Andrea L. Vincent

Impaired Complex-I-Linked Respiration and ATP Synthesis in Primary Open-Angle Glaucoma Patient Lymphoblasts

PURPOSE Following the recent demonstration of increased mitochondrial DNA mutations in lymphocytes of POAG patients, the authors sought to characterize mitochondrial function in a separate cohort of POAG. METHODS Using similar methodology to that previous applied to Lebers hereditary optic neuropathy (LHON) patients, maximal adenosine triphosphate (ATP) synthesis and cellular respiration rates, as well as cell growth rates in glucose and galactose media, were assessed in transformed lymphocytes from POAG patients (n = 15) and a group of age- and sex-matched controls (n = 15). RESULTS POAG lymphoblasts had significantly lower rates of complex-I-driven ATP synthesis, with preserved complex-II-driven ATP synthesis. Complex-I driven maximal respiration was also significantly decreased in patient cells. Growth in galactose media, where cells are forced to rely on mitochondrial ATP production, revealed no significant differences between the control and POAG cohort. CONCLUSIONS POAG lymphoblasts in the study cohort exhibited a defect in complex-I of the oxidative phosphorylation pathway, leading to decreased rates of respiration and ATP production. Studies in LHON and other diseases have established that lymphocyte oxidative phosphorylation measurement is a reliable indicator of systemic dysfunction of this pathway. While these defects did not impact lymphoblast growth when the cells were forced to rely on oxidative ATP supply, the authors suggest that in the presence of a multitude of cellular stressors as seen in the early stages of POAG, these defects may lead to a bioenergetic crisis in retinal ganglion cells and an increased susceptibility to cell death.

Insights into keratoconus from a genetic perspective

Keratoconus is a progressive and non‐inflammatory thinning of the cornea, which may result in severe visual impairment due to irregular curvature and scarring. It can occur in isolation but is often seen in association with other systemic or ocular disorders. There is a well‐recognised genetic component to keratoconus, as evidenced by family and twin studies; however, the aetiology of the disease is complex with both genetic and environmental factors playing a role. Over the last decade significant progress has been made in identifying genetic risk factors for keratoconus. Multiple approaches have been taken including candidate gene studies and genome‐wide studies. VSX1 remains as the best characterised keratoconus gene but only accounts for rare cases. Other candidate genes with a role to play include SOD1, other corneal dystrophy genes such as ZEB1 and TGFBI and collagen genes. Family‐based studies have recently led to the identification of the MIR184 gene for keratoconus with cataract and to the DOCK9 gene in a family with isolated keratoconus. Numerous other linkages have been reported and new sequencing technologies are set to rapidly expand the number of identified keratoconus genes in these regions. Similarly, recent genome‐wide association studies in case‐controlled cohorts have identified common variations in and around HGF, RAB3GAP1 and LOX as candidate risk factors for keratoconus. These gene identifications are beginning to reveal the molecular aetiology of keratoconus but despite this recent progress, there remain numerous genetic risk factors to be identified for this relatively common yet complex disease.

Efficacy of wide-field digital retinal imaging for retinopathy of prematurity screening.

Background:  To evaluate the efficacy of wide‐field digital retinal imaging for retinopathy of prematurity screening.

Inherited corneal disease: the evolving molecular, genetic and imaging revolution

Advances in molecular genetics and in vivo ocular imaging modalities have enhanced our understanding of the corneal dystrophies. To date at least 11 genes have been identified, in which mutations manifest in corneal disease. In addition there are at least eight other loci identified to which corneal dystrophies have been linked. The information gained from the knowledge of gene function, aberrant protein production, or altered enzyme activity in the cornea, has resulted in greater knowledge of the pathophysiological mechanisms in these disorders. In vivo confocal microscopy has recently enabled microstructural study of dystrophic corneas throughout the disease course, rather than being limited to histopathological analysis of tissue removed at corneal transplantation. This perspective article summarizes the current knowledge, with emphasis on the genes, mutant proteins and resultant mechanisms that lead to manifestations of disease, along with characteristic findings with in vivo confocal microscopy.

Ocular Manifestations of Juvenile Paget Disease

OBJECTIVES To determine the prevalence and spectrum of retinal changes in juvenile Paget disease. METHODS Observational case series and literature review with analysis. Patients with clinical and molecular evidence of juvenile Paget disease were recruited by members of the International Hyperphosphatasia Collaborative Group. Participants underwent ophthalmic examinations consisting of at least best-corrected Snellen visual acuity and dilated fundal examination or color fundus photography. A MEDLINE literature search was performed, and all identified case reports were reviewed for information regarding ocular phenotype. RESULTS Fourteen eyes from 7 patients were examined. The mean (SD) patient age was 22 (8) years, and 4 patients were female. Retinal abnormalities were evident in 12 of 14 eyes and were reported among an additional 12 patients in the literature. Retinal abnormalities included mottling of the retinal pigment epithelium, peripapillary atrophy, angioid streaks, and choroidal neovascularization. Cumulative number of retinal abnormalities was strongly associated with increasing age. CONCLUSIONS Juvenile Paget disease is associated with progressive retinopathy characterized by the development of angioid streaks, which may be complicated by choroidal neovascularization, the predominant cause of visual loss. Osteoprotegerin or its signaling pathway may have a role in calcification of Bruch membrane and in the pathogenesis of angioid streaks. Retinopathy in patients with juvenile Paget disease may be a sign of a more generalized vascular disorder.

Further genetic and clinical insights of posterior polymorphous corneal dystrophy 3.

IMPORTANCE Posterior polymorphous corneal dystrophy (PPCD) is a very rare disorder characterized by primary changes of the posterior corneal layers. Sequence variants in 3 genes are associated with the development of PPCD, including ZEB1 that is responsible for PPCD3. Evidence suggests at least 1 more gene remains to be identified. OBJECTIVE To determine the molecular genetic cause of PPCD3. DESIGN We performed extensive ophthalmological examination, including rotating Scheimpflug imaging technology and specular microscopy, and direct sequencing of the ZEB1 coding region. Comprehensive review of published PPCD3-causing variants was undertaken. SETTING Ophthalmology department of a university hospital. PARTICIPANTS Four Czech probands. MAIN OUTCOMES AND MEASURES Results of ophthalmological examination and direct sequencing of the ZEB1 coding region. RESULTS The following 2 novel frameshift mutations within ZEB1 were identified: c.2617dup in exon 8 in a 22-year-old woman, considered to be most likely de novo in origin, and c.698dup in exon 6 in a 20-year-old man. The first patient had mild changes consistent with PPCD and bilateral best-corrected visual acuity of 1.00. The corneal phenotype of the patient in the second case was more severe, with best-corrected visual acuity of 0.40 OD and 0.05 OS. Corneas of both probands were abnormally steep (keratometry readings, flat ≥ 47.4 diopters [D] and steep ≥ 49.2 D) with increased pachymetry values but no pattern indicative of keratoconus. Specular microscopy in both patients revealed reduced endothelial cell density (range, 1055/mm² to 1655/mm²). Both probands had a history of surgery for inguinal hernia; the male patient also reported hydrocele. CONCLUSIONS AND RELEVANCE Nucleotide changes within the coding region of ZEB1 underlie the pathogenesis of PPCD in 4 of 23 Czech probands (17%). The cumulative de novo ZEB1 mutation rate is at least 14%. Possible involvement of ZEB1 sequence variants not readily identified by direct sequencing of coding regions needs to be further investigated. Our findings also have implications for patient counseling.

Computerized corneal topography in a paediatric population with Down syndrome

Purpose: To characterize abnormal corneal topographic changes using corneal computerized videokeratography (CVK) in a paediatric population with Down syndrome, and in their parents.

Screening glaucoma genes in adult glaucoma suggests a multiallelic contribution of CYP1B1 to open-angle glaucoma phenotypes.

Background:  Despite increasing knowledge of the genetic pathophysiology of glaucoma, mutations in known genes account for less than 15% of disease. Gene screening predominantly remains a research tool rather than an essential part of the clinical work‐up. We aimed to determine the mutational spectrum and frequency in the genes implicated in glaucoma, in a range of glaucoma and ‘glaucoma suspect’ (GS) participants, with a positive family history.

Progression of diabetic retinopathy after bariatric surgery

To assess the impact of bariatric surgery on the progression of diabetic retinopathy in patients with Type 2 diabetes.

Corneal dystrophies and genetics in the International Committee for Classification of Corneal Dystrophies era: a review

Many of the corneal dystrophies have now been genetically characterized, and a system was established in 2008 by The International Committee for Classification of Corneal Dystrophies (IC3D) in an attempt to standardize the nomenclature. IC3D provided a classification system whereby all dystrophies can be categorized on the basis of the underlying genetic knowledge. Since that time, further work has established even more phenotypic and allelic heterogeneity than anticipated, particular for Fuchs endothelial corneal dystrophy and posterior polymorphous dystrophy. Using genome-wide association studies, a number of genes are now implicated both in normal corneal quantitative traits, such as central corneal thickness, as well as in disease. There is also a trend towards functional characterization of the genetic variants involved to elucidate the pathophysiology of these entities. This review article will provide an overview of the knowledge to date, with an emphasis on findings since the IC3D classification was published in 2008.Many of the corneal dystrophies have now been genetically characterized, and a system was established in 2008 by The International Committee for Classification of Corneal Dystrophies (IC3D) in an attempt to standardize the nomenclature. IC3D provided a classification system whereby all dystrophies can be categorized on the basis of the underlying genetic knowledge. Since that time, further work has established even more phenotypic and allelic heterogeneity than anticipated, particular for Fuchs endothelial corneal dystrophy and posterior polymorphous dystrophy. Using genome‐wide association studies, a number of genes are now implicated both in normal corneal quantitative traits, such as central corneal thickness, as well as in disease. There is also a trend towards functional characterization of the genetic variants involved to elucidate the pathophysiology of these entities. This review article will provide an overview of the knowledge to date, with an emphasis on findings since the IC3D classification was published in 2008.