Menu

Filtros terapéuticos MARCA SPO

BAJA VISION Perú + Filtros terapéuticos MARCA SPO opciónal con medida para patologías visuales USOS: Glaucoma, Atrofia Óptica, Albinismo, Acromatopsia, Pseudoafaquia, Pre-operatorio de cataratas, Degeneración macular, Retinitis pigmentaria, Ceguera nocturna, Retinopatía Diabética, Fotofobia, Afaquia
 
» » Genetics in Eye Care - Genética en Cuidado de los Ojos ( Articulo Científico - Scientific article )

A+ A-
Infolentes Infolentes Author
Title: Genetics in Eye Care - Genética en Cuidado de los Ojos ( Articulo Científico - Scientific article )
Author: Infolentes
Rating 5 of 5 Des:
Here, we review concepts in genetic testing as well as specifically discuss new advances in gene therapy for AMD and Fabry disease. By A...
Here, we review concepts in genetic testing as well as specifically discuss new advances in gene therapy for AMD and Fabry disease.
By Albert M. Morier, MA, OD, and Ricki Lewis, PhD

GOAL STATEMENT:

Because gene sequencing has become more streamlined and less expensive during the last decade, researchers have amassed a wealth of critical information to help facilitate the diagnosis and treatment of several major ocular disorders. Here, we will help the practicing optometrist garner a better understanding of human genetics and how it is becoming an essential element of contemporary eye care.


FACULTY/EDITORIAL BOARD:

Albert Morier, MA, OD, and Ricki Lewis, PhD

CREDIT STATEMENT:

This course is COPE approved for 2 hour of CE credit. COPE ID 38087-SD. Check with your local state licensing board to see if this counts toward your CE requirements for relicensure.

JOINT-SPONSORSHIP STATEMENT:

This continuing education course is joint-sponsored by the Pennsylvania College of Optometry.

DISCLOSURE STATEMENT:

Drs. Morier and Lewis received an unrestricted medical grant from Genzyme Pharmaceuticals.

Advancements in genetics and molecular biology have expanded exponentially during the last 60 years. Enhanced instrumentation and computing power have changed the landscape of molecular research. Until recently, such studies in eye care generally centered upon an understanding of Mendelian genetics (dominant and recessive disorders) and population genetics (knowing which conditions are more prevalent in certain populations).
Because gene sequencing has become more streamlined and less expensive during the last decade, researchers have amassed a wealth of critical information to help facilitate the diagnosis and treatment of several major ocular disorders. Here, we will help the practicing optometrist garner a better understanding of human genetics and how it is becoming an essential element of contemporary eye care.

THE BASICS OF GENE STUDIES

Sequencing the first human genome took more than a decade. Now, applying next-generation methods that use microfluidics to sequence many copies of its small segments, a human genome can be sequenced in just days. Thousands of people already have had either their exomes (the 1.5% of the genome that encodes proteins and accounts for 85% of inherited diseases) or their complete genomic construct sequenced.
During the late 1980s and 1990s, genetic linkage studies were considered to be an important tool for determining the prevalence of common single-gene disorders, such as sickle cell disease and Marfan syndrome. Shortly after the turn of the millennium, however, researchers moved away from genetic linkage studies and began conducting genome-wide association studies (GWASs) to evaluate more specific genetic associations and variants found in populations of patients believed to have the same disease.
In the GWAS approach, fluo-rescently labeled probes are used to highlight single-base sites in the genome, where more than 1% of the population exhibits variability. These sites are called single-nucleotide polymorphisms (SNPs). Bioinformatic algorithms search the data for SNP patterns that are much more prevalent among the individuals with the trait in question. However, many of the earliest GWASs returned weak and inconclusive results because the approach simply detected genetic associations, not underlying disease causes. Nonetheless, to this day, the GWAS technique remains a powerful tool to interrogate sequenced genomes for the chromosomal sites where specific genes of interest are likely to exist.
Results from the first successful GWAS ever conducted were published in Science in 2005. In this study, Robert J. Klein, PhD, and associates evaluated 96 patients with polymorphisms associated with age-related macular degeneration (AMD) and 50 control subjects.1 They determined that, among 116,204 SNPs genotyped, an intronic and common variant in the complement factor H (CFH) gene was present in those with AMD.1 More specifically, in individuals homozygous for the risk allele, the likelihood of AMD was increased by a factor of 7.4.1
There are more than 25 genes reported to influence the risk of AMD, including CFH, ARMS2 and HTRA1.2Environmental factors, such as smoking and excessive sunlight exposure, play a major role in the onset of AMD as well.3-7 Smoking typically increases an indi vidual's likelihood of developing AMD by two to three times.5 The exact mechanism of retinal damage due to smoking is unknown, but long-term oxidative insult has been suggested.6 Other environmental factors linked to the onset of AMD include excessive alcohol consumption and infections by certain pathogens (e.g., Chlamydia pneumoniae).7-11

GENETIC VARIATION AND MUTATION

Every individual has hundreds of genetic variants--most of which are recessive.12 Unfortunately, however, the language used to describe these variants can be somewhat confusing.
A mutation is a change in the DNA sequence from what is most commonly found in a particular population (and often is referred to as the "wild type" phenotype). It is considered a type of polymorphism (which simply means "many forms") that is present in less than 1% of a population.
There are several types of mutations. A point mutation is an alteration of a single base. It is considered "nonsense" if it generates a stop codon that truncates the encoded protein, or "missense" if it substitutes one amino acid type for another. A missense mutation only affects the phenotype if it alters a protein in a way that impacts its function in a detectable manner. Another type of point mutation affects a splice site, which is the DNA sequence at which noncoding parts of pre-messenger RNAs (introns) are cut out. Altering a splice site can add or remove segments to a messenger RNA, altering the size of the encoded protein.
Chromosome-level mutations include deletions and duplications as well as rearrangements (inversions and translocations). The genome is also peppered with many copy number variants (CNVs), which range from repeats of just a few nucleotides to vast, million-base duplications or deletions. Chromosomal microarray tests using comparative genome hybridization detect the CNVs that are correlated to such conditions as autism and developmental delay. A type of CNV mutation that causes more than a dozen neurological disorders is the expanded repeat, which typically is a triplet or quadruplet.
Keith H. Baratz, MD, and Wil-liam Brown, OD, of the Mayo Clinic Department of Ophthalmology and associates have discovered a strong association between the transcription factor 4 gene (TCF4) on chromosome 18 and Fuchs' corneal dystrophy.13 They performed a GWAS to compare 100 affected study participants with 200 controls. The GWAS simultaneously evaluated 330,000 alleles between the affected and unaffected subjects. The strength of the association between Fuchs' and the variation at the TCF4 gene was unprecedented. The researchers determined that the TCF4 gene may be responsible for 75% of Fuchs' corneal dystrophy cases.13

MONOGENIC VS. MULTIFACTORIAL DISORDERS

For many years, human genetics was chiefly associated with mono-genic (or Mendelian) traits and diseases. Since then, we've learned that the most common health conditions are, in fact, multifactorial-- meaning that they are caused by at least one gene-related complication and one or more ancillary/environmental factors.
* Monogenic conditions. The classic "modes of inheritance" for monogenic traits are autosomal recessive (e.g., Usher syndrome), autosomal dominant (e.g., some forms of Stargardt macular dystrophy) and X-linked recessive (e.g., red/green colorblindness). An auto-somal condition affects both sexes. An allele (gene variant) is dominant if the associated trait requires only one copy. An allele is recessive, however, if the trait requires two inherited copies.
For any particular gene, a homo-zygote has two identical alleles, while a heterozygote inherits a normal allele and a mutant allele. Individuals who have two different variants of a gene are termed "compound heterozygotes." A male carrier of an X-linked gene mutation is hemizygous, because he has only one gene copy. Genetic counselors consult family history charts (pedigrees) and apply Men-del's laws to predict the likelihood that certain individuals inherit a particular monogenic condition.
* Multifactorial conditions. In contrast to the predictable mono-genic inheritance, multifactorial traits and conditions are determined by many factors--each contributing to different aspects of the phenotype. They do not recur with predictable frequency, and are not amenable to gene therapy in the way that monogenic traits are (unless the applied therapy targets a common phenotype that is shared by different forms of the condition, such as the ability of anti-VEGF agents to control blood vessel growth in neovascular AMD).

NUANCES OF PHENOTYPE

Genetic heterogeneity refers to the same or very similar phenotypes (clinical presentations) that correspond to genotypes in different genes. The Leber congenital amau-roses (LCAs) offer a compelling example of this phenomenon. The LCAs are considered early-onset, severe subtypes of RP--although there is some disagreement about classifying them as distinct disorders. All of these disorders are considered retinal dystrophies.
Because the biochemical pathways that functionally link the retinal pigment epithelium (RPE) to the photoreceptors are com plex, many proteins (including the enzymes that catalyze the reactions) and their genes are implicated in the 18 types of LCA associated with specific genes. Simply stated, Leber congenital amaurosis can occur in many ways.
Sixteen of the 18 recognized monogenic forms of LCA are inherited in an autosomal recessive manner. Genetic tests can help confirm a clinical diagnosis when phenotypes overlap and range in both severity and course. For example--mutations inGUCY2D cause very poor vision but no night blindness and a normal-appearing fundus, whereas mutations in RDH12 cause night blindness and a characteristic shredded/fishnet retinal appearance.

Several terms are used to describe nuances of gene expression:
  • Pleiotropy is the term applied to a genetic disease that affects more than one organ system. Fabry disease, for example, affects the heart, kidney and brain, and may exhibit several ocular manifestations. It is an X-linked, recessive deficiency of alpha galactosidase A (a lysosomal enzyme).
  • Variable expressivity refers to different degrees of severity in the same genotype among individuals.
  • Incomplete penetrance references the percentage of people with a specific genotype who actually develop the associated phenotype. Degree of penetrance reflects disease severity. Huntington's, for example, is one of the most highly penetrant inherited diseases. If he or she lives long enough, every individual who inherits the expanded triplet repeat mutation eventually develops symptoms of Hunting-ton's. In contrast, the autosomal dominant trait polydactyly (extra digits) is incompletely penetrant, because some individuals who have affected parents and children develop the normal number of digits.
Recommendations on Genetic Testing
In 2012, the American Academy of Ophthalmology published its “Recommendations for Genetic Testing of Inherited Eye Diseases,” which emphasize the importance of distinguishing monogenic from multifactorial ocular diseases, and also advise when it is appropriate to order a genetic test.54 Some of the specific recommendations include:
1. Offer genetic testing if symptoms match those of a known monogenic disorder, such as retinitis pigmentosa.
2. Use tests from Clinical Laboratories Improvement Amendment (CLIA)-approved labs. Consult databases and the literature to interpret results.
3. Provide patients with their test results so that they can research clinical trial opportunities.
4. Discourage patients from using direct-to-consumer genetic tests––many of which do not provide physician expertise or genetic counseling services.
5. Suggest sequencing exomes and genomes only in a research setting, until these approaches are integrated into medical practice.
6. Do not order a genetic test for a multifactorial disorder because individual gene variants contribute only partially (and unevenly) to overall risk.
7. Do not test asymptomatic patients under age 18 for untreatable disorders. Keep in mind that there is no universal consensus for in-office genetic testing of AMD.
Additionally, more comprehensive guidelines are anticipated in the near future.

GENE AND STEM CELL THERAPY

Gene therapy is indicated for pathologies that have not yet destroyed cells. When cells have degenerated, however, replacing them with healthy versions is a more logical approach.
Since 2007, more than 230 patients have received gene therapy for LCA2.14,15 Most of these treatment procedures have been extremely successful. In gene therapy for LCA2, approximately 15 billion adeno-associated viruses carrying the wild type human RPE65 gene are introduced into the subretinal space.
For retinal dystrophies in which the RPE and/or photoreceptors are degenerating or depleted, a stem cell approach may be more promising. For example, two Phase I/II prospective clinical trials are underway to treat Stargardt macular dystrophy and dry AMD with RPE cells derived from human embryonic stem cells.16 The procedure appears to be safe, and dramatically effective, in some of the few patients treated so far.
Human embryonic stem cells are a controversial, and perhaps unnecessary, source of healthy cells. RPE derived from induced pluripotent stem cells that are cultured from the patient's own fibroblasts--and are therefore autologous--are another therapeutic option. In addition, the RPE itself appears to harbor its own stem cells that may one day be activated to heal from within.
Sally Temple, PhD, and Jeffrey Stern, MD, PhD, are pioneering an investigation of RPE stem cells (RPESCs).17 They culture adult RPE from medical waste, isolate individual cells and apply biochemicals that enable the cells to function as stem cells. This process facilitates the generation and self-renewal of thousands of RPE cells in the dish. These cells might be used in allogeneic transplants or in drug discovery.

GENETIC TESTING FOR AMD

In-office genetic testing for macu-lar degeneration is gaining in popularity. Choroidal neovascularization (CNV) is responsible for approximately 90% of severe vision loss related to AMD.18,19 It occurs when abnormal blood vessels migrate through Bruch's membrane. Subsequent hemorrhaging causes irreparable damage to photoreceptors as well as rapid vision loss.20,21
As primary eye care providers, a key challenge is how to accurately identify subsets of patients who are at the highest risk for conversion to CNV. The etiology of AMD is complex, with genetic considerations prominently factoring into the disease pathogenesis. Researchers affiliated with the US Twin Study of AMD concluded that genetic factors account for approximately 46% to 71% of macular variation and overall disease severity.22

In recent years, several polymorphisms in genes involved in the complement pathway, lipid metabolism, extracellular matrix remodeling and oxidative stress have been associated with AMD. This suggests that AMD has several molecular mechanisms.
Multiple research groups have developed gene-based AMD risk prediction models that can incorporate and account for various demographic and environmental factors.23-27 The first-generation genetic tests for AMD, such as Macula Risk (ArcticDx), did not incorporate a clinical assessment, making it difficult for clinicians to interpret genetic risk within the context of current disease status.
The second-generation genetic tests for AMD account for current disease status, genetic risk and lifestyle factors when calculating a comprehensive risk score. The latest such tests are Macula Risk NXG (ArcticDx) and RetnaGene (Sequenom).
* Macula Risk NXG analyzes 15 AMD-associated variations in 12 different genes including CFH, C3 and ARMS2--all of which were included in its first generation test. Leveraging recent discoveries of novel AMD-associated genes, Mac-ula Risk NXG includes the cholesterol metabolism genes (CETP, LIPC,ABCA1 and APOE), as well as the extracellular matrix remodel-ling genes (TIMP3 and COL8A1). Other complement pathway genes (CFI, C2, CFB) also are included.
The ordering clinician is required to provide information about dru-sen size and presence of CNV or geographic atrophy in each eye. Furthermore, the test requires physicians to include the patient's age, height, weight and smoking history. The DNA sample is obtained through a cheek swab. The results predict an individual's risk of progression to advanced AMD within two, five and 10 years, and patients are categorized into one of five risk groups (patients in risk Group Five are at the highest risk). Macula Risk NXG has a reported sensitivity and specificity of greater than 80% and a 10-year predictive accuracy of 0.895.25
* RetnaGene is indicated to predict the risk of wet AMD in white patients aged 55 years or more who already have signs of early or intermediate AMD. This test incorporates macular phenotype (expressed as the AREDS Simple Scale Score), age and smoking history. Additionally, RetnaGene evaluates for 12 genetic variations in eight genes (CFH, CFHR4, CFHR5, C3, C2, CFB, ARMS2 and F13B).28 Like Macula Risk NXG, the DNA analysis is performed with a cheek swab.
RetnaGene calculates the risk of progression to CNV within two, five and 10 years, and categorizes the patient as high, moderate or low risk. The test is reported to have a 10-year predictive accuracy of 0.96.29
Anti-VEGF therapy offers wet AMD patients hope for a previously untreatable disease. Despite unequivocal evidence indicating that treatment must be administered soon after conversion to wet AMD, many patients still are mismanaged.30-32 Fortunately, the next generation of genetic tests represent a powerful tool that we can use to screen our high-risk patients, monitor them closely and refer them to a retina specialist immediately upon disease conversion.

GENETIC CONSIDERATIONS IN FABRY DISEASE

Ocular manifestations of genetic diseases can help eye care providers more readily identify life-threatening conditions, such as Fabry disease--a single-gene, X-linked lysosomal storage disorder that causes progressive complications within the kidneys, brain and heart.
Fabry disease is a debilitating and eventually fatal condition that was first described by Johannes Fabry in Germany and William Anderson in England at the end of the nineteenth century.33 It is one of more than 50 lysosomal storage disorders, and occurs in an estimated one in 40,000 men.1,34,35 The incidence in women has been estimated to be twice as high as that in men, but its true prevalence in women is unknown.36
Measured enzyme activity levels of less than 2% can be found in many hemizygous men who subsequently become prone to life-threatening complications in vital organs and other morbidities secondary to Fabry disease. Evidence-based research has confirmed that most mutation-positive women will experience signs and/or symptoms of the disease, although possibly later than age-matched men.37-39
The initial symptoms of Fabry disease can include angiokeratomas (telangiectatic cutaneous lesions), acroparesthesia (severe pain in hands and feet), hypohidrosis (inability to sweat) and gastrointestinal complications.40 These are not fatal consequences of the disease, but they may have a significant impact on the patient's quality of life.
Ocular manifestations of Fabry disease have been published by several investigators.40-51 Any ocular signs of the disease suggest that a fatal, insidious condition is lurking within the patient's genome, slowly damaging his or her kidneys, heart and brain.

The most commonly reported ocular finding is corneal verticilla-ta, a bilateral, whorl-like pattern of radiating, cream-colored lines usually found in the inferior cornea. These deposits can range from faint to pronounced, and are located at the level of Bowman's membrane. They can be seen as early as six months of age and are fully apparent by age 10.41,50
A number of drugs also may result in corneal verticillata, including amiodarone, chloroquine, indomethacin, chloropromazine, naproxen, ibuprofen and tamoxifen.51Corneal whorling from both Fabry disease and amiodarone occur at the same level within the cornea.52,53 It is important to note that patients who present with corneal whorling on amiodarone therapy may additionally have hypertrophic cardiomyopathy as a result of Fabry disease. So, it's crucial not to simply attribute the presentation to amiodarone use, especially if the patient is young.
Remember that ocular manifestations of Fabry disease often are present at a very young age, well before the signs and symptoms of renal disease, stroke or hyper-trophic cardiomyopathy develop. Thus, early diagnosis by an eye care provider--in conjunction with enzyme replacement therapy--may reduce the morbidity and mortality associated with the condition.
We are only now learning how to better use genetic information to help make accurate, timely diagnoses for inherited diseases. Soon, this information will help researchers develop novel interventions. In the meantime, eye care providers should acquire a working knowledge of genetic inheritance patterns for the most common sight-threatening conditions.
Dr. Morier is in private practice in Schenectady, NY, and an associate clinical professor of ophthalmology at Albany Medical Center. Dr. Lewis is a geneticist and science writer based in Schenectady. They have received an unrestricted medical grant from Genzyme Pharmaceuticals, but have no direct financial interest in any of the products mentioned.

REFERENCES

  1. Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in age-related macular degeneration. Science. 2005 Apr 15;308(5720):385-9.
  2. DeAngelis NM, Silveira AC, Carr EA, Kim IK. Genetics of Age-related macular degeneration current concepts, future directions. Semin Ophthalmol. 2011 May;26(3):77-93.
  3. Swaroop A, Chew E, Bowes-Rickman C, Abecasis G. Unraveling a multifactorial late-onset disease: from genetic susceptibility to disease mechanisms for age-related macular degeneration. Annu Rev Genomics Hum Genet. 2009;10:19-43.
  4. Priya RR, Chew E, Swaroop A. Genetic Studies of age-related mac-ular degeneration. Lessons, challenges and opportunities for disease management. Ophthalmology. 2012 Dec;119(12):2526-36.
  5. Seddon JM, Willett WC, Speizer FE, Hankinson SE. A prospective study of cigarette smoking and age-related macular degeneration in women. JAMA. 1996 Oct 9;276(14):1141-6.
  6. Espinosa-Heidmann DG, Suner IJ, Catanuto P, et al. Cigarette smoke-related oxidants and the development of sub-RPE deposits in an experimental animal model of dry AMD. Invest Ophthalmol Vis Sci. 2006 Feb;47(2):729-37.
  7. Cruickshanks KJ, Klein R, Klein BE, Nondahl DM. Sunlight and the 5-year incidence of early age-related maculopathy: the Beaver Dam Eye Study. Arch Ophthalmol. 2001 Feb;119(2):246-50.
  8. Cho E, Hankinson SE, Willett WC, et al. Prospective study of alcohol consumption and the risk of age-related macular degeneration. Arch Ophthalmol. 2000 May;118(5):681-8.
  9. Ishida O, Oku H, Ikeda T, et al. Is Chlamydia pneumoniae infection a risk factor for age-related macular degeneration? Br J Ophthalmol. 2003 May;87(5):523-4.
  10. Winkler BS, Boulton ME, Gottsch JD, Sternberg P. Oxidative damage and age related macular degeneration. Mol Vis. 1999 Nov;5:32.
  11. Algvere PV, Marshall J, Seregard S. Age-related maculopathy and the impact of blue light hazard. Acta Ophthalmol Scand. 2006 Feb;84(1):4-15.
  12. Xue Y, Chen Y, Ayub Q, Huang N, et al. Deleterious- and disease-allele prevalence in healthy individuals: insights from current predictions, mutation databases, and population-scale resequencing. Amer J Hum Gen. 2012 Dec;91(6):1022-32.
  13. Baratz KH, Tosakulwong N, Ryu E, et al. E2-2 protein and Fuchs's corneal dystrophy. N Engl J Med. 2010 Sep 9;363(11):1016-24.
  14. Bainbridge JW, Smith AJ, Barker SS, et al. Effect of gene therapy on visual function in Leber's congenital amaurosis. N Engl J Med. 2008 May 22;358(21):2231-9.
  15. Maguire AM, Simonelli F, Pierce EA, et al. Safety and efficacy of gene transfer for Leber's congenital amaurosis. N Engl J Med. 2008 May 22;358(21):2240-8.
  16. Schwartz SD, Hubschman JP, Heilwell G, et al. Embryonic stem cell trials for macular degeneration: a preliminary report. Lancet. 2012 Feb 25;379(9817):713-20.
  17. Salero E, Blenkinsop T, Corneo B, et al. Adult human RPE can be activated into a multipotent stem cell that produces mesenchymal derivatives. Cell Stem Cell. 2012 Jan 6;10(1):88-95.
  18. Ferris FL 3rd, SL Fine, L Hyman. Age-related macular degeneration and blindness due to neovascular maculopathy. Arch Ophthal-mol. 1984 Nov;102(11):1640-2.
  19. Ferris FL 3rd, A Patz. Macular edema: a major complication of diabetic retinopathy. Trans New Orleans Acad Ophthalmol. 1983;31:307-16.
  20. Hyman LG, Lilienfeld AM, Ferris FL 3rd, Fine SL. Senile macular degeneration: a case-control study. Am J Epidemiol. 1983 Aug;118(2):213-27.
  21. Bressler SB. Relationship of drusen and abnormalities of the retinal pigment epithelium to the prognosis of neovascular macular degeneration. The Macular Photocoagulation Study Group. Arch Ophthalmol. 1990 Oct;108(10):1442-7.
  22. Seddon JM, Cote J, Page WF, et al. The US twin study of age-related macular degeneration: relative roles of genetic and environmental influences. Arch Ophthalmol. 2005 Mar;123(3):321-7.
  23. Zanke B, Hawken S, Carter R, Chow D. A genetic approach to stratification of risk for age-related macular degeneration. Can J Ophthalmol. 2010 Feb;45(1):22-7.
  24. Seddon JM, Reynolds R, Maller J, et al. Prediction model for prevalence and incidence of advanced age-related macular degeneration based on genetic, demographic, and environmental variables. Invest Ophthalmol Vis Sci. 2009 May;50(5):2044-53.
  25. Yu Y, Reynolds R, Rosner B, et al. Prospective assessment of genetic effects on progression to different stages of age-related mac-ular degeneration using multistate Markov models. Invest Ophthalmol Vis Sci. 2012 Mar 21;53(3):1548-56.
  26. Seddon JM, Reynolds R, Maller J, et al. Risk models for progression to advanced age-related macular degeneration using demographic, environmental, genetic and ocular factors. Invest Ophthalmol Vis Sci. 2009 May;50(5):2044-53.
  27. Hageman GS, Gehrs K, Lejnine S, et al. Clinical validation of a genetic model to estimate the risk of developing choroidal neo-vascular age-related macular degeneration. Hum Genomics. 2011 Jul;5(5):420-40.
  28. Mitchell P, Foran S. Age-Related Eye Disease Study severity scale and simplified severity scale for age-related macular degeneration. Arch Ophthalmol. 2005 Nov;123(11):1598-9.
  29. Perlee LT, Bansal AT, Gehrs K, et al. Inclusion of genotype with fundus phenotype improves accuracy of predicting choroidal neovas-cularization and geographic atrophy. Ophthalmology. 2013 Mar 20. [Epub ahead of print]
  30. Macular Photocoagulation Study Group. Five-year follow-up of fellow eyes of patients with age-related macular degeneration and unilateral extrafoveal choroidal neovascularization. Arch Ophthalmol. 1993 Sep;111(9):1189-99.
  31. Arias L, Armadá F, Donate J, et al. Delay in treating age-related macular degeneration in Spain is associated with progressive vision loss. Eye (Lond). 2009 Feb;23(2):326-33.
  32. Cervantes-Castañeda RA, Banin E, Hemo I, et al. Lack of benefit of early awareness to age-related macular degeneration. Eye (Lond). 2008 Jun;22(6):777-81.
  33. Fabry J. A contribution to the understanding of modular hemorrhagic purpura. Arch Dermatol Syphilis. 1898;43:187-200.
  34. Staretz-Chacham O, Lang TC, LaMarca ME, et al. Lysosomal storage disorders in the newborn. Pediatrics. 2009 Apr;123(4):1191-207.
  35. Desnick R, Ioannou Y, Eng C, et al. Alpha-Galactosidase A Deficiency: Fabry disease. In: Scriver CR, Beaudet A, Sly WS (eds.). The Metabolicand Molecular Bases of Inherited Disease, 8th ed. New York: McGraw-Hill; 2001:3733-74.
  36. Laney DA, Fernhoff PM. Diagnosis of Fabry disease via analysis of family history. J Genet Couns. 2008 Feb;17(1):79-83.
  37. Brady RO, Gal AE, Bradley RM, et al. Enzymatic defect in Fabry's disease. Ceramidetrihexosidase deficiency. N Engl J Med. 1967 May 25;276(21):1163-7.
  38. Deegan PB, Baehner AF, Barba Romero MA, et al. Natural history of Fabry disease in females in the Fabry Outcome Survey. J Med Genet. 2006 Apr;43(4):347-52.
  39. Wilcox WR, Oliveira JP, Hopkin RJ, et al. Females with Fabry dis-easefrequently have major organ involvement: lessons from the Fabry Registry. Mol Genet Metab. 2008 Feb;93(2):112-28.
  40. Wang RY, Lelis A, Mirocha J, Wilcox WR. Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of life. Genet Med. 2007 Jan;9(1):34-45.
  41. Zarate YA, Hopkin RJ. Fabry's disease. Lancet. 2008 Oct 18;372(9647):1427-35.
  42. Bloomfield SE. Eye findings in the diagnosis of Fabry's disease. Patients with renal failure. JAMA. 1978 Aug 18;240(7):647-9.
  43. Franceschetti AT. Fabry disease: ocular manifestations. Birth Defects Orig Artic Ser. 1976;12:195-208.
  44. Hauser AC, Lorenz M, Voigtlander T, et al. Results of an ophthal-mologic screening programme for identification of cases with Anderson-Fabry disease. Ophthalmologica. 2004;218:207-9.
  45. Libert J, Toussaint D. Tortuosities of retinal and conjunctival vessels in lysosomal storage diseases. Birth Defects Orig Artic Ser. 1982;18: 347-58.
  46. Mastropasqua L, Nubile M, Lanzini M, et al. Corneal and con-junctival manifestations in Fabry disease: in vivo confocal microscopy study. Am J Ophthalmol. 2006 Apr;141(4):709-18.
  47. Nguyen TT, Gin T, Nicholls K, et al. Ophthalmological manifestations of Fabry disease: a survey of patients at the Royal Melbourne Fabry Disease Treatment Centre. Clin Experiment Ophthalmol. 2005 Apr;33(2):164-8.
  48. Orssaud C, Dufier J, Germain D. Ocular manifestations in Fabry disease: a survey of 32 hemizygous male patients. Clin Experiment Ophthalmol. 2005 Apr;33(2):164-8.
  49. Samiy N. Ocular features of Fabry disease: diagnosis of a treatable life-threatening disorder. Surv Ophthalmol. 2008 Jul-Aug;53(4):416-23.
  50. Sher NA, Letson RD, Desnick RJ. The ocular manifestations in Fabry's disease. Arch Ophthalmol. 1979 Apr;97(4):671-6.
  51. Sodi A, Ioannidis AS, Mehta A, et al. Ocular manifestations of Fabry's disease: data from the Fabry Outcome Survey. Br J Ophthal-mol. 2007 Feb;91(2):210-4.
  52. Spaeth GL, Frost P. Fabry's disease. Its ocular manifestations. Arch Ophthalmol. 1965 Dec;74(6):760-9.
  53. Falke K, Buttner A, Schittkowski M, et al. The microstructure of cornea verticillata in Fabry disease and amiodarone-induced kera-topathy: a confocal laser-scanning microscopy study. Graefes Arch Clin Exp Ophthalmol. 2009 Apr;247(4):523-34.
  54. The American Academy of Ophthalmology. Recommendations for Genetic Testing of Inherited Eye Diseases: Report of the American Academy of Ophthalmology Task Force on Genetic Testing - Novem-ber 2012. Available at:http://one.aao.org/CE/PracticeGuidelines/ ClinicalStatements_Content.aspx?cid=f84ff8ef-9772-42ea-a168-8e096ac24d00. Accessed May 20, 2013.
  55. Crick FH. On protein synthesis. Symp Soc Exp Biol. 1958;12: 138-63.


Posted by
Etiquetas:

Share to:

en agosto 07, 2013

About Author

Advertisement

Publicar un comentario

Suscribirse a: Enviar comentarios (Atom)
 
Top