Sarah Chamney

The Phenotypic Variability of Retinal Dystrophies Associated With Mutations in CRX, With Report of a Novel Macular Dystrophy Phenotype.

PURPOSE To present a detailed phenotypic and molecular study of a series of 18 patients from 11 families with retinal dystrophies consequent on mutations in the cone-rod homeobox (CRX) gene and to report a novel phenotype. METHODS Families were ascertained from a tertiary clinic in the United Kingdom and enrolled into retinal dystrophy studies investigating the phenotype and molecular basis of inherited retinal disease. Eleven patients were ascertained from the study cohorts and a further seven from investigation of affected relatives. Detailed phenotyping included electrodiagnostic testing and retinal imaging. Bidirectional Sanger sequencing of all exons and intron-exon boundaries of CRX was performed on all 18 reported patients and segregation confirmed in available relatives. RESULTS Based on clinical characteristics and electrophysiology, four patients had Leber congenital amaurosis (LCA), two had rod-cone dystrophy (RCD), five had cone-rod dystrophy (CORD), one had cone dystrophy (COD), and six had macular dystrophy with different phenotypes observed within 5 of 11 families. The macular dystrophy patients presented between 35 to 50 years of age and had visual acuities at last review ranging from 0.2 to 1.5 logMAR (20/32 to 20/630 Snellen). All 18 patients were heterozygous for a mutation in CRX with seven novel mutations identified. There was no evident association between age of onset and position or type of CRX mutation. De novo mutations were confirmed in three patients. CONCLUSIONS Mutations in CRX demonstrate significant phenotypic heterogeneity both between and within pedigrees. A novel, adult-onset, macular dystrophy phenotype is characterized, further extending our knowledge of the etiology of dominant macular dystrophies.

Iris Flocculi as an Ocular Marker of ACTA2 Mutation in Familial Thoracic Aortic Aneurysms and Dissections

Abstract Non-syndromic familial thoracic aortic aneurysms and dissections (TAAD) are inherited in an autosomal dominant manner. We report a missense mutation in the smooth muscle α-actin (ACTA2; MIM*102620) gene in a 3 generational family from Northern Ireland in which iris flocculi were an ocular marker of the disease.

Amniotic band syndrome associated with an atypical iris and optic nerve defect

We report the case of an 8-year-old boy who presented with right cleft lip and palate, left Tessier number 3 and 11 clefts, and limb abnormalities because of amniotic band syndrome. He was found to have an atypical iris and optic disk nasal defect and a right-sided ptosis, which have not been previously reported with amniotic band syndrome.

A mutation in the Norrie disease gene (NDP) associated with familial exudative vitreoretinopathy.

A mutation in the Norrie disease gene ( NDP ) associated with familial exudative vitreoretinopathy

Biotinidase Deficiency, Bilateral Optic Atrophy, and a Visual Field Defect

Abstract We present an update on the ophthalmic status of a female patient with biotinidase deficiency who has attended our clinic for over 30 years. She is the only reported case of juvenile-onset glaucoma associated with biotinidase deficiency. Her intraocular pressure, optic nerve appearance, and visual field defect have, however, remained stable throughout her follow-up. We feel that this patient’s visual field defect is a result of optic atrophy due to biotinidase deficiency in early life rather than glaucomatous damage.

Impact of healthcare strategies on patterns of paediatric sight impairment in a developed population: 1984–2011

PurposeThe aim of our study was to analyse paediatric sight-impairment trends in Northern Ireland (NI) over a 28-year period to better understand the impact which changes in health-care provision may be having on childhood blindness and to enable us to assess our progress towards achieving the World Health Organisation (WHO) aims.MethodsA database of Certificates of Visual Impairment completed for NI children aged <16 years was used to determine the cause of sight impairment from 1984 to 2011. Causes were classified into preventable or treatable conditions and analysed for trends.ResultsFive hundred and ninety-eight children were registered as having impaired vision over the 28-year period. A total of 22% had preventable or treatable conditions. Optic atrophy was the most common cause responsible for 16% of registrations followed by albinism (12%), cerebral visual impairment (11%), congenital cataract (8%), retinopathy of prematurity (ROP) (8%), and congenital motor nystagmus (7%). The incident rate (per million population aged <16 years) for registerable vision loss due to congenital cataract decreased from 5.89 (CI 2.82–10.83) in 1984–1987 to 2.63 (CI 0.72–6.74) in 2008–2011. For ROP, the incident rate peaked during 2000–2003 at 8.87 (CI 4.85–14.88). Thereafter, there was a statistically significant reduction in incident rate to 1.98 (CI 0.41–5.77) in 2008–2011 (P=0.008).ConclusionsSight-impairment registrations due to preventable or treatable causes have decreased over the past 28 years. This is likely due to better surgical techniques and improved refractive care for conditions such as congenital cataract and ongoing research and treatment protocols for conditions such as ROP. Future advances in this area may help to further reduce the burden of childhood sight impairment and improve quality of life for these patients.

The ocular phenotype of stiff-skin syndrome

PurposeStiff skin syndrome (SSS; MIM#184900) is a rare autosomal dominantly inherited Mendelian disorder characterised by thickened and stone-hard indurations of the skin, mild hypertrichosis, and limitation of joint mobility with flexion contractures. It is autosomal dominant with high penetrance and results from mutations in the fibrillin 1 (FBN1; MIM*134797) gene. Here we present the associated ocular phenotype in a two generation nonconsanguineous Northern Irish family.MethodsThe affected patients underwent complete ophthalmic and orthoptic assessment and genetic testing.ResultsAll three patients had ophthalmoplegia of varying degrees. Direct sequencing of the FBN1 gene detected a heterozygous pathogenic mutation (c.4710G>C; p.Trp1570Cys) in all affected patients.ConclusionsThis is the first report of ophthalmoplegia in association with SSS.

Discrete Conditional Phase-Type Model Utilising a Multiclass Support Vector Machine for the Prediction of Retinopathy of Prematurity

Retinopathy of prematurity (ROP) is a rare disease in which retinal blood vessels of premature infants fail to develop normally, and is one of the major causes of childhood blindness throughout the world. The Discrete Conditional Phase-type (DC-Ph) model consists of two components, the conditional component measuring the inter-relationships between covariates and the survival component which models the survival distribution using a Coxian phase-type distribution. This paper expands the DC-Ph models by introducing a support vector machine (SVM), in the role of the conditional component. The SVM is capable of classifying multiple outcomes and is used to identify the infants risk of developing ROP. Class imbalance makes predicting rare events difficult. A new class decomposition technique, which deals with the problem of multiclass imbalance, is introduced. Based on the SVM classification, the length of stay in the neonatal ward is modelled using a 5, 8 or 9 phase Coxian distribution.

Mutational Analysis of the Rhodopsin Gene in Sector Retinitis Pigmentosa

Abstract Background: To determine the role of rhodopsin (RHO) gene mutations in patients with sector retinitis pigmentosa (RP) from Northern Ireland. Design: A case series of sector RP in a tertiary ocular genetics clinic. Participants: Four patients with sector RP were recruited from the Royal Victoria Hospital (Belfast, Northern Ireland) and Altnagelvin Hospital (Londonderry, Northern Ireland) following informed consent. Methods: The diagnosis of sector RP was based on clinical examination, International Society for Clinical Electrophysiology of Vision (ISCEV) standard electrophysiology, and visual field analysis. DNA was extracted from peripheral blood leucocytes and the coding regions and adjacent flanking intronic sequences of the RHO gene were polymerase chain reaction (PCR) amplified and cycle sequenced. Main Outcome Measure: Rhodopsin mutational status. Results: A heterozygous missense mutation in RHO (c.173C > T) resulting in a non-conservative substitution of threonine to methionine (p. Thr58Met) was identified in one patient and was absent from 360 control individuals. This non-conservative substitution (p.Thr58Met) replaces a highly evolutionary conserved polar hydrophilic threonine residue with a non-polar hydrophobic methionine residue at position 58 near the cytoplasmic border of helix A of RHO. Conclusions: The study identified a RHO gene mutation (p.Thr58Met) not previously reported in RP in a patient with sector RP. These findings outline the phenotypic variability associated with RHO mutations. It has been proposed that the regional effects of RHO mutations are likely to result from interplay between mutant alleles and other genetic, epigenetic and environmental factors.