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The association between abusive head trauma and retinal hemorrhages is well documented. As such, ophthalmic review in suspected nonaccidental injury has become routine. However, there is a paucity of reports focusing on ocular trauma and retinal detachment presenting as unilateral findings in nonaccidental injury and in the absence of other signs of physical abuse. This report identifies 2 suspected cases of nonaccidental injury in infants presenting to a tertiary care center with retinal detachment presumed secondary to severe unilateral direct ocular trauma. The fellow eye was normal in both cases. Findings were inconsistent with the reported histories from parents.

Contains fulltext : 168098.pdf (Publisher’s version ) (Open Access) Purpose: Mutation of RGR, encoding retinal G-protein coupled receptor was originally reported in association with retinal dystrophy in 1999. A single convincing recessive variant segregated perfectly in one family of five affected and two unaffected siblings. At least one further individual, homozygous for the same variant has since been reported. The aim of this report was to reevaluate the findings in consideration of data from a whole genome sequencing (WGS) study of a large cohort of retinal dystrophy families. Methods: Whole genome sequencing was performed on 599 unrelated probands with inherited retinal disease. Detailed phenotyping was performed, including clinical evaluation, electroretinography, fundus photography, fundus autofluorescence imaging (FAF) and spectral-domain optical coherence tomography (OCT). Results: Overall we confirmed that affected individuals from six unrelated families were homozygous for both the reported RGR p.Ser66Arg variant and a nearby frameshifting deletion in CDHR1 (p.Ile841Serfs119*). All had generalized rod and cone dysfunction with severe macular involvement. An additional proband was heterozygous for the same CDHR1/RGR haplotype but also carried a second null CDHR1 mutation on a different haplotype. A comparison of the clinical presentation of the probands reported here with other CDHR1-related retinopathy patients shows the phenotypes to be similar in presentation, severity, and rod/cone involvement. Conclusions: These data suggest that the recessive retinal disorder previously reported to be due to homozygous mutation in RGR is, at least in part, due to variants in CDHR1 and that the true consequences of RGR knock-out on human retinal structure and function are yet to be determined.

Importance Enhanced S-cone syndrome (ESCS) forms part of the differential diagnosis of night blindness in childhood. Objective To report in detail the clinical phenotype and molecular genetic findings in a series of children with ESCS. Design, Setting and Participants Nine children with ESCS from 5 families underwent full ophthalmic examination, electrophysiological testing, and retinal imaging at a genetic eye disease clinic of a tertiary referral eye hospital. Bidirectional Sanger sequencing of all exons and intron-exon boundaries of NR2E3 was performed. Main Outcomes and Measures Results of ophthalmic examination and sequence analysis of NR2E3. Results In total, 5 girls and 4 boys with a diagnosis of ESCS were included in the study. All patients had developed nyctalopia from early childhood. Visual acuity ranged from 0.00 to 1.20 logMAR (20/20 to 20/320 Snellen). All patients had hyperopia. Three patients had nummular pigmentary lesions along the arcades as typically seen in adults, 4 patients had mild pigmentary disturbance or white dots along the arcades, and 2 patients had a normal retinal appearance, although their fundus autofluorescence imaging demonstrated foci of increased autofluorescence along the arcades. Three patients had macular schisis-like changes on optical coherence tomography. Eight patients had electrophysiological testing at a mean age of 8.6 years (age range, 3-14 years), and in each patient the findings were consistent with the diagnosis of ESCS. Direct sequencing of NR2E3 identified 3 previously described mutations and 4 novel mutations. Seven patients were compound heterozygous for mutations in NR2E3 , and 2 additional sibling patients were presumed to be homozygous for a missense change based on parental sequencing. Conclusions and Relevance In this sample, children with ESCS had an early onset of night blindness and hyperopia but no nystagmus. Based on this study, children with ESCS may initially manifest a normal fundus appearance but later develop mottled retinal pigment epithelium change along the arcades, followed by the appearance of white dots in the same distribution. Fundus autofluorescence imaging is abnormal in children with a normal fundus appearance. The electrophysiological findings are pathognomonic and allow targeted molecular screening and a specific diagnosis.

Phosphatidylcholine (PC) is the major glycerophospholipid in eukaryotic cells and is an essential component in all cellular membranes. The biochemistry of de novo PC synthesis by the Kennedy pathway is well established, but less is known about the physiological functions of PC. We identified two unrelated patients with defects in the Kennedy pathway due to biallellic loss-of-function mutations in phosphate cytidylyltransferase 1 alpha (PCYT1A), the rate-limiting enzyme in this pathway. The mutations lead to a marked reduction in PCYT1A expression and PC synthesis. The phenotypic consequences include some features, such as severe fatty liver and low HDL cholesterol levels, that are predicted by the results of previously reported liver-specific deletion of murine Pcyt1a. Both patients also had lipodystrophy, severe insulin resistance, and diabetes, providing evidence for an additional and essential role for PCYT1A-generated PC in the normal function of white adipose tissue and insulin action.

Inherited retinal dystrophies are a major cause of childhood blindness. Here, we describe the identification of a homozygous frameshift mutation (c.1194_1195delAG, p.Arg398Serfs*9) in TUB in a child from a consanguineous UK Caucasian family investigated using autozygosity mapping and whole-exome sequencing. The proband presented with obesity, night blindness, decreased visual acuity, and electrophysiological features of a rod cone dystrophy. The mutation was also found in two of the proband's siblings with retinal dystrophy and resulted in mislocalization of the truncated protein. In contrast to known forms of retinal dystrophy, including those caused by mutations in the tubby-like protein TULP-1, loss of function of TUB in the proband and two affected family members was associated with early-onset obesity, consistent with an additional role for TUB in energy homeostasis.

Purpose To ascertain the range of histopathological diagnoses made from tissues removed during ophthalmic surgical procedures over two years from one NHS Trust. During this period, joint recommendations were published by the Royal College of Pathologists (RCPath) and the Royal College of Ophthalmologists (RCOphth) in the United Kingdom, regarding the referral of ophthalmic pathology specimens, stating that in order to avoid delayed or missed diagnoses, with certain exceptions, all tissues obtained from ophthalmic surgical procedures should be sent for histopathological examination. This policy was implemented locally from January 2011. Methods This was a retrospective case note review of the ophthalmic histopathology specimens sent between January 2010 and December 2011, at the Mid Essex Hospital Services NHS Trust. Patient demographics and histopathological diagnoses were determined for each. Results Over the two-year period, 268 specimens were sent for ophthalmic histopathological examination. In 2010, 112 samples were sent, with 18 malignancies detected (16.1%). In 2011, 156 samples were sent, with 30 malignancies identified (19.2%). The most common diagnosis was basal cell carcinoma, comprising 43/48 malignancies (89.6%). Conclusion Since the local implementation of the joint guidelines from the RCPath and RCOphth, there was an increase in the number of ophthalmic histopathology specimens sent within this Trust, with a 3.1% increase in the number of malignancies detected. We believe that this improvement in detection of ocular malignancies justifies the increased burden on the histopathology service from the ophthalmology unit within this Trust.

Leber Congenital Amaurosis (LCA) and Early Childhood Onset Severe Retinal Dystrophy are clinically and genetically heterogeneous retinal disorders characterised by visual impairment and nystagmus from birth or early infancy. We investigated the prevalence of sequence variants in AIPL1 in a large cohort of such patients (n = 392) and probed the likelihood of disease-causation of the identified variants, subsequently undertaking a detailed assessment of the phenotype of patients with disease-causing mutations. Genomic DNA samples were screened for known variants in the AIPL1 gene using a microarray LCA chip, with 153 of these cases then being directly sequenced. The assessment of disease-causation of identified AIPL1 variants included segregation testing, assessing evolutionary conservation and in silico predictions of pathogenicity. The chip identified AIPL1 variants in 12 patients. Sequencing of AIPL1 in 153 patients and 96 controls found a total of 46 variants, with 29 being novel. In silico analysis suggested that only 6 of these variants are likely to be disease-causing, indicating a previously unrecognized high degree of polymorphism. Seven patients were identified with biallelic changes in AIPL1 likely to be disease-causing. In the youngest subject, electroretinography revealed reduced cone photoreceptor function, but rod responses were within normal limits, with no measurable ERG in other patients. An increasing degree and extent of peripheral retinal pigmentation and degree of maculopathy was noted with increasing age in our series. AIPL1 is significantly polymorphic in both controls and patients, thereby complicating the establishment of disease-causation of identified variants. Despite the associated phenotype being characterised by early-onset severe visual loss in our patient series, there was some evidence of a degree of retinal structural and functional preservation, which was most marked in the youngest patient in our cohort. This data suggests that there are patients who have a reasonable window of opportunity for gene therapy in childhood.

PMCID: PMC3454532.-- et al., Leber congenital amaurosis (LCA) is an infantile-onset form of inherited retinal degeneration characterized by severe vision loss. Two-thirds of LCA cases are caused by mutations in 17 known disease-associated genes (Retinal Information Network (RetNet)). Using exome sequencing we identified a homozygous missense mutation (c.25G>A, p.Val9Met) in NMNAT1 that is likely to be disease causing in two siblings of a consanguineous Pakistani kindred affected by LCA. This mutation segregated with disease in the kindred, including in three other children with LCA. NMNAT1 resides in the previously identified LCA9 locus and encodes the nuclear isoform of nicotinamide mononucleotide adenylyltransferase, a rate-limiting enzyme in nicotinamide adenine dinucleotide (NAD +) biosynthesis. Functional studies showed that the p.Val9Met alteration decreased NMNAT1 enzyme activity. Sequencing NMNAT1 in 284 unrelated families with LCA identified 14 rare mutations in 13 additional affected individuals. These results are the first to link an NMNAT isoform to disease in humans and indicate that NMNAT1 mutations cause LCA. © 2012 Nature America, Inc. All rights reserved., This work was supported by grants from the US National Institutes of Health (RO1-EY12910 (E.A.P.), R03-DK082446 (M.J.F.), R01-GM097409 (E.N.-O.), P30HD026979 (M.J.F. and R.X.) and P30EY014104 (Massachusetts Eye and Ear Infirmary core support)); the Foundation Fighting Blindness USA (I.A., A.D.B., E.L.B., S.S.B., Q.L., A.T.M., D.S.M., E.A.P., J.-A.S., S.M.-S. and A.R.W.); the Rosanne Silbermann Foundation (E.A.P.); the Penn Genome Frontiers Institute (E.A.P. and X.G.); the Institutional Fund to the Center for Biomedical Informatics by the Loyola University Stritch School of Medicine (X.G.); the Foerderer Award for Excellence from the Children’s Hospital of Philadelphia (M.J.F. and X.G.); the from the Division of Child Development and Metabolic Disease at the Children’s Hospital of Philadelphia (M.J.F.); the Clinical and Translational Research Center at the Children’s Hospital of Philadelphia (UL1-RR-024134) (M.J.F. and E.A.P.); the Department of Biotechnology, the Government of India and the Champalimaud Foundation, Portugal (C.K.); the Hyderabad Eye Research Foundation (C.K.); a senior research fellowship from the Council for Scientific and Industrial Research (R.S.); the Foundation Voir et Entendre, Ville de Paris and Région Ille de France (C.Z.); RP Fighting Blindness (UK) (A.R.W.); Fight For Sight (UK) (A.D.B., S.S.B., A.T.M., D.S.M. and A.R.W.); Moorfields Eye Hospital National Institute of Health Research (NIHR) British Research Council (BRC) for Ophthalmology (A.D.B., S.S.B., A.T.M., D.S.M. and A.R.W.); and the Special Trustees of Moorfields Eye Hospital (A.D.B., S.S.B., A.T.M., D.S.M. and A.R.W.).This project is funded, in part, by the Penn Genome Frontiers Institute under a grant with the Pennsylvania Department of Health, which disclaims responsibility for any analyses, interpretations or conclusions.

Purpose To identify patients with autosomal recessive retinal dystrophy caused by mutations in the gene, retinal dehydrogenase 12 (RDH12), and to report the associated phenotype. Methods After giving informed consent, all patients underwent full clinical evaluation. Patients were selected for mutation analysis based upon positive results from the Asper Ophthalmics Leber congenital amaurosis arrayed primer extansion (APEX) microarray screening, linkage analysis, or their clinical phenotype. All coding exons of RDH12 were screened by direct Sanger sequencing. Potential variants were checked for segregation in the respective families and screened in controls, and their pathogenicity analyzed using in silico prediction programs. Results Screening of 389 probands by the APEX microarray and/or direct sequencing identified bi-allelic mutations in 29 families. Seventeen novel mutations were identified. The phenotype in these patients presented with a severe early-onset rod-cone dystrophy. Funduscopy showed severe generalized retinal pigment epithelial and retinal atrophy, which progressed to dense, widespread intraretinal pigment migration by adulthood. The macula showed severe atrophy, with pigmentation and yellowing, and corresponding loss of fundus autofluorescence. Optical coherence tomography revealed marked retinal thinning and excavation at the macula. Conclusions RDH12 mutations account for approximately 7% of disease in our cohort of patients diagnosed with Leber congenital amaurosis and early-onset retinal dystrophy. The clinical features of this disorder are highly characteristic and facilitate candidate gene screening. The term RDH12 retinopathy is proposed as a more accurate description.

PURPOSE. Mutations of C2ORF71 have recently been reported to be associated with autosomal recessive (AR) retinitis pigmentosa (RP) in humans and with visual defects in zebrafish. C2ORF71 is located on 2p23.2 and encodes a 1288-amino-acid protein of unknown function, predominately expressed in the photoreceptors. The study was conducted to determine the prevalence of mutations in C2ORF71 in a cohort of probands with AR retinal degeneration and to detect coding sequence variation in controls.METHODS. A combination of high-resolution DNA melting (HRM) analysis and automated DNA sequencing was used to screen for C2ORF71 in 286 affected unrelated individuals. Among them, 95 subjects had Leber congenital amaurosis, and 191 had AR RP. In a similar fashion 151 European and 40 South Asian control DNAs were screened.RESULTS. Overall, 40 DNA sequence variants were detected, with 17 novel polymorphisms found in the control subjects (8 missense, 7 synonymous, and 2 other). Importantly, 11 novel sequence variants (6 missense and 5 synonymous) in 20 alleles were detected in the cohort of patients but not in the controls. Only one proband was a compound heterozygote but segregation analysis revealed her unaffected father to be homozygous for one of the putative mutations.CONCLUSIONS. C2ORF71 is a highly polymorphic gene (average heterozygosity of coding region in controls: 2.118 x 10(-3)) with many rare variants that confound mutation detection. Further analysis will determine the spectrum of retinal disease caused by mutations in C2ORF71 and distinguish true pathogenic alleles from the high background of polymorphism elucidating the role of this rare cause of RP in the visual process. (Invest Ophthalmol Vis Sci. 2011; 52:1880-1886) DOI:10.1167/iovs.10-6043

INTRODUCTION: Previous studies have investigated intraocular pressure (IOP) measurements through conventional soft (hydrogel) therapeutic contact lenses, and have found that an accurate IOP can be recorded in normal eyes, and in eyes with abnormal anterior segments. The IOP measurement through soft contact lenses may be affected by the water content and centre thickness of the lens. Silicone hydrogel contact lenses are now being used as therapeutic contact lenses due to their high oxygen permeability. The purpose of this study is to investigate if IOP can be accurately measured in a subject wearing a silicone hydrogel contact lens. METHODS: In a cohort study, the IOP was measured with a Goldmann applanation tonometer without a contact lens and then repeated with a hydrogel contact lens in situ. RESULTS: The IOP of 20 eyes of 10 volunteers with no ocular pathology was measured. The mean difference (+/-S.D.) found between IOP measurement with (mean 15.55+/-1.70 mmHg) and without (mean 16.05+/-1.90 mmHg) contact lens was found to be -0.5+/-0.89 mmHg. Statistical analysis was performed which revealed a correlation coefficient of 0.89. No significant statistical difference was found between the two groups with paired t-test (p=0.19). CONCLUSION: Accurate measurement of IOP by applanation tonometry can be achieved through a silicone hydrogel contact lens.

Importance We describe novel ocular phenotypic features caused by mutations in ADAMTS18 . The exact role of ADAMTS18 in ocular disease is unclear, and our work further contributes to the understanding of this gene and its protein. Objective To expand the phenotypic characterization in patients with homozygous mutations in ADAMTS18 and report novel mutational data. Design, Setting, and Participants A case series with genetic investigations was conducted at tertiary referral clinical and university settings. Three families participated. Main Outcome Measures Phenotype and genotype description of 3 families. Results Four affected patients from 3 families with an unusual ocular phenotype had full ophthalmic and systemic examination. A single affected individual in the first family had bilateral microcornea, ectopic pupils, and cone-rod dystrophy. In a second family, 2 brothers showed bilateral microcornea, childhood cataract, ectopia lentis, rhegmatogenous retinal detachment, and cone-rod dystrophy. In the third family, a single affected individual had the same features as those in family 2, without ectopia lentis. Causative mutations were sought using homozygosity mapping, Sanger sequencing, and massively parallel sequencing of the whole exome. Novel homozygous mutations in ADAMTS18 were identified, consisting of c.1067T>A [p.L356*] in the first proband, c.2159G>C [p.C720S] in the 2 affected brothers, and c.1952G>A [p.R651Q] in the third proband. All 3 mutations are predicted to be pathogenic. Conclusions and Relevance Mutations in ADAMTS18 are associated with ocular developmental abnormalities including microcornea, ectopia lentis, and early onset of cone-rod dystrophy. This report provides further evidence that ADAMTS18 plays a key role in ocular development. Physicians should consider screening ADAMTS18 in patients with microcornea and cone-rod dystrophy.

A 24-year-old woman presented to Accident and Emergency with a 2 day history of gradually worsening left upper-quadrant abdominal pain associated with pyrexia and with intermittent hypertension over the past year. Abdominal ultrasonography showed a welldefined 10 cm mixed echogenic mass superior to the left kidney. A computed tomography (CT) scan showed a 1012 cm soft tissue mass in the left upper abdomen between the left kidney and the spleen, with a welldefined smooth outline (Figure 1). The exact location of the lesion was uncertain, as the left adrenal gland was not properly visualized. Magnetic resonance imaging (MRI) showed the mass attached to the upper pole of the left kidney, showing multiple locules containing fluid with the adrenal gland compressed medially (Figure 2). A metaiodobenzylguanidine (MIBG) scan showed areas of increased uptake lying above the left kidney, suggesting a phaeochromocytoma. A venogram was performed to ensure this was a separate mass to the kidney and it showed that the relative functions of both kidneys were equal (50%). Urinary and plasma

Item does not contain fulltext This study was undertaken to investigate the prevalence of sequence variants in LCA5 in patients with Leber congenital amaurosis (LCA), early-onset retinal dystrophy (EORD), and autosomal recessive retinitis pigmentosa (arRP); to delineate the ocular phenotypes; and to provide an overview of all published LCA5 variants in an online database. Patients underwent standard ophthalmic evaluations after providing informed consent. In selected patients, optical coherence tomography (OCT) and fundus autofluorescence imaging were possible. DNA samples from 797 unrelated patients with LCA and 211 with the various types of retinitis pigmentosa (RP) were screened by Sanger sequence analysis of all LCA5 exons and intron/exon junctions. Some LCA patients were prescreened by APEX technology or selected based on homozygosity mapping. In silico analyses were performed to assess the pathogenicity of the variants. Segregation analysis was performed where possible. Published and novel LCA5 variants were collected, amended for their correct nomenclature, and listed in a Leiden Open Variation Database (LOVD). Sequence analysis identified 18 new probands with 19 different LCA5 variants. Seventeen of the 19 LCA5 variants were novel. Except for two missense variants and one splice site variant, all variants were protein-truncating mutations. Most patients expressed a severe phenotype, typical of LCA. However, some LCA subjects had better vision and intact inner segment/outer segment (IS/OS) junctions on OCT imaging. In two families with LCA5 variants, the phenotype was more compatible with EORD with affected individuals displaying preserved islands of retinal pigment epithelium. One of the families with a milder phenotype harbored a homozygous splice site mutation; a second family was found to have a combination of a stop mutation and a missense mutation. This is the largest LCA5 study to date. We sequenced 1,008 patients (797 with LCA, 211 with arRP) and identified 18 probands with LCA5 mutations. Mutations in LCA5 are a rare cause of childhood retinal dystrophy accounting for approximately 2% of disease in this cohort, and the majority of LCA5 mutations are likely null. The LCA5 protein truncating mutations are predominantly associated with LCA. However, in two families with the milder EORD, the LCA5 gene analysis revealed a homozygous splice site mutation in one and a stop mutation in combination with a missense mutation in a second family, suggesting that this milder phenotype is due to residual function of lebercilin and expanding the currently known phenotypic spectrum to include the milder early onset RP. Some patients have remaining foveal cone structures (intact IS/OS junctions on OCT imaging) and remaining visual acuities, which may bode well for upcoming treatment trials.

PURPOSE. To investigate the prevalence of sequence variants in the gene SPATA7 in patients with Leber congenital amaurosis (LCA) and autosomal recessive, severe, early-onset retinal dystrophy (EORD) and to delineate the ocular phenotype associated with SPATA7 mutations.METHODS. Patients underwent standard ophthalmic evaluation after providing informed consent. One hundred forty-one DNA samples from patients with LCA and EORD had been analyzed for mutations by using a microarray, with negative results. One additional patient underwent SPATA7 screening due to a region of autozygosity surrounding this gene. A further patient was screened who had a compatible ocular phenotype. The entire SPATA7 coding sequence was assayed, including the intron-exon junctions, by using a combination of direct DNA sequencing and high-resolution melting screening.RESULTS. Screening of SPATA7 identified several known and novel single-nucleotide polymorphisms (SNPs). Affected individuals from five unrelated families were identified to have coding changes. Clinical features demonstrated a severe infantile onset retinal dystrophy, similar to Leber congenital amaurosis. The retina had widespread retinal pigment epithelial atrophy, with minimal pigment migration into the neurosensory retina. Fundus autofluorescence imaging showed a parafoveal annulus of increased autofluorescence. High-definition optical coherence tomography showed preservation of the inner segment/outer segment junction at the fovea.CONCLUSIONS. Mutations in SPATA7 are a rare cause of childhood retinal dystrophy accounting for 1.7% of disease in this cohort. Affected patients present in infancy with severe visual loss, but may have some preservation of the photoreceptor structure in the central retina. (Invest Ophthalmol Vis Sci. 2011;52:3032-3038) DOI:10.1167/iovs.10-7025