ABSTRACT
PurposeInherited cataract, opacification of the lens, is the most common worldwide cause of blindness in children. We aimed to identify the genetic cause of isolated autosomal-dominant lamellar cataract in a five-generation British family.MethodsWhole exome sequencing (WES) was performed on two affected individuals of the family and further validated by direct sequencing in family members.ResultsA novel missense mutation NM_001040667.2:c.190A>G;p.K64E was identified in the DNA-binding-domain of heat-shock transcription factor 4 (HSF4) and found to co-segregate with disease.ConclusionWe have identified a novel mutation in HSF4 in a large British pedigree causing dominant congenital lamellar cataract. This is the second mutation in this gene found in the British population. This mutation is likely to be dominant negative and affect the DNA-binding affinity of HSF4.
Subject(s)
Cataract/genetics , Heat Shock Transcription Factors/genetics , Mutation, Missense , Child , Female , Humans , Male , Pedigree , Exome SequencingABSTRACT
PURPOSE: To assess the difference in binocular visual fields (VFs) in patients who underwent bilateral cataract surgery with either multifocal (MF; Tecnis ZM900, AMO) intraocular lenses (IOLs) or monofocal IOLs with powers adjusted to give monovision (MV; Akreos AO, Bausch&Lomb). SETTING: St George's & Moorfields Eye Hospital, London. METHODS: Prospective exploratory study. Binocular Esterman VFs (Humphrey Field Analyser II) were compared between 10 participants with MV and 16 participants with MF IOLs. The dominant eye in MV participants had 0 to -0.50DS and the non-dominant eye had between -1.0DS and -1.5DS. Best-corrected Snellen visual acuity for all 52 eyes was six out of nine or better. The main outcome measure was Esterman Efficiency Score. Incidence of suboptimal VF results (≥1 Unseen Locations--ULs) and mean testing times in the two groups were compared. RESULTS: There was no statistically significant difference in the incidence of suboptimal VF results in these two groups (P=0.662). Test durations in the two groups were not significantly different (P=0.650). However, 3/10 MV plots (33%) had markedly suboptimal right hemi-fields (distance-dominant eye) compared with 0/15 MF plots. Additionally, the MV group accounted for 79% of total ULs (20/29) and all these ULs were distributed in areas outside or bordering the true binocular VFs. CONCLUSIONS: All included VFs met the UK driving standards criteria. The pattern of VF defects encountered in the MV group is of interest because the majority of ULs (13/20; 65%) corresponded to the monocular VFs of the distance-dominant eye.
Subject(s)
Cataract/physiopathology , Lens Implantation, Intraocular , Lenses, Intraocular , Vision, Binocular/physiology , Vision, Monocular/physiology , Visual Fields/physiology , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Prospective Studies , Visual AcuityABSTRACT
OBJECTIVE: To assess changes in basic ophthalmic training of accident and emergency (A&E) senior house officers (SHOs) in the last 10 years, their own perceived level of confidence and the availability of appropriate equipment in their departments. METHODS: A standardised structured questionnaire from a telephone survey carried out in 1993 was used. One SHO from each A&E department listed in the British Association of Emergency Medicine directory of 2003 was chosen at random and interviewed. RESULTS: 168 A&E departments were contacted and 133 SHOs were successfully interviewed (response rate 79.2%). The number of A&E departments with a slit lamp increased by 25.7% from 1993, and slit lamp training increased by 21%. There was no significant change in the prevalence of training in the management of eye emergencies (74.0% in 1993 vs 77.4% in 2003) and the proportion of SHOs who felt confident in dealing with these cases was unchanged. CONCLUSIONS: A&E departments are better equipped with slit lamps 10 years on, and staff are being trained to use them. This has unfortunately not improved the confidence levels in dealing with eye emergencies, reflecting the lack of adequate basic ophthalmic training for A&E SHOs. Recent changes in postgraduate medical training could provide a platform to bring about the changes required.
Subject(s)
Clinical Competence/statistics & numerical data , Emergency Service, Hospital/statistics & numerical data , Eye Diseases/diagnosis , Eye Diseases/therapy , Internship and Residency/statistics & numerical data , Emergency Medicine/education , Health Care Surveys , Humans , Longitudinal Studies , Ophthalmology/education , Ophthalmology/instrumentation , Prospective Studies , United KingdomABSTRACT
PURPOSE: Ventilated patients in the intensive care unit (ICU) often develop exposure keratopathy. This predisposes to the development of bacterial keratitis, which in ICU is often bilateral, with a high risk of perforation. As regular examinations of all ventilated patients by ophthalmologists would be impractical, the purpose of this study was to assess whether ICU staff can screen reliably for keratopathy. METHODS: A prospective study was performed in a general adult ICU. Twice each week, two junior ICU doctors examined the lid position and ocular surface of all patients who had been continuously sedated for more than 24 h, using fluorescein and a pen torch with a blue filter. An ophthalmologist performed similar examinations using a portable slit lamp. RESULTS: A total of 48 ocular examinations were performed in 18 patients. Exposure keratopathy was found by the ophthalmologist in 37.5% of examinations and by ICU doctors in 31.3% of examinations. ICU doctors had a sensitivity of 77.8% and a specificity of 96.7% in detecting keratopathy, when compared with the findings of the ophthalmologist. All cases missed by ICU doctors had punctate erosions of less than 5% of the corneal surface. Keratopathy was significantly commoner in patients with incomplete lid closure than in patients with closed lids (70.0 vs 28.9%; two-tailed Fisher's exact test P=0.027). CONCLUSIONS: ICU staff can perform screening examinations for exposure keratopathy with reasonable sensitivity and specificity. Regular screening by ICU staff would facilitate appropriate treatment of exposure keratopathy and promote earlier identification of cases of keratitis.
Subject(s)
Critical Care/methods , Keratitis/diagnosis , Respiration, Artificial/adverse effects , Adult , Aged , Aged, 80 and over , Clinical Competence/standards , Cross Infection/diagnosis , Female , Humans , Keratitis/etiology , Length of Stay , Male , Middle Aged , Ophthalmology/standards , Prospective Studies , Pseudomonas Infections/diagnosis , Young AdultABSTRACT
The implementation of modernizing medical careers (MMC) has resulted in some specialties being allocated very inexperienced trainees such as ophthalmology. We aim to describe the process of implementation of MMC and how it may affect the service provision in smaller specialities such as ophthalmology. A methodical approach in a district hospital setting was used to provide early core training to such trainees involving managerial support. The quality of service provided by newer trainees can be enhanced by providing early structured training during induction to create an atmosphere of enthusiasm and continued learning. This example can be used in other units and specialties.
Subject(s)
Education, Medical, Graduate/methods , Medical Staff, Hospital/education , Ophthalmology/education , England , HumansABSTRACT
AIM: To identify whether the risk of an intraoperative complication of phakoemulsification cataract surgery increases with age. METHODS: 1441 consecutive patients undergoing phakoemulsification cataract surgery were assessed preoperatively, and data on the occurrence of intraoperative complications were collected prospectively. Data were entered into a computerised database, and logistic regression was used to examine evidence of an association between age and the risk of an intraoperative complication. In addition, the rates of intraoperative complications were compared between patients > or =88 years and those <88 years, and between patients > or =96 years and those <96 years. RESULTS: No significant association was found between age and the risk of an intraoperative complication. The authors found little evidence that patients > or =88 years were at a greater risk of an intraoperative complication than those <88 years, or that those > or =96 years are at increased risk; however, numbers were small. CONCLUSIONS: These results suggest that age alone is not a major risk factor for any intraoperative complications occurring during phakoemulsification cataract surgery. This has implications not just for tailoring the risk of complications occurring to individual patients but also for meaningful comparisons between national complication rates and those of individual surgeons, and better selection of cases suitable for instruction.
Subject(s)
Intraoperative Complications , Phacoemulsification/adverse effects , Age Distribution , Age Factors , Aged , Aged, 80 and over , Humans , Middle Aged , Prospective Studies , Risk FactorsABSTRACT
BACKGROUND: The authors recently identified three large genetically unrelated families with an identical 17 base pair duplication mutation in exon 4 of the PITX3 gene. Here, they report the detailed clinical phenotype. METHODS: Affected and unaffected individuals in the three families with autosomal dominant posterior polar cataract underwent full clinical examination and donated blood samples for DNA extraction and molecular genetic studies. RESULTS: In all three families, an identical 17 base pair duplication mutation in PITX3 was identified which co-segregated with disease status in the family. All affected individuals had bilateral progressive posterior polar cataracts. In one family, posterior polar cataract was the only clinical abnormality but in the other two families, one of 10 affected individuals and four of 11 affected individuals also had anterior segment mesenchymal dysgenesis (ASMD). CONCLUSION: Mutations in the PITX3 gene in humans result in posterior polar cataract and variable ASMD. The gene encodes a transcription factor which has a key role in lens and anterior segment development. The mechanism by which the mutant protein gives rise to such a regional pattern of lens opacity remains to be elucidated.
Subject(s)
Cataract/genetics , Homeodomain Proteins/genetics , Mutation , Transcription Factors/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Anterior Eye Segment/abnormalities , Cataract/physiopathology , Child , Chromosome Aberrations , Family Health , Female , Genes, Dominant/genetics , Humans , Male , Pedigree , Phenotype , Visual Acuity/physiologyABSTRACT
AIM: To devise a simple, robust scoring system for assessing the risk of intraoperative complications in patients undergoing cataract surgery. METHODS: 1441 consecutive patients undergoing phacoemulsification cataract surgery were assessed preoperatively according to weighted criteria. According to the points of risk they accumulated using this system, the patients were preoperatively allocated to one of four risk groups. Data were prospectively collected on the occurrence of intraoperative complications and entered into a computerised database. The total rate of intraoperative complications for each risk group as well as the rate of each reported complication for each risk group were calculated. RESULTS: The rate of intraoperative complications increased in frequency through the risk groups: 1 = 4.32%, 2 = 7.45%, 3 = 13.48%, and 4 = 32.00% (p<0.001). Furthermore, the following complications also increased in frequency through the risk groups in their own right (p<0.05 in each case): posterior capsule rupture, vitreous loss, incomplete capsulorrhexis, zonule dehiscence, wound burn/leak, and lost nuclear fragment into vitreous cavity. CONCLUSION: These results suggest that candidates for cataract surgery can be simply and uniformly assessed preoperatively and categorised to a "risk group" according to their risk of intraoperative complications. This allows for: (1) individualised counselling on the chances of operative complications, (2) meaningful comparisons between national complication rates and those of individual units or surgeons, and (3) better selection of cases suitable for instruction.
Subject(s)
Intraoperative Complications , Phacoemulsification/adverse effects , Preoperative Care/methods , Aged , Aged, 80 and over , Clinical Competence , Female , Humans , Male , Prospective Studies , Risk Assessment/methods , Risk Factors , Severity of Illness IndexSubject(s)
Contact Lenses/adverse effects , Eye Infections/microbiology , Keratitis/etiology , Adult , Humans , Male , Myopia/therapyABSTRACT
AIM: To audit the prevalence of retinopathy of prematurity (ROP) in a level 2 status neonatal unit. METHODS: Data were collected prospectively over 9 years from September 1989 to September 1998. Preterm infants were examined according to the Royal College of Ophthalmologists' guidelines and retinopathy graded following the International Classification of ROP. ROP 3-5 was analysed using logistic regression in relation to time, and to gestational age and birth weight. RESULTS: 383 babies were examined. Mean gestational age fell over the 9 year period (p=0.051) as did mean birth weight (p<0.001). There was a decrease in the number of infants with ROP grades 3-5 over the 9 years (p=0.045 and, when adjusted for gestational age and birth weight, the decrease in ROP 3-5 was significant (p=0.03). CONCLUSIONS: This study found a significant reduction in the incidence of ROP during the 9 years of the study period, despite a decrease in mean gestational age of and birth weight. The reduced incidence of ROP is attributed to improvements in ventilation techniques and overall care of the neonate, in particular the use of prenatal steroids and surfactant.
Subject(s)
Infant, Premature, Diseases/epidemiology , Retinopathy of Prematurity/epidemiology , Birth Weight , Gestational Age , Humans , Incidence , Infant, Newborn , Infant, Premature, Diseases/pathology , Logistic Models , London/epidemiology , Longitudinal Studies , Prevalence , Retinopathy of Prematurity/pathologyABSTRACT
OBJECTIVE: To determine the visual outcome and surgical complication rates of patients with isolated inherited congenital cataract. DESIGN: Retrospective noncomparative case series. PARTICIPANTS: Patients and their families were ascertained from the genetic eye clinic and outpatient databases of Moorfields Eye Hospital, London, and invited to participate in the study. Four hundred twenty-two individuals from 72 pedigrees with this form of autosomal dominant cataract underwent ophthalmologic assessment. MAIN OUTCOME MEASURES: Visual acuity and surgical complications (glaucoma, retinal detachment, amblyopia). RESULTS: In this study 49.4% of patients (46.8% of those operated) achieved a visual acuity (VA) of 20/40 or better, 35.9% (36.1% of those operated) a VA between 20/50 and 20/200, and 14.7% (17.1% of those operated) worse than 20/200. Opacities that were more diffuse or did not lie close to the visual axis were associated with a better prognosis for vision; 6.6% had glaucoma and 5.0% had retinal detachment develop. CONCLUSIONS: Patients with isolated inherited congenital cataract have a better visual and surgical outcome than those with coexisting ocular and systemic abnormalities. The improved prognosis is related in part to the lack of other developmental abnormalities of the eye, and, because inherited cataracts are often partial at birth, surgery may be delayed to later infancy and childhood when there is a lower incidence of surgical complications and refractive correction is easier. Certain inherited phenotypes (lamellar, pulverulent, polymorphic, coralliform, and cortical) also seem to have a better prognosis, and this should be borne in mind when counseling these families. A large number of the patients in this study underwent surgery many years previously, when surgical outcomes were less favorable, and thus the results of this study establish only a minimum acuity dataset for the purposes of counseling.
Subject(s)
Cataract Extraction , Cataract/congenital , Visual Acuity , Adolescent , Adult , Aged , Aged, 80 and over , Cataract/genetics , Child , Child, Preschool , Female , Genes, Dominant , Humans , Infant , Infant, Newborn , Intraoperative Complications , Male , Middle Aged , Pedigree , Postoperative Complications , Prognosis , Retrospective StudiesABSTRACT
AIM: To determine the relative risk of a poor visual outcome following posterior capsule rupture during cataract surgery. METHODS: Prospective data were collected on consecutive eyes undergoing cataract extraction. The patient's age, preoperative visual acuity, ocular comorbidity, grade of surgeon, and operative complications were documented. The best spectacle corrected visual acuity was recorded at discharge from the hospital service. RESULTS: From a total of 1533 cases, 1420 (92.6%) eyes had complete follow up data. Posterior capsule rupture occurred in 59 (4.1%) cases. Eyes with posterior capsule rupture were 3.8 times more likely to have a final best spectacle corrected visual acuity less than 6/12. CONCLUSIONS: Eyes having posterior capsule rupture during cataract surgery have a significant risk of reduced visual acuity.
Subject(s)
Lens Capsule, Crystalline/injuries , Phacoemulsification/adverse effects , Clinical Competence , Follow-Up Studies , Humans , Prognosis , Prospective Studies , Risk Assessment , Rupture , Treatment Outcome , Visual AcuityABSTRACT
AIMS: To determine the relation between pH of anaesthetic solutions and patient perception of pain with peribulbar injection of local anaesthesia. METHODS: This prospective randomised controlled double blind pilot study involved 60 consecutive patients who received a peribulbar block with either a standard acidic local anaesthetic of 5 ml 2% lignocaine and 5 ml of 0.5% bupivacaine (solution A), or an alkalinised solution composed of the same anaesthetic agents but with a pH of 7.44 (solution B). Before surgery patients were asked to grade the pain of both the preoperative dilating drops and the peribulbar injection using a visual analogue scale. RESULTS: The mean pain scores were similar in the two treatment groups-slightly higher (4.97) in group B who received the buffered solution, compared with group A (4.84) who received the plain solution. The small difference (-0.13, 95% confidence limits -1.6 and +1.3) was not significant. There was, however, a highly significant association between pain threshold ("drop pain") and injection pain levels (p<0.0001). CONCLUSION: This study showed no difference in the reduction in the pain experienced by patients undergoing peribulbar anaesthesia with pH buffered local anaesthetic. The study suggests the importance of "pain threshold" as a confounder and also showed the considerable pain felt by some patients on instillation of the preoperative dilating drops.
Subject(s)
Anesthetics, Local , Bupivacaine , Lidocaine , Pain Measurement/methods , Pain Threshold/drug effects , Analysis of Variance , Double-Blind Method , Female , Humans , Male , Ophthalmic Solutions , Pain/prevention & control , Pain Measurement/drug effects , Pilot Projects , Prospective StudiesABSTRACT
Inherited cataract is a clinically and genetically heterogeneous disease that most often presents as a congenital autosomal dominant trait. Here we report linkage of a three-generation family of Pakistani origin with autosomal dominant cataract "zonular nuclear" pulverulent type (CZNP) on chromosome 1q21.1. Genome wide-linkage analysis excluded all the known cataract loci except on chromosome 1q. Significantly positive 2-point lod score values (Z=3.01 at theta=0) were obtained for markers D1S305 and D1S2721, which are known to flank the gene for connexin 50 (Cx50) or gap junction protein alpha-8 (Gja8). Previously a mutation in this gene has been reported in a British family with zonular pulverulent cataract (CZP). Here we describe a second mutation (E48K) in connexin 50 that confirms the involvement of this gene in cataractogenesis.
Subject(s)
Cataract/congenital , Cataract/genetics , Eye Proteins/genetics , Mutation, Missense , Connexins , Eye Proteins/physiology , Female , Genetic Markers , Humans , Male , Models, Biological , Pakistan , PhenotypeABSTRACT
AIMS: To determine the different morphologies of autosomal dominant cataract (ADC), assess the intra- and interfamilial variation in cataract morphology, and undertake a genetic linkage study to identify loci for genes causing ADC and detect the underlying mutation. METHODS: Patients were recruited from the ocular genetic database at Moorfields Eye Hospital. All individuals underwent an eye examination with particular attention to the lens including anterior segment photography where possible. Blood samples were taken for DNA extraction and genetic linkage analysis was carried out using polymorphic microsatellite markers. RESULTS: 292 individuals from 16 large pedigrees with ADC were examined, of whom 161 were found to be affected. The cataract phenotypes could all be described as one of the eight following morphologies-anterior polar, posterior polar, nuclear, lamellar, coralliform, blue dot (cerulean), cortical, and pulverulent. The phenotypes varied in severity but the morphology was consistent within each pedigree, except in those affected by the pulverulent cataract, which showed considerable intrafamilial variation. Positive linkage was obtained in five families; in two families linkage was demonstrated to new loci and in three families linkage was demonstrated to previously described loci. In one of the families the underlying mutation was isolated. Exclusion data were obtained on five families. CONCLUSIONS: Although there is considerable clinical heterogeneity in ADC, the phenotype is usually consistent within families. There is extensive genetic heterogeneity and specific cataract phenotypes appear to be associated with mutations at more than one chromosome locus. In cases where the genetic mutation has been identified the molecular biology and clinical phenotype are closely associated.
Subject(s)
Cataract/genetics , Adolescent , Adult , Cataract/pathology , Child , Child, Preschool , Female , Humans , Male , Mutation/genetics , Pedigree , PhenotypeABSTRACT
Loci for autosomal dominant "zonular pulverulent" cataract have been mapped to chromosomes 1q (CZP1) and 13q (CZP3). Here we report genetic refinement of the CZP3 locus and identify underlying mutations in the gene for gap-junction protein alpha-3 (GJA3), or connexin46 (Cx46). Linkage analysis gave a significantly positive two-point LOD score (Z) at marker D13S175 (maximum Z [Zmax]=>7.0; maximum recombination frequency [thetamax] =0). Haplotyping indicated that CZP3 probably lies in the genetic interval D13S1236-D13S175-D13S1316-cen-13pter, close to GJA3. Sequencing of a genomic clone isolated from the CZP3 candidate region identified an open reading frame coding for a protein of 435 amino acids (47,435 D) that shared approximately 88% homology with rat Cx46. Mutation analysis of GJA3 in two families with CZP3 detected distinct sequence changes that were not present in a panel of 105 normal, unrelated individuals. In family B, an A-->G transition resulted in an asparagine-to-serine substitution at codon 63 (N63S) and introduced a novel MwoI restriction site. In family E, insertion of a C at nucleotide 1137 (1137insC) introduced a novel BstXI site, causing a frameshift at codon 380. Restriction analysis confirmed that the novel MwoI and BstXI sites cosegregated with the disease in families B and E, respectively. This study identifies GJA3 as the sixth member of the connexin gene family to be implicated in human disease, and it highlights the physiological importance of gap-junction communication in the development of a transparent eye lens.
Subject(s)
Cataract/genetics , Chromosomes, Human, Pair 13/genetics , Connexins/genetics , Amino Acid Sequence , Base Sequence , Cataract/congenital , Female , Genetic Markers/genetics , Genotype , Humans , Lod Score , Male , Molecular Sequence Data , Pedigree , Point Mutation/geneticsABSTRACT
Anterior polar cataract can occur as a sporadic finding, in association with other ocular abnormalities or as an inherited, autosomal dominant disorder. We have demonstrated linkage in a family with autosomal dominant anterior polar cataract to the short arm of chromosome 17, locating the gene to the region 17p12-13. All affected members of this large family had an opacity at the anterior pole of the lens that varied only in size and the effect on visual acuity. Anterior polar cataract is thought to have a minimal effect on visual acuity although in the affected members of this family there was a high incidence of unilateral amblyopia.
Subject(s)
Cataract/genetics , Chromosomes, Human, Pair 17/genetics , Genetic Linkage , Cataract/physiopathology , Female , Humans , Male , Pedigree , Visual AcuityABSTRACT
CZP1, a locus for autosomal dominant "zonular pulverulent" cataract, previously had been linked with the Duffy blood-group-antigen locus on chromosome 1q. Here we report genetic refinement of the CZP1 locus and show that the underlying mutation is present in GJA8, the gene for connexin50. To map the CZP1 locus we performed linkage analysis using microsatellite markers on two distantly related branches of the original Ev. pedigree, which now spans eight generations. Significantly positive two-point LOD score (Z) values were obtained for markers D1S2669 (maximum Z [Zmax] = 4.52; maximum recombination frequency [thetamax] = 0) and D1S514 (Zmax = 4.48; thetamax = 0). Multipoint analysis gave Zmax = 5.22 (thetamax = 0) at marker D1S2669. Haplotyping indicated that CZP1 probably lies in the genetic interval D1S2746-(20.6 cM)-D1S2771. Sequence analysis of the entire protein-coding region of the GJA8 gene from the pedigree detected a C-->T transition in codon 88, which introduced a novel MnlI restriction-enzyme site that also cosegregated with the cataract. This missense mutation is predicted to result in the nonconservative substitution of serine for a phylogenetically conserved proline (P88S). These studies provide the first direct evidence that GJA8 plays a vital role in the maintenance of human lens transparency and identify the genetic defect believed to underlie the first inherited disease to be linked to a human autosome.