A novel missense mutation in HSF4 causes autosomal-dominant congenital lamellar cataract in a British family.

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.

Posterior polar cataract is the predominant consequence of a recurrent mutation in the PITX3 gene.

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.

Reduced incidence of retinopathy of prematurity.

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.

Pain perception with pH buffered peribulbar anaesthesia: a pilot study.

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.

Corneal infiltration after recurrent corneal epithelial erosion.

AIMS: To describe the clinical features of patients with a history of recurrent corneal epithelial erosion who develop acute corneal infiltration. METHODS: The records were reviewed of patients who had previously been examined and treated for recurrent corneal epithelial erosion and who presented again with signs suggestive of a microbial keratitis. RESULTS: 11 patients were described; one patient presented with similar signs on two occasions. There was typically a paracentral epithelial defect > 2 mm in diameter with an associated stromal infiltrate and an intense anterior uveitis. Three patients had a hypopyon, and four developed a subepithelial ring infiltrate. Samples were taken for microscopy and bacterial culture, with a positive isolate from two of 12 episodes (16%). Treatment with topical antibiotics and topical corticosteroid resulted in rapid re-epithelialisation and a reduction of inflammation. There was good visual outcome for all eyes, with a recurrence or symptoms of epithelial erosion in only one eye after a mean follow up period of 18 months. CONCLUSIONS: Corneal infiltrates are an uncommon complication of recurrent corneal epithelial erosion. Despite the intensity of the infiltration the majority are culture negative using established techniques. There is typically rapid resolution and a good visual outcome, with a tendency for the episode to mark the end of further symptoms of epithelial erosion.

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.

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.