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cover story An Approach to Genetic Eye Diseases for the Comprehensive Eye Care Provider Many resources are available for you and your patients to navigate this complex field. By Johnny Tang, MD T he prospect of managing patients with genetic eye diseases can be daunting and heart wrenching for patients and their families and challenging for the eye care provider. Patients’ questions are typically along the lines of: What causes this? What can be done about this? Who else in my family is at risk? What are the risks to my (potential) children? As the eye care specialist, you may be at the front line for these evaluations, and it is important to be as up-to-date as possible—or at the very least know where to locate information regarding the answers to these questions. Fortunately, recent advances in the understanding of the causes of genetic eye diseases have improved specialists’ ability to diagnose them and provide more detailed explanations of disease pathogenesis. The increased availability of molecular diagnostic techniques has also enhanced the ability to provide a correct diagnosis and offer more accurate prognostic information. Approach to Patients with Genetic Eye Disease A detailed medical, ophthalmologic, and family history, along with a slit-lamp and dilated fundus examination, are critical elements for evaluating patients with suspected genetic eye diseases. A careful examination could reveal findings such as iris transillumination and blunting of the foveal reflex in cases of ocular albinism. The presence of posterior subcapsular cataracts, attenuation of retinal vessels, pallor of the optic nerve, and the appearance of bone spicules in the retinal periphery could indicate retinitis pigmentosa. In another patient, 34 Advanced Ocular Care july/august 2012 the presence of yellowish pisciform and bull’s eye maculopathy may indicate a diagnosis of Stargardt disease. It would be prudent to also keep in mind unilateral cases or atypical presentations that may indicate a masquerade syndrome rather than an inherited retinal dystrophy. Ideally, further testing in patients suspected of having a genetic eye disease should be performed by an eye care provider experienced in genetic disorders. Examples of tests include corneal pachymetry,1 autofluorescence, electroretinogram, dark adaptometry, visual field, contrast, and color vision testing. Autofluorescence would be useful in patients with significant disease involving the macula to highlight regions of healthy retinal pigment epithelium.2 Color vision testing is important in cases of achromatopsia and inherited color deficiency. A number of conditions may decrease contrast sensitivity, which has a significant impact on the quality of vision. Other tests like kinetic visual fields, such as those obtained with a Goldmann perimeter, are particularly important to map scotomas in patients with retinitis pigmentosa. All of these tests can provide a useful baseline for known or suspected diagnoses, but they can also help to clinically rule out other diseases. An example would be obtaining an electroretinogram in cases of suspected Stargardt disease to rule out other conditions that may appear phenotypically similar, such as cone-rod dystrophy. This is an important consideration, because the genetic mutations responsible for these two conditions and the diseases’ prognoses are different. This additional information can help enhance a patient’s visual potential cover story Table. Available Genes for Testing via EyeGenea Diagnoses Eligible for Inclusion Genes That May Be Tested Albinism Recessive: TYR, OCA2, TYRP1, SLC45A1 X-linked: GPR143 (OA1) Aniridia and other developmental eye anomalies PAX6, WT1, DCDC1, ELP4 Axenfeld-Rieger syndrome PITX2, FOXC1 Best disease BEST1 Bietti crystalline corneo-retinal dystrophy CYP4V2 Choroideremia CHM Chronic progressive external ophthalmoplegia/Kearns-Sayre Mitochondrial gene panel syndrome; mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes; myoclonus epilepsy associated with ragged red fibers; neuropathy, ataxia, and retinitis pigmentosa Cone rod dystrophy ABCA4, RPGR, CRX, GUCY2D (codon R838) Congenital cranial dysinnervation disorders KIF21A, CHN1, SALL4, TUBB3 Congenital stationary night blindness RHO, NYX Corneal dystrophy TGFBI, KRT3, KRT12 Doyne honeycomb dystrophy EFEMP1 Familial exudative vitreal retinopathy FZD4, LRP5, NDP, TSPAN12 Glaucoma CYP1B1, OPTN, MYOC Hermansky-Pudlak syndrome HPS1 and HPS3 Infantile neuroaxonal dystrophy PLA2G6 Juvenile X-linked retinoschisis RS1 Leber hereditary optic neuropathy LHON panel (MT-ND4, MT-ND1, MT-ND6/mutations 11778G>A, 3460G>A, 14484T>C, and 14459G>A) Lowe syndrome OCRL Microphthalmia and anophthalmia SIX6, SOX2, OTX2, CHX10 Optic atrophy type 1 OPA1 Pantothenate kinase-associated neuropathy PANK2 Pattern dystrophy RDS Retinitis pigmentosa and retinal degenerations Dominant: (panel including RHO, PRPH2, RP1, IMPDH1, PRPF8, NR2E3, PRPF3, TOPORS, PRPF31, KLHL7), CA4, CRB1, CTRP5 X-linked: RPGR, RP2 Retinoblastoma RB1 Sorsby fundus dystrophy TIMP3 Stargardt disease ABCA4, ELOVL4, RDS a Adapted from www.nei.nih.gov/resources/eyegene/tableforgenes.asp. july/august 2012 Advanced Ocular Care 35 cover story through maximizing contrast in their surroundings, lowvision aids, or training on eccentric fixation techniques. Molecular Diagnostics Once a phenotypic category is established by careful ophthalmologic examination, a more accurate diagnosis may be achieved through the use of molecular diagnostic techniques. A number of diseases that appear phenotypically similar may be genetically distinct and vice versa.3 A determination of carrier status, through laboratory testing when available, may provide assurance that a couple is not at risk of having affected children, or it may alert to the need for prenatal diagnostic evaluation and follow-up. Also, knowing specific mutations responsible for disease may open up avenues for patients to become eligible for certain clinical trials. Genetic testing can be performed by nonprofit Clinical Laboratory Improvement Amendments or CLIAcertified laboratories like the Carver Laboratory (www. carverlab.org). Additional listings of available genetics laboratories can be found at www.ncbi.nlm.nih.gov/ sites/genetests/?db=genetests and can be searched via GeneTests.org (discussed later). A free resource that all providers should be aware of is the National Ophthalmic Disease Genotyping and Phenotyping Network’s eyeGENE, launched by the National Eye Institute. The initial concept for eyeGENE began in 2003 when the National Eye Institute hosted a meeting that included patients, clinicians, and scientists. The meeting ended with the consensus that there was a need for a coordinated effort to establish more widely available resources for genetic eye diseases. The eyeGENE Network consists of a central processing center, DNA repository, volunteer CLIA laboratories, and a shared genotype/phenotype database. The first patient’s DNA specimen was processed in 2006. The goal of the network is to provide free and accurate diagnostic information to patients with genetic eye diseases and to create a database of genotype-phenotype information that can be used for future research. A list of conditions and genes tested by eyeGENE is presented in the Table. For additional information on eyeGENE and how to submit specimens, visit www.nei.nih.gov/resources/eyegene.asp. Informational Repositories PubMed.gov and associated databases from the National Institutes of Health’s National Center for Biotechnology Information (www.ncbi.nlm.nih.gov) offer both traditional indexing of the biomedical journal literature and information with which to increase knowledge of genetic diseases, their molecular basis, diagnostic and therapeutic options, and what patients and their families need to know about genetic risks, prognosis, and potential therapies. Gene Reviews/ 36 Advanced Ocular Care july/august 2012 Gene Tests (www.ncbi.nlm.nih.gov/sites/genetests) is a publicly funded resource for genetic testing and information, which provides additional insights and links to support groups and research-funding opportunities. The Foundation Fighting Blindness provides an excellent source of information for patients www.blindness.org. The foundation is the world’s largest, private nonprofit charity devoted to finding a cure for inherited ocular disorders. Google Scholar (http://scholar.google.com) has a number of features that help you find free and open-access articles and books as well as search citations. Genetic Counseling Due to the implications for patients and their families, genetic counseling is an important element in the management plan for patients with genetic ocular disorders. If counseling is not available at your practice, then a referral to a counseling center is recommended. A genetic counselor would be in the best position to carefully obtain a family history and, most importantly, discuss the chances that the disease will appear in other and/or future family members. Scheduled screenings of at-risk individuals and family members may prevent blindness through early diagnosis and treatment. Genetic counseling is also important because these disorders often put emotional stress on the family, and counseling may help patients adjust to complex information and cope with a new diagnosis. Conclusion The process of evaluating and managing patients with genetic eye disorders can be demanding. Fortunately, there are a number of resources that are available to aid both the caregiver and the patient in the process. Currently, research into the eye’s molecular biology has yielded a wealth of information we can provide to our patients. It is hoped that continued work in areas of gene therapy, stem cell transplantation, and retinal prosthetic devices will translate into improved treatments and eventually cures. n Johnny Tang, MD, is the director of the Retina and Uveitis Service at the Louis Stokes VA Medical Center, associate program director of the Case Western Residency Program in Ophthalmology, and assistant professor of ophthalmology at Case Western School of Medicine in Cleveland. Dr. Tang may be reached at [email protected]. 1. Tang J, Gokhale PA, Brooks SE, et al. Increased corneal thickness in patients with ocular coloboma. J AAPOS, 2006. 10(2):175-177. 2. Chen Y, Roorda A, Duncan JL. Advances in imaging of Stargardt disease. Adv Exp Med Biol. 2010;664: 333-340. 3. Bernstein PS, Leppert M, Singh N, et al. Genotype-phenotype analysis of ABCR variants in macular degeneration probands and siblings. Invest Ophthalmol Vis Sci. 2002;43(2):466-473.