21.2 at theta = 0.01, CI = 0.001-0.05), DXS443 (Zmax = 14.2 at theta = 0.03, CI = 0.004-0.09), DXS365 (Zmax = 24.5 at theta = 0.008, CI = 0.001-0.04). Key recombinants placed RS between DXS43 distally and DXS999 proximally. Multipoint linkage analysis gave odds of 344:1 in favour of this location for RS and supported the map Xpter-(DXS207, DXS1053)-DXS43-1 cM-RS-1 cM-DXS999-DXS443-DXS365-DXS1052-Xcen.

Chromosome Mapping↗
PubMed1996

Phenotypic expression in von Hippel-Lindau disease: correlations with germline VHL gene mutations.

Von Hippel-Lindau disease is an autosomal dominantly inherited familial cancer syndrome predisposing to retinal and central nervous system haemangioblastomas, renal cell carcinoma, and phaeochromocytoma. VHL disease shows variable expression and interfamilial differences in predisposition to phaeochromocytoma. In a previous study of 65 VHL kindreds with defined VHL mutations we detected significant differences between VHL families with and without phaeochromocytoma such that missense mutations were more common and large deletions or protein truncating mutations less frequent in phaeochromocytoma positive families. To investigate the significance and cause of this association further, we studied 138 VHL kindreds for germline mutations and calculated the age related tumour risks for different classes of VHL gene mutations. Using SSCP, heteroduplex and Southern analysis we identified a germline VHL gene mutation in 101 families (73%). Direct sequencing of the VHL coding region further increased the mutation detection rate to 81%. In addition to precise presymptomatic diagnosis, identification of a VHL gene mutation can provide an indication of the likely phenotype. We found that large deletions and mutations predicted to cause a truncated protein were associated with a lower risk of phaeochromocytoma (6% and 9% at 30 and 50 years, respectively) than missense mutations (40% and 59%, respectively) and that missense mutations at codon 167 were associated with a high risk of phaeochromocytoma (53% and 82% at ages 30 and 50 years). Cumulative probabilities of renal cell carcinoma did not differ between the two groups (deletion/ truncation mutations: 8% and 60%, and missense mutations: 10% and 64% at ages 30 and 50 years, respectively). Age related risks for haemangioblastoma were similar in the two mutation groups, with the age related risks of cerebellar haemangioblastoma slightly less (35% and 64% v 38% and 75% at ages 30 and 50 years) and retinal haemangioblastoma slightly higher (45% and 72% v 37% and 64% at ages 30 and 50 years) in the missense mutation group than in the deletion/protein truncation group. These results provide valuable data for counselling VHL families and indicate that specific VHL mutations may be associated with different tumour susceptibility risks. There was no evidence of a generalised increase in age related tumour risks for missense mutations, suggesting that missense mutations predisposing to phaeochromocytoma have tissue specific effects, possibly because the VHL protein has several functions, the importance of which varies from tissue to tissue, or because the proteins which interact with VHL differ between different tissues.

Adolescent↗