Ординатура / Офтальмология / Английские материалы / Shields Textbook of Glaucoma, 6th edition_Allingham, Damji, Freedman_2010

b.Obstruction of Schlemm canal (e.g., sickled red blood cells) 2. Elevated episcleral venous pressure

a.Carotid-cavernous fistula

b.Cavernous sinus thrombosis

c.Retrobulbar tumors

d.Thyrotropic exophthalmos

e.Superior vena cava obstruction

f.Mediastinal tumors

g.Sturge-Weber syndrome

h.Elevated episcleral venous pressure

ANGLE-CLOSURE GLAUCOMA MECHANISMS

A. Anterior (“ pulling” mechanism)

1.Contracture of membranes a. Neovascular glaucoma

b. Iridocorneal endothelial syndrome c. Posterior polymorphous dystrophy

d. Penetrating and nonpenetrating trauma

2.Contracture of inflammatory precipitates B. Posterior (“ pushing” mechanism)

1.With pupillary block

a. Pupillary block glaucoma b. Lens-induced mechanisms

(1) Intumescent lens

(2) Subluxation of lens

(3) Mobile lens syndrome c. Posterior synechiae

(1) Iris-intraocular lens block in pseudophakia

(2) Uveitis with posterior synechiae

(3) Iris-vitreous block in aphakia

2.Without pupillary block a. Plateau iris syndrome

b. Ciliary block (malignant) glaucoma c. Lens-induced mechanisms

(1) Intumescent lens

(2) Subluxation of lens

(3) Mobile lens syndrome

d. After lens extraction (forward vitreous shift) e. Secondary to scleral buckling surgery

f. Secondary to panretinal photocoagulation g. Central retinal vein occlusion

h. Intraocular tumors

(1) Malignant melanoma

(2) Retinoblastoma

i. Cysts of the iris and ciliary body j. Retrolenticular tissue contracture

(1) Retinopathy of prematurity (retrolental fibroplasia)

(2) Persistent hyperplastic primary vitreous

DEVELOPMENTAL ANOMALIES OF THE ANTERIOR CHAMBER ANGLE

A. High insertion of anterior uvea

1.Congenital (infantile) glaucoma

2.Juvenile glaucoma

3. Glaucomas associated with other developmental anomalies

B.Incomplete development of trabecular meshwork/Schlemm canal 1. Axenfeld-Rieger syndrome

2. Peters anomaly

3. Glaucomas associated with other developmental anomalies

C.Iridocorneal adhesions

1.Broad strands (Axenfeld-Rieger syndrome)

2.Fine strands that contract to close angle (aniridia)

aClinical examples cited in this table do not represent an all-inclusive list of the glaucomas.

Figure 7.2 Open-angle forms of glaucoma may be of the pretrabecular (A), trabecular (B), or posttrabecular (C) type. Angle-closure forms of glaucoma may be of the anterior “pulling” type (D) or the posterior “pushing” type. The latter may occur with (E) or without (F) pupillary block. Arrows indicate location of force pushing the iris or lens-iris diaphragm forward. A third basic mechanism is developmental abnormalities of the anterior chamber angle.

In the posterior mechanisms of angle-closure glaucoma without pupillary block, increased pressure in the posterior portion of the eye pushes the lens-iris or vitreous-iris diaphragm forward. Examples include malignant (ciliary block) glaucoma, plateau iris syndrome, intraocular tumors, cysts of the iris and ciliary body, and contracture of retrolenticular tissue.

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Developmental Anomalies of the Anterior Chamber Angle

These glaucomas are not readily separated into open-angle and angle-closure mechanisms, but typically represent incomplete development of structures in the conventional aqueous outflow pathway. Clinically recognized developmental defects include a high insertion of the anterior uvea, as in congenital (infantile) glaucoma, and many of the glaucomas associated with other developmental abnormalities. In other cases, the defect may manifest as an incompletely developed trabecular meshwork or Schlemm canal (e.g., Peters anomaly) or as iridocorneal adhesions (e.g., Axenfeld-Rieger syndrome).

KEY POINTS

The many clinical forms of glaucoma are commonly classified by (a) cause or (b) mechanism. The former is based on the underlying disorder that leads through a multistage pathway to alterations in aqueous humor dynamics or optic neuropathy with subsequent visual field loss.

The mechanistic classification is based on alterations in the anterior chamber angle, which may result from the underlying initiating abnormality and lead to the elevated IOP. The mechanistic classification is divided into open-angle and angleclosure mechanisms and developmental anomalies of the anterior chamber angle. These groups are then subdivided according to the underlying cause and specific structural alterations.

The ongoing revolution in molecular genetics will likely change our current understanding of disease. This new knowledge will increasingly guide the classification of many types of glaucoma (as discussed in Chapter 8).

REFERENCES

1.Pavlin CJ, Ritch R, Foster FS. Ultrasound biomicroscopy in plateau iris syndrome. Am J Ophthalmol. 1992;113:390-395.

2.Alward WLM. Molecular genetics of glaucoma: effects on the future of disease classification. In: Van Buskirk EM, Shields MB, eds. 100 Years of Progress in Glaucoma. Philadelphia, PA: Lippincott-Raven; 1997:143.

3.Semina EV, Reiter R, Leysens NJ, et al. Cloning and characterization of a novel bicoid-related homeobox transcription factor gene, RIEG, involved in Rieger syndrome. Nat Genet. 1996;14:392-399.

4.Mirzayans F, Gould DB, Heon E, et al. Axenfeld-Rieger syndrome resulting from mutation of the FKHL7 gene on chromosome 6p25. Eur J Hum Genet. 2000;8(1):71-74.

5.Phillips JC, del Bono EA, Haines JL, et al. A second locus for Rieger syndrome maps to chromosome 13q14. Am J Hum Genet. 1996;59(3): 613-619.

6.Allingham RR, Liu Y, Rhee DJ. The genetics of primary open-angle glaucoma: a review. Exp Eye Res. 2009;88:837-844.

7.Héon E, Sheth BP, Kalenak JW, et al. Linkage ofautosomal dominant iris hypoplasia to the region of the Rieger syndrome locus. Hum Mol Genet. 1995;4:1435-1439.

8.Nishimura D, Swiderski R, Alward W, et al. The forkhead transcription factor gene FKHL7 is responsible for glaucoma phenotypes which map to 6p25. Nat Genet. 1998;19:140-147.

9.Mears AJ, Jordan T, Mirzayans F, et al. Mutations of the forkhead/winged-helix gene, FKHL7, in

patients with Axenfeld-Rieger anomaly. Am J Hum Genet. 1998;63:1316-1328.

10. Barkan O. Glaucoma: classification, causes, and surgical control—results of microgonioscopic research. Am J Ophthalmol. 1938;21:1099-1117.

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Shields > SECTION II - The Clinical Forms of Glaucoma >

8 - Molecular Genetics and Pharmacogenomics of the Glaucomas

Authors: Allingham, R. Rand

Title: Shields Textbook of Glaucoma, 6th Edition Copyright ©2011 Lippincott Williams & Wilkins

> Table of Contents > SECTION II - The Clinical Forms of Glaucoma > 8 - Molecular Genetics and Pharmacogenomics of the Glaucomas

8

Molecular Genetics and Pharmacogenomics of the Glaucomas

This chapter introduces the reader to the shift from a “single gene, rare disease” concept to a “compl ex and multiple gene disease” model. By reading this c hapter, you will learn about the expectations of how genomic testing will pave the way to individualized treatment for patients with various forms of glaucoma. It begins with highlighting the difference between single genes, which when mutated may result in striking clinical phenotypes (e.g., Axenfeld-Rieger syndrome), versus genes that may have DNA sequence variants (known as polymorphisms) that, with or without environmental contributions, can be associated with more common forms of glaucoma (e.g., exfoliation syndrome). Insights into the etiology and pathogenesis of various forms of glaucoma gleaned from analysis of DNA, RNA, or protein are then described. These insights will likely lead to new targets for glaucoma therapy that are beyond simply lowering intraocular pressure (IOP). The chapter ends with a discussion of pharmacogenomics and how genomic testing may help clinicians develop more rational, personalized treatment for their patients.

This chapter begins with three cases to illustrate the promising application of molecular medicine in the clinical context.

Figure 8.1 Optic disc photos (A) showing very thin neuroretinal rim in each eye. Visual fields (B) showing advanced nerve fiber bundle defects encroaching on fixation in the left visual field and within 10 degrees in the right visual field.

CASES

Please review each of these clinical scenarios and keep them in mind as you go through this chapter. Comments will be made on each of these cases later in the chapter.

Case 1

A 17-year-old female patient presents to your office reporting blurred and gradually decreasing vision. On examination, her visual acuity is 20/20 OU and the IOP is 30 mm Hg OU. Her angles are open and normal by gonioscopy Central corneal thicknesses measure 503 µm OD and 498 µm OS. She has neartotal cupping of both optic nerves (Fig. 8.1A). Visual field testing demonstrates defects within 10 degrees of fixation OU (Fig. 8.1B).

On inquiring further, you learn that her mother and sister also have glaucoma that developed relatively early in life. The mother is blind in one eye, and the sister's eyes are stable after having glaucoma surgery in both eyes.

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Figure 8.2 Appearance of the anterior and posterior segments of the mother's right eye. The patient asks several insightful questions:

What do I have?

Will I go blind if I don't receive treatment, and what is my best treatment option?

What are the chances that any future biological children of mine would also get this disease?

Can anything be done other than medications and surgery to treat my condition?

Case 2

A 40-year-old Scandinavian man has a mother with advanced exfoliative glaucoma (Fig. 8.2). He wants to know his chances of developing the same condition.

Case 3

A 68-year-old woman presents for advice about her glaucoma diagnosis and its impact on her children. She brings along her personal “smart card” that con tains her medical history, past visual fields, optic disc imaging, and genomic sequence.

At diagnosis, her IOPs measured 33 mm Hg in both eyes, and her central corneal thickness measurements were 584 µm OD and 566 µm OS. She was otherwise asymptomatic, and she was treated for glaucoma on the basis of the appearance of the neuroretinal rim of her optic disc (Fig. 8.3).

Figure 8.3 Case demonstrating progression of glaucoma based on right optic disc photos (A) and right visual fields (B) over 18 years despite medical and surgical treatments with IOP reduction and fluctuation between 7 and 13 mm Hg. (Modified from Moroi SE, Richards JE. Glaucoma and genomic medicine. Glaucoma Today. 2008;1:16-24, with permission.)

Over the following 18 years, her IOPs fluctuated between 7 mm Hg and 13 mm Hg with medical and surgical treatments. Despite this management, she developed progressive cupping of the optic disc and visual field loss (Fig. 8.3, center and right) over time. She asks: “Will the same thing happen to my children?”

THE HUMAN GENOME

Genes for glaucoma are found throughout the human genome (Fig. 8.4). There are approximately 20,500 genes encoded in the 6 billion base pairs that make up human DNA distributed on 46 chromosomes (1). In addition, 37 “mitochondrial” genes are encoded i n the circular mitochondrial DNA that is inherited through the mother. An offshoot of the Human Genome Project (http://www.genome.gov/10001772) was the International HapMap project (http://www.hapmap.org/), which permitted the identification and cataloguing of genetic sequence variants among individuals across diverse populations. These variants are known as single-nucleotide polymorphisms, or SNPs (pronounced “snips”). These SNPs are recognized as markers for

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chromosomal regions where genetic variants are shared among individuals of a given ethnic group. By taking advantage of these conserved DNA blocks marked by these SNPs, early successes have shown promise to identify certain SNPs as potential markers for disease. Future research may shed further insight on disease onset, disease severity, and treatment response, thus paving the way toward the advent of “personalized medicine.”

Figure 8.4 Chromosomal location of genes and loci for various forms of openor closed-angle glaucoma are found throughout the human genome. Only the Y chromosome is believed not to harbor a gene or locus for glaucoma.

Figure 8.5 Overview of application of linkage and association approaches to identify genes as markers for complex diseases and quantitative traits. The appropriate approach selected for a study depends on the frequency of the genetic variant and the penetrance of the disease mutation. (Modified from Moroi SM, Raoof DA, Reed DM, et al. Progress toward personalized medicine for glaucoma. Expert Rev Ophthalmol. 2009;4(2):145-161.)

Mendelian (“Single Gene”) versus Non-Mendelian (Com plex) Diseases

Mendelian disorders are typically rare diseases that follow Mendelian patterns of inheritance—the laws of segregation of alleles and the law of independent assortment. Common examples of Mendelian patterns of inheritance include autosomal-dominant, autosomal-recessive, and X-linked inheritance. Clinicians are familiar with these rare or uncommon clinical disorders because of the striking clinical phenotypes, such as juvenile open-angle glaucoma (JOAG), illustrated in Case 1, and others involving anterior segment dysgenesis, such as Axenfeld-Rieger syndrome. The genetics of such cases represent the “single gene—single disease” model.

In contrast, non-Mendelian, or complex, disorders do not follow the classical rules of Mendelian inheritance. Examples include quantitative traits that result from the additive effects of many genetic or environmental effects, polygenic traits that happen only if defects are present in more than one gene, traits displaying incomplete penetrance, codominant inheritance in which each of the three genotypic combinations for an allele have a different phenotype, imprinting effects caused by chemical modifications to the DNA, or mitochondrial inheritance. Representative conditions and diseases include exfoliation, normal-tension glaucoma, and chronic open-angle glaucoma (COAG).

There are various approaches used to identify a single gene or multiple genes that are involved in inherited disorders. These approaches can also be applied to the discovery of genes underlying treatment outcomes in the field of pharmacogenetics (how an individual's genes affect the way the individual's body responds to a medication or treatment) and pharmacogenomics (the study of drug responses in the context of the entire genome). (The topic of pharmacogenetics and pharmacogenomics is addressed later in this chapter.) The selection of a particular approach or method depends on the frequency of the disease mutation and the penetrance of the mutation (the frequency with which the presence of a particular genotype in an organism results in the corresponding phenotype) (Fig. 8.5).

Two common approaches used to identify genetic variants that contribute to inherited diseases are termed linkage analysis and association analysis. Linkage studies involve genetic mapping based on the cotransmission of genetic markers and phenotypes from one generation to the next in one or more families. Association studies involve comparison of cases to controls to assess the relative contribution of genetic variants or environmental effects to the trait being studied. In addition, association studies may also be designed to study a quantitative trait, such as IOP, in a single large cohort.

Primary Glaucomas

Primary Congenital Glaucoma

Primary congenital glaucoma (PCG) is an uncommon disease with a frequency ranging from 1 in 1250 (among the Roma population of Slovakia) to 1 in 10,000 (2). The anterior segment often reveals an anteriorly inserted iris, with a maldeveloped angle and trabecular meshwork. Most cases of PCG are sporadic; in familial cases, autosomal-recessive inheritance is most common. Most of these patients require surgical management because current glaucoma medications and lasers are generally ineffective

for this form of glaucoma. Two loci have been identified for the infantile form of congenital glaucoma:

2p211 and 1p36. The gene within the 2p21 locus, which accounts for the majority of familial cases, was identified in 1997 and encodes the protein cytochrome P4501B1 (CYP4501B1).

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Although the ocular substrate for cytochrome P450B1 remains unknown, this enzyme is likely to play an

important role in ocular development (3). Libby and colleagues have shown that mutant Cyp1b1-/- mice deficient in cytochrome P450B1, where both copies of the Cyp1b1 gene are nonfunctional, develop focal defects in the anterior chamber angle, including an increase in basal lamina of the trabecular meshwork and a small or absent Schlemm canal. Other experiments testing for genes that enhance or suppress angle abnormalities in Cyp1b1 identified the tyrosinase gene (Tyr) as a modifier whose deficiency exacerbates defects in Cyp1b1 mutant mice (3). Eyes lacking cytochrome P450B1 and tyrosinase demonstrated severe dysgenesis that was alleviated by the administration of L-DOPA, a normal product of tyrosinase. Thus, a pathway involving tyrosinase appears to be important in anterior chamber angle development.

Juvenile-Onset Open-Angle Glaucoma

JOAG is an autosomal-dominant form of COAG with an early age of onset. It is characterized by extremely high IOP with subsequent damage to the optic nerve and visual field. Affected eyes are often myopic. This disease usually begins between the ages of 4 and 35 years, often in individuals with a strong family history. In patients with JOAG, response to drug or laser treatment is generally poor and surgical intervention is often required.

JOAG was first linked to chromosome 1q21-31 by Sheffield and colleagues in 1993. Four years later, mutations were found in the responsible gene, the trabecular meshwork glucocorticoid response gene (TIGR, later renamed myocilin (4)). At least five loci are now mapped for JOAG. Of all cases of JOAG, approximately 10% to 20% are caused by mutations in the myocilin gene (5).

Revisiting Case 1

The phenotype is classic for JOAG. A mutation in the myocilin gene was suspected, and hence the gene was sequenced. A single base change, C?T (Pro370Leu) in exon 3, was found (6). This missense mutation was found in the mother and the two affected daughters, but not in the father. Armed with this information, one can now respond to the patient's queries:

What do I have? JOAG

Will I go blind if I don't receive treatment, and what is my best treatment option?

The Pro370Leu mutation is aggressive and leads to blindness if the pressure elevation is not treated. The best treatment option at present is aggressive IOP lowering with medication initially, and then surgery (e.g., trabeculectomy with an antimetabolite) if medical treatment does not lower the IOP to an appropriate target range.

What are the chances that any future biologic children of mine would also get this disease? JOAG is autosomal dominant with high penetrance, so the risk is approximately 50%.

Can anything be done other than medications and surgery to treat my condition?

Not at present, but additional strategies may become possible in the future, including gene replacement and alteration of the trabecular meshwork cellular and extracellular milieu to enhance outflow facility.

Adult-Onset Chronic Open-Angle Glaucoma

The high prevalence of COAG, variability in age of onset, and nonpenetrance (lack of phenotypic expression of a disease despite carrying the genetic mutation) in some pedigrees indicate that most cases of COAG are not inherited as a single-gene defect but as a “complex” trait that does not demonstrate simple Mendelian inheritance. Interplay among various environmental and genetic factors, or among