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“Marfan Syndrome” or “any old iron” and “eyes”

Authors:
McConnell V

Institution:
Northern Ireland Regional Genetics Service

Abstract:
Hereditary Hyperferritinaemia cataract syndrome (HHCS) is an autosomal dominantly inherited condition first described in 1995. Cardinal features observed in HHCS are constant high serum ferritin unresponsive to iron depletion, no signs of iron overload, normal blood cell counts & normal transaminases and early onset (+/-familial) usually bilateral cataract. There is a variable phenotype re ferritin levels & cataract severity and is caused by variants in Iron Responsive element (IRE) & exon 1 of ferritin light chain gene (FTL) gene.

We report a case of a 19 year old male who was referred to Genetics Service for assessment of possible Marfan syndrome prior to cataract surgery. He has a history of bilateral cataracts detected at 5 year with recent 1 year deterioration with progressive posterior subcapsular cataracts requiring surgery. He required conservative management for spontaneous left apical pneumothorax at 17 and coincidental high serum ferritin during hospitalization. Significant paternal history of cataracts.  Subsequent clinical assessment, genetic and non-genetic investigations confirmed he is a heterozygous pathogenic variant, c.-167C>T in IRE of FTL gene carrier confirming HHCS.

This case illustrates that HHCS should be considered in anyone presenting with early onset cataracts and +/- family history of similar phenotype and iron studies completed.

Case report: Oliver McFarlane Syndrome with secondary choroidal neovascularisation

Authors:
Dr. Aruni Makuloluwa, Ms. Savita Madhusudhan

Institution:
St. Paul’s Eye Unit, Royal Liverpool University Hospital, Liverpool L7 8XP

Abstract:
13 year old Caucasian female with history of nyctalopia from early childhood and amblyopia right eye, was diagnosed with Oliver McFarlane Syndrome on genetic testing with whole exome sequencing showing 2 mutations on PNPLA6 gene at the age of ten. There is no history of consanguinity or family history of eye problems. Corrected visual acuities are 6/60 and 6/9 in right and left eyes, respectively. Fundal examination showed normal discs and vessels (unlike typical retinitis pigmentosa), chorioretinal degeneration with clumps of pigment deposited in posterior pole and just beyond mid-peripheral retina and pigmented scars in both maculae. She was diagnosed with macular choroidal neovascularisation (CNV) in the right eye in 2015 and treated with a single antiVEGF intravitreal injection; reactivation in 2017 was treated similarly. She is now monitored closely with a plan to treat on a pro re nata basis if her CNV reactivates. She is also under endocrinology review. There are less than 20 cases of Oliver McFarlane described world-wide and no association with macular CNV has been previously described. We would like to discuss Oliver McFarlane Syndrome in detail and highlight other inherited chorioretinal dystrophies associated with secondary CNV.

Next-generation sequencing reveals a novel heterozygous PMPCA variant associated with isolated optic atrophy

Authors:
Neringa Jurkute, Patrizia Amati-Bonneau, Guy Leanars, Pascal Reynier, Majida Charif, Naushin Waseem, Anthony G. Robson, Indran Davagnanam, Andrew R. Webster, Patrick Yu-Wai-Man

Institution:
UCL
Moorfields Eye Hospital NHS Trust

Abstract:
Autosomal recessive spinocerebellar ataxia type 2 (OMIM 213200) is a rare genetic condition characterised by non-progressive cerebellar ataxia and variable degree of brain atrophy. This particular phenotype has been reported in patients carrying homozygous or compound heterozygous mutations in PMPCA (9q34.3). This gene encodes the alpha subunit of the mitochondrial processing peptidase (a-MPP), which is a primary heterodimeric enzyme responsible for the maturation of the majority of nuclear-encoded mitochondrial proteins. More recently, recessive PMPCA mutations have been reported in a family with slowly progressive cerebellar ataxia. Only one case of blindness has been reported in a patient with ataxia carrying a compound heterozygous two missense PMPCA mutations (c.1066G>A; p.Gly356Ser and c.1129G>A; p.Ala377Thr). Here, we report on two siblings from a non-consanguineous family manifesting isolated optic atrophy with normal cerebral and cerebellar volume on MRI and carrying a novel heterozygous PMPCA variant (c.1249G>A, p.Gly417Arg), where we speculate on the possible dominant inheritance of PMPCA gene. Our report extends the genotypic and phenotypic spectrum of PMPCA-related disease.

Evaluation of positive retinal gene panel results from the Genetic Eye Clinic in Bristol Eye Hospital

Authors:
Nervine Meshad  MBChB Mcs FRCS Phd, ,Rishi Trivedi, Samantha Hunt, Amanda Churchill BSc MBChB PhD, FRCOphth

Institution:
Bristol Eye Hospital NHS Trust

Abstract:
Purpose
This study aimed to evaluate both the likelihood of obtaining a positive molecular diagnosis in patients with a retinal dystrophy attending Bristol Eye Hospital Genetic Eye Clinic and trends in phenotype genotype correlation.
Method
Medical notes were reviewed for all patients who had undergone genetic testing for an inherited retinal dystrophy over a 5 year period 2012-2017. Results of gene panel testing and other clinical diagnostic tests were used to create a database. The percentage of positive genetic results was calculated and trends in phenotype-genotype correlation examined.
Results
36 unrelated individuals were identified as having genetic testing using retinal gene panels from the NHS laboratories at the Manchester Centre for Genomic Medicine. Twenty four (67%) were positive for a pathological DNA variant in a gene known to cause an inherited retinal dystrophy; 10 received negative results and 2 received a result of variants of unclear pathological significance. The clinical diagnoses of those with positive results were non- syndromic retinitis pigmentosa (16), Usher syndrome (3), Stargardt disease (2), adult vitelliform dystrophy (1), Best disease (1) and Lebers Congenital amaurosis (1). The USH2A gene contained the most DNA variants in our cohort. Phenotype-genotype correlations were complicated and inconsistent for any given clinical diagnosis.
Conclusion
Our results show that genetic testing in a carefully triaged clinical group can be successful in providing a genetic diagnosis in two thirds of individuals. This is higher than some previous reports. A difference in phenotypic presentation was observed between individuals with variants in the same gene, particularly in USH2A, which caused both syndromic and non-syndromic RP. Phenotype genotype correlations do exist but are uncommon in this cohort. The ability to test against a large panel of genes increases the likelihood of detecting a pathological DNA variant but using this information to provide prognostic information is fraught with difficulties due to the variability seen in the natural history of retinal dystrophies.

Clinical outcomes in patients with 13q deletion syndrome and retinoblastoma: a single-centre experience

Authors:
SLC Brothwell, C Hitchcott, M McCalla & H Jenkinson

Institution:
Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, UK

Abstract:
Patients with 13q deletion are at risk of retinoblastoma (RB) and other clinical features. Limited literature exists regarding chemotherapy toxicity, late effects and long term outcomes. We performed a retrospective case-series review of patients with proven 13q deletion (n = 22) who underwent treatment for RB at a National Retinoblastoma Centre 1992 – 2017. 

Median age at diagnosis was 7 months; 50% of patients presented with leukocoria (median duration of symptoms  8 weeks). Bilateral RB was present in 14 (64%) patients and dysmorphic features present in 16 (73%)  patients.

Ten (45.5%) patients underwent systemic chemotherapy. Substantial toxicity was observed; 50%  infection-related admissions; 4 (40%) had delayed count recovery; 2 Vincristine toxicity and in 2 treatment was stopped due to toxicity. Hearing loss occurred in 27% of patients, 50% in the absence of systemic chemotherapy. At follow up 95% were alive, 90% of patients demonstrated poor growth, 89% global developmental impairment and 59% ongoing medical /educational needs.

Patients with 13q deletion syndrome are at risk of chemotherapy-related toxicity.  This information will assist clinicians when planning treatment and newer, localised chemotherapy options may be preferable. Correlation between clinical features and genetics (pending) may help predict toxicity more precisely and guide management further.

Is wide-field retinal imaging alone appropriate for angioma screening in low risk patients with possible Von Hippel Lindau syndrome?

Authors:
Sonja Mansfield Smith, Rahul Makam, Louise Allen

Institution:
Cambridge University Hospitals NHS Trust

Abstract:
70% of Von Hippel Lindau (VHL) gene carriers will develop retinal angiomata. Regular ophthalmic screening of identified and potential gene carriers is undertaken to enable early management. The risk of new angiomata developing is low if a gene carrier reaches adulthood without one.

Patients attending the Eastern Region VHL clinic usually have wide-field digital retinal (Optos) imaging in addition to dilated fundoscopy. Recent workforce issues have necessitated a change to screen low risk patients primarily with Optos imaging, with additional fundoscopy when image quality is poor. 

We audited the performance of Optos screening over 12 months. 81 patients attended the VHL clinic: 28(35%) patients had previously detected angiomata and were excluded. The age range of the remaining 53 patients was 4 to 55 (median 23) years. Previously normal dilated fundoscopy had been documented.  Optos image quality was considered good in 90 (85%) of the 106 images. No new angiomata were identified. 10 patients required additional fundoscopy: 12 images had a restricted view of the inferior retina and 4 had blob artifacts. Patient feedback was positive, with Optos being well tolerated and preferred to dilated fundoscopy.

Wide-field digital retinal imaging is well tolerated and may be considered in low risk patients having VHL screening.

Characterisation of missense variants in PRPF31 and their contribution to retinitis pigmentosa

Authors:
Gabrielle Wheway1*, Liliya Nazlamova1, Nervine Meshad2, Samantha Hunt2, Nicola Jackson3, Amanda Churchill2*

1. Centre for Research in Biosciences, University of the West of England, Bristol, UK
2. Bristol Eye Hospital, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
3. Clinical Genetics Service, University Hospitals Bristol NHS Foundation Trust, Bristol, UK

Institution:
University of Southampton

Abstract:
PURPOSE. The purpose of this study was to investigate the pathogenicity of uncharacterised missense variants in PRPF31. 

METHODS. We carried out in-depth in silico splicing and structural characterisation of published missense variants, and those annotated as ‘uncertain significance’ in ClinVar in PRPF31. We used cell studies in vitro to characterise the cellular biochemistry of one specific novel variant, c.341T>A, p.Ile114Asn, found in an individual attending the genetic eye clinic at Bristol Eye Hospital.

RESULTS.  We provide novel insights into PRPF31 genetics. One variant assumed to be missense is likely to be affecting splicing rather than causing single amino acid changes. We provide evidence that the common disease mechanism in RP is haploinsufficiency, due to insolubility of protein. We provide evidence that three ClinVar variants denoted as uncertain significance are indeed likely pathogenic, and confirm this for one variant (c.341T>A, p.Ile114Asn), using clinical and in vitro studies.

CONCLUSIONS. We provide insights into PRPF31 genetics, and PRPF31 protein structure and function, which will aid more accurate prediction of pathogenicity of missense variants of uncertain significance.

Parameters of cone system function measured using a portable electroretinography device in patients with ABCA4 retinopathy with and without peripheral involvement as determined by ultra-widefield autofluorescence imaging

Authors:
Diana Butu,1 April Q Neville,2 Talha Soorma,1 Ana Fakin,1,3 Christopher J Hammond,4,5 Andrew R Webster,1,3 Michel Michaelides,1,3 Omar A Mahroo1-5
1. UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL;
2. Clinical Research Facility, Moorfields Eye Hospital, 162 City Road, London EC1V 2PD;
3. Medical Retina and Inherited Retinal Disease Service, Moorfields Eye Hospital, 162 City Road, London EC1V 2PD;
4. Department of Ophthalmology, King’s College London, St Thomas’ Hospital Campus, Westminster Bridge Road, London SE1 7EH;
5. Department of Twin Research and Genetic Epidemiology, King’s College London, St Thomas’ Hospital Campus, Westminster Bridge Road, London SE1 7EH

Institution:
UCL Institute of Ophthalmology

Abstract:
Purpose

In ABCA4 retinopathy (Stargardt disease), patients are grouped electrophysiologically into those with limited macular involvement or generalised retinal involvement based on abnormality in the full-field cone electroretinogram (ERG). We explored whether cone ERG parameters obtained with a hand-held device differed depending on presence of peripheral retinal involvement on ultra-widefield autofluorescence.
Methods
Patients underwent recording of photopic ERGs in clinic with skin electrodes (RETeval system, LKC) and ultra-widefield autofluorescence (AF) imaging (Optos plc). ERG parameters were graded with reference to >500 control subjects (TwinsUK cohort). Peripheral AF involvement was defined as abnormalities beyond the posterior pole.
Results
Of 40 patients (22 females; mean age 46), twenty-two (55%) had peripheral disease on AF. ERG recordings were well-tolerated, taking under 5 min. Mean b-wave and flicker amplitudes were lower, and peak times longer, in patients with peripheral AF involvement (p<0.05). These patients had greater proportions of subnormal ERG amplitudes (p<0.05): proportions with subnormal b-wave and flicker amplitudes were 90.5% and 77.8% respectively in patients with peripheral involvement; proportions were 22.2% and 11.8% respectively in those without peripheral involvement.
Conclusions
Patients with evidence of peripheral AF involvement had on average lower ERG parameters, and the majority of this group had abnormal ERG parameters.

UKEGG, Amanda Churchill, thanking our 2018 Keynote Lecturer, Professor Robert MacLaren, Oxford University

Congratulations to Sonja Mansfield Smith, Addenbrooks Hospital and Diana Butu, UCL for winning the best poster and free paper at the 2018 UKEGG meeting