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Purpose of Review: The molecular basis of a number of inherited diseases that affect the eyelids has been elucidated over the last two decades. Due to the vast number of these diseases, a clinician may become overwhelmed by the volume of data, making it difficult to incorporate newer information into his or her clinical practice. This article intends to review the recent developments of inherited diseases that affect the eyelids that a typical oculoplastic surgeon will encounter., Recent Findings: This review proposes categorizing genetic diseases affecting the eyelids on rarity and whether the disease manifests itself at birth or later in life. Based on this classification system the following 10 diseases (the first five manifesting at birth, the last five later in life) are considered more likely to be encountered by the typical oculoplastic surgeon and reviewed in detail: blepharophimosis-ptosis-epicanthus inversus syndrome, congenital fibrosis of the extraocular muscles, lymphedema-distichiasis syndrome, neurofibromatosis type 1, congenital myasthenic syndrome, oculopharyngeal muscular dystrophy, chronic progressive external ophthalmoplegia, myotonic dystrophy, neurofibromatosis type 2, and basal cell nevus syndrome. The remaining known genetic disorders that affect the eyelids are considered less likely to be encountered by the typical oculoplastic surgeon and are listed in tabular form., Summary: It is prudent for the oculoplastic surgeon to be knowledgeable of inherited disorders that affect the eyelids to aid in accurate diagnosis, counseling, and treatment. The development of future therapies may at some point make treatment of these diseases no longer surgical., Video Abstract: http://links.lww.com/COOP/A4.

Objective: To describe the clinical and genetic characteristics of patients with autosomal recessive bestrophinopathy (ARB)., Design: Retrospective case series., Participants: Ten patients with ARB from 7 different families., Methods: All patients underwent a complete ophthalmic examination, including dilated fundus examination, fundus photography, and fluorescein angiography (FA). In all probands, fundus autofluorescence (FAF) imaging, spectral-domain optical coherence tomography (OCT), full-field electroretinography (ERG), electro-oculography (EOG), and Goldmann perimetry were performed. In selected patients, multifocal ERG was performed. Blood samples were obtained to analyze the BEST1 gene for biallelic mutations that confirmed the diagnosis of ARB., Main Outcome Measures: Age at onset; visual acuity; fundus appearance; characteristics on FA, FAF, OCT, full-field ERG, and EOG; BEST1 gene mutations; and genotype-phenotype correlation., Results: The age at onset varied widely, from 2 to 54 years. A spectrum of fundus abnormalities was observed, such as multifocal yellowish subretinal deposits, subretinal fibrous scars, and cystoid intraretinal fluid collections in the macula. All ARB patients were hyperopic, and some had shallow anterior chamber angles that predisposed them to angle-closure glaucoma. The EOG results were abnormal in all patients. The full-field ERG results were abnormal in 8 ARB patients, whereas 2 patients demonstrated normal cone and rod responses on full-field ERG. Nine ARB patients carried biallelic mutations in the BEST1 gene, and in 1 patient with a characteristic ARB phenotype, only 1 mutation could be identified. Seven different mutations were detected, including 4 novel mutations., Conclusions: Autosomal recessive bestrophinopathy is a recognizable phenotype caused by autosomal recessively inherited mutations in the BEST1 gene. A differential diagnosis with other conditions can be made on the basis of marked autofluorescence changes in combination with an absent light rise on the EOG that outweighs the full-field ERG abnormalities, which point to the BEST1-related hereditary nature of the disease. A number of currently available therapeutic options should be considered in ARB, a disease that seems to be a suitable candidate for future gene therapy., (Copyright © 2013 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Lysosomal storage diseases represent a group of about 50 genetic disorders. The deficiencies of lysosomal and non-lysosomal proteins cause an accumulation of compounds which are normally degraded within the lysosome. There are currently no therapeutic options to cure patients suffering from a lysosomal storage disease. Due to their progressive nature there is considerable morbidity and mortality. Thus, an early treatment to maintain major systemic functions is of utmost importance. While so far only symptomatic therapies are in use, the newly available enzyme replacement therapies offer a real causal approach for selected storage diseases. Many of these disorders are characterised by pathognomonic eye findings. Therefore, the ophthalmological examination provides the opportunity for an early and non-invasive diagnosis and a chance to initiate early treatment. This review is intended to give a survey of the most common lysosomal storage diseases, particularly with regard to ophthalmological changes as well as illustrate new therapeutic options., (© Georg Thieme Verlag KG Stuttgart · New York.)

Fabry disease is a rare X-linked storage disorder leading to an accumulation of globotriaosylceramides in all cells carrying lysosomes. As the accumulation occurs in most organs, different medical specialties are involved in the diagnostics and therapy of Fabry disease. With this review of the 3 main specialties (cardiology, nephrology, and neurology) and, in addition, the adjacent specialties (ophthalmology and dermatology), we aim to discuss the division-related responsibilities and want to suggest an organ-related additional therapy besides enzyme replacement therapy., (Copyright 2010 Elsevier Inc. All rights reserved.)

Recently, preliminary results of three clinical gene therapy trials for early onset retinitis pigmentosa--Leber congenital amaurosis--suggested that treating this degenerative retinal disease by gene transfection can be safe and efficient to restore a visual function. The definitive validation of this therapeutic approach depends on the long-term results. The forthcoming availability of gene therapy in ophthalmology prompts the implementation: of 1) recruitment, 2) phenotyping and genotyping of affected patients, 3) and creation of a hereditary retinopathy registry.

Gene therapy represents a promising therapeutic option for many inherited and acquired retinal diseases. Recombinant adeno-associated viral vectors (AAV) are the most efficient tools to transfer genes in vivo to the retina. The recent identification of dozens of novel AAV serotypes enormously expands on the versatility of AAV as vector system for in vivo somatic gene transfer. The results from the forthcoming trials with AAV in the retina of patients with Leber Congenital Amaurosis will be critical for the rapid development of AAV-based therapeutics for retinal diseases.

The use of nanoparticles as carriers for the delivery of therapeutic materials to target tissues has became popular in recent years and has demonstrated great potentials for the treatments of a wide range of diseases. In this review, we summarize the advantages of nanotechnology as a common gene delivery strategy with emphasis on ocular therapy. Particular attention is paid to the CK30-PEG compacted DNA nanoparticles that have been successfully tested in the eye, lung, and brain. These particles resulted in higher transfection efficiency and longer duration of expression than other non-viral vectors without any toxicity or other side effects. They have been safely used clinically and are efficient for a broad range of gene therapy applications. The review also discusses mechanisms of nanoparticle uptake and internalization by cells, obstacles and limitations to the use of this technology, as well as novel methodologies to optimize nanoparticle driven gene expression.

Over the last decade there have been major advances in our understanding of the molecular pathology of inherited retinal dystrophies. This paper reviews recent advances in the identification of genetic mutations underlying infantile-onset inherited retinal disorders and considers how this knowledge may lead to novel therapeutic approaches.

The field of molecular genetics is evolving to encompass techniques that are directly relevant to the diagnosis and management of eye disease. Therefore, pediatric ophthalmologists must have a knowledge base that includes basic genetic concepts and their application to current clinical care.

The eye has always provided a diagnostic window for hereditary and acquired systemic diseases. Of the more than 6,000 known hereditary diseases, many are associated with changes of the visual system. Some are isolated genetic diseases of the eye, others are associated with additional ocular or systemic disorders (syndromes). In recent years, the recognition of genetic diseases as a leading cause of severe visual impairment in adults and in children has led to efforts to determine the underlying defects as well as to develop diagnostic and therapeutic molecular genetic tools. Also, education of ophthalmologists about these diseases will foster the prevention of and therapeutic approaches for genetic blindness. In this article, current knowledge on the clinical manifestations, aetiology and management of genetic diseases of the eye has been summarised.

Defects in the RPE65 gene, which is selectively expressed in the retinal pigment epithelium (RPE), result in blindness and gradual photoreceptor cell degeneration. Experiments were conducted to assess the efficacy of gene replacement therapy in restoring retinal function in RPE65-/- dogs. Long-term effects of RPE65 gene therapy were assessed using visual behavioral testing and electroretinographic (ERG) recordings at 10-12 weeks and 6-9 months after surgery in five affected dogs. Subretinal injections of similar dosages of two constructs were performed in affected dogs at the ages of 4-30 months: rAAV.RPE65 into one eye and, in four of five dogs, rAAV.GFP contralaterally. Before surgery all RPE65-/- dogs were behaviorally blind with either no or very low-amplitude ERG responses to light stimuli. Marked improvements in visual behavior and ERG responses were observed as early as 4 weeks after surgery in affected animals. Except for light-adapted 50 Hz ERG flicker responses, all ERG parameters tested increased significantly in the eyes treated with the rAAV.RPE65 construct at the early follow-up. Gradual progressive improvements in ERG responses were observed in the RPE65-treated eyes over time. An unexpected finding was that on long-term follow-up, marked improvement of photopic ERG responses were also observed in the contralateral control eye in both young and older dogs. These results are promising for future clinical trials of human patients with retinal degenerative diseases, such as Leber congenital amaurosis, that result from RPE65 gene defects.

We present an overview of the current status of basic science and translational research being applied to gene therapy for eye disease, focusing on diseases of the retina. We discuss the viral and nonviral methods being used to transfer genes to the retina and retinal pigment epithelium, and the advantages and disadvantages of each approach. We review the various genetic and somatic treatment strategies that are being used for genetically determined and acquired diseases of the retina, including gene replacement, gene silencing by ribozymes and antisense oligonucleotides, suicide gene therapy, antiapoptosis, and growth factor therapies. The rationales for the specific therapeutic approaches to each disease are discussed. Schematics of gene transfer methods and therapeutic approaches are presented together with a glossary of gene transfer terminology.

Leber congenital amaurosis (LCA) is the most common inherited cause of blindness in childhood and is characterised by a severe retinal dystrophy before the age of one year. Six genes have been identified that together account for approximately half of all LCA patients. These genes are expressed preferentially in the retina or the retinal pigment epithelium. Their putative functions are quite diverse and include retinal embryonic development (CRX), photoreceptor cell structure (CRB1), phototransduction (GUCY2D), protein trafficking (AIPL1, RPGRIP1), and vitamin A metabolism (RPE65). The molecular data for CRB1 and RPE65 support previous hypotheses that LCA can represent the severe end of a spectrum of retinal dystrophies. Given the diverse mechanisms underlying the disease, future therapies of LCA may need to be tailored to certain genetically defined subgroups. Based on experimental evidence in mice and dogs, patients with disturbed retinal metabolism of vitamin A through a mutation in the RPE65 gene will likely be the first candidates for future therapeutic trials.

To date, 118 loci have been associated with photoreceptor degenerative disease. In this review, we will discuss recent advances in the identification of genes that cause progressive photoreceptor cell death when mutated. We will focus on 12 genes isolated within the last two years that have been shown to be photoreceptor-specific, or that have provided insight into photoreceptor biology and the mechanisms of photoreceptor cell death. To aid in understanding the biologic basis for these diseases, we also briefly review photoreceptor biology. Finally, we report on recent advances towards the treatment of these disorders.

Retinoblastoma, the most common intraocular malignancy ill childhood, has served as a paradigm for the study of genetic mechanisms of oncogenesis. The retinoblastoma susceptibility gene RB1 was the first tumor suppressor gene to be cloned, and genetic and molecular biologic studies of this tumor have greatly expanded the understanding of the mechanics of tumorigenesis. Human retinoblastoma has essentially no naturally occuring animal counterpart. The development of transgenic murine models of retinoblastoma have created an experimental tool for manipulation of a tumor gene system in vivo. These models have also enabled studies of new therapeutic modalities. This review outlines the development of the transgenic murine models of retinoblastoma, together with the genetic mechanisms of retinoblastoma origin. Current therapeutic innovations developed by means of the transgenic models are described.

Purpose: To report microesotropia in twins as a unique example of the role of heredity in primary microstrabismus., Methods: Clinical records of the examinations of monozygotic twins with primary microstrabismus were reviewed., Result: Microstrabismus with different clinical findings was present in monozygotic twins. The family history and personal history of the patients were not significant., Conclusion: Microstrabismus can be seen as primary ocular motility problem without previous infantile esotropia or anisometropia. Genetic factors as well as intrauterine environment and developmental factors may affect sensorimotor development of the infant and cause ocular motility problems. Both twins should be examined for ocular motility disorders even in the absence of complaints.

Retinal angiomas are benign vascular hamartomatous lesions with important systemic and visual implications. Early diagnosis and treatment of retinal angiomas with an appropriate systemic workup for associated systemic diseases can prevent visual loss and morbidity and mortality. Tumors less than 3 mm in diameter usually can be ablated with laser photocoagulation. Cryotherapy should be reserved for eyes in which media opacities prohibit use of the laser or the tumor is located in an area of shallow serous detachment or in the extreme peripheral retina. Macular puckers or tractional macular detachments caused by retinal angiomas can be treated effectively by pars plana vitrectomy combined with photocoagulation or cryotherapy to the retinal angioma. Penetrating diathermy is a useful alternative therapy for large tumors but is fraught with risks of hemorrhage and inadvertent retinal breaks with or without vitreous loss or retinal detachment. We have found proton-beam irradiation to be an efficacious and safe treatment for large retinal angiomas (> 3 mm) and for cases complicated by exudative retinal detachments or for tumors involving the optic nerve. We believe this new, noninvasive therapy is a significant advance in the treatment of complicated retinal angiomas or for those tumors that have failed to respond to conventional measures.

Recent technical advances have led to the demonstration of the molecular basis of many genetic eye diseases. Methods now in use have been able to both suppress and insert genes in vitro and in vivo in ocular cells. The combination of this new knowledge and these techniques offers the potential for a new therapeutic approach to diseases that currently have no treatments. The scientific basis of gene therapy is introduced and then the current state of research is discussed in relation to the eye and ocular tissues.