Anthony T Moore

Great Ormond Street Hospital for Children NHS Foundation Trust, Londinium, England, United Kingdom

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Publications (204)1221.23 Total impact

  • Ophthalmology 11/2015; DOI:10.1016/j.ophtha.2015.09.045 · 6.14 Impact Factor
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    ABSTRACT: To characterize photoreceptor structure and mosaic integrity in subjects with R9AP- and RGS9-associated retinal dysfunction (Bradyopsia) and compare to previous observations in other cone dysfunction disorders such as Oligocone Trichromacy. Observational case series METHODS: Setting: Moorfields Eye Hospital (United Kingdom) and Medical College Wisconsin (USA). Six eyes of three subjects with disease-causing variants in R9AP or RGS9. Detailed retinal imaging using spectral-domain optical coherence tomography and confocal adaptive-optics scanning light ophthalmoscopy. Cone density at 100 μm from foveal center ranged from 123,132 cones/mm(2) to 140,013 cones/mm(2). Cone density ranged from 30,573 to 34,876 cones/mm(2) by 600 μm from center and 15,987 to 16,253 by 1400 μm from center, in keeping with data from normal subjects. Adaptive-optics imaging identified a small, focal hypo-reflective lesion at the foveal center in both eyes of the subject with RGS9-associated disease, corresponding to a discrete outer retinal defect also observed on spectral-domain optical coherence tomography; however the photoreceptor mosaic remained intact at all other observed eccentricities. Bradyopsia and Oligocone Trichromacy share common clinical symptomatology and cannot be discerned on standard clinical findings alone. Adaptive-optics imaging previously demonstrated a sparse mosaic of normal wave-guiding cones remaining at the fovea, with no visible structure outside the central fovea in Oligocone Trichromacy. In contrast, the subjects presented in this study with molecularly confirmed Bradyopsia had a relatively intact and structurally normal photoreceptor mosaic, allowing the distinction between these disorders based on the cellular phenotype and suggesting different pathomechanisms. Copyright © 2015 Elsevier Inc. All rights reserved.
    American Journal of Ophthalmology 09/2015; DOI:10.1016/j.ajo.2015.08.032 · 3.87 Impact Factor
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    ABSTRACT: Multiple isoforms of dystrophin (Dp427, Dp260, Dp140, Dp71) are expressed differentially in the central nervous system (CNS) including the retinal layers. Disruption of these protein products is responsible for cognitive dysfunction, electroretinogram (ERG) abnormalities and behavioural disorders in Duchenne muscular dystrophy (DMD). We studied the ocular characteristics and neuropsychiatric profile of 16 DMD boys. The ISCEV standard, full-field flash ERGs were assessed. Intellectual ability and behavioural disturbances were measured. All genotypes were associated with mildly abnormal photopic ERG a:b-wave amplitude ratios. In addition, we identified the following genotype/phenotype correlations: boys with mutations upstream of exon 30 (ie, isolated Dp427 altered expression) showed normal scotopic a:b ratios, abnormal photopic oscillatory potential OP2 and normal scotopic OP2. Conversely, all boys with DMD mutations downstream of exon 30 showed profoundly 'negative' scotopic ERGs (a:b ratios >1). In these patients, the involvement of Dp260 isoform resulted in the absence of slow rod pathway signalling in15 Hz scotopic flicker ERGs. These boys had abnormal scotopic OP2 and normal photopic OP2. Finally, children with mutations also affecting Dp71 were associated with more pronounced electronegative ERGs. When correlating ERGs to neurodevelopmental outcome, we found a positive correlation between negative scotopic ERGs and neurodevelopmental disturbances, and the most severe findings were in boys with Dp71 disruption. These findings suggest a strong association between DMD mutations affecting different DMD isoforms with characteristically abnormal scotopic ERGs and severe neurodevelopmental problems. The role of the ERG as a potential biomarker for dystrophin function in the CNS and response to novel genetic therapies warrants further exploration.European Journal of Human Genetics advance online publication, 17 June 2015; doi:10.1038/ejhg.2015.135.
    European journal of human genetics: EJHG 06/2015; DOI:10.1038/ejhg.2015.135 · 4.35 Impact Factor
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    ABSTRACT: Achromatopsia (ACHM) is an autosomal recessive disorder characterized by color blindness, photophobia, nystagmus and severely reduced visual acuity. Using homozygosity mapping and whole-exome and candidate gene sequencing, we identified ten families carrying six homozygous and two compound-heterozygous mutations in the ATF6 gene (encoding activating transcription factor 6A), a key regulator of the unfolded protein response (UPR) and cellular endoplasmic reticulum (ER) homeostasis. Patients had evidence of foveal hypoplasia and disruption of the cone photoreceptor layer. The ACHM-associated ATF6 mutations attenuate ATF6 transcriptional activity in response to ER stress. Atf6(-/-) mice have normal retinal morphology and function at a young age but develop rod and cone dysfunction with increasing age. This new ACHM-related gene suggests a crucial and unexpected role for ATF6A in human foveal development and cone function and adds to the list of genes that, despite ubiquitous expression, when mutated can result in an isolated retinal photoreceptor phenotype.
    Nature Genetics 06/2015; 47(7). DOI:10.1038/ng.3319 · 29.35 Impact Factor
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    ABSTRACT: Incontinentia pigmenti (IP) is an X-linked, dominant genodermatosis usually fatal in utero in males. In rare circumstances, survival is possible due to abnormal karyotype or somatic mosaicism. In this report, the mechanism and significance of loss of detectable mutation in peripheral blood leukocytes of a somatic mosaic male is discussed and an alternative approach to achieving molecular diagnosis presented. A male patient is reported, who initially presented at 2 days of age with a rash and seizure. Clinical assessment and histology of a skin biopsy were consistent with a diagnosis of IP. He was subsequently found to have bilateral retinal detachments. Screening for the common deletion in IKBKG was negative. A novel nonsense variant, c.937C>T (p.Gln313*) in IKBKG was identified at an approximate level of 15% in a blood sample taken at 10 days of age, but was undetectable in a sample taken at 3 years most likely due to selective apoptosis of mutant cells. Samples taken from the patient when he was 5-6 years of age identified the mutation at a low level in hair root and urine but not in blood or buccal cells. The detection of the mutation in cells derived from all germ layers indicates a de novo event at an early stage of embryogenesis. This is the first report of a nonsense mutation in a male IP patient. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 05/2015; 167(7). DOI:10.1002/ajmg.a.37004 · 2.16 Impact Factor
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    ABSTRACT: Background: Mutations in RPE65 cause Leber's congenital amaurosis, a progressive retinal degenerative disease that severely impairs sight in children. Gene therapy can result in modest improvements in night vision, but knowledge of its efficacy in humans is limited. Methods: We performed a phase 1-2 open-label trial involving 12 participants to evaluate the safety and efficacy of gene therapy with a recombinant adeno-associated virus 2/2 (rAAV2/2) vector carrying the RPE65 complementary DNA, and measured visual function over the course of 3 years. Four participants were administered a lower dose of the vector, and 8 were administered a higher dose. In a parallel study in dogs, we investigated the relationship among vector dose, visual function, and electroretinography (ERG) findings. Results: Improvements in retinal sensitivity were evident, to varying extents, in six participants for up to 3 years, peaking at 6 to 12 months after treatment and then declining. No associated improvement in retinal function was detected by means of ERG. Three participants had intraocular inflammation, and two had clinically significant deterioration of visual acuity. The reduction in central retinal thickness varied among participants. In dogs, RPE65 gene therapy with the same vector at lower doses improved vision-guided behavior, but only higher doses resulted in improvements in retinal function that were detectable with the use of ERG. Conclusions: Gene therapy with rAAV2/2 RPE65 vector improved retinal sensitivity, albeit modestly and temporarily. Comparison with the results obtained in the dog model indicates that there is a species difference in the amount of RPE65 required to drive the visual cycle and that the demand for RPE65 in affected persons was not met to the extent required for a durable, robust effect. (Funded by the National Institute for Health Research and others; number, NCT00643747.).
    New England Journal of Medicine 05/2015; 372(20). DOI:10.1056/NEJMoa1414221 · 55.87 Impact Factor
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    ABSTRACT: PurposeMicrocephaly with or without chorioretinopathy, lymphedema or intellectual disability (MCLID) is an autosomal dominant condition. Mutations in KIF11 have been found to be causative in approximately 75% of cases. This study describes the ocular phenotype in patients with confirmed KIF11 mutations.Methods Standard ophthalmic examination and investigation including visual acuity, refraction and fundus examination was carried out in all patients. Fundus autofluorescence imaging (FAF) was performed in three patients, and four patients underwent spectral domain optical coherence tomography (OCT). Flash electroretinography (ERG) was performed in seven patients, and five underwent additional pattern electroretinography (PERG).ResultsThe patients ranged in age from 2 to 10 years. Most presented with visual acuity loss. Fundus examination revealed lacunae of chorioretinal atrophy. Pigmentary macular changes and optic disc pallor were present in three of seven patients. Fundus autofluorescence demonstrated hypoautofluorescence at the macula in two of three patients. The lacunae of chorioretinal atrophy were hypoautofluorescent. The OCT showed atrophic maculae in three of four patients. Follow-up in one patient showed no deterioration of the vision over a 9-year period. The lesions appear not to be progressive on the follow-up imaging. Electrophysiology showed generalized rod and cone dysfunction and severe macular dysfunction. Inner retinal dysfunction was evident in three of seven patients.Conclusions Patients with KIF11 mutations show a specific ocular phenotype with variable expressivity and intrafamilial variability. Macular atrophy and dysfunction have not been consistently documented before. The fundus lesions appear non-progressive. The findings assist in providing an accurate diagnosis and thus improving the management and follow-up of patients with this syndrome.
    Acta ophthalmologica 05/2015; DOI:10.1111/aos.12759 · 2.84 Impact Factor
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    Ophthalmology 04/2015; 122(4):e22. DOI:10.1016/j.ophtha.2014.08.041 · 6.14 Impact Factor
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    ABSTRACT: We have identified TUBGCP4 variants in individuals with autosomal-recessive microcephaly and chorioretinopathy. Whole-exome sequencing performed on one family with two affected siblings and independently on another family with one affected child revealed compound-heterozygous mutations in TUBGCP4. Subsequent Sanger sequencing was performed on a panel of individuals from 12 French families affected by microcephaly and ophthalmic manifestations, and one other individual was identified with compound-heterozygous mutations in TUBGCP4. One synonymous variant was common to all three families and was shown to induce exon skipping; the other mutations were frameshift mutations and a deletion. TUBGCP4 encodes γ-tubulin complex protein 4, a component belonging to the γ-tubulin ring complex (γ-TuRC) and known to regulate the nucleation and organization of microtubules. Functional analysis of individual fibroblasts disclosed reduced levels of the γ-TuRC, altered nucleation and organization of microtubules, abnormal nuclear shape, and aneuploidy. Moreover, zebrafish treated with morpholinos against tubgcp4 were found to have reduced head volume and eye developmental anomalies with chorioretinal dysplasia. In summary, the identification of TUBGCP4 mutations in individuals with microcephaly and a spectrum of anomalies in eye development, particularly photoreceptor anomalies, provides evidence of an important role for the γ-TuRC in brain and eye development. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
    The American Journal of Human Genetics 03/2015; 96(4). DOI:10.1016/j.ajhg.2015.02.011 · 10.93 Impact Factor
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    ABSTRACT: To present a detailed clinical and molecular study of four patients from two consanguineous families with a similar childhood-onset retinal dystrophy resulting from novel homozygous nonsense mutations in RBP3. Four children with mutations in RBP3 encoding interphotoreceptor binding protein (IRBP) were ascertained by whole exome sequencing and subsequent direct Sanger sequencing. Detailed phenotyping was performed including full clinical evaluation, electroretinography, fundus photography, fundus autofluorescence (FAF) imaging and spectral domain optical coherence tomography (OCT). Results of ophthalmic examination, whole exome sequence analysis and Sanger sequence analysis. Two novel homozygous nonsense mutations (c.1530T>A ; p.Y510* and c.3454G>T ; p.E1152*) in RBP3 were identified in four patients from two families. All four patients had a similar, unusual retinal dystrophy characterized by childhood onset high myopia, generalized rod and cone dysfunction and an unremarkable fundus appearance. FAF imaging showed multiple paracentral foci of low autofluorescence in one patient and patchy increased FAF in the region of the vascular arcades in another. The OCT showed loss of outer retinal bands over peripheral macular areas in all 4 cases. This report is the first to describe the retinal dystrophy in children caused by homozygous nonsense RBP3 mutations highlighting the requirement for IRBP in normal eye development and visual function. Longitudinal study will reveal if the four children reported here will progress to a more typical retinitis pigmentosa phenotype previously described in adults with RBP3 mutations. RBP3 related disease should be considered in children with high myopia and retinal dystrophy, particularly when there are no significant fundus changes. Copyright © 2015 by Association for Research in Vision and Ophthalmology.
    Investigative Ophthalmology &amp Visual Science 03/2015; 56(4). DOI:10.1167/iovs.15-16520 · 3.40 Impact Factor
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    Gerald Liew · Anthony T Moore · Andrew R Webster · Michel Michaelides ·
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    ABSTRACT: Purpose: To determine the efficacy and prognostic factors associated with carbonic anhydrase inhibitors (CAI) in the treatment of cystoid macular edema (CME) in retinitis pigmentosa (RP). Methods: Cohort study of 81 subjects who were assessed before and after treatment. Spectral domain-optical coherence tomography (SD-OCT) was used to quantify CME. A reduction of at least 11% in central subfield (CSF) thickness was defined as objective evidence of response. Results: In the 125 eyes that received topical dorzolamide, 40.0% demonstrated a response to treatment with a mean reduction in OCT CSF thickness of 105 µm (95% confidence interval (CI) 82, 128). Mean starting visual acuity (VA) increased from 6/15 to 6/12 after a median time on treatment of 3.0 months. In patients prescribed oral acetazolamide, 28.1% of eyes (41.2% of patients) showed improvement in mean OCT CSF thickness of 115 µm (95% CI 52, 177) over a median treatment interval of 4.0 months. VA improved from 6/15 to 6/12. Eyes that responded to topical dorzolamide were more likely to have autosomal recessive than autosomal dominant RP (44.6% vs 23.3%, p=0.02), and a higher mean baseline OCT CSF than eyes that did not respond (p=0.02). Conclusions: We report that 40.0% of eyes (53.1% of patients) showed an objective improvement in CME after treatment with topical dorzolamide and 28.1% of eyes (41.2% of patients) after treatment with oral acetazolamide. Autosomal recessive RP and greater initial central retinal thickness predicted response to treatment with topical dorzolamide. Copyright © 2015 by Association for Research in Vision and Ophthalmology.
    Investigative Ophthalmology &amp Visual Science 02/2015; 56(3). DOI:10.1167/iovs.14-15995 · 3.40 Impact Factor
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    ABSTRACT: Defects in USH2A cause both isolated retinal disease and Usher syndrome (ie, retinal disease and deafness). To gain insights into isolated/nonsyndromic USH2A retinopathy, we screened USH2A in 186 probands with recessive retinal disease and no hearing complaint in childhood (discovery cohort) and in 84 probands with recessive retinal disease (replication cohort). Detailed phenotyping, including retinal imaging and audiological assessment, was performed in individuals with two likely disease-causing USH2A variants. Further genetic testing, including screening for a deep-intronic disease-causing variant and large deletions/duplications, was performed in those with one likely disease-causing change. Overall, 23 of 186 probands (discovery cohort) were found to harbour two likely disease-causing variants in USH2A. Some of these variants were predominantly associated with nonsyndromic retinal degeneration (‘retinal disease-specific’); these included the common c.2276 G>T, p.(Cys759Phe) mutation and five additional variants: c.2802 T>G, p.(Cys934Trp); c.10073 G>A, p.(Cys3358Tyr); c.11156 G>A, p.(Arg3719His); c.12295-3 T>A; and c.12575 G>A, p.(Arg4192His). An allelic hierarchy was observed in the discovery cohort and confirmed in the replication cohort. In nonsyndromic USH2A disease, retinopathy was consistent with retinitis pigmentosa and the audiological phenotype was variable. USH2A retinopathy is a common cause of nonsyndromic recessive retinal degeneration and has a different mutational spectrum to that observed in Usher syndrome. The following model is proposed: the presence of at least one ‘retinal disease-specific’ USH2A allele in a patient with USH2A-related disease results in the preservation of normal hearing. Careful genotype-phenotype studies such as this will become increasingly important, especially now that high-throughput sequencing is widely used in the clinical setting.
    European journal of human genetics: EJHG 02/2015; 23(10). DOI:10.1038/ejhg.2014.283 · 4.35 Impact Factor
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    ABSTRACT: Background: Oliver-McFarlane syndrome is characterised by trichomegaly, congenital hypopituitarism and retinal degeneration with choroidal atrophy. Laurence-Moon syndrome presents similarly, though with progressive spinocerebellar ataxia and spastic paraplegia and without trichomegaly. Both recessively inherited disorders have no known genetic cause. Methods: Whole-exome sequencing was performed to identify the genetic causes of these disorders. Mutations were functionally validated in zebrafish pnpla6 morphants. Embryonic expression was evaluated via in situ hybridisation in human embryonic sections. Human neurohistopathology was performed to characterise cerebellar degeneration. Enzymatic activities were measured in patient-derived fibroblast cell lines. Results: Eight mutations in six families with Oliver-McFarlane or Laurence-Moon syndrome were identified in the PNPLA6 gene, which encodes neuropathy target esterase (NTE). PNPLA6 expression was found in the developing human eye, pituitary and brain. In zebrafish, the pnpla6 curly-tailed morphant phenotype was fully rescued by wild-type human PNPLA6 mRNA and not by mutation-harbouring mRNAs. NTE enzymatic activity was significantly reduced in fibroblast cells derived from individuals with Oliver-McFarlane syndrome. Intriguingly, adult brain histology from a patient with highly overlapping features of Oliver-McFarlane and Laurence-Moon syndromes revealed extensive cerebellar degeneration and atrophy. Conclusions: Previously, PNPLA6 mutations have been associated with spastic paraplegia type 39, Gordon-Holmes syndrome and Boucher-Neuhäuser syndromes. Discovery of these additional PNPLA6-opathies further elucidates a spectrum of neurodevelopmental and neurodegenerative disorders associated with NTE impairment and suggests a unifying mechanism with diagnostic and prognostic importance.
    Journal of Medical Genetics 12/2014; 52(2). DOI:10.1136/jmedgenet-2014-102856 · 6.34 Impact Factor

  • Acta ophthalmologica 12/2014; 93(5). DOI:10.1111/aos.12592 · 2.84 Impact Factor
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    ABSTRACT: Mutations in Prominin-1 (Prom1) gene are known to cause retinitis pigmentosa and Stargardt disease, both of which are associated with progressive photoreceptor cell death. There are no effective therapies for either disorder. The aim of this study was to investigate the mechanism of the retinal degeneration in Prom1-deficient mouse models. We constructed Prom1 knockout mice with two distinct genetic backgrounds of C57BL/6 and C57BL/6xCBA/NSlc, and investigated the photoreceptor degeneration by means of histology and functional tests. In addition, we examined the effect of light on the Prom1-/- retina by rearing the mice in the normal light/dark cycle and completely dark conditions. Finally, we investigated if the retinoic-acid derivative Fenretinide slowed the pace of retinal degeneration in these mouse models. The Prom1-/- knockout mice with both backgrounds developed photoreceptor degeneration after eye opening, but the CB57/BL6 background mice developed photoreceptor cell degeneration much faster than the C57BL/6xCBA/NSlc mice, demonstrating genetic background dependency. Interestingly, our histological and functional examination showed that the photoreceptor cell degeneration of Prom1 knockout mice was light dependent, and was almost completely inhibited when the mutant mice were kept in the dark. The Prom1 knockout retina showed strong downregulation of expression of the visual cycle components, Rdh12 and Abca4. Furthermore, administration of Fenretinide, which lowers the level of the toxic lipofuscin, slowed the degeneration of photoreceptor cells. These findings improve our understanding of the mechanism of cell death in Prominin1 related disease and provide evidence that fenretinide may be worth studying in human disease. Copyright © 2014 by Association for Research in Vision and Ophthalmology.
    Investigative Ophthalmology &amp Visual Science 11/2014; 56(1). DOI:10.1167/iovs.14-15479 · 3.40 Impact Factor
  • Ravjit Singh · Kaoru Fujinami · Anthony T Moore ·
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    ABSTRACT: Purpose: To report a case of branch retinal artery occlusion and prepapillary loop in a 10-year-old girl. Methods: Case report with funduscopic and fluorescein angiography imaging. Results: A 10-year-old girl presented with a history of the sudden onset of a superior visual field defect in her right eye. Fundus findings were consistent with thrombosis in a prepapillary arterial loop causing an inferior branch retinal artery occlusion. Conclusion: Bilateral congenital prepapillary vascular loops are rare, and are usually asymptomatic. However, they can be complicated by vitreous hemorrhage and thrombosis. Such thrombotic events may be precipitated by hemodynamic or intravascular changes associated with exercise.
    Retinal Cases & Brief Reports 11/2014; 8(2):124-6. DOI:10.1097/ICB.0000000000000020
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    ABSTRACT: Retinitis pigmentosa (RP) is a group of genetically and clinically heterogeneous inherited degenerative retinopathies caused by abnormalities of photoreceptors or retinal pigment epithelium in the retina leading to progressive sight loss. Rhodopsin is the prototypical G-protein-coupled receptor located in the vertebrate retina and responsible for dim light vision. Here, novel M39R and N55K variants were identified as causing an intriguing sector phenotype of RP in affected patients, with selective degeneration in the inferior retina. In order to gain insights into the molecular aspects associated with this sector RP phenotype, whose molecular mechanism remains elusive, the mutations were constructed by site-directed mutagenesis, expressed in heterologous systems and studied by biochemical, spectroscopic and functional assays. M39R and N55K opsins had variable degrees of chromophore regeneration when compared to WT opsin, but showed no gross structural misfolding or altered trafficking. M39R showed a faster rate for transducin activation than WT rhodopsin with a faster metarhodopsinII decay, whereas N55K presented a reduced activation rate and an altered photobleaching pattern. N55K also showed an altered retinal release from the opsin binding pocket upon light exposure, affecting its optimal functional response. Our data suggest that these sector RP mutations cause different protein phenotypes which may be related to their different clinical progression. Overall, these findings illuminate the molecular mechanisms of sector RP associated with rhodopsin mutations.
    Journal of Biological Chemistry 10/2014; 289(52). DOI:10.1074/jbc.M114.609958 · 4.57 Impact Factor
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    ABSTRACT: Purpose To describe the clinical and molecular characteristics of patients with childhood-onset Stargardt disease (STGD). Design Retrospective case series. Participants Forty-two patients who were diagnosed with STGD in childhood at a single institution between January 2001 and January 2012. Methods A detailed history and a comprehensive ophthalmic examination were undertaken, including color fundus photography, autofluorescence imaging, spectral-domain optical coherence tomography (SD-OCT), and pattern and full-field electroretinograms. The entire coding region and splice sites of ABCA4 were screened using a next-generation, sequencing-based strategy. The molecular genetic findings of childhood-onset STGD patients were compared with those of adult-onset patients. Main Outcome Measures Clinical, imaging, electrophysiologic, and molecular genetic findings. Results The median ages of onset and the median age at baseline examination were 8.5 (range, 3–16) and 12.0 years (range, 7-16), respectively. The median baseline logarithm of the minimum angle of resolution visual acuity was 0.74. At baseline, 26 of 39 patients (67%) with available photographs had macular atrophy with macular/peripheral flecks; 11 (28%) had macular atrophy without flecks; 1 (2.5%) had numerous flecks without macular atrophy; and 1 (2.5%) had a normal fundus appearance. Flecks were not identified at baseline in 12 patients (31%). SD-OCT detected foveal outer retinal disruption in all 21 patients with available images. Electrophysiologic assessment demonstrated retinal dysfunction confined to the macula in 9 patients (36%), macular and generalized cone dysfunction in 1 subject (4%), and macular and generalized cone and rod dysfunction in 15 individuals (60%). At least 1 disease-causing ABCA4 variant was identified in 38 patients (90%), including 13 novel variants; ≥2 variants were identified in 34 patients (81%). Patients with childhood-onset STGD more frequently harbored 2 deleterious variants (18% vs 5%) compared with patients with adult-onset STGD. Conclusions Childhood-onset STGD is associated with severe visual loss, early morphologic changes, and often generalized retinal dysfunction, despite often having less severe fundus abnormalities on examination. One third of children do not have flecks at presentation. The relatively high proportion of deleterious ABCA4 variants supports the hypothesis that earlier onset disease is often owing to more severe variants in ABCA4 than those found in adult-onset disease.
    Ophthalmology 10/2014; 122(2). DOI:10.1016/j.ophtha.2014.08.012 · 6.14 Impact Factor
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    ABSTRACT: Purpose: Gene therapy trials for inherited photoreceptor disorders are planned. Anatomical metrics to select the best candidates and outcomes are needed. Adaptive optics (AO) imaging enables visualization of photoreceptor structure, although analytical tools are lacking. Here we present criteria to assess residual photoreceptor integrity in achromatopsia (ACHM). Methods: Two AOSLOs, at the Medical College of Wisconsin and Moorfields Eye Hospital, were used to image the photoreceptor mosaic of 11 subjects with ACHM and 7 age-matched controls. Images were obtained, processed, and montaged using previously described methods. Cone density and reflectivity were quantified to assess residual cone photoreceptor structure. Results: All subjects with ACHM had reduced numbers of cone photoreceptors, albeit to a variable degree. In addition, the relative cone reflectivity varied greatly. Interestingly, subjects with GNAT2-associated ACHM had the greatest number of residual cones and the reflectivity of those cones was significantly greater than that of the cones in the subjects with CNGA3/CNGB3-associated ACHM. Conclusions: We present cone reflectivity as a metric that can be used to characterize cone structure in ACHM. This method may be applicable to subjects with other cone disorders. In ACHM, we hypothesize that cone numerosity (and/or density) combined with cone reflectivity could be used to gauge the therapeutic potential. As gene replacement would not be expected to add cones, reflectivity could be a more powerful AO-metric for monitoring the cellular response to treatment and could provide a more immediate indicator of efficacy than behavioral measures, which may take longer to change.
    Investigative Ophthalmology &amp Visual Science 10/2014; 55(11). DOI:10.1167/iovs.14-14225 · 3.40 Impact Factor
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    ABSTRACT: 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.
    Investigative Ophthalmology &amp Visual Science 09/2014; 55(10). DOI:10.1167/iovs.14-14715 · 3.40 Impact Factor

Publication Stats

6k Citations
1,221.23 Total Impact Points


  • 2006-2015
    • Great Ormond Street Hospital for Children NHS Foundation Trust
      • Clinical and Academic Department of Ophthalmology (CADO)
      Londinium, England, United Kingdom
  • 1998-2015
    • University College London
      • Institute of Ophthalmology
      Londinium, England, United Kingdom
  • 1987-2015
    • Moorfields Eye Hospital NHS Foundation Trust
      • Department of Medical Retina
      Londinium, England, United Kingdom
  • 2014
    • UCL Eastman Dental Institute
      Londinium, England, United Kingdom
  • 2013
    • Central Manchester University Hospitals NHS Foundation Trust
      Manchester, England, United Kingdom
  • 2007-2013
    • University of Cambridge
      • Department of Medical Genetics
      Cambridge, England, United Kingdom
  • 2011
    • UK Department of Health
      Londinium, England, United Kingdom
  • 2009
    • City University London
      Londinium, England, United Kingdom
  • 2002
    • University of Leeds
      Leeds, England, United Kingdom
  • 2000
    • London Research Institute
      Londinium, England, United Kingdom
  • 1995
    • Ninewells Hospital
      Dundee, Scotland, United Kingdom
  • 1993-1994
    • Institute of Genetics and Molecular Medicine
      Edinburgh, Scotland, United Kingdom
    • Memorial University of Newfoundland
      Saint John's, Newfoundland and Labrador, Canada