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Biomedical subjects

A T Moore

Publications and source records attributed to A T Moore.

At least 55 records · Page 3Linked to original sources
PubMed2001

PAX6 haploinsufficiency causes cerebral malformation and olfactory dysfunction in humans.

PAX6 is widely expressed in the central nervous system. Heterozygous PAX6 mutations in human aniridia cause defects that would seem to be confined to the eye. Magnetic resonance imaging (MRI) and smell testing reveal the absence or hypoplasia of the anterior commissure and reduced olfaction in a large proportion of aniridia cases, which shows that PAX6 haploinsuffiency causes more widespread human neuro developmental anomalies.

Adult↗
PubMed2000

MRI of the intraorbital optic nerve in patients with autosomal dominant optic atrophy.

Measurements of the intraorbital optic nerve were made using high-resolution coronal MRI in 10 adults with autosomal dominant optic atrophy. Comparisons were made with previous studies of 10 normal adult subjects. The cross-sectional diameters of the optic nerve and the perineural subarachnoid space were measured and a ratio of there diameters at anterior, mid and posterior positions along the optic nerve was determined. We found a statistically significant difference in the mean optic nerve: sheath ratio between the control group and patients with autosomal dominant optic atrophy. At anterior, mid and posterior locations along the optic nerve it is significantly smaller in patients with optic atrophy. We have demonstrated that the loss of ganglion cells, previously documented in dominant optic atrophy, is associated with a significant loss of optic nerve tissue and thinning of the nerve along its length.

Case-Control Studies↗
PubMed2000

Autosomal dominant cone-rod retinal dystrophy (CORD6) from heterozygous mutation of GUCY2D, which encodes retinal guanylate cyclase.

OBJECTIVE: To describe the clinical features of autosomal dominant cone-rod retinal dystrophy (CRD) in a British family mapping to chromosome 17p12-p13 (CORD6), with a heterozygous mutation (Glu837Asp/ Arg838Ser) of GUCY2D. DESIGN: A prospective, clinical family survey. PATIENTS: Ten affected members of a family with autosomal dominant CRD. METHODS: Full clinical examinations were undertaken. Selected affected family members underwent electrophysiologic evaluation, scotopic static perimetry, dark adaptometry, and color vision assessment. MAIN OUTCOME MEASURES: Clinical appearance and electroretinographic responses. RESULTS: Typical clinical and electroretinographic features of childhood-onset CRD were recorded. In addition, moderate myopia and pendular nystagmus were seen in affected individuals. Color vision assessment in the youngest affected individual showed no color discrimination on a tritan axis, but retention of significant red-green discrimination. Electronegative electroretinogram responses were seen on electrophysiology in the only young family member examined. CONCLUSIONS: The phenotype associated with GUCY2D CRD is clinically distinct from that associated with other dominant CRD loci. Unusual electroretinographic responses may indicate that this mutation of GUCY2D is associated with early defects in photoreceptor synaptic transmission to second-order neurons.

Adolescent↗
PubMed2000

Who should manage primary retinal detachments?

PURPOSE: To determine whether the outcome of primary retinal reattachment surgery in a subregion is improved by surgery being performed in a specialist vitreoretinal unit (VRU). METHODS: A subregional, population-based, retrospective audit cycle of primary retinal reattachment surgery was conducted by independent investigators. The subregion was defined as the catchment area of a teaching hospital (TH) with a specialist VRU and three neighbouring district general hospitals (DGHs). During the initial audit period (January 1989 to December 1990), 142 cases were treated at all four hospitals: TH/VRU (83), DGH-A (15), DGH-B (13), and DGH-C (31). Policy changes after the initial audit led to primary retinal reattachment surgery being predominantly performed by the VRU. During the re-audit period (September 1995 to August 1997), 160 cases were treated at two hospitals: VRU (148) and DGH-C (12). The outcome measure employed was complete retinal reattachment after a single procedure with a minimum follow-up of 12 months. RESULTS: The success rate for primary retinal reattachment surgery in the subregion improved from 76.1% to 88.8% (p = 0.006) following the policy changes. The success rate of the vitreoretinal specialists in the VRU (90%) was greater than the general ophthalmologists in the DGHs (ranging from 47% to 77%), despite case selection by the general ophthalmologists. The number of cases treated by the VRU increased by 156% in the 6.5 year interval between the two audits due to a widespread change in the model of care for primary retinal detachments (both within and outside the subregion). During the re-audit period, the VRU treated 348 primary retinal detachments (including referrals from outside the subregion), achieving a success rate of 86.8% with a single procedure and 97.4% with further surgery. This primary success rate included 35 cases (10%) treated by vitrectomy with silicone oil tamponade who did not undergo silicone oil removal. CONCLUSIONS: The outcome of primary retinal reattachment surgery can be improved if surgery is performed by a specialist VRU. It is suggested that the current standard for retinal reattachment with a single procedure should be set in the region of 85% to 90%. Changing the model of care so that primary retinal reattachment surgery is predominantly performed by a specialist VRU has important resource implications.

England↗
PubMed2000

Genetic susceptibility to age related macular degeneration.

Age related macular degeneration (AMD) is the leading cause of visual impairment in the elderly and a major cause of blindness in the developed world. The disease can take two forms, geographic atrophy and choroidal neovascularisation. The pathogenesis of AMD is poorly understood. There are undoubtedly environmental and other risk factors involved and the adverse effect of smoking is well established. Several studies have shown that genetic factors are important but leave uncertainty about the magnitude and nature of the genetic component and whether it varies with the type of AMD. Several hereditary retinal dystrophies show similarities to AMD and these genes are potential candidate susceptibility genes. Particular interest has focused on the ABCR gene which is responsible for autosomal recessive Stargardt macular dystrophy. It has been claimed that heterozygotes for ABCR mutations are predisposed to AMD but the data are conflicting. Studies of the genes responsible for autosomal dominant Sorsby fundus dystrophy, Doyne honeycomb retinal dystrophy, and Best disease have given negative results. In one large AMD family, linkage has been reported to markers in 1q25-q31. Recent data suggest that the ApoE epsilon4 allele may be associated with reduced risk of AMD. A better understanding of the genetic factors in AMD would contribute to understanding the pathogenesis. If those at risk could be identified it may be possible to modify lifestyle or develop novel therapies in the presymptomatic stage to prevent disease or decrease its severity.

Age Factors↗
PubMed2000

The genetics of childhood cataract.

Human congenital cataract has a diverse aetiology. In the proportion of cases where the cause is genetic, the disease shows wide phenotypic and genetic heterogeneity. Over the past few years, much research has been devoted to mapping the genes that underlie the disorder. This has been helped by the extensive array of naturally occurring and genetically engineered mouse cataract models and the abundance of human candidate genes. Most progress to date has been in the identification of genetic mutations causing autosomal dominant congenital cataract where eight genes have been implicated in cataractogenesis. Overall there is good correlation between the genetic mutations so far identified and the resulting lens phenotype but it is clear that mutations at more that one locus may give rise to similar forms of cataract. The identification of genes causing inherited forms of cataract will improve our understanding of the mechanisms underlying cataractogenesis in childhood and provide further insights into normal lens development and physiology. Perhaps more importantly, it is likely that some of the genes causing early onset cataract will be implicated in age related cataract which remains the commonest cause of blindness in the world.

Animals↗
PubMed2000

RP1 protein truncating mutations predominate at the RP1 adRP locus.

PURPOSE: Recent reports have shown that the autosomal dominant retinitis pigmentosa (adRP) phenotype linked to the pericentric region of chromosome 8 is associated with mutations in a gene designated RP1. Screening of the whole gene in a large cohort of patients has not been undertaken to date. To assess the involvement and character of RP1 mutations in adRP, the gene was screened in a panel of 266 unrelated patients of British origin and a Pakistani family linked to this locus. METHODS: Patients exhibiting the adRP phenotype were screened for mutations in the four exons of the RP1 gene by heteroduplex analysis and direct sequencing. Linkage of the Pakistani family was achieved using microsatellite markers. Polymerase chain reaction (PCR) products were separated by nondenaturing polyacrylamide gel electrophoresis. Alleles were assigned to individuals, which allowed calculation of LOD scores. Microsatellite marker haplotyping was used to determine ancestry of patients carrying the same mutation. RESULTS: In the 266 British patients and 1 Pakistani family analyzed, 21 loss-of-function mutations and 7 amino acid substitutions were identified, some of which may also be disease-causing. The mutations, many of which were deletion or insertion events, were clustered in the 5' end of exon 4. Most mutations resulted in a premature termination codon in the mRNA. Haplotype analysis of nine patients carrying an R677X mutation suggested that these patients are not ancestrally related. CONCLUSIONS: RP1 mutations account for 8% to 10% of the mutations in our cohort of British patients. The most common disease-causing mechanism is deduced to be one involving the presence of a truncated protein. Mutations in RP1 have now been described in adRP patients of four ethnically diverse populations. The different disease haplotype seen in the nine patients carrying the same mutation suggests that this mutation has arisen independently many times, possibly due to a mutation hot spot in this part of the gene.

Cohort Studies↗
PubMed1999

Clinical characteristics of ocular angiomatosis in von Hippel-Lindau disease and correlation with germline mutation.

OBJECTIVES: To examine the epidemiologic and clinical characteristics of the ocular manifestations of von Hippel-Lindau (VHL) disease and to detect phenotype-genotype relationships of disease severity. DESIGN: A cross-sectional clinical and molecular genetic study. PATIENTS AND METHODS: One hundred eighty-three affected VHL gene carriers from 81 unrelated pedigrees were interviewed and examined; clinical data were also obtained from 12 living and 39 deceased affected relatives. DNA extracted from venous blood was used to identify mutations in the VHL gene. RESULTS: The prevalence of ocular angiomatosis (hemangioblastomas) in von Hippel-Lindau disease was 67.8% (124/183), and the mean number of angiomas in gene carriers was 1.85 (range, 0-15). Neither prevalence nor angioma count increased with age. Severe vision loss in 1 or both eyes was associated with presentation at a young age. The cumulative probability of incurring vision loss by age 50 years was 35% in all gene carriers, 55% in those with angiomatosis, and significantly worse in those coming to us with symptoms. Angiomas were nonrandomly distributed in the fundus, occurring rarely at the posterior pole (1% of retinal tumors) and commonly on the optic disc (8% of eyes) and supratemporal retina. Complications of ocular angiomatosis included disc and retinal neovascularization; secondary angioma formation; retinal detachment, exudation, and membrane; and retinal and vitreous hemorrhage. Germ-line VHL mutations were detected in 161 of 183 patients and 69 (85%) of 81 pedigrees and included deletions (n= 16), missense (mutations causing amino acid substitutions; n = 24), nonsense (premature stop codons; n = 15), frameshift (n = 13), and splice-site (n = 1) mutations. There was no association between the type or position of mutation and the severity of ocular angiomatosis. CONCLUSIONS: A systematic clinical description of a large cohort of VHL gene carriers further defines the ocular phenotype. There is no general influence of germline mutation on severity of ocular disease in VHL. CLINICAL RELEVANCE: The ophthalmic and molecular genetic description of patients with VHL disease.

Adolescent↗
PubMed1999

A clinical and molecular genetic analysis of solitary ocular angioma.

OBJECTIVES: To determine whether ocular angioma can occur in the absence of von Hippel Lindau (VHL) syndrome, to define the clinical characteristics of sporadic (non-VHL) angioma, and to estimate a prevalence for sporadic ocular angioma. DESIGN AND PARTICIPANTS: A cross-sectional study of a cohort of patients with apparent sporadic ocular angiomatosis recruited from throughout the United Kingdom. INTERVENTION: Clinical details and a family history were obtained for the patients in the cohort. Systematic ocular examination and further systemic screening were performed on the patients and relatives when possible. Leukocyte DNA was examined for VHL germline mutations. MAIN OUTCOME MEASURES: Patients with solitary and typical VHL-like ocular angioma, without clinical and family histories for VHL, were selected as possible sporadic (non-VHL) ocular angioma cases. An estimate of the population prevalence of sporadic (non-VHL) ocular angioma was made from patients presenting in the East Anglian region of the United Kingdom over a 25-year period. RESULTS: From 32 patients referred, 17 had typical solitary ocular angioma and no evidence of other VHL complications in themselves or in family members. All 17 patients were negative for germline VHL mutations. The mean age of presentation was 30.9 years (median, 27.5; range, 3-52); 11 of 17 eyes suffered visual loss and 4 of 17 tumors occurred on the optic disc. The estimated prevalence of non-VHL ocular angioma was 9.0 x 10(-6), 95% confidence interval (CI) = 3.3 - 19 x 10(-6) (1 in 110,000 persons, 95% CI = 1 in 53,000-300,000). CONCLUSIONS: Sporadic ocular angioma can occur in the absence of VHL disease but appears less prevalently than VHL itself. The age of presentation, degree of visual morbidity, complications, morphology, and anatomic location of tumors are similar to those seen in VHL disease.

Adult↗
PubMed1999

Lens biology: development and human cataractogenesis.

Cataract, or opacification of the lens of the eye, is the commonest cause of visual impairment world-wide. It is only treatable at present by surgical removal. Recent advances in our understanding of the genetics of human cataract, in particular the inherited congenital form, together with the development of an array of animal models have provided valuable new insights into normal vertebrate lens biology and the mechanisms that underlie cataract formation. In this article, we review the current state of research in these areas and discuss thinking regarding the relationship between the phenotypes observed and the underlying genotype in inherited cataract.

Animals↗
PubMed1999

The lens.

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Cataract↗
PubMed1998

Clinical features in affected individuals from 21 pedigrees with dominant optic atrophy.

OBJECTIVE: To assess phenotypic variation of affected individuals from British families with autosomal dominant optic atrophy. DESIGN: Eighty-seven patients from 21 families showing evidence of linkage to chromosome 3q were identified via the Genetic Clinic of Moorfields Eye Hospital, London, England. Genetic linkage analysis was carried out with markers from chromosome 3q28-qter. Patients underwent clinical examination and psychophysical and electrophysiological testing. RESULTS: Best-corrected visual acuity ranged from 20/20 (6/6 m) to light perception. Although visual acuity was not significantly worse in older patients in the group (chi2=3.20, df=4, P>.50), it did deteriorate with age in one third of the families. Subtle or temporal pallor of the optic disc occurred in 96 (55%) of 174 eyes and total atrophy in 76 (44%). Tritanopia was found in 6 (7.5%) of 80 patients; 65 (81.2%) had a mixed color deficit. A cecocentral scotoma was found in the vast majority. Peripheral motion detection threshold was elevated in areas of visual field with raised mean surround sensitivity but not elsewhere. Pattern visual evoked potentials were of reduced amplitude and delayed. Pattern electroretinograms showed a reduced N95 component in keeping with primary ganglion cell dysfunction. CONCLUSIONS: There is wide intrafamilial and interfamilial phenotypic variation in autosomal dominant optic atrophy, with visual function in some, but not all, families deteriorating with age. There is evidence of degeneration of the ganglion cell layer predominantly from central retina, but this is not the exclusive result of either parvocellular or magnocellular cell loss.

Adolescent↗
PubMed1998

Dominant optic atrophy: exclusion and fine genetic mapping of the candidate gene, HRY.

Autosomal dominant optic atrophy (OPA1) maps to Chromosome (Chr) 3q28, and the disease interval has been refined to within 1.4 cM, flanked by the markers D3S3669 and D3S3562. HRY, the human homolog of the Drosophila segmentation gene, hairy, maps by in situ hybridization to the chromosomal region 3q28-q29. We screened for mutations in HRY in 36 patients from 18 pedigrees with dominant optic atrophy and a group of normal control individuals. Heteroduplex mutation analysis and direct sequencing of all four coding exons and one upstream putative untranslated exon were performed. No disease-associated sequence alterations were identified. A polymorphism in the untranslated region of exon 2 was found, with four alleles. PCR amplification of this part of exon 2 in four of the pedigrees affected by autosomal dominant optic atrophy mapping to chromosome 3q, followed by haplotype analysis, showed recombination between HRY and OPA1 in one pedigree. This allows us to genetically position HRY in relation to known microsatellite markers in the region, placing HRY telomeric to marker D3S3562 and centromeric to D3S1305. This is outside the published critical disease interval for dominant optic atrophy. We have, therefore, excluded HRY as the gene for dominant optic atrophy by sequence analysis, mapped it genetically, and identified a polymorphism in our population.

Animals↗
PubMed1998

Demonstration of a founder effect and fine mapping of dominant optic atrophy locus on 3q28-qter by linkage disequilibrium method: a study of 38 British Isles pedigrees.

Dominant optic atrophy, a hereditary optic neuropathy causing decreased visual acuity, colour vision deficits, a centro-caecal scotoma and optic nerve pallor, has been mapped to a genetic interval of 1.4 cM between loci D3S3669 and D3S3562 on chromosome 3q28-qter. In order to further refine the critical disease interval, and to test the power of haplotype analysis and linkage disequilibrium mapping, we identified a total of 38 families with dominant optic atrophy, unrelated on the basis of genealogy, from a data base of genetic eye disease families originating from the British Isles. They were studied with 12 highly polymorphic microsatellite markers spanning a region of 12 cM around the dominant optic atrophy locus (OPA1). Allelic frequency analysis [chi-squared test, likelihood ratio test (LRT) and P values] and haplotype parsimony analysis showed evidence of a founder effect in 36 of the 38 pedigrees. Six markers (D3S3669, D3S1523, D3S3642, D3S2305, D3S3590 and D3S3562), spanning 1.4 cM across the disease-associated region, demonstrated significant linkage disequilibrium by LRT (P < 0.05). A peak LRT value of 10.86 (P < 0.0005, lambda = 0.4) occurred at D3S3669. On linkage disequilibrium multipoint analysis the maximum lod score of 8.01 is achieved at D3S1523, and 95% confidence intervals suggest that OPA1 lies within ca. 400 kb of D3S1523.

Alleles↗