Download An Approach to genetic eye diseases for the comprehensive eye

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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
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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
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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.